WO2023247769A1 - Dosage regimen for axl inhibitor - Google Patents

Dosage regimen for axl inhibitor Download PDF

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WO2023247769A1
WO2023247769A1 PCT/EP2023/067153 EP2023067153W WO2023247769A1 WO 2023247769 A1 WO2023247769 A1 WO 2023247769A1 EP 2023067153 W EP2023067153 W EP 2023067153W WO 2023247769 A1 WO2023247769 A1 WO 2023247769A1
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optionally substituted
axli
subject
administered
treatment
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PCT/EP2023/067153
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French (fr)
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Nigel MCCRACKEN
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Bergenbio Asa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • compositions and methods for treating AXL-related diseases, such as cancer, in a subject relate to compositions and methods for treating AXL-related diseases, such as cancer, in a subject.
  • present disclosure relates to administration of inhibitors of AXL activity or expression (AXLi).
  • AXL (also known as UFO, ARK, and Tyro7; nucleotide accession numbers NM_021913, NM_001699, NM_001278599; protein accession numbers NP_068713, NP_001690, NP_001265528) is a receptor protein tyrosine kinase (RTK) that comprises a C-terminal extracellular ligand binding domain and N-terminal cytoplasmic region containing the catalytic domain.
  • RTK receptor protein tyrosine kinase
  • the extracellular domain of AXL has a unique structure that juxtaposes immunoglobulin and fibronectin Type III repeats and is reminiscent of the structure of neural cell adhesion molecules.
  • GAS6 growth arrest specific-6
  • Protein S Protein S.
  • the AXL extracellular domain has been shown to undergo homophilic interactions that mediate cell aggregation, suggesting that one important function of AXL may be to mediate cell-cell adhesion.
  • AXL is predominantly expressed in the vasculature in both endothelial cells (EC's) and vascular smooth muscle cells (VSMC's) and in cells of the myeloid lineage and is also detected in breast epithelial cells, chondrocytes, Sertoli cells and neurons.
  • AXL has been found to serve as a key checkpoint for interferon (IFN) signalling (Rothlin et al, 2007; Huang et al, 2015); in the context of viral responses, the Zika virus has been found to antagonize the IFN action by interacting with AXL (Chen et al, 2018).
  • IFN interferon
  • Axl-/- mice exhibit no overt developmental phenotype and the physiological function of AXL in vivo is not clearly established in the literature.
  • AXL and/or its ligand has also been reported in a wide variety of solid tumor types including, but not limited to, breast, renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, and uveal melanoma as well as in myeloid leukemias. Furthermore, it possesses transforming activity in NIH3T3 and 32D cells. It has been demonstrated that loss of Axl expression in tumor cells blocks the growth of solid human neoplasms in an in vivo MDA-MB-231 breast carcinoma xenograft model. Taken together, these data suggest AXL signalling can independently regulate EC angiogenesis and tumor growth and thus represents a novel target class for tumor therapeutic development.
  • AXL and GAS6 proteins are upregulated in a variety of other disease states including endometriosis, vascular injury and kidney disease and AXL signalling is functionally implicated in the latter two indications.
  • AXL-GAS6 signalling amplifies platelet responses and is implicated in thrombus formation.
  • AXL may thus potentially represent a therapeutic target for a number of diverse pathological conditions including solid tumors, including, but not limited to, breast, renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma and uveal melanoma; liquid tumors, including but not limited to, leukemias (particularly myeloid leukemias) and lymphomas; endometriosis, vascular disease I injury (including but not limited to restenosis, atherosclerosis and thrombosis), psoriasis; visual impairment due to macular degeneration; diabetic retinopathy and retinopathy of prematurity; kidney disease (including but not limited to glomerulonephritis, diabetic nephropathy, renal disease due to hypertension, and renal transplant rejection), rheumatoid arthritis; osteoporosis, osteoarthritis and cataracts.
  • solid tumors including, but not limited to, breast, renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma
  • AXL inhibitors In view of the role played by AXL in numerous pathological conditions, the development of safe and effective AXL inhibitors has been a topic of interest in recent years. Different groups of AXL inhibitors are discussed in, inter alia, US20070213375, US 20080153815, US20080188454, US20080176847, US20080188455, US20080182862, US20080188474, US20080117789, US20090111816, WG2007/0030680, WG2008/045978, WG2008/083353, WG2008/0083357, WG2008/083354, WG2008/083356, WG2008/080134, WG2009/054864, and WG/2008/083367.
  • AXL inhibitors with one or more other agents is discussed in, for example, WO/2010/083465 and WO/2017/193680, with WO/2017/193680 focussing on combinations of AXL inhibitors with agents having immune- regulatory or modulatory activity.
  • inhibition of AXL with the small molecule Bemcentinib (BGB324 I R428) was found to enhance the efficacy of immune checkpoint inhibitor treatment with anti PD1 and/or anti CTLA4.
  • Combination of AXL inhibitors with immune checkpoint inhibitor treatment and chemotherapy and I or radiotherapy is discussed in, for example, WO/2021/191197.
  • the present disclosure provides a method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose.
  • AXLi an inhibitor of AXL activity or expression
  • the loading dose is administered on days 1 , 2, and / or 3 of the dosage regimen. Preferably the loading dose is administered on days 1 and 2 of the dosage regimen.
  • the loading dose may be about 100 to 300 mg, such as about 150 to 250 mg, about 175 to 225 mg, or about 190 to 210 mg. In some preferred embodiments, the loading dose is about 200 mg.
  • the loading dose may be about 50 to 250 mg, such as about 100 to 200 mg, about 125 to 175 mg, or about 140 to 160 mg. In some preferred embodiments, the loading dose is about 150 mg.
  • the loading dose may be about 50 to 150 mg, such as about 75 to 125 mg, or about 90 to 110 mg. In some preferred embodiments, the loading dose is about 100 mg.
  • the loading dose may be about 200 mg, about 150 mg, or about 100 mg administered to the subject once daily. In some preferred embodiments, the loading dose is about 200 mg, about 150 mg, or about 100 mg administered to the subject once daily on days 1 and 2 of the dosage regimen.
  • the maintenance dose is administered beginning on day 2, 3, or 4 of the dosage regimen.
  • the maintenance dose is administered beginning on day 3 of the dosage regimen.
  • the maintenance dose may be administered on day 2, 3, or 4 and on each subsequent day of the dosage regimen.
  • the maintenance dose may be administered on day 3 and on each subsequent day of the dosage regimen.
  • the maintenance dose may be administered to the subject once daily, for example once daily on day 3 and on each subsequent day of the dosage regimen.
  • the maintenance dose may be about 50% of the loading dose.
  • the maintenance dose may be about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg, or may be about 60 to 90 mg, about 65 to 85 mg, or about 70 to 80 mg.
  • Preferably the maintenance dose may be about 100 mg or about 75 mg.
  • the maintenance dose may be about 100 mg or about 75 mg administered to the subject once daily, for example once daily on day 3 and on each subsequent day of the dosage regimen.
  • the maintenance dose may be the same as the loading dose.
  • the loading and maintenance dose may be about 100 mg, about 125 mg, or about 150 mg.
  • the loading and maintenance dose may be about 100 mg, about 125 mg, or about 150 mg administered to the subject once daily, for example once daily on day 3 and on each subsequent day of the dosage regimen.
  • the present disclosure also provides a method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosing regimen comprising administering a constant dose of AXLi on day 1 and on each subsequent day of the dosage regimen.
  • the constant dose may be about 125 mg or about 150 mg.
  • the constant dose may be about 125 mg or about 150 mg administered to the subject once daily, for example once daily on day 1 and on each subsequent day of the dosage regimen.
  • the constant dose may be about 75 mg, about 100 mg, or about 150 mg.
  • the constant dose may be about 75 mg, about 100 mg, or about 150 mg administered to the subject once daily, for example once daily on day 1 and on each subsequent day of the dosage regimen.
  • the constant dose may be about 100 mg administered to the subject once daily, for example once daily on day 1 and on each subsequent day of the dosage regimen.
  • the maintenance dose or constant dose may be administered to the subject daily until treatment with the AXLi is stopped.
  • the maintenance dose or constant dose may be administered to the subject once daily until treatment with the AXLi is stopped.
  • T reatment with the AXLi may be stopped when a treatment endpoint is reached for the subject.
  • the treatment endpoint may be one or more of: partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status); disease progression (progressive disease [PD] status) prompting treatment withdrawal; and toxicity and I or incidence of adverse events requiring treatment withdrawal.
  • the AXLi is administered to the subject under fed conditions. That is, the AXLi may be administered to the subject before, at the same time, or after food, for example, within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes of the subject consuming I ingesting food.
  • the food is preferably a meal, such as a high fat and I or high protein meal.
  • the AXL-related disease is cancer, a fibrotic disorder, or neurofibromatosis.
  • the AXL-related disease is cancer.
  • the cancer may be selected from the group consisting of: lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma.
  • the cancer is acute myeloid leukemia (AML) and I or lung cancer, preferably non-small-cell lung cancer (NSCLC).
  • the AXLi is administered in combination with: one or more immune checkpoint modulator (ICM); and I or one or more chemotherapeutic agent and I or radiotherapy.
  • the AXLi is administered in combination with an anti-PD-1 antibody.
  • the anti-PD1 antibody is pembrolizumab
  • the AXLi is administered in combination with an anthracycline.
  • the anthracycline is doxorubicin.
  • the AXLi is administered in combination with an ICM and an anthracycline.
  • the anthracycline is doxorubicin
  • the AXLi is administered in combination with a platinum-based chemotherapeutic.
  • the platinum-based chemotherapeutic is carboplatin or cisplatin.
  • the AXLi is administered in combination with an antifolate chemotherapeutic.
  • the antifolate chemotherapeutic is pemetrexed.
  • the AXLi is administered in combination with a platinum-based chemotherapeutic, an antifolate chemotherapeutic, and an anti-PD-1 antibody.
  • the AXLi may be administered in combination with carboplatin, pemetrexed, and pembrolizumab
  • the AXLi may be a compound of formula (I): as decribed in more detail elsewhere herein.
  • the AXLi is bemcentinib.
  • Figure 1 Overlay of individual pharmacokinetic concentration-time profiles (bemcentinib and total radioactivity) for a single oral dose of 200 mg 14 C-bemcentinib following administration in a fed state to 6 healthy volunteers.
  • Figure 1A axis scale (x-y): linear-linear.
  • Figure 1 B axis scale (x-y): linear-logarithmic. Shown is plasma bemcentinib (ng/mL) with time postdose (h). Dashed horizontal line represents the lower limit of quantification (2.00 ng/mL).
  • the present disclosure provides a method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi).
  • AXLi is: administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose; is administered to the subject in a dosage regimen in which a constant dose level is administered to the subject; and I or is administered to the subject under fed conditions.
  • AXL inhibitors are discussed in, inter alia, US20070213375, US 20080153815, US20080188454, US20080176847, US20080188455, US20080182862, US20080188474, US20080117789, US20090111816, W02007/0030680, W02008/045978, W02008/083353, W02008/0083357, W02008/083354, W02008/083356, W02008/080134, W02009/054864, and WO/2008/083367.
  • the AXL inhibitor is a compound of formula (I): wherein:
  • R 2 and R 3 are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R 9 -OR 8 , -R 9 -O-R 10 -OR 8 , -R 9 -O-R 10 -O-R 10 -OR 8 , -R 9 -O-R 10 -CN, -R 9 -O-R 10 -C(O) OR 8 , -R 9 -O-R 10 -C(O)N(R 6 )R 7 , -R 9 -O-R
  • the AXLi is a compound of formula (I) as defined in WO 2021/204713 A1 at 12 line 11 to page 49 line 14.
  • the compound of formula (I) is selected from the group consisting of:
  • the AXLi is selected from the group consisting of:
  • the AXL inhibitor is 1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)- /V 3 -((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole- 3,5-diamine.
  • AXL inhibitor is bemcentinib (CAS No. 1037624-75-1 ; UNII 0ICW2LX8AS)
  • Amino refers to the -NH2 radical.
  • Carboxy refers to the -C(O)OH radical.
  • Niro refers to the -NO2 radical.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1 -methylethyl (/so-propyl), n-butyl, n-pentyl, 1 ,1 -dimethylethyl (f-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
  • the term "lower alkyl” refers to an alkyl radical having one to six carbon atoms.
  • Optionally substituted alkyl refers to an alkyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O )OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )S(O) 2 R 20 , -S(O) t OR 20 (where t is 1 or 2), -S(O) P R 20 (where p is 0, 1 or 2), and -S(O) 2 N(R 20 ) 2 where each R 20 is independently selected from the group consisting of hydrogen, alky
  • Alkenyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, for example, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, and penta-1 , 4-dienyl.
  • Optionally substituted alkenyl refers to an alkenyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O )OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )S(O) 2 R 20 , -S(O) t OR 20 (where t is 1 or 2), -S(O) P R 20 (where p is 0, 1 or 2), and -S(O) 2 N(R 20 ) 2 where each R 20 is independently selected from the group consisting of hydrogen,
  • Alkynyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, optionally containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • Optionally substituted alkynyl refers to an alkynyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O )OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )S(O) 2 R 20 , -S(O) t OR 20 (where t is 1 or 2), -S(O) P R 20 (where p is 0, 1 or 2), and -S(O) 2 N(R 20 ) 2 where each R 20 is independently selected from the group consisting of
  • “Straight or branched alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, and n-butylene.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain.
  • Optionally substituted straight or branched alkylene chain refers to an alkylene chain, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O )OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )S(O) 2 R 20 , -S(O) t OR 20 (where t is 1 or 2), -S(O) P R 20 (where p is 0, 1 or 2), and -S(O
  • “Straight or branched alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, and n-butenylene.
  • the alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • Optionally substituted straight or branched alkenylene chain refers to an alkenylene chain, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O )OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )S(O) 2 R 20 , -S(O) t OR 20 (where t is 1 or 2), -S(O) P R 20 (where p is 0, 1 or 2), and -S
  • “Straight or branched alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms, for example, propynylene, and n-butynylene.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond.
  • the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • Optionally substituted straight or branched alkynylene chain refers to an alkynylene chain, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O )OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )S(O) 2 R 20 , -S(O) t OR 20 (where t is 1 or 2), -S(
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 14 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, or tricyclic system and which may include spiro ring systems.
  • An aryl radical is commonly, but not necessarily, attached to the parent molecule via an aromatic ring of the aryl radical.
  • an "aryl" radical as defined herein can not contain rings having more than 7 members and cannot contain rings wherein two non-adjacent ring atoms thereof are connected through an atom or a group of atoms (/.e., a bridged ring system).
  • Aryl radicals include, but are not limited to, aryl radicals derived from acenaphthylene, anthracene, azulene, benzene, 6,7,8,9-tetrahydro-5/7-benzo[7]annulene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, and phenanthrene.
  • Optionally substituted aryl refers to an aryl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted hetero
  • Alkyl refers to a radical of the formula -Rb-R c where Rb is an alkylene chain as defined above and R c is one or more aryl radicals as defined above, for example, benzyl and diphenylmethyl.
  • Optionally substituted aralkyl refers to an aralkyl radical, as defined above, wherein the alkylene chain of the aralkyl radical is an optionally substituted alkylene chain, as defined above, and each aryl radical of the aralkyl radical is an optionally substituted aryl radical, as defined above.
  • alkenyl refers to a radical of the formula -Rd-R c where Rd is an alkenylene chain as defined above and R c is one or more aryl radicals as defined above.
  • Optionally substituted aralkenyl refers to an aralkenyl radical, as defined above, wherein the alkenylene chain of the aralkenyl radical is an optionally substituted alkenylene chain, as defined above, and each aryl radical of the aralkenyl radical is an optionally substituted aryl radical, as defined above.
  • Alkynyl refers to a radical of the formula -R e R c where R e is an alkynylene chain as defined above and R c is one or more aryl radicals as defined above.
  • Optionally substituted aralkynyl refers to an aralkynyl radical, as defined above, wherein the alkynylene chain of the aralkynyl radical is an optionally substituted alkynylene chain, as defined above, and each aryl radical of the aralkynyl radical is an optionally substituted aryl radical, as defined above.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, spiro or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, more preferably from five to seven carbons and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • a bridged ring system is a system wherein two non-adjacent ring atoms thereof are connected through an atom or a group of atoms, wherein the atom or the group of atoms are the bridging element.
  • a bridged cycloalkyl (monovalent) radical is norbornanyl (also called bicyclo[2.2.1]heptanyl).
  • a non-bridged ring system is a system which does not contain a bridging element, as described above.
  • a fused ring system is a system wherein two adjacent ring atoms thereof are connected through an atom or a group of atoms.
  • An example of a fused cycloalkyl (monovalent) radical is decahydronaphthalenyl (also called decalinyl).
  • a spiro ring system is a system wherein two rings are joined via a single carbon (quaternary) atom.
  • spiro cycloalkyl (monovalent) radical is spiro[5.5]undecanyl.
  • Monocyclic cycloalkyl radicals do not include spiro, fused or bridged cycloalkyl radicals, but do include for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic radicals include fused, spiro or bridged cycloalkyl radicals, for example, C10 radicals such as adamantanyl (bridged) and decalinyl (fused), and C7 radicals such as bicyclo[3.2.0]heptanyl (fused), norbornanyl and norbornenyl (bridged), as well as substituted polycyclic radicals, for example, substituted C7 radicals such as 7,7-dimethylbicyclo[2.2.1]heptanyl (bridged).
  • C10 radicals such as adamantanyl (bridged) and decalinyl (fused)
  • C7 radicals such as bicyclo[3.2.0]heptanyl (fused), norbornanyl and norbornenyl (bridged)
  • substituted polycyclic radicals for example, substituted C7 radicals such as 7,7-dimethylbicyclo[2.2.1]heptanyl (bridged).
  • Optionally substituted cycloalkyl refers to a cycloalkyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted hetero
  • Cycloalkylalkyl refers to a radical of the formula -RbR g where Rb is an alkylene chain as defined above and R g is a cycloalkyl radical as defined above.
  • Optionally substituted cycloalkylalkyl refers to a cycloalkylalkyl radical, as defined above, wherein the alkylene chain of the cycloalkylalkyl radical is an optionally substituted alkylene chain, as defined above, and the cycloalkyl radical of the cycloalkylalkyl radical is an optionally substituted cycloalkyl radical, as defined above.
  • Cycloalkylalkenyl refers to a radical of the formula -RdR g where Rd is an alkenylene chain as defined above and R g is a cycloalkyl radical as defined above.
  • Optionally substituted cycloalkylalkenyl refers to a cycloalkylalkenyl radical, as defined above, wherein the alkenylene chain of the cycloalkylalkenyl radical is an optionally substituted alkenylene chain, as defined above, and the cycloalkyl radical of the cycloalkylalkenyl radical is an optionally substituted cycloalkyl radical as defined above.
  • Cycloalkylalkynyl refers to a radical of the formula -R e R g where R e is an alkynylene radical as defined above and R g is a cycloalkyl radical as defined above.
  • Optionally substituted cycloalkylalkynyl refers to a cycloalkylalkynyl radical, as defined above, wherein the alkynylene chain of the cycloalkylalkynyl radical is an optionally substituted alkynylene chain, as defined above, and the cycloalkyl radical of the cycloalkylalkynyl radical is an optionally substituted cycloalkyl radical as defined above.
  • Halo refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, and
  • Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
  • Haloalkynyl refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring system radical which comprises one to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include spiro or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
  • bridged heterocyclyl examples include, but are not limited to, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.3.1]nonanyl, diazabicyclo[3.2.2]nonanyl and oxazabicyclo[2.2.1]heptanyl.
  • a "bridged /V-heterocyclyl” is a bridged heterocyclyl containing at least one nitrogen, but which optionally contains up to four additional heteroatoms selected from O, N and S.
  • a non-bridged ring system is a system wherein no two non-adjacent ring atoms thereof are connected through an atom or a group of atoms.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, 1 ,4-diazepanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, octahydro-1/7-pyrrolo[3,2-c]pyridinyl, octahydro-1 /7-pyrrolo[2, 3- c]pyridinyl, octahydro-1/7-pyrrolo[2,3-b]pyridinyl, octahydro-1/7-pyrrolo[3,
  • Optionally substituted heterocyclyl refers to a heterocyclyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocycl
  • /V-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the /V-heterocyclyl radical to the rest of the molecule may be through a nitrogen atom in the /V-heterocyclyl radical or through a carbon in the /V-heterocyclyl radical.
  • Optionally substituted /V-heterocyclyl refers to an /V-heterocyclyl, as defined above, which is optionally substituted by one or more substituents as defined above for optionally substituted heterocyclyl.
  • Heterocyclylalkyl refers to a radical of the formula -RbRh where Rb is an alkylene chain as defined above and Rh is a heterocyclyl radical as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkylene chain at the nitrogen atom.
  • Optionally substituted heterocyclylalkyl refers to a heterocyclylalkyl radical, as defined above, wherein the alkylene chain of the heterocyclylalkyl radical is an optionally substituted alkylene chain, as defined above, and the heterocyclyl radical of the heterocyclylalkyl radical is an optionally substituted heterocyclyl radical, as defined above.
  • Heterocyclylalkenyl refers to a radical of the formula -RdRh where Rd is an alkenylene chain as defined above and Rh is a heterocyclyl radical as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkenylene chain at the nitrogen atom.
  • Optionally substituted heterocyclylalkenyl refers to a heterocyclylalkenyl radical, as defined above, wherein the alkenylene chain of the heterocyclylalkenyl radical is an optionally substituted alkenylene chain, as defined above, and the heterocyclyl radical of the heterocyclylalkenyl radical is an optionally substituted heterocyclyl radical, as defined above.
  • Heterocyclylalkynyl refers to a radical of the formula -R e Rh where R e is an alkynylene chain as defined above and Rh is a heterocyclyl radical as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkynylene chain at the nitrogen atom.
  • Optionally substituted heterocyclylalkynyl refers to a heterocyclylalkynyl radical, as defined above, wherein the alkynylene chain of the heterocyclylalkynyl radical is an optionally substituted alkynylene chain, as defined above, and the heterocyclyl radical of the heterocyclylalkynyl radical is an optionally substituted heterocyclyl radical, as defined above.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • a heteroaryl radical is commonly, but not necessarily, attached to the parent molecule via an aromatic ring of the heteroaryl radical.
  • the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include spiro or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized.
  • the aromatic ring of the heteroaryl radical need not contain a heteroatom, as long as one ring of the heteroaryl radical contains a heteroatom.
  • heteroaryl for the purposes of this disclosure.
  • a "heteroaryl" radical as defined herein can not contain rings having more than 7 members and cannot contain rings wherein two non-adjacent members thereof are connected through an atom or a group of atoms (/.e., a bridged ring system).
  • heteroaryl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1 ,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1 ,4]dioxepinyl, benzo[b][1 ,4]oxazinyl, benzo[b]azepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-c(]pyrimidinyl, benzotriazolyl
  • Optionally substituted heteroaryl refers to a heteroaryl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl
  • /V-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the /V-heteroaryl radical to the rest of the molecule may be through a nitrogen atom in the /V-heteroaryl radical or through a carbon atom in the /V- heteroaryl radical.
  • Optionally substituted /V-heteroaryl refers to an /V-heteroaryl, as defined above, which is optionally substituted by one or more substituents as defined above for optionally substituted heteroaryl.
  • Polycyclic heteroaryl containing more than 14 ring atoms refers to a 15- to 20-membered ring system radical comprising hydrogen atoms, one to fourteen carbon atoms, one to eight heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • a "polycyclic heteroaryl containing more than 14 ring atoms” radical is commonly, but not necessarily, attached to the parent molecule via an aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms" radical.
  • the "polycyclic heteroaryl containing more than 14 ring atoms" radical may be a bicyclic, tricyclic or tetracyclic ring system, which may include fused or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the "polycyclic heteroaryl containing more than 14 ring atoms" radical may be optionally oxidized and the nitrogen atom may also be optionally quaternized.
  • the aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms" radical need not contain a heteroatom, as long as one ring of the "polycyclic heteroaryl containing more than 14 ring atoms" radical contains a heteroatom.
  • polycyclic heteroaryl containing more than 14 ring atoms examples include, but are not limited to, 6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl, 6,7- dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl, 6,7,8,9-tetrahydro-5/7- cyclohepta[4,5]thieno[2,3-c(]pyrimidin-4-yl, 6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2- c/]pyrimidin-4-yl, 6,7-dihydro-5/7-benzo[2,3]azepino[4,5-c]pyridazin-3-yl, (Z)- dibenzo[£>,f][1 ,4]thiazepin-11-yl
  • Optionally substituted polycyclic heteroaryl containing more than 14 ring atoms is meant to include "polycyclic heteroaryl containing more than 14 ring atoms" radicals, as defined above, which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substitute
  • Heteroarylalkyl refers to a radical of the formula -RbRi where Rb is an alkylene chain as defined above and Rj is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkylene chain at the nitrogen atom.
  • Optionally substituted heteroarylalkyl refers to a heteroarylalkyl radical, as defined above, wherein the alkylene chain of the heteroarylalkyl radical is an optionally substituted alkylene chain, as defined above, and the heteroaryl radical of the heteroarylalkyl radical is an optionally substituted heteroaryl radical, as defined above.
  • Heteroarylalkenyl refers to a radical of the formula -RdRi where Rd is an alkenylene chain as defined above and Rj is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkenylene chain at the nitrogen atom.
  • Optionally substituted heteroarylalkenyl refers to a heteroarylalkenyl radical, as defined above, wherein the alkenylene chain of the heteroarylalkenyl radical is an optionally substituted alkenylene chain, as defined above, and the heteroaryl radical of the heteroarylalkenyl radical is an optionally substituted heteroaryl radical, as defined above.
  • Heteroarylalkynyl refers to a radical of the formula -R e Rj where R e is an alkynylene chain as defined above and Rj is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkynylene chain at the nitrogen atom.
  • Optionally substituted heteroarylalkynyl refers to a heteroarylalkynyl radical, as defined above, wherein the alkynylene chain of the heteroarylalkynyl radical is an optionally substituted alkynylene chain, as defined above, and the heteroaryl radical of the heteroarylalkynyl radical is an optionally substituted heteroaryl radical, as defined above.
  • Hydroalkyl refers to an alkyl radical as defined above which is substituted by one or more hydroxy radicals (-OH).
  • C7-C12 alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms
  • C4-Ci2cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms.
  • the total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
  • the compounds of formula (I), or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present disclosure includes tautomers of any said compounds.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the barrier to rotation is high enough to allow for the isolation of the conformers (Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994; Chapter 14). Atropisomerism is significant because it introduces an element of chirality in the absence of stereogenic atoms.
  • the disclosure is meant to encompass atropisomers, for example in cases of limited rotation around the single bonds emanating from the core triazole structure, atropisomers are also possible and are also specifically included in the compounds of the disclosure.
  • the AXLi is preferably administered orally, for example as as an oral capsule.
  • the AXLi may be administered via installation through a feeding tube.
  • the AXLi may be administered by other suitable administration routes as described elsewhere herein.
  • an AXL-related disease is one which in which dysfunction of Axl expression or activity is a contributing factor.
  • the AXL-related disease may be one in which overexpression of AXL is a contributing factor. Overexpression of AXL and/or its ligand has been reported in a wide variety of solid tumor types, as well as in other disease states including vascular injury and kidney disease.
  • the AXL- related disease may be one in which tissue infiltration with AXL+ve cells, such as AXL+ve immune suppressive dendritic cells, NK cells, or macrophages is a contributing factor.
  • the AXL-related disease may be a cancer, or a fibrotic disorder, characterised by expression or overexpression of AXL.
  • the AXL-related disease may be a cancer, or a fibrotic disorder, characterised by tissue infiltration with AXL+ve cells, such as AXL+ve immune suppressive dendritic cells, NK cells, or macrophages.
  • the AXL-related disease may be selected from: Immune disorders, cardiovascular disorders, thrombosis, diabetes, immune checkpoint disorders, neurofibromatosis, fibrotic disorders (fibrosis), or proliferative diseases such as cancer, particularly metastatic cancer.
  • Axl is known to play a role in many cancers of epithelial origin.
  • the AXL-related disease is a proliferative disease.
  • a proliferative disease in one in which excessive proliferation of cells contributes to the pathogenesis of the disease.
  • Exemplary proliferative diseases include: cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, and cirrhosis of the liver.
  • the AXL-related disease is a neoplastic disease.
  • a neoplastic disease is one in which abnormal and excessive growth (termed neoplasia) of cells I tissue occurs. Neoplasia is the abnormal growth and proliferation of abnormal cells or abnormal amounts of cells, which can be due to a benign or malignant process.
  • Exemplary neoplastic diseases include: myeloproliferative diseases, myelodysplastic syndromes (MDS), and acute myeloid leukemias (AML).
  • the AXL-related disease is a solid tumour. In other preferred embodiments, the AXL-related disease is a liquid tumour (which may also be referred to as a hematologic cancer, or hematologic malignancy). In some preferred embodiments of the disclosure, the AXL-related disease is cancer.
  • the cancer may be one or more of the following cancers: Leukemias such as but not limited to acute myelocytic leukemias (AMLs) such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome, acute leukemia, acute lymphocytic leukemia, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, nonHodgkin's disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasma
  • cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.
  • the cancer may be selected from the group consisting of: lung cancer, small-cell lung cancer, non-small-cell lung cancer, histocytoma, glioma, astrocyoma, osteoma, gastrointestinal cancer, bowel cancer, colon cancer, breast cancer, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, urothelial carcinoma, bladder cancer, pancreas cancer, brain cancer, glioblastoma, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma, mesothelioma, lymphomas, and leukemias.
  • the cancer may be selected from lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, prostate cancer, ovarian cancer, colorectal cancer, glioma cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma.
  • the cancer may be metastatic.
  • the cancer may be one or more solid cancer tumors, including, but not limited to, lung cancer, non-small cell lung carcinoma, breast, renal, endometrial, ovarian, thyroid, and, melanoma, prostate carcinoma, sarcoma, gastric cancer and uveal melanoma.
  • the cancer may be one or more liquid tumors, including but not limited to, leukemias (particularly myeloid leukemias) and lymphomas.
  • the cancer may be one or more leukaemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myelocytic leukaemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukaemia leukaemias and myelodysplastic syndrome, chronic leukaemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera.
  • the cancer may be one or more lymphomas such as but not limited to Hodgkin's disease, non-Hodgkin's disease.
  • the AXL-related disease may be a leukemia, such as acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • the AXL-related disease may be a lung cancer, such as non-small-cell lung cancer.
  • the AXL-related disease may be fibrosis (including but not limited to lung fibrosis and liver fibrosis) or a fibrotic disorder.
  • Fibrotic disorders of interest include strabismus, scleroderma, keloid, Nephrogenic systemic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), systemic sclerosis, cardiac fibrosis, non-alcoholic steatohepatitis (NASH), and other types of liver fibrosis, primary biliary cirrhosis, renal fibrosis, cancer, and atherosclerosis.
  • IPF idiopathic pulmonary fibrosis
  • CF cystic fibrosis
  • NASH non-alcoholic steatohepatitis
  • liver fibrosis primary biliary cirrhosis
  • renal fibrosis cancer
  • atherosclerosis the chronic development of fibrosis in tissue leads to marked alterations in
  • the AXL-related disease may be neurofibromatosis.
  • Neurofibromatoses are a group of genetic disorders that cause tumours to form on nerve tissue. Tumours in these disorders are usually noncancerous (benign) but can become cancerous (malignant).
  • NF1 neurofibromatosis type 1
  • NF2 neurofibromatosis type 2
  • schwannomatosis schwannomatosis.
  • the AXL-related disease may be neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and I or schwannomatosis.
  • the AXL-related disease may be a neurofibroma and / or a schwannoma.
  • the AXL-related disease may be selected from: endometriosis, vascular disease I injury (including but not limited to restenosis, atherosclerosis and thrombosis), psoriasis; visual impairment due to macular degeneration; diabetic retinopathy and retinopathy of prematurity; kidney disease (including but not limited to glomerulonephritis, diabetic nephropathy and renal transplant rejection), rheumatoid arthritis; osteoarthritis, osteoporosis and cataracts.
  • the AXL-related disease may be an immune checkpoint disorder.
  • Immune checkpoint disorders of interest include: Chronic viral infections, Melanoma, Colorectal cancer, Breast cancer, Ovarian cancer, Non-small cell lung cancer (NSCLC), Prostate cancer, Renal cell cancer, Pancreatic cancer, Esophagus cancer, Bladder cancer, Myeloma, Kidney cancer, Bladder cancer, Brain tumor, and Lymphoma.
  • the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose. In other embodiments of the methods of the disclosure, the AXLi is administered to the subject in a dosage regimen in which a constant dose level is administered to the subject.
  • these dosage regimens have improved efficacy and/or reduced toxicity as compared to other AXLi dosage regimens when used in the treatment of AXL-related diseases.
  • a “loading dose” is an initial higher dose of AXLi given for a “loading period” at the beginning of a course of treatment, before the dose is reduced to a maintenance level (“maintenance dose”).
  • the loading dose serves to allow the AXLi to reach a desired steady-state concentration in the body at which the AXLi has a desired therapeutic effect, while the maintenance dose serves to maintain the desired steady-state concentration of AXLi in the body.
  • a regimen comprising a “constant dose level” is one which the same dose is administered to the subject throughout the dosing regimen (that is, one where in effect the “loading dose” and “maintenance dose” are the same).
  • the AXLi may be administered to the subject QD (quaque die; every day). That is, the AXLi may be administered to the subject daily (on each day of the dosage regimen). In some preferred embodiments, the AXLi may be administered to the subject once daily.
  • the term "loading dose” refers to an initial higher dose of AXLi given at the beginning of a course of treatment. That is, a “loading dose” is a dose that is initially administered to a subject during a course of treatment, and may also be referred to, for example, as an “initial dose”, “starting dose”, “first dose”, or “first dose level”. The loading dose is administered over a loading period, to allow the AXLi to reach a desired steady-state concentration in the body at which the AXLi has a desired therapeutic effect.
  • the loading dose of AXLi may be about 50 to 150 mg, about 60 to 140 mg, about 70 to 130 mg, about 75 to 125 mg, about 80 to 120 mg, about 85 to 115 mg, about 90 to 110 mg, about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg. In some embodiments, the loading dose of AXLi may be about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg. In some preferred embodiments, the loading dose of AXLi may be about 100 mg.
  • the loading dose of AXLi may be about 50 to 250 mg, about 100 to 200 mg, about 110 to 190 mg, about 120 to 180 mg, about 125 to 175 mg, about 130 to 170 mg, about 135 to 165 mg, about 140 to 160 mg, about 145 to 155 mg, about 146 to 154 mg, about 147 to 153 mg, about 148 to 152 mg, or about 149 to 151 mg.
  • the loading dose of AXLi may be about about 145 to 155 mg, about 146 to 154 mg, about 147 to 153 mg, about 148 to 152 mg, or about 149 to 151 mg.
  • the loading dose of AXLi may be about 150 mg.
  • the loading dose of AXLi may be about 100 to 300 mg, about 150 to 250 mg, about 160 to 240 mg, about 170 to 230 mg, about 175 to 225 mg, about 180 to 220 mg, about 185 to 215 mg, about 190 to 210 mg, about 195 to 205 mg, about 196 to 204 mg, about 197 to 203 mg, about 198 to 202 mg, or about 199 to 201 mg.
  • the loading dose of AXLi may be about about 195 to 205 mg, about 196 to 204 mg, about 197 to 203 mg, about 198 to 202 mg, or about 199 to 201 mg.
  • the loading dose of AXLi may be about 200 mg.
  • the loading period is the period over which the loading dose is administered to the subject, for example, a period of 1 , 2, 3, 4, 5, 6, or 7 days at the beginning of a course of treatment.
  • the loading period may preferably be 1 , 2, or 3 days, such as days 1 , 2, and 3 of the dosage regimen. In some most preferred embodiments the loading period may be 2 days, such as days 1 and 2 of the dosage regimen.
  • the loading dose may be administered on days 1 , 2, 3, and / or 4 of the dosage regimen, such as on days 1 , 2, 3, and 4 of the dosage regimen.
  • the loading dose may be administered on days 1 , 2, and I or 3, of the dosage regimen, such as on days 1 , 2, and 3 of the dosage regimen, or on day 1 of the dosage regimen.
  • the loading dose may be administered on days 1 and 2 of the dosage regimen.
  • the loading dose may be about 100 mg administered on days 1 , 2, and I or 3, of the dosage regimen, such as on days 1 , 2, and 3 of the dosage regimen, or on day 1 of the dosage regimen. In some embodiments, the loading dose may be about 100 mg administered on days 1 and 2 of the dosage regimen.
  • the loading dose is about 150 mg administered on days 1 , 2, and I or 3, of the dosage regimen, such as on days 1 , 2, and 3 of the dosage regimen, or on day 1 of the dosage regimen. In some preferred embodiments, the loading dose is about 150 mg administered on days 1 and 2 of the dosage regimen.
  • the loading dose is about 200 mg administered on days 1 , 2, and I or 3, of the dosage regimen, such as on days 1 , 2, and 3 of the dosage regimen, or on day 1 of the dosage regimen. In some most preferred embodiments, the loading dose is about 200 mg administered on days 1 and 2 of the dosage regimen. Maintenance dose
  • the term "maintenance dose” refers to a dose of AXLi given to a subject following the loading period.
  • the maintenance dose is typically a reduced dose as compared to the loading dose, and may also be referred to, for example, as a “subsequent dose”, “reduced dose”, “second dose”, or “second dose level”.
  • the maintenance dose is administered over a maintenance period, to maintain a desired steady-state concentration of AXLi in the body.
  • the maintenance dose of AXLi may be about 30 to 120 mg, about 35 to 115 mg, about 45 to 105 mg, about 50 to 100 mg, about 55 to 95 mg, about 60 to 90 mg, about 65 to 85 mg, about 70 to 80 mg, about 71 to 79 mg, about 72 to 78 mg, about 73 to 77 mg, or about 74 to 76 mg.
  • the maintenance dose of AXLi may be about about 70 to 80 mg, about 71 to 79 mg, about 72 to 78 mg, about 73 to 77 mg, or about 74 to 76 mg.
  • the maintenance dose of AXLi may be about 75 mg.
  • the loading dose of AXLi may be about 150 mg and the maintenance dose of AXLi may be about 75 mg.
  • the maintenance dose of AXLi may be about 50 to 150 mg, about 60 to 140 mg, about 70 to 130 mg, about 75 to 125 mg, about 80 to 120 mg, about 85 to 115 mg, about 90 to 110 mg, about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg.
  • the maintenance dose of AXLi may be about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg.
  • the maintenance dose of AXLi may be about 100 mg.
  • the loading dose of AXLi may be about 200 mg and the maintenance dose of AXLi may be about 75 mg.
  • the loading dose of AXLi may be about 200 mg administered on days 1 and 2 of the dosage regimen, and the maintenance dose of AXLi may be about 100 mg administered on day 3 and each subsequent day of the dosage regimen.
  • the maintenance dose may be about 45-55%, such as about 46-54%, about 47-53%, about 48-52%, or about 49-51% of the loading dose. In some such embodiments, the maintenance dose may be about 50% of the loading dose.
  • the maintenance dose may be about 50% of the loading dose. That is, the loading dose may be reduced by about 50% to determine the maintenance dose.
  • the loading dose may be about 200 mg and the maintenance dose may be about 50% of the loading dose (100 mg), or the loading dose may be about 150 mg and the maintenance dose may be about 50% of the loading dose (75 mg).
  • the maintenance dose may be about 95-100%, such as about 96- 100%, about 97-100%, about 98-100%, or about 99-100% of the loading dose. In some such embodiments, the maintenance dose may be about 100% of the loading dose. In some preferred embodiments, the maintenance dose may be about 100% of the loading dose. That is, in some embodiments the maintenance dose may the same as the loading dose. By way of example, the loading dose may be about 200 mg and the maintenance dose may be about 100% of the loading dose (200 mg), or the loading dose may be about 150 mg and the maintenance dose may be about 100% of the loading dose (150 mg). Similalry, the loading dose may be about 100 mg and the maintenance dose may be about 100% of the loading dose (100 mg).
  • Regimens in which the maintenance dose is the same as the loading dose may also be referred to as regimens in which a constant dose level is administered to the subject, as described more fully elsewhere herein. Such regimens may be preferred in methods of the disclosure in which the AXLi is administered in combination with one or more further treatment and I or therapeutic agent, as described more fully elsewhere herein.
  • the maintenance period is the period over which the maintenance dose is administered to the subject following the loading period described above, for example, a period of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days following the loading period. That is, for a dosage regimen of a given duration, the maintenance period is the duration of the dosage regimen as described elsewhere herein, minus the loading period as described elsewhere herein.
  • the maintenance period may be the day following the last day of the loading period (for example day 3 where a loading dose is administered on days 1 and 2) and each subsequent day of the dosage regimen, which may be until treatment with the AXLi is stopped, for example when a treatment endpoint as described more fully elsewhere herein is reached for the subject.
  • the maintenance period may be 11 , 12, or 13 days, such as days 2-14, days 3-14, or days 4-14 of a 14 day dosage regimen.
  • the maintenance period may be 12 days, such as days 3-14 of the dosage regimen.
  • the maintenance period may be 18, 19, or 20 days, such as days 2-21 , days 3-21 , or days 4-21 of a 21 day dosage regimen.
  • the maintenance period may be 19 days, such as days 3-21 of the dosage regimen.
  • the maintenance dose may be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, and I or 31 of the dosage regimen.
  • the maintenance dose may be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, and I or each subsequent day of the dosage regimen. This is illustrated in the following non-limiting examples.
  • the maintenance dose may be administered on days 2, 3, 4, 5, 6, and / or 7 of the dosage regimen.
  • the maintenance dose may be administered on days 3, 4, 5, 6, and / or 7 of the dosage regimen, such as days 3, 4, 5, 6, and 7 of the dosage regimen.
  • the maintenance dose may be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and I or 14 of the dosage regimen.
  • the maintenance dose may be administered on days 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and I or 14 of the dosage regimen, such as on days 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and 14 of the dosage regimen.
  • the maintenance dose may be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and I or 21 of the dosage regimen.
  • the maintenance dose may be administered on days 3, 4, 5, 6,
  • the maintenance dose may be administered beginning on day 2, 3, or 4 of the dosage regimen. In some preferred embodiments, the maintenance dose may be administered beginning on day 3 of the dosage regimen.
  • the maintenance dose may be administered on day 2, 3, or 4 and on each subsequent day of the dosage regimen.
  • the maintenance dose may be administered on day 3 and on each subsequent day of the dosage regimen such as on day 3 of the dosage regimen, and on each subsequent day until treatment with the AXLi is stopped.
  • the maintenance dose may be administered on days 3, 4, 5, 6, and 7 of the dosage regimen.
  • the maintenance dose may be administered on days 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and 14 of the dosage regimen.
  • the maintenance dose may be administered on days 3, 4, 5, 6, 7,
  • the maintenance dose is about 75 mg administered on day 3 of the dosage regimen and on each subsequent day until treatment with the AXLi is stopped.
  • the loading dose is preferably about 150 mg administered on days 1 and 2 of the dosage regimen.
  • the maintenance dose is about 100 mg administered on day 3 of the dosage regimen and on each subsequent day until treatment with the AXLi is stopped.
  • the loading dose is preferably about 200 mg administered on days 1 and 2 of the dosage regimen.
  • the method comprises administering the loading dose of the AXLi on days 1 and 2 of the dosage regimen, and thereafter administering the maintenance dose of the AXLi. In some preferred embodiments, the method comprises administering the loading dose of the AXLi on days 1 and 2 of the dosage regimen, and administereing the maintenance dose on day 3 and on each subsequent day of the dosage regimen. Constant dose
  • Embodiments of the methods of the disclosure include those in which an AXLi is administered to the subject in a dosage regimen in which a constant AXLi dose level is administered to the subject.
  • a regimen comprising a “constant dose level” is one in which the same dose is administered to the subject throughout the dosing regimen (that is, one where in effect the “loading dose” and “maintenance dose” are the same).
  • Such regimens may be preferred in methods of the disclosure in which the AXLi is administered in combination with one or more further treatment and I or therapeutic agent, as described more fully elsewhere herein.
  • the constant dose level of AXLi may be about 30 to 120 mg, about 35 to 115 mg, about 45 to 105 mg, about 50 to 100 mg, about 55 to 95 mg, about 60 to 90 mg, about 65 to 85 mg, about 70 to 80 mg, about 71 to 79 mg, about 72 to 78 mg, about 73 to 77 mg, or about 74 to 76 mg.
  • the constant dose level of AXLi may be about about 70 to 80 mg, about 71 to 79 mg, about 72 to 78 mg, about 73 to 77 mg, or about 74 to 76 mg.
  • the constant dose level of AXLi may be about 75 mg.
  • the constant dose level of AXLi may be about 50 to 150 mg, about 60 to 140 mg, about 70 to 130 mg, about 75 to 125 mg, about 80 to 120 mg, about 85 to 115 mg, about 90 to 110 mg, about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg.
  • the constant dose level of AXLi may be about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg.
  • the constant dose level of AXLi may be about 100 mg. In a most preferred regimen comprising a “constant dose level” the constant dose level of AXLi is about 100 mg.
  • the constant dose level of AXLi may be about 75 to 175 mg, about 90 to 155 mg, about 95 to 155 mg, about 100 to 150 mg, about 105 to 145 mg, about 110 to 140 mg, about 115 to 135 mg, 120 to 130 mg, about 121 to 129 mg, about 122 to 128 mg, about 123 to 127 mg, or about 124 to 126 mg.
  • the constant dose level of AXLi may be about 120 to 130 mg, about 121 to 129 mg, about 122 to 128 mg, about 123 to 127 mg, or about 124 to 126 mg.
  • the constant dose level of AXLi may be about 125 mg.
  • the constant dose level of AXLi may be about 50 to 250 mg, about 100 to 200 mg, about 110 to 190 mg, about 120 to 180 mg, about 125 to 175 mg, about 130 to 170 mg, about 135 to 165 mg, about 140 to 160 mg, about 145 to 155 mg, about 146 to 154 mg, about 147 to 153 mg, about 148 to 152 mg, or about 149 to 151 mg.
  • the constant dose level of AXLi may be about about 145 to 155 mg, about 146 to 154 mg, about 147 to 153 mg, about 148 to 152 mg, or about 149 to 151 mg.
  • the constant dose level of AXLi may be about 150 mg.
  • the constant dose of AXLi may be administered to the subject daily for the duration of the dosage regimen, such as on day 1 and on each subsequent day of the dosage regimen, which may be until treatment with the AXLi is stopped, for example when a treatment endpoint as described more fully elsewhere herein is reached for the subject.
  • the constant dose may be administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, and I or 31 of the dosage regimen.
  • the constant dose may be administered on days 1 , 2, 3, 4, 5, 6, and / or 7 of the dosage regimen, preferably days 1 ,
  • the constant dose may be administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and / or 14 of the dosage regimen, preferably days 1 , 2,
  • the constant dose may be administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and I or 21 of the dosage regimen, preferably on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 of the dosage regimen.
  • the constant dose is about 150 mg administered on day 1 of the dosage regimen and on each subsequent day until treatment with the AXLi is stopped.
  • the duration of the dosage regimen may be about 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days, or more. In some embodiments, the duration of the dosage regimen may be about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52 weeks, or more. In some embodiments, the duration of the dosage regimen may be about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 months, or more.
  • the duration of the dosage regimen may be about 24, 48, 72 or 96 weeks.
  • the duration of the dosage regimen may be any length of time until treatment with the AXLi is stopped (which may also be referred to as “withdrawn”, or “discontinued”), for example when a treatment endpoint is reached for the subject.
  • Treatment endpoints for completion I discontinuation of AXLi treatment may be based on futility in terms of efficacy, or intolerability I toxicity in terms of safety.
  • Treatment endpoints for completion I discontinuation of AXLi treatment may also be based on utility in terms of efficacy, such as partial or complete disease remission.
  • the methods of the disclosure may comprise administering the maintenance dose of AXLi beginning, for example, on day 3 of the dosage regimen, and continuing to administer the maintenance dose to the subject daily until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject.
  • the methods of the disclosure may comprise administering the constant dose of AXLi beginning on day 1 of the dosage regimen, and continuing to administer the constant dose to the subject daily until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject.
  • Treatment endpoints which may result in treatment with the AXLi being stopped (“withdrawn”, or “discontinued”) include, for example:
  • Partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status), as may be assessed, for example, by % bone marrow myeloblasts, normal maturation of cell lines, reduction in tumour burden, and I or absence of detectable tumours.
  • Slowing or absence of disease progression (attaining stable disease [SD] status), as may be assessed, for example, by changes in % bone marrow myeloblasts, slowing or absence of tumour enlargement, and I or slowing or absence of increase in tumour burden.
  • SD stable disease
  • any positive patient outcome selected from: prolonged survival, progression-free survival, hematologic improvement (as may be assessed, for example, by increased blood haemoglobin, platelet count, and I or neutrophil count), bone marrow response (as may be assessed, for example, by: bone marrow with ⁇ 5% myeloblasts; 30%, 40%, 50% or more reduction in bone marrow myeloblasts; absence of circulating myeloblasts and myeloblasts with Auer rods; absence of extramedullary disease), hematologic recovery (as may be assessed, for example, by: >11 g/dL haemoglobin, >100x109/L platelets, and I or >1x109/L neutrophils in peripheral blood), tumour shrinkage (for example, a reduction in tumour volume of 5, 10, 20, 30, 40% or more), reduction in tumour burden (for example, a reduction in tumour burden of 5, 10, 20, 30, 40% or more), slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, negative
  • CT computed tomography
  • MRI magnetic resonance imaging
  • X-ray imaging for example, mammography
  • ultrasound imaging nuclear imaging, for example positron emission tomography (PET), PET/CT scans, bone scans, gallium scans, or metaiodobenzylguanidine (MIBG) scans
  • PET positron emission tomography
  • MIBG metaiodobenzylguanidine
  • BBI bioluminescence imaging
  • FLI fluorescence imaging
  • BD ToF infrared-based 3D Time-of-Flight camera
  • Preferred treatment endpoints which may result in treatment with the AXLi being stopped (“withdrawn”, or “discontinued”) include:
  • AXLi treatment may be continued for a period after first determination if this is deemed to be due to AXLi effect and there are no tolerability concerns.
  • a treatment endpoint which may result in treatment with the AXLi being stopped is 1 , 2, 3, 4, 5, 6 or more months of CR status.
  • references to treatment being “stopped” mean that treatment with the therapeutic agent, such as AXLi, is ceased.
  • Alternative terms such as “withdrawn”, “discontinued”, etc. may be used interchangeably with “stopped”.
  • references to “treatment withdrawal” mean treatment of the subject with the therapeutic agent, such as AXLi, is ceased.
  • Alternative terms such as “treatment discontinuation”, “treatment to be stopped”, etc. may be used interchangeably.
  • the AXLi may be administered to the subject QD (quaque die; every day).
  • the AXLi may be administered to the subject daily. That is, the AXLi may be administered to the subject on each day of the dosage regimen, which may include days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14 , 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and beyond until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject.
  • the duration of the dosage regimen is about 7 days
  • the AXLi may be administered to the subject on days 1 , 2, 3, 4, 5, 6, and 7 of the dosage regimen.
  • the duration of the dosage regimen is about 14 days
  • the AXLi may be administered to the subject on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, and 14 of the dosage regimen.
  • the AXLi may be administered to the subject once daily. That is, the AXLi may be administered to the subject once on each day of the dosage regimen, which may be once on each of days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14 , 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and beyond until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject.
  • the duration of the dosage regimen is about 7 days
  • the AXLi may be administered to the subject once on each of days 1 , 2, 3, 4, 5, 6, and 7 of the dosage regimen.
  • the duration of the dosage regimen is about 14 days
  • the AXLi may be administered to the subject once on each of days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, and 14 of the dosage regimen.
  • the dosage regimen may comprise multiple treatment cycles of the AXLi.
  • a “treatment cycle” refers to a period of treatment that is repeated on a regular schedule. For example, a course of treatment given for one week, two weeks, or three weeks may be referred to as one treatment cycle. This cycle may be repeated to make up a course of treatment - i.e. a course of treatment comprising multiple treatment cycles.
  • the dosage regimen may represent a course of treatment comprising multiple treatment cycles.
  • the length of each treatment cycle may be about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.
  • the length of each treatment cycle may be about 3 weeks.
  • the first treatment cycle may comprise administering a loading dose and maintenance dose of the AXLi as described more fully elsewhere herein - for example the first treatment cycle may comprise administering a loading dose of about 200 mg on days
  • the second and subsequent treatment cycle may comprise administering a maintenance dose of the AXLi as described more fully elsewhere herein - for example the second and subsequent treatment cycles may comprise administering a maintenance dose of about 100 mg on day 1 and each subsequent day of the second and subsequent treatment cycles (for example on days 1-21 of subsequent 3-week treatment cycles).
  • the first and subsequent treatment cycles may comprise administering a constant dose of the AXLi as described more fully elsewhere herein - for example the first and subsequent treatment cycles may comprise administering a constant dose of about 150 mg on each day of each cycle (for example on days 1-21 of 3-week treatment cycles).
  • the AXL-related disease is cancer. In some other embodiments, the AXL-related disease is a fibrotic disorder.
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 200 mg administered on days 1 and
  • the maintenance dose is about 100 mg administered on day 3 and each subsequent day of the dosage regimen.
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 200 mg administered on day 1 of the dosage regimen; and, the maintenance dose is about 100 mg on day 2 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 200 mg administered on days 1 , 2, and 3 of the dosage regimen; and, the maintenance dose is about 100 mg administered on day 4 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 150 mg administered on days 1 and 2 of the dosage regimen; and, the maintenance dose is about 75 mg administered on day 3 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 150 mg administered on day 1 of the dosage regimen; and, the maintenance dose is about 75 mg on day 2 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 150 mg administered on days 1 , 2, and 3 of the dosage regimen; and, the maintenance dose is about 75 mg administered on day 4 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising administering a constant dose of about 75 mg of AXLi on day 1 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising administering a constant dose of about 100 mg of AXLi on day 1 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising administering a constant dose of about 125 mg of AXLi on day 1 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • a method for treating cancer in a subject comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising administering a constant dose of about 150 mg of AXLi on day 1 and each subsequent day of the dosage regimen.
  • an AXLi such as bemcentinib
  • the AXLi which may be bemcentinib, is preferably administered to the subject under fed conditions, as described more fully elsewhere herein.
  • AXLi concomitant administration of AXLi with a therapeutic agent that alters gastric pH or alters gastric acid production (as described in more detail below) can influence absorption and subsequent subject exposure to the AXLi.
  • a therapeutic agent that alters gastric pH or alters gastric acid production can influence absorption and subsequent subject exposure to the AXLi.
  • use of therapeutic agents that alter gastric pH, such as proton pump inhibitors result in increased pH in the stomach and therefore a reduction in the solubility of bemcentinib and its subsequent absorption.
  • the level of the loading and I or maintenance dose of AXLi may differ dependent on whether the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production.
  • the level of the constant dose of AXLi may differ dependent on whether the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production.
  • the loading, maintenance dose, and I or constant dose of AXLi may be increased by about 100% if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production, such as a therapeutic agent that increases gastric pH or decreases gastric acid production.
  • the skilled person is readily able to determine the increased dose levels based on the loading, maintenance, and constant doses described elsewhere herein.
  • the loading, maintenance, and constant doses described elsewhere herein are readily able to determine the increased dose levels based on the loading, maintenance, and constant doses described elsewhere herein.
  • the loading and I or maintenance dose of AXLi may be increased by about 100% of the loading or maintenance doses detailed elsewhere herein if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production, such as a therapeutic agent that increases gastric pH or decreases gastric acid production.
  • a loading dose of about 200 mg may be increased to about 400 mg if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production.
  • a maintenance dose of about 100 mg may be increased to about 200 mg if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production.
  • the constant dose of AXLi may be increased by about 100% of the constant doses detailed elsewhere herein if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production, such as a therapeutic agent that increases gastric pH or decreases gastric acid production.
  • a constant dose of about 150 mg may be increased to about 300 mg if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production.
  • a constant dose of about 100 mg may be increased to about 200 mg if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production.
  • the loading and I or maintenance dose, or constant dose may be increased to a level in accordance with the above embodiments - e.g. increased by about 100%.
  • the increased dose may be administered to the subject at the increased level for the remainder of the duration of the dosage regimen.
  • the maintenance dose may be increased to about 200 mg for day 4 and each subsequent day of the dosage regimen.
  • the constant dose may be increased to about 300 mg for day 4 and each subsequent day of the dosage regimen.
  • the therapeutic agent that alters gastric pH or alters gastric acid production may be any therapeutic intervention that is administered to modulate gastric pH or gastric acid production.
  • the therapeutic agent that alters gastric pH or alters gastric acid production may be a drug for treatment of acid related disorders.
  • drugs for acid related disorders are categorised in the World Health Organization’s (WHO) Anatomical Therapeutic Chemical Classification System under ATC code A02 and are categorised in the Medical Dictionary for Regulatory Activities (MedDRA) under code A02.
  • a subcategory of these is drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD; ATC A02B).
  • GORD gastro-oesophageal reflux disease
  • the therapeutic agent that alters gastric pH or alters gastric acid production may be a therapeutic agent that increases gastric pH or decreases gastric acid production.
  • the therapeutic agent that alters gastric pH or alters gastric acid production may be a gastroprotective agent, a gastric acid synthesis inhibitor, or an agent that neutralises gastric acid.
  • Such agents include:
  • PPI Proton pump inhibitors
  • ATC A02BC Proton pump inhibitors
  • the PPI may be: omeprazole, lansoprazole, dexlansoprazole, dexrabeprazole, vonoprazan, tegoprazan, esomeprazole, pantoprazole, rabeprazole, and I or ilaprazole.
  • H2 receptor antagonists (H2RA; ATC A02BA), which block the action of histamine at H2 receptors of parietal cells in the stomach thereby reducing gastric acid production.
  • the H2 antagonist may be cimetidine, ranitidine, famotidine, nizatidine, roxatidine, ranitidine bismuth citrate, lafutidine, lavoltidine, and I or niperotidine.
  • Antacids which contain alkaline ions that chemically neutralise gastric acid.
  • the antacid may be an aluminium salt, a calcium salt, a magnesium salt, and / or a sodium salt.
  • the antacid may be aluminium hydroxide, algeldrate, aluminium phosphate, dihydroxialumini sodium carbonate, aluminium acetoacetate, aloglutamol, aluminium glycinate, calcium carbonate, calcium silicate, magnesium carbonate, magnesium oxide, magnesium peroxide, magnesium silicate, magnesium trisilicate, magnesium hydroxide, sodium bicarbonate, magaldrate, almagate, hydrotalcite, almasilate, and I or bismuth subsalicylate.
  • Prostaglandins such as misoprostol and I or enprostil.
  • GORD gastro-oesophageal reflux disease
  • Other drugs for peptic ulcer and gastro-oesophageal reflux disease such as carbenoxolone, sucralfate, pirenzepine, methiosulfonium chloride, bismuth subcitrate, proglumide, gefarnate, sulglicotide, acetoxoIone, zolimidine, troxipide, bismuth subnitrate, alginic acid, and I or rebamipide.
  • the therapeutic agent that alters gastric pH or alters gastric acid production may be a therapeutic agent that increases gastric pH above pH 2,0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0.
  • the therapeutic agent may increase gastric pH above pH 3.5, such as above pH 3.6, 3.7, 3.8, 3.9, or 4.0.
  • the therapeutic agent that alters gastric pH or alters gastric acid production may be a therapeutic agent that increases gastric pH out of the range of pH 1.5 to 4.0, such as out of the range of pH 1.5 to pH 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0.
  • the therapeutic agent may increase gastric pH out of the range of pH 2.0 to 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0.
  • the therapeutic agent may increase gastric pH out of the range of pH 3.0 to 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. As outlined elsewhere herein, these effecs on gastric pH may be via reduction of gastric acid secretion and I or neutraliseation of gastric acid.
  • the consumption of food can result in a number of physiological changes influencing the pharmacokinetics of drug compounds, including, for example, changes in gastric and intestinal pH, delayed gastric emptying, increased bile secretion, and increased splanchnic and hepatic blood flow.
  • the present authors have unexpectedly discovered that administration of AXLi to subjects under fed conditions is associated with both increased exposure to the AXLi, and reduced variability in exposure between subjects. Without being bound by theory, it is speculated that the reduced PK variability and increased exposure with food could be a result of the inhibition of efflux transporters within the Gl tract, or increased amount of transport through the lymphatic system due to the increased lipid content within the Gl tract due to the addition of food.
  • the surprising decrease in variability observed with fed state doses allows the dose of AXLi to be reduced, which will in turn reduce the incidence of adverse effects associated with AXLi administration.
  • the methods of the disclosure may comprise administering the AXLi to the subject under fed conditions. That is, the AXLi may be administered to the subject pc (post cibum; after meals).
  • the AXLi is administered to the subject under fed conditions.
  • drug administration under “fed conditions” means drug administration such that administration and I or absorption of the drug occurs while the subject is the prandial absorptive phase - that is, in the period following ingestion of food when the body is digesting the food and absorbing nutrients (and in which catabolism exceeds anabolism).
  • Drug administration under “fed conditions” also encompasses scenarios in which subjects receive nutrition in liquid form (for example, an enteral nutrition feed, composition comprising blended foodstuffs, or other processed food replacement) which may be via enteral or parenteral administration routes. In such cases, drug administration (such as AXLi administration) may still be administered orally, or via installation through a feeding tube.
  • drug administration under “fed conditions” means drug administration concomitant with food consumption I ingestion, which may be food consumption I ingestion before, at the same time, and I or after drug administration.
  • drug administration may occur before or during a bolus or infusion feed period (for example to allow for gastro-intestinal and digestive and metabolic “rest” from feeding).
  • Administration under “fed conditions” may also be referred to as e.g. administration in a “fed state”, administration “with food”, etc.
  • drug administration under “fasted conditions” or in a “fasted state” means administration in a period in which no food is consumed by the subject - as is described more fully below.
  • administering the AXLi under fed conditions may comprise administering the AXLi to the subject before, at the same time, and I or after food consumption I ingestion.
  • administering the AXLi under fed conditions may comprise administering the AXLi to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes of the subject consuming I ingesting food.
  • the AXLi is administered to the subject within about 240 minutes of the subject consuming I ingesting food.
  • within about 240 minutes of consuming I ingesting food means within the window of time of 240 minutes before or after consuming I ingesting food.
  • administering the AXLi under fed conditions may comprise administering the AXLi to the subject less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed I ingested food.
  • the AXLi is administered to the subject less than about 240 minutes after the subject has consumed I ingested food.
  • administering the AXLi under fed conditions may comprise administering the AXLi to the subject not more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes before the subject has consumed I ingested, or will consume I ingest, food.
  • the AXLi is administered to the subject not more than about 240 minutes before the subject has consumed I ingested, or will consume I ingest, food.
  • administering the AXLi under fed conditions may comprise administering the AXLi to the subject at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed I ingested food.
  • administering the AXLi under fed conditions comprises administering the AXLi to the subject within about 0-240 minutes, such as about 30-240 minutes, 60-240 minutes, 90-240 minutes, 120-240 minutes, 150-240 minutes, 180-240 minutes, or 210-240 minutes of the subject consuming I ingesting food, or such as about 0-210 minutes, 0-180, 0- 150, 0-120, 0-90, 0-60, or 0-30 minutes of the subject consuming I ingesting food.
  • administering the AXLi under fed conditions comprises administering the AXLi to the subject within about 5-60 minutes, such as about 10-50 minutes, or about 20-40 minutes of the subject consuming I ingesting food.
  • administering the AXLi under fed conditions may comprise administering the AXLi to the subject within 240 minutes of the subject consuming I ingesting food. That is, administering the AXLi to the subject not more than about 240 minutes before the subject has consumed I ingested, or will consume I ingest, food and less than about 240 minutes after the subject has consumed I ingested food.
  • the food may comprise or may be a meal, such as a high-fat and I or high-protein meal.
  • the food may comprise, or may be, oral nutritional supplements (ONS).
  • the food may comprise, or may be an enteral nutrition feed, such as a high-fat and I or high-protein meal formulated for enteral administration.
  • the food may comprise, or may be a parenteral nutrition feed, such as a high-fat and I or high-protein meal formulated for parenteral administration.
  • the food may be consumed I ingested by the oral route.
  • the food may be consumed I ingested by the enteral route, which may be via the nasogastric (NG), percutaneous endoscopic gastrostomy (PEG), or nasojejunal (NJ) route.
  • the food may be consumed I ingested by the parenteral route.
  • a high-fat meal is one which contains about 800-1000 kcal with about 500-600 kcal from fat and 250 kcal from carbohydrates.
  • An example high-fat meal is two eggs fried in butter, two strips of bacon, two slices of toast with butter, 120 ml of hash brown potatoes and 240 ml of whole milk. Substitutions in this example meal can be made provided the meal provides similar amounts of calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity.
  • a high-fat meal is one which contains between about 700-1100 kcal, between about 750-1050 kcal, or between about 800-1000 kcal, wherein about 45, 50, 55, 60, 65, or 70% of the caloric content comes from fats.
  • about 10, 15, 20, 25, 30, or 35 % of the caloric content may come from carbohydrates.
  • a high-fat meal is one which more than about 25%, such as more than about 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, or 70% of the total caloric content of the meal comes from fats, either saturated or unsaturated.
  • a high-fat meal is one in which more than about 35% of the total caloric content of the meal comes from fats, either saturated or unsaturated.
  • a high- fat meal is one in which more than about 45% of the total caloric content of the meal comes from fats, either saturated or unsaturated. In some preferred embodiments, a high-fat meal is one in which more than about 50% of the total caloric content of the meal comes from fats, either saturated or unsaturated. In some embodiments, a high-fat meal is one in which about 25-65%, such as about 35-65%, 45-65%, 50-65%, or 55-65% of the total caloric content of the meal comes from fats, either saturated or unsaturated.
  • a high-protein meal is one in which more than about 15%, such as more than about 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35% of the total caloric content of the meal comes from protein. In some embodiments, a high-protein meal is one which more than about 20% of the total caloric content of the meal comes from protein.
  • drug administration under “fasted conditions”, “fasting conditions”, in a “fasted state”, or “fasting conditions” means administration in a period in which no food is consumed by the subject - for example, following an overnight fast and with no food consumed until at least 1 , 2, 3, or 4 hours after drug administration.
  • Administration under “fasted conditions” may also be referred to as e.g. administration in “fasting conditions”, in a “fasted state”, in “fasting conditions”, administration “without food”, etc.
  • the methods of the disclosure may comprise administering the AXLi to the subject under fasted conditions.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject following an overnight fast.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject following an overnight fast, and at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject consumes I ingests any food.
  • the AXLi may be administered at least about 1 hour before the subject consumes I ingests any food.
  • An “overnight” fast may be a period of about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours overnight during which the subject does not consume I ingest any food.
  • an “overnight” fast may be a period of about 4 or more hours overnight during which the subject does not consume I ingest any food, “does not consume food” may mean that the subject does not consume I ingest anything other than water.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject on an empty stomach.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject on an empty stomach, and at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject consumes I ingests any food.
  • the AXLi may be administered at least about 1 hour before the subject consumes I ingests any food.
  • An “empty stomach” may mean that the subject has not consumed I ingested food for a period of about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours prior to administration of the AXLi.
  • an “empty stomach” may mean that the subject has not consumed I ingested food for a period of about 4 or more hours prior to administration of the AXLi.
  • “has not consumed food” may mean that the subject has not consumed I ingested anything other than water.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject has consumed I ingested, or will consume I ingest, food.
  • the AXLi may be administered to the subject at least about 120 minutes before the subject has consumed I ingested, or will consume I ingest, food.
  • the AXLi may be administered to the subject at least about 60 minutes before the subject has consumed I ingested, or will consume I ingest, food.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject at least about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours after the subject last consumed I ingested food.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject at least about 4 or more hours after the subject last consumed I ingested food.
  • the AXLi may be administered to the subject at least about 8 hours after the subject last consumed I ingested food.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject has consumed I ingested, or will consume I ingest, food, and at least about 1 , 2, 3, or more preferably 4, 5, 6, 7, 8, 9, or 10 hours after the subject last consumed I ingested food.
  • the AXLi may be administered to the subject at least about 60 minutes before the subject has consumed I ingested, or will consume I ingest, food, and at least about 8 hours after the subject last consumed I ingested food.
  • the AXLi may be administered to the subject at least about 240 minutes before the subject has consumed I ingested, or will consume I ingest, food, and at least about 4 hours after the subject last consumed I ingested food.
  • administering the AXLi under fasted conditions may comprise administering the AXLi to the subject on an empty stomach, preferably after an overnight fast, and at least about 1 hour before the subject consumes I ingests any food.
  • the AXLi may be administered with water.
  • the AXLi described herein may be administered in combination with one or more further treatment and I or therapeutic agent, either simultaneously or sequentially in any order.
  • treatments and therapeutic agents include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs, such as chemotherapeutic agents), immunotherapy (the administration of active agents, including, e.g. cell-based therapies or drugs, such as immune checkpoint modulators (ICM)), and I or radiotherapy.
  • chemotherapy the administration of active agents, including, e.g. drugs, such as chemotherapeutic agents
  • immunotherapy the administration of active agents, including, e.g. cell-based therapies or drugs, such as immune checkpoint modulators (ICM)
  • ICM immune checkpoint modulators
  • a “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action.
  • Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors.
  • Chemotherapeutic agents include compounds used in “targeted therapy”, immuno-oncology drugs such as checkpoint inhibitors, and conventional chemotherapy.
  • the AXLi may be administered in combination with one or more chemotherapeutic agent.
  • chemotherapeutic agents which may be used in the disclosed methods include: Lenalidomide (REVLIMID®, Celgene), Vorinostat (ZOLINZA®, Merck), Panobinostat (FARYDAK®, Novartis), Mocetinostat (MGCD0103), Everolimus (ZORTRESS®, CERTICAN®, Novartis), Bendamustine (TREAKISYM®, RIBOMUSTIN®, LEVACT®, TREANDA®, Mundipharma International), erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi- Aventis), 5-Fll (fluorouracil, 5-fluorouracil, CAS No.
  • gemcitabine Lilly
  • PD-0325901 CAS No. 391210-10-9, Pfizer
  • cisplatin cisdiamine, dichloroplatinum(ll), CAS No. 15663-27-1
  • carboplatin CAS No. 41575-94-4
  • paclitaxel TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.
  • trastuzumab HERCEPTIN®, Genentech
  • temozolomide 4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9-carboxamide, CAS No.
  • tamoxifen (Z)-2-[4-(1 ,2-diphenylbut-1-enyl)phenoxy]-N,N- dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD, and rapamycin.
  • chemotherapeutic agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (siroli
  • calicheamicin calicheamicin gammal l, calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33:183- 186); dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubi
  • chemotherapeutic agents used in the treatment of anal cancer include: Gardasil, Gardasil 9, Recombinant Human Papillomavirus (HPV) Nonavalent Vaccine, Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine.
  • chemotherapeutic agents used in the treatment of bladder cancer include: Atezolizumab, Avelumab, Balversa (Erdafitinib), Bavencio (Avelumab), Cisplatin, Doxorubicin Hydrochloride, Durvalumab, Erdafitinib, Imfinzi (Durvalumab), Keytruda (Pembrolizumab), Nivolumab, Opdivo (Nivolumab), Pembrolizumab, Tecentriq (Atezolizumab), Thiotepa, Valrubicin, and Valstar (Valrubicin).
  • chemotherapeutic agents used in the treatment of bone cancer include: Cosmegen (Dactinomycin), Dactinomycin, Denosumab, Doxorubicin Hydrochloride, Methotrexate, Trexall (Methotrexate), and Xgeva (Denosumab).
  • chemotherapeutic agents used in the treatment of brain tumors include: Afinitor (Everolimus), Afinitor Disperz (Everolimus), Avastin (Bevacizumab), Bevacizumab, BiCNll (Carmustine), Carmustine, Carmustine Implant, Everolimus, Gliadel Wafer (Carmustine Implant), Lomustine, Mvasi (Bevacizumab), Temodar (Temozolomide), and Temozolomide.
  • chemotherapeutic agents used in the treatment of breast cancer include: Abemaciclib, Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Ado- Trastuzumab Emtansine, Afinitor (Everolimus), Afinitor Disperz (Everolimus), Alpelisib, Anastrozole, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane), Atezolizumab, Capecitabine, Cyclophosphamide, Docetaxel, Doxorubicin Hydrochloride, Ellence (Epirubicin Hydrochloride), Enhertu (Fam-Trastuzumab Deruxtecan- nxki), Epirubicin Hydrochloride, Eribulin Mesylate, Everolimus, Exemestane, 5-Fll (Fluorouracil Injection), Fam-Trastuzumab Deruxtecan-nxki
  • chemotherapeutic agents used in the treatment of cervical cancer include: Avastin (Bevacizumab), Bevacizumab, Bleomycin Sulfate, Hycamtin (Topotecan Hydrochloride), Keytruda (Pembrolizumab), Mvasi (Bevacizumab), Pembrolizumab, Topotecan Hydrochloride.
  • chemotherapeutic agents used in the treatment of colon and rectal cancer include: Avastin (Bevacizumab), Bevacizumab, Camptosar (Irinotecan Hydrochloride), Capecitabine, Cetuximab, Cyramza (Ramucirumab), Eloxatin (Oxaliplatin), Erbitux (Cetuximab), 5-Fll (Fluorouracil Injection), Fluorouracil Injection, Ipilimumab, Irinotecan Hydrochloride, Keytruda (Pembrolizumab), Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil Hydrochloride), Mvasi (Bevacizumab), Nivolumab, Opdivo (Nivolumab), Oxaliplatin, Panitumumab, Pembrolizumab, Ramucirumab, Regorafenib, Stivarga (Regorafenib), Trifluridine
  • chemotherapeutic agents used in the treatment of ovarian, fallopian tube, or primary peritoneal cancer include: Alkeran (Melphalan), Avastin (Bevacizumab), Bevacizumab, Carboplatin, Cisplatin, Cyclophosphamide, Doxorubicin Hydrochloride, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride Liposome, Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Hycamtin (Topotecan Hydrochloride), Lynparza (Olaparib), Melphalan, Niraparib Tosylate Monohydrate, Olaparib, Paclitaxel, Rubraca (Rucaparib Camsylate), Rucaparib Camsylate, Taxol (Paclitaxel), Thiotepa, Topotecan Hydrochloride, Zejula (Niraparib Tosylate Monohydrate,
  • chemotherapeutic agents used in the treatment of non-small cell lung cancer include: Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Afatinib Dimaleate, Afinitor (Everolimus), Afinitor Disperz (Everolimus), Alecensa (Alectinib), Alectinib, Alimta (Pemetrexed Disodium), Alunbrig (Brigatinib), Amivantamab-vmjw, Atezolizumab, Avastin (Bevacizumab), Bevacizumab, Wegatinib, Cabozantinib, Carboplatin, Capmatinib, Cemiplimab-rwlc, Ceritinib, Crizotinib, Cyramza (Ramucirumab), Dabrafenib Mesylate, Dacomitinib, Docetaxel, Doxorubicin Hydrochloride, Durvaluma
  • An example of preferred chemotherapeutic agents for use in treatment of non-small cell lung cancer is carboplatin in combination with pemetrexed.
  • Another example of preferred chemotherapeutic agents for use in treatment of non-small cell lung cancer is carboplatin in combination with pemetrexed and pembrolizumab.
  • Another example of preferred chemotherapeutic agents for use in treatment of non-small cell lung cancer is cisplatin in combination with pemetrexed.
  • Another example of preferred chemotherapeutic agents for use in treatment of non-small cell lung cancer is cisplatin in combination with pemetrexed and pembrolizumab.
  • AXLi is administered in combination with chemotherapeutic agents (such as in combination with pembrolizumab, or in combination with carboplatin, pemetrexed, and pembrolizumab) for treatment of non-small cell lung cancer
  • dosage regimens in which a constant dose level of AXLi is administered to the subject may be preferred.
  • chemotherapeutic agents used in the treatment of small cell lung cancer include: Afinitor (Everolimus), Atezolizumab, Bendamustine, Carboplatin, Cisplatin, Cyclophosphamide, Docetaxel, Doxorubicin Hydrochloride, Durvalumab, Etopophos (Etoposide Phosphate), Etoposide, Etoposide Phosphate, Everolimus, Gemcitabine (Gemza), Hycamtin (Topotecan Hydrochloride), Irinotecan, Keytruda (Pembrolizumab), Lurbinectedin, Mechlorethamine Hydrochloride, Methotrexate, Mustargen (Mechlorethamine Hydrochloride), Nivolumab, Opdivo (Nivolumab), Paclitaxel, Pembrolizumab, Tecentriq (Atezolizumab), Topotecan Hydrochloride, Trexall (Methotrexate,
  • chemotherapeutic agents used in the treatment of melanoma include: Aldesleukin, Binimetinib, Braftovi (Encorafenib), Cobimetinib, Cotellic (Cobimetinib), Dabrafenib Mesylate, dacarbazine, Encorafenib, IL-2 (Aldesleukin), Imlygic (Talimogene Laherparepvec), lnterleukin-2 (Aldesleukin), Intron A (Recombinant Interferon Alfa-2b), Ipilimumab, Keytruda (Pembrolizumab), Mekinist (Trametinib), Mektovi (Binimetinib), Nivolumab, Opdivo (Nivolumab), Peginterferon Alfa-2b, PEG-lntron (Peginterferon Alfa-2b), Pembrolizumab, Proleukin (Aldesleukin), Re
  • chemotherapeutic agents used in the treatment of mesothelioma include: Alimta (Pemetrexed Disodium), Carboplatin, Cisplatin , Bevacizumab, Nivolumab, Ipilimumab, and Pemetrexed Disodium.
  • chemotherapeutic agents used in the treatment of AML include: ATRA, Arsenic Trioxide, Azacitidine, Cerubidine (Daunorubicin Hydrochloride), Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Daunorubicin Hydrochloride, Daunorubicin Hydrochloride and Cytarabine Liposome, Daurismo (Glasdegib Maleate), Decitabine, Dexamethasone, Doxorubicin Hydrochloride, Enasidenib Mesylate, Etoposide, Fludarabine, Gemtuzumab Ozogamicin, Gilteritinib Fumarate, Glasdegib Maleate, Idamycin PFS (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idhifa (Enasidenib Mesylate), Ivosidenib, Midostaurin, Mitoxantrone Hydrochloride, My
  • chemotherapeutic agents used in the treatment of pancreatic cancer include: Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Afinitor (Everolimus), Capecitabine, Cisplatin, Entrectinib, Erlotinib Hydrochloride, Everolimus, 5-FU (Fluorouracil Injection), Fluorouracil Injection, Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Irinotecan Hydrochloride Liposome, Larotrectinib, Lynparza (Olaparib), Mitomycin C, Olaparib, Onivyde (Irinotecan Hydrochloride Liposome), Paclitaxel Albumin- stabilized Nanoparticle Formulation, Pembrolizumab, Rucaparib, Sunitinib Malate, Sutent (Sunitinib Malate), and Tarceva (Erlotinib Hydrochloride).
  • chemotherapeutic agents used in the treatment of renal cancer include: Afinitor (Everolimus), Afinitor Disperz (Everolimus), Aldesleukin, Axitinib, Avastin (Bevacizumab), Avelumab, Axitinib, Bavencio (Avelumab), Bevacizumab, Cabometyx (Cabozantinib-S- Malate), Cabozantinib-S-Malate, Everolimus, IL-2 (Aldesleukin), Inlyta (Axitinib), lnterleukin-2 (Aldesleukin), Ipilimumab, Keytruda (Pembrolizumab), Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Mvasi (Bevacizumab), Nexavar (Sorafenib Tosylate), Nivolumab, Opdivo (N
  • chemotherapeutic agents used to treat solid tumors anywhere in the body include: Entrectinib, Keytruda (Pembrolizumab), Larotrectinib Sulfate, Rozlytrek (Entrecti nib), and Vitrakvi (Larotrectinib Sulfate).
  • Combination treatments are also included in the definition of “chemotherapeutic agent” used herein.
  • Examples of combination treatments of chemotherapeutic agents include: gemcitabine-cisplatin, MVAC (methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin), PCV (procarbazine hydrochloride, lomustine, vincristine sulfate), AC (doxorubicin hydrochloride, cyclophosphamide), AC-T (doxorubicin hydrochloride, cyclophosphamide, paclitaxel), CAF (cyclophosphamide, doxorubicin hydrochloride, fluorouracil), CMF (cyclophosphamide, methotrexate, fluorouracil), FEC (fluorouracil, epirubicin hydrochloride, cyclophosphamide), TAC (docetaxel, doxorubicin hydrochlor
  • chemotherapeutic agent include: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole),
  • SERMs
  • chemotherapeutic agent therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), ofatumumab (ARZERRA®, GSK), pertuzumab (PERJETATM, OMNITARGTM, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), MDX- 060 (Medarex).
  • therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab
  • chemotherapeutic agent antibodies drug conjugates, in particular AXL antibody drug conjugates.
  • AXL antibody drug conjugates include gemtuzumab ozogamicin (MYLOTARG®, Wyeth), enapotamab vedotin (HuMax®-AXL-ADC, Genmab), CAB-AXL-ADC (BioAtla).
  • Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the conjugates of the disclosure include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab,
  • ADCs are a class of biopharmaceutical drugs designed as targeted therapies, and which comprise an antibody (or functional fragment thereof) linked to a payload or drug.
  • the payload may be a cytotoxic drug, for example one or more of the anti-cancer chemotherapeutic agents described above.
  • the antibody portion of the ADC specifically targets an antigen present on a target cell - for example a tumour antigen on tumour cells - delivering the payload to the target cell.
  • the specific targeting of ADCs limits their side effects and gives a wider therapeutic window than other chemotherapeutic agents.
  • the chemotherapeutic agent may be an antibody-drug conjugate.
  • the antibody-drug conjugate may comprise as its antibody portion one the antibodies disclosed elsewhere herein.
  • the antibody-drug conjugate may comprise as its payload one or more of the anti-cancer chemotherapeutic agents disclosed elsewhere herein.
  • the antibody-drug conjugate may comprise as its payload an anthracycline, such as doxorubicin, or a taxane, such as docetaxel.
  • the antibody drug conjugate may be gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, or moxetumomab pasudotox.
  • chemotherapeutic agents are known to influence pathways involved in the immune response.
  • the class of cytotoxic chemotherapeutic agents called anthracyclines are known to induce a Type I Interferon response mimicking immune responses to viruses, and the clinical response to antracycline therapy correlates with a Type I IFN gene signature (Sistigue et al 2014; Zitvogel et al, 2015).
  • AXL serves as a key checkpoint for interferon (IFN) signaling
  • stimulating IFN signaling in the context of AXL- inhibition could lead to enhanced anticancer T cell responses during immune checkpoint inhibition.
  • the chemotherapeutic agent may be a chemotherapeutic agent which induces an immune response in the subject.
  • the chemotherapeutic agent may be a chemotherapeutic agent which induces a type I interferon response in the subject.
  • the chemotherapeutic agent may be an anthracycline.
  • the chemotherapeutic agent may be selected from the group consisting of: Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, and Valrubicin.
  • the chemotherapeutic agent may be doxorubicin.
  • the chemotherapeutic agent may be a platinum-based chemotherapeutic.
  • the chemotherapeutic agent may be selected from the group consisting of: cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin.
  • the chemotherapeutic agent may be carboplatin.
  • the chemotherapeutic agent may be an antifolate chemotherapeutic.
  • the chemotherapeutic agent may be selected from the group consisting of: pemetrexed, methotrexate, pralatrexate, and trimetrexate.
  • the chemotherapeutic agent may be pemetrexed.
  • the combination chemotherapeutic agent may comprise a platinum-based chemotherapeutic and an antifolate chemotherapeutic.
  • a particularly preferred combination is carboplatin and pemetrexed, which may be used for example in combination with an anti-PD1 antibody such as pembrolizumab.
  • the combination of carboplatin, pemetrexed, and pembrolizumab may be particualry preferred when the AXL- related disease to be treated is non small-cell lung cancer.
  • dosage regimens in which a constant dose level of AXLi is administered to the subject may be preferred.
  • the combination chemotherapeutic agent may comprise cytarabine.
  • Combination with cytarabine may be particualry preferred when the AXL-related disease to be treated is AML.
  • the combination chemotherapeutic agent may comprise an EGFR targeted therapy, such as an EGFR inhibitor and / or a HER2 targeted therapy, such as a HER2 inhibitor.
  • the EGFR targeted therapy may be selected from the group consisting of: gefitinib, erlotinib, osimertinib, lapatinib, brigatinib, rociletinib, olmutinib, toartinib, naquotinib, mavelertinib, neratinib, dacomitinib, mobocertinib, and vandetanib.
  • the EGFR targeted therapy may be selected from the group consisting of: cetuximab, panitumumab, necitumumab.
  • the HER2 targeted therapy may be selected from the group consisting of: lapatinib, afatinib, canertinib, pelitinib, neratinib, dacomitinib, and tucatinib.
  • the HER2 targeted therapy may be selected from the group consisting of: trastuzumab, pertuzumab, margetuximab, trastuzumab emtansine, and trastuzumab deruxtecan.
  • Immune checkpoint modulators function to modulate the immune response to diseases, such as the AXL-related diseases of this disclosure. This may be achieved in a number of ways, such as increasing the activity of stimulatory pathways and decreasing the activity of inhibitory pathways.
  • AXL-related diseases such as cancer are known to be able control tumour growth and in some cases lead to elimination of tumours.
  • Therapeutic targeting of tumor immune regulators has resulted in the development of successful immunotherapeutic approaches for cancer treatment - for example agents blocking the activity of negative regulators of T cell immunity, such as a cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor-1 (PD-1).
  • CTLA-4 cytotoxic T-lymphocyte antigen 4
  • PD-1 programmed death receptor-1
  • the AXLi may be administered in combination with one or more ICM.
  • the immune checkpoint modulator may be an immune checkpoint inhibitor (ICI).
  • ICI immune checkpoint inhibitor
  • an agent which acts at T cell co-inhibitory receptors such as CTLA-4, PD-1 , PD-L1 , BTLA, TIM-3, VISTA, LAG-3, and TIGIT.
  • the immune checkpoint modulator may be a T cell co-stimulatory agonist.
  • an agonist of a T-cell co-stimulatory receptor such as CD28, ICOS, 4- 1 BB, 0X40, GITR, CD27, TWEAKR, HVEM, and TIM-1.
  • the immune checkpoint modulator may act at dendritic cell co- stimulatory receptors, such as CD40 and 4-1 BB.
  • the immune checkpoint modulator may be an immune checkpoint modulating antibody.
  • the immune checkpoint modulator may be selected from the group consisting of: anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD- L1 antibodies, anti-4-1 BB antibodies, anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti-CD28 antibodies, anti-CD40 antibodies, anti-LAG3 antibodies, anti-ICOS antibodies, anti-TWEAKR antibodies, anti-HVEM antibodies, anti-TIM-1 antibodies, anti-TIM- 3 antibodies, anti-VISTA antibodies, and anti-TIGIT antibodies.
  • the immune checkpoint modulator may be selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti- 4-1 BB antibodies, anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti- CD40 antibodies, and anti-LAG3 antibodies.
  • the immune checkpoint modulator may be selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies.
  • the immune checkpoint modulator may be an anti-PD-1 antibody.
  • ICMs suitable for use in the methods described herein include atezolizumab, avelumab, camrelizumab, cemiplimab, dostarlimab, durvalumab, ipilimumab, sintilimab, tislelizumab, toripalimab, tremelimumab, pembrolizumab, nivolumab, and urelumab, and those which can be identified by the drug candidate identifiers AMP-514/MEDI0680 (Medlmmune/AstraZeneca), MPDL3280A (Genentech/Roche), MEDI4736 (Medlmmune/AstraZeneca), MSB0010718C (EMD Serono), BMS-936559 (Bristol-Myers Squibb), PF-05082566 (Pfizer), MEDI6469 (Medlmmune/AstraZeneca), MEDI6383 (rOX40L
  • the anti-PD1 antibody is selected from pembrolizumab, nivolumab, MEDI0680, PDR001 (spartalizumab), Camrelizumab, ALINP12, Pidilizumab Cemiplimab (REGN-2810), AMP 224, BGB-A317 (Tisleizumab), and BGB-108.
  • the anti-PD-L1 antibody is selected from atezolizumab (Tecentriq), BMS-936559/MDX 1105, durvalumab/MEDI4736, and MSB0010718C (Avelumab).
  • the anti- CTLA-4 antibody is selected from ipilimumab and Tremelimumab.
  • the anti-GITR antibody or GITR agonist is selected from MEDI1873, TRX518, GWN323, MK- 1248, MK 4166, BMS-986156 and INCAGN1876.
  • the anti-OX40 antibody or 0X40 agonist is selected from MEDI0562, MEDI6383, MOXR0916, RG7888, OX40mAb24, INCAGN1949, GSK3174998, and PF-04518600.
  • two or more immune checkpoint modulators may be administered.
  • Results have shown that an improved synergistic effect can be obtained when at least two different immune checkpoint (activity) modulators are employed, especially when such immune checkpoint (activity) modulators act at different cell receptor sub-types.
  • the combination of at least one immune checkpoint inhibitor and at least one T cell co-stimulatory receptor agonist or dendritic cell co-stimulatory receptor agonist may be administered.
  • At least one of the two or more immune checkpoint (activity) modulators is an anti- CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody.
  • the combination of an anti-CTLA-4 antibody and an anti-PD-1 antibody has proven to be particularly effective.
  • the TKI may be used in combination with two ICMs, such as nivolumab and ipilimumab. In some cases the TKI is used incombination with three ICMs.
  • the two or more immune checkpoint (activity) modulators may include: (i) an immune checkpoint inhibitor, and (ii) a T cell co-stimulatory receptor agonist or a dendritic cell co-stimulatory receptor agonist.
  • the two or more immune checkpoint (activity) modulators may include: (i) an anti-CTLA-4 antibody; and/or (ii) either an anti-PD-1 antibody or an anti-PD-L1 antibodies.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • the anti-PD-1 antibody is pembrolizumab, nivolumab, spartalizumab Camrelizumab, Pidilizumab, or Cemiplimab.
  • the anti-PD-1 antibody is pembrolizumab or nivolumab.
  • the anti-PDL1 antibody is Atezolizumab (CAS number 1380723-44-3), Avelumab (CAS number 1537032-82-8), or Durvalumab (CAS number 1428935-60-7).
  • the two or more immune checkpoint (activity) modulators may be administered concurrently. In other embodiments the two or more immune checkpoint (activity) modulators may be administered separately and I or sequentially in any order.
  • the immune checkpoint modulator includes, or is: pembrolizumab; ipilimumab; ipilimumab and nivolumab; ipilimumab and pembrolizumab; tremelilumab and durvalumab.
  • the two or more immune checkpoint (activity) modulators may be ipilimumab and pembrolizumab, or ipilimumab and nivolumab.
  • the combination ICM may comprise an anti-PD1 antibody, such as pembrolizumab.
  • an anti-PD1 antibody such as pembrolizumab.
  • a particularly preferred ICM is pembrolizumab, which may be used for example in combination with a platinum-based chemotherapeutic and an antifolate chemotherapeutic, such as carboplatin and pemetrexed.
  • carboplatin, pemetrexed, and pembrolizumab may be particularly preferred when the AXL-related disease to be treated is non small-cell lung cancer.
  • the ICM may comprise an anti-PD1 antibody, an anti-PDL1 antibody, or an anti-PD1 antibody and anti-CTLA4 antibody.
  • the ICM may comprise pembrolizumab, atezolizumab, cemiplimab (cemiplimab-rwlc), or nivolumab and ipilimumab.
  • the ICM may be administered in combination with a platinum-based chemotherapeutic and an antifolate chemotherapeutic, such as carboplatin and pemetrexed.
  • the ICM may be administered in combination with an anti- VEGF-A antibody, such as bevacizumab.
  • the ICM may be administered in combination with a taxane chemotherapeutic, such as paclitaxel.
  • the ICM may be administered in combination with a platinum-based chemotherapeutic, such as carboplatin.
  • the ICM may be administered in combination with a taxane chemotherapeutic and a platinumbased chemotherapeutic, such as paclitaxel and carboplatin.
  • the ICM may be administered in combination with an anti-VEGF-A antibody, a taxane chemotherapeutic, and a platinum-based chemotherapeutic, such as bevacizumab, paclitaxel, and carboplatin.
  • the ICM may be administered in combination with a platinum-based chemotherapeutic, such as carboplatin or cisplatin.
  • a platinum-based chemotherapeutic such as carboplatin or cisplatin.
  • Such ICMs and combinations may be particualry preferred when the AXL-related disease to be treated is non small-cell lung cancer.
  • Radiotherapy may refer to the medical use of ionizing radiation as part of cancer treatment to control or eradicate malignant cells. Radiotherapy may be used for curative, adjuvant, or palliative treatment. Suitable types of radiotherapy include conventional external beam radiotherapy, stereotactic radiation therapy (e.g., Axesse, Cyberknife, Gamma Knife, Novalis, Primatom, Synergy, X-Knife, TomoTherapy or Trilogy), Intensity-Modulated Radiation Therapy, particle therapy (e.g., proton therapy), brachytherapy, delivery of radioisotopes, intraoperative radiotherapy, Auger therapy, Volumetric modulated arc therapy (VMAT), Virtual simulation, 3-dimensional conformal radiation therapy, and intensity-modulated radiation therapy.
  • stereotactic radiation therapy e.g., Axesse, Cyberknife, Gamma Knife, Novalis, Primatom, Synergy, X-Knife, TomoTherapy or Trilogy
  • radiatiotherapy uses high-energy radiation to shrink tumors and kill cancer cells.
  • the radiation may be, for example, X-rays, gamma rays, or charged particles.
  • Modes of cell killing through radiation include DNA damage either directly or by creating free radicals within cells that in turn damage DNA.
  • Radiation may be delivered by a machine outside the body (external-beam radiation therapy), or may come from radioactive material placed in the body near cancer cells (internal radiation therapy, also called brachy therapy).
  • internal radiation therapy also called brachy therapy
  • radioactive substances such as radioactive iodine, are used which travel in the blood to kill cancer cells.
  • the radiotherapy may be administered in a regimen designed to minimize any immunosuppressive effects of the radiation.
  • a regimen designed to minimize any immunosuppressive effects of the radiation For example, preclinical evidence indicates high radiation doses above 12-18 Gy result in an attenuation of tumor immunogenicity (Vanpouille- Box C., et al., Nat Commun 2017; 8: 15618).
  • circulating lymphocytes are particularly radiosensitive (see Yovino S., et al., Cancer Invest 2013; 31 : 140-144); this indicates radiotherapy regimens aimed at stimulating an anti-tumour immune response should aim to minimise both (1) the amount of vasculature exposed in each treatment, and (2) the number of exposures in the treatment regimen.
  • Radiation dosages may be fractionated and administered in sequence; for example, on consecutive days until the total desired radiation dose is delivered.
  • Specifically contemplated embodiments of the disclosure include: Methods in which the AXLi is administered in combination with cytarabine.
  • Methods in which the AXLi is administered in combination with an EGFR targeted therapy such as an EGFR inhibitor and / or a HER2 targeted therapy, such as a HER2 inhibitor.
  • the AXLi is administered in combination with an anti-PD1 antibody and an anthracycline.
  • the anti-PD1 antibody is pembrolizumab.
  • the anthracycline is doxorubicin.
  • the anti-PD1 antibody is pembrolizumab.
  • the anti-PD1 antibody may be administered to the subject before, concurrently with, or after the AXLi.
  • the dose of anti-PD1 antibody may be about 200 mg.
  • the anti-PD1 antibody may be administered to the subject by intravenous infusion.
  • the anti-PD1 antibody may be administered to the subject by intravenous infusion over about 30 minutes.
  • the anti-PD1 antibody may be administered in a Q3W (once every 3 weeks) dosage regimen. Administration of the anti-PD1 antibody may begin on any of day 1 , 2, 3, 4,
  • administration of the anti-PD1 antibody begins on day 1 of the AXLi dosage regimens described more fully elsewhere herein.
  • the platinum-based chemotherapeutic is carboplatin.
  • the platinum-based chemotherapeutic may be administered to the subject before, concurrently with, or after the AXLi.
  • the dose of platinum-based chemotherapeutic may be about Area Under the Curve 5 (AUC5) based on the Calvert formula for calculating carboplatin dosing (Calvert et al. J Clin Oncol. 1989;7:1748-1756).
  • the platinum-based chemotherapeutic may be administered to the subject by intravenous infusion.
  • the platinumbased chemotherapeutic may be administered to the subject by intravenous infusion over about 15 minutes or over about 30 minutes.
  • the platinum-based chemotherapeutic may be administered in a Q3W (once every 3 weeks) dosage regimen. Administration of the platinum-based chemotherapeutic may begin on any of day 1 , 2, 3, 4, 5,
  • administering begins on day 1 of the AXLi dosage regimens described more fully elsewhere herein.
  • the antifolate chemotherapeutic is pemetrexed.
  • the antifolate chemotherapeutic may be administered to the subject before, concurrently with, or after the AXLi.
  • the dose of antifolate chemotherapeutic may be about 500 mg/m 2 .
  • the antifolate chemotherapeutic may be administered to the subject by intravenous infusion.
  • the antifolate chemotherapeutic may be administered to the subject by intravenous infusion over about 10 minutes.
  • the antifolate chemotherapeutic may be administered in a Q3W (once every 3 weeks) dosage regimen.
  • Administration of the antifolate chemotherapeutic may begin on any of day 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 of the AXLi dosage regimens described more fully elsewhere herein.
  • administration of the antifolate chemotherapeutic begins on day 1 of the AXLi dosage regimens described more fully elsewhere herein.
  • the AXLi is administered in combination with an anti-PD1 antibody, a platinum-based chemotherapeutic, and an antifolate chemotherapeutic.
  • an anti-PD1 antibody is pembrolizumab
  • the platinum-based chemotherapeutic is carboplatin
  • the antifolate chemotherapeutic is pemetrexed.
  • the disclosed dosage regimens reduce the toxicity and I or side effects associated with treatment of a subject with an AXLi.
  • the disclosed dosage regimens increase the efficacy of treatment associated with administration of an AXLi to a subject.
  • the present disclosure provides a method of reducing the toxicity and I or side effects associated with administration of an AXLi to a subject; and I or increasing the efficacy of treatment associated with administration of an AXLi to a subject; the method comprising administering the AXLi in a dosage regimen according to the disclosure.
  • the reduction in toxicity and I or side effects, or the increase in efficacy may be measured relative to an alternative, comparator, dosage regimen, for example a regimen employing a different constant AXLi dose level, different loading and I or maintenance dose levels, different loading and I or maintenance periods, and / or a longer or shorter duration of treatment.
  • treatment or “treating” in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis, prevention) is also included.
  • the level of toxicity is measured as the incidence of Treatment Emergent Adverse Events (TEAE) occurring after a period of treatment, such as 21 days of treatment, at a given total dose of AXLi.
  • a treatment-emergent AE (TEAE) is defined as any event not present before exposure to the AXLi or any event already present that worsens in either intensity or frequency after exposure to the AXLi.
  • the incidence of AE with the dosage regimens of the disclosure may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of AE in an alternative, comparator, dosage regimen.
  • Adverse events may be graded according to NCI-CTCAE Version 5.0 (v5.0, published November 27, 2017).
  • the incidence of AEs with the dosage regimen of this disclosure is 50% of the incidence of AE in the corresponding comparator dosage regimen.
  • the level of toxicity is measured as the incidence of Serious Adverse Events (SAE) occurring after a period of treatment, such as 21 days of treatment, at a given total dose of AXLi.
  • SAE Serious Adverse Events
  • a serious adverse event (SAE) is defined as any event that results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. Hospitalization for elective procedures or for protocol compliance is not considered an SAE.
  • Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered SAEs when, based upon appropriate medical judgment, they may jeopardize the patient or may require medical or surgical intervention to prevent 1 of the outcomes listed in this definition.
  • the incidence of SAE with the dosage regimens of the disclosure may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of SAE in an alternative, comparator, dosage regimen.
  • Adverse events may be graded according to NCI- CTCAE Version 5.0 (v5.0, published November 27, 2017).
  • the level of toxicity is measured as the incidence of Dose Limiting Toxicity (DLT) occurring after a period of treatment, such as 21 days of treatment, at a given total dose of AXLi.
  • the incidence of DLT with the dosage regimens of the disclosure may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of DLT in an alternative, comparator, dosage regimen.
  • the incidence of DLTs with the dosage regimen of this disclosure is 50% of the incidence of DLT in the corresponding comparator dosage regimen.
  • a DLT as used herein is defined as any of the following events, except those that are clearly due to underlying disease or extraneous causes:
  • Any nonhematologic AE >Grade 3 in severity should be considered a DLT, with the following exceptions: o Grade 3 fatigue lasting ⁇ 3 days; o Grade 3 diarrhoea, nausea, or vomiting if persistent ⁇ 7 days with optimum prophylactic medication per standard of care;
  • o Grade 3 is defined as ANC ⁇ 1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >38 degrees C (100.4 degrees F) for more than 1 hour
  • o Grade 4 is defined as ANC ⁇ 1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >38 degrees C (100.4 degrees F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated.
  • the level of toxicity is measured as the incidence of QT / QTc prolongation.
  • QT I QTc prolongation is a measure of delayed ventricular repolarisation, and excessive QT / QTc prolongation can predispose the myocardium to development of early after-depolarisations, which in turn can trigger re-entrant tachycardias.
  • Prolongation of the QT / QTc interval has been noted with tyrosine kinase inhbiitors, including AXL inihibtors such as bemcentinib.
  • the incidence of QT/QTc adverse events may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of QT/QTc AEs in a corresponding comparator dosage regimen.
  • Methods for measuring QT interval and QT / QTc prologation are known to the person skilled in the art, for example using electrocardiography.
  • the dosage regimens of this disclosure may provide for an optimal balance of treatment efficacy (as may be assessed by the outcomes outlined below), toxicity and I or incidence of adverse events (as may be assessed as outlined above).
  • the dosage regimens of this disclosure may provide for an optimal balance of AXLi treatment efficacy and incidence of QT / QTc prolongation, and I or an an optimal balance of AXLi treatment efficacy and incidence of disease-driven QT / QTc prolongation.
  • the dosage regimens of this disclosure elicit a change in QTc of less than about 30 ms, such as less than about 29, 28, 27, 26, 25, 24, 23, 22, 21 , 20, or 19 ms. In some preferred cases, the dosage regimens of this disclosure elicit a change in QTc of less than about 20 ms. Stated alternatively, in some cases, the dosage regimens of this disclosure do not prolong the QTc interval by more than about 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 ms. In some preferred cases, the dosage regimens of this disclosure do not prolong the QTc interval by more than about 20 ms.
  • the level of efficacy is measured as the proportion of subjects achieving at least stable disease [SD] after a period of treatment with AXLi (i.e the proportion of subjects achieving either stable disease [SD], a partial response [PR], or a complete response [CR],
  • the proportion of subjects achieving at least SD may be at least 110%, such as at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, of the proportion of subjects achieving at least stable disease [SD] in an alternative, comparator, dosage regimen.
  • the proportion of subjects achieving at least SD with the dosage regimen of this disclosure is 160% of the proportion of subjects achieving at least a partial response [SD] in the corresponding comparator dosage regimen.
  • assessment of response to treatment with AXLi may be based on any commonly used criteria for assessing response rate - for example, RECIST (or mRECIST, or iRECIST; Response Evaluation Criteria in Solid Tumors) criteria for solid tumours, or Lugano Classification Criteria (using the New “Cheson” Criteria) for lyphoma.
  • RECIST or mRECIST, or iRECIST
  • Response Evaluation Criteria in Solid Tumors criteria for solid tumours
  • Lugano Classification Criteria using the New “Cheson” Criteria
  • the level of efficacy is measured as the proportion of subjects achieving one or more of the following outcomes:
  • Partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status), as may be assessed, for example, by % bone marrow myeloblasts, normal maturation of cell lines, reduction in tumour burden, and I or absence of detectable tumours.
  • any positive patient outcome selected from: prolonged survival, progression-free survival, hematologic improvement (as may be assessed, for example, by increased blood haemoglobin, platelet count, and / or neutrophil count), bone marrow response (as may be assessed, for example, by: bone marrow with ⁇ 5% myeloblasts; 30%, 40%, 50% or more reduction in bone marrow myeloblasts; absence of circulating myeloblasts and myeloblasts with Auer rods; absence of extramedullary disease), hematologic recovery (as may be assessed, for example, by: >11 g/dL haemoglobin, >100x109/L platelets, and I or >1x109/L neutrophils in peripheral blood), tumour shrinkage (for example, a reduction in tumour volume of 5, 10, 20, 30, 40% or more), reduction in tumour burden (for example, a reduction in tumour burden of 5, 10, 20, 30, 40% or more), slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden,
  • the proportion of subjects achieving one or more of these may be at least 110%, such as at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, of the proportion of subjects achieving the same outcomes with an alternative, comparator, dosage regimen.
  • the disclosed dosage regimens may also increase AXLi exposure in a subject; and I or reduce variability in AXLi exposure in a subject.
  • the present disclosure also provides a method of increasing AXLi exposure in a subject; and I or reducing variability in AXLi exposure in a subject; the method comprising administering the AXLi in a dosage regimen according to the disclosure.
  • exposure refers to the level of a drug achieved in the body. In pharmacokinetics, drug exposure is most often estimated by area under the curve (AUC) methods, but may also be reported as parameters such as Cmax (maximum concentration) or Tmax (time at maximum concentration), as will be understood and readily derivable by the person skilled in the art. In some cases, the increase in exposure and I or reduction in variability in exposure is measured relative to an alternative, comparator, dosage regimen, for example a regimen in which AXLi is administered to the subject in a fasted state, or a regimen in which fed or fasted state administration is not controlled.
  • the variability in exposure may be less than 95%, such as less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5% of the variability in exposure in a comparator dosage regimen.
  • the subjects are selected as suitable for treatment with the treatments of this disclosure before the treatments are administered.
  • subjects who are considered suitable for treatment are those subjects who are expected to benefit from, or respond to, the treatment.
  • To “benefit from” or “respond to” can refer to any beneficial therapeutic effect observed in the subject to which a treatment was administered. This may be any overall clinical benefit derived from the treatment - for example, prolonged survival, partial or complete disease remission, slowing or absence of disease progression, tumour shrinkage (for example, a reduction in tumour volume of 5, 10, 20, 30, 40% or more), reduction in tumour burden (for example, a reduction in tumour burden of 5, 10, 20, 30, 40% or more), slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, or improved quality of life.
  • subjects may be selected on the basis of the amount or pattern of expression or activity of a marker protein of interest, for example STK11, or STK11IP.
  • subjects may be selected based on response I benefit (or lack thereof) derived from a previously administered treatment, for example an immune checkpoint modulator, or a combination treatment comprising one or more chemotherapeutic agent and an immune checkpoint modulator.
  • subjects may be selected on the basis of both: the amount or pattern of expression or activity of a marker protein of interest; and, response I benefit (or lack thereof) derived from a previously administered treatment.
  • subjects may be selected based on identifying subjects having an AXL-related disease characterised by the presence of cells having modified STK11 activity or expression.
  • the modified STK11 activity or expression is decreased STK11 activity or expression.
  • subjects may be selected based on identifying subjects that have previously been treated with an immune checkpoint modulator (ICM) and I or chemotherapeutic agent (such as the ICMs and chemotherapeutic agents described in more detail elsewhere herein) and which did not respond to treatment with the ICM and I or chemotherapeutic agent.
  • ICM immune checkpoint modulator
  • I or chemotherapeutic agent such as the ICMs and chemotherapeutic agents described in more detail elsewhere herein
  • the AXL-related disease to be treated in the methods of the disclosure may be characterised by the presence of cells having modified STK11 activity or expression, such as decreased STK11 activity or expression.
  • a subject who “did not respond” to treatment with an ICM and I or chemotherapeutic agent is a subject who did not derive any clinical benefit from said treatment.
  • this may be a subject in which no slowing or absence of disease progression was observed following said treatment, or no slowing or absence of disease progression was attributable to said treatment.
  • this may be a subject in which no reduction in tumour volume was observed following said treatment, or no reduction in tumour volume was attributable to said treatment.
  • this may be a subject in which a less than 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10% reduction in tumor volume was observed following said treatment, or less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% reduction in tumor volume was attributable to said treatment.
  • this may be a subject in which no reduction in tumour burden was observed following said treatment with the ICM, or in which no reduction in tumour burden was attributable to said treatment. In some embodiments, this may be a subject in which less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% reduction in tumor burden was observed following treatment with said treatment, or less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% reduction in tumor burden was attributable to said treatment.
  • subjects may be selected based on the methods described in WO2021/214492.
  • expression refers to the transcription of a gene’s DNA template to produce the corresponding mRNA and translation of this mRNA to produce the corresponding gene product (i.e. , a peptide, polypeptide, or protein) as well as the “expression” of a protein in one or more forms that may have been modified post translation.
  • Suitable means for determining or detecting level and patterns of expression, including gene expression are readily known to those skilled in the art - for example, by microarray analysis, Western blotting or by PCR techniques such as QPCR. Altered expression may also be detected by analysing protein content of samples using methods such as ELISA, PET or SELDI-TOF MS, or by analytical techniques such as 2Dgel electrophoresis.
  • modified STK11 activity or expression may be assessed using the experimental methods described in the Examples of WO2021/214492 (whole exome sequence analysis of tumour biopsy material).
  • decreased STK11 activity or expression may be assessed by determining the level of activity or expression of STK111P. In some embodiments, increased activity or expression of STK111 P relative to a control is indicative of decreased STK11 activity or expression. In some embodiments, decreased activity or expression of STK111 P relative to a control may be indicative of decreased STK11 activity or expression.
  • increased STK11 activity or expression may be assessed by determining the level of activity or expression of STK111 P.
  • increased activity or expression of STK11 IP relative to a control is indicative of increased STK11 activity or expression.
  • decreased activity or expression of STK11IP relative to a control may be indicative of increased STK11 activity or expression.
  • modifed (increased or decreased) expression may be assessed by determining copy number of the gene encoding a protein of interest - for example, STK11 or STK111P - relative to a control sample, wherein an increase in the copy number indicates an increased level of expression and a decrease in the copy number indicates a decreased level of expression.
  • modified (increased or decreased) expression is assessed by determining the level of a protein or mRNA of interest - for example, STK11 or STK11IP - relative to a control sample.
  • modified (increased or decreased) activity or expression may be assessed by determining the presence or absence of a mutation in the nucleotide, mRNA, or amino acid protein sequence of a protein of interest. Suitable means for determining or detecting the presence or absence of such mutations are well known to those skilled in the art - for example, nucleotide sequencing, DNA hybridization, restriction enzyme digestion methods.
  • modified STK11 activity or expression may be assessed by determining the presence or absence of a STK11 mutation and / or a STK11 IP mutation.
  • the STK11 mutation and I or STK11IP mutation may be a mutation selected from: a mutation in the nucleotide sequence encoding STK11 or STK11IP; a mutation in a regulatory sequence controlling expression of the nucleotide sequence encoding STK11 or STKHIP; or, a mutation in a nucleotide encoding a protein which interacts with the transcription product of the STK11 or STK111 P gene.
  • the STK11 mutation and I or STK111 P mutation is a mutation in the translation product of the STK11 or STK111P gene. In some embodiments, the STK11 mutation and I or STK111P mutation is a mutation in the transcription product of the STK11 or STK111P gene. In some embodiments, the STK11 mutation and I or STK111P mutation is a mutation in a miRNA that regulates expression of STK11 and I or STK111P.
  • the STK11 mutation may be an inactivating mutation. In some embodiments, the STK11 mutation may be an activating mutation. In some embodiments the STK11IP mutation may be an activating mutation. In some embodiments the STK11IP mutation may be an inactivating mutation. In some embodiments the STK11 mutation may be L160P, LD140PY, or D115V. In some embodiments, the STK11P mutation may be E30V, LG334FW, W162C, or R1065Q.
  • the STK11 mutation may result in a reduced level of activity or expression of STK11 protein. In some embodiments, the STK11 mutation may result in an increased level of activity or expression of STK11 protein. In some embodiments, the STK111 P mutation may result in an increased level of activity or expression of STK111 P protein. In some embodiments, the STK111 P mutation may result in a decreased level of activity or expression of STK11IP protein. In some embodiments the STK11IP mutation may result in an altered pattern of activity or expression of STK11 protein, and I or altered subcellular localisation of STK11 protein. For example, increased cytosolic sequestration of STK11 protein and I or reduced localisation of STK11 protein to the nucleus.
  • an “activating” mutation is one which results in the transcription and I or translation product of a gene having increased function (which may be either increased activity or expression).
  • an “inactivating” mutation is one which results in the transcription and I or translation product of a gene having reduced or no function (which may be either decreased activity or expression).
  • the mutation may be mutation in a nucleotide, mRNA, or protein sequence.
  • the increased or decreased activity or expression is determined in a sample derived from a subject. That is, the methods of the disclosure may be performed in vitro or ex vivo on a sample isolated from a subject.
  • the sample may comprise or may be derived from: a quantity of blood; a quantity of serum derived from the subject’s blood which may comprise the fluid portion of the blood obtained after removal of the fibrin clot and blood cells; a quantity of pancreatic juice; a tissue sample or biopsy; a urine sample; or cells isolated from said subject.
  • a sample may be taken from any tissue or bodily fluid.
  • the sample may include or may be derived from a tissue sample, biopsy, resection or isolated cells from a subject.
  • the sample may be a tissue sample.
  • the sample may be a sample of tumor tissue, such as neoplastic tumor tissue.
  • the sample may be one that is obtained by a tumor biopsy.
  • the sample may be taken from a bodily fluid, more preferably one that circulates through the body. Accordingly, the sample may be a blood sample or lymph sample. In some embodiments, the sample is a urine sample or a saliva sample. In some other embodiments, the sample is a blood sample or blood-derived sample.
  • the blood derived sample may be a selected fraction of a subject’s blood, e.g. a selected cellcontaining fraction or a plasma or serum fraction.
  • a selected cell-containing fraction may contain cell types of interest which may include white blood cells (WBC), particularly peripheral blood mononuclear cells (PBC) and/or granulocytes, and/or red blood cells (RBC).
  • WBC white blood cells
  • PBC peripheral blood mononuclear cells
  • RBC red blood cells
  • methods according to the present disclosure may involve detection of a marker polypeptide or nucleic acid in the blood, in white blood cells, peripheral blood mononuclear cells, granulocytes and/or red blood cells.
  • the sample may be fresh or archival.
  • archival tissue may be from the first diagnosis of a subject, or a biopsy at a relapse.
  • the sample may be a fresh biopsy.
  • control may be a reference sample or a reference dataset.
  • the reference may be a sample that has been previously obtained from an individual or individuals with a known degree of suitability - for example, from an individual or individuals known to be responsive to the treatments disclosed herein.
  • the reference may be a dataset obtained from analyzing a reference sample.
  • Controls may be positive controls in which the target molecule is known to be present, or expressed at high level, or may be negative controls in which the target molecule is known to be absent or expressed at low level.
  • Controls may be samples of tissue that are from individuals who are known to benefit from the treatment. The tissue may be of the same type as the sample being tested. For example, a sample of tumor tissue from an individual may be compared to a control sample of tumor tissue from an individual who is known to be suitable for the treatment, such as an individual who has previously responded to the treatment.
  • the control may be a sample obtained from the same individual as the test sample, but from a tissue known to be healthy. Thus, a sample of cancerous tissue from an individual may be compared to a non-cancerous tissue sample.
  • the control is a cell culture sample.
  • control may be a sample from a comparable AXL-related disease that is not characterized by modified activity or expression of STK11 and I or STK11IP. In some other cases, the control may be a sample of healthy tissue. In some preferred embodiments, the control is of the same sample type as the test sample - for example, a sample of the same tissue type as the AXL-related disease. In some other preferred embodiments, the control is a reference sample or dataset obtained from an individual or individuals known to be responsive to the AXLi or combination therapies disclosed herein.
  • the subject may be an animal, mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an a
  • the subject may be any of its forms of development, for example, a foetus.
  • the subject has, is suspected of having, or has received a diagnosis of, an AXL-related disease, such as cancer or fibrosis.
  • an AXL-related disease such as cancer or fibrosis.
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e. , prophylaxis, prevention is also included.
  • the agents eg. AXLi
  • the agents are administered in a therapeutically or prophylactically effective amount.
  • terapéuticaally-effective amount or “effective amount” as used herein, pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • prophylactically-effective amount refers to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • the subjects treated are in need of the described treatment.
  • a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an AXLi.
  • therapeutically effective amount is an amount sufficient to show benefit to a subject. Such benefit may be at least amelioration of at least one symptom.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors.
  • the subject may have been tested to determine their eligibility to receive the treatment according to the methods disclosed herein.
  • the method of treatment may comprise a step of determining whether a subject is eligible for treatment, using a method disclosed herein.
  • the treatment may involve administration of the AXLi alone or in further combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • compositions according to the present disclosure are preferably pharmaceutical compositions.
  • Pharmaceutical compositions according to the present disclosure, and for use in accordance with the present disclosure may comprise, in addition to the active ingredient, i.e. a conjugate compound, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such a gelatin.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • the AXLi is comprised in a pharmaceutical composition, optionally further comprising a pharmaceutically acceptable excipient.
  • the present disclosure provides agents and reagents, as well as compositions and kits comprising these agents and reagents, for use in the disclosed methods, and the use such agents and reagents, as well as compositions and kits comprising these agents and reagents, in the manufacture of a medicament for use in the methods of the disclosure.
  • appropriate dosages of the AXLi and compositions comprising the active element can vary from subject to subject. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the subject.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • a suitable dose of each active compound is in the range of about 100 ng to about 25 mg (more typically about 1 pg to about 10 mg) per kilogram body weight of the subject per day.
  • the active compound is a salt, an ester, an amide, a prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • the term “about” refers to any minimal alteration in a stated absolute value (e.g., the dose, concentration, or amount of a therapeutic agent) that does not change the stated efficacy, activity, action, results, etc. In some cases, the term “about” may include ⁇ 10% of a specified numerical value.
  • the term “about” includes the stated value (e.g., “about 1%” includes 1 % as well as minimal alterations thereof), and a preferred embodiment of a numerical value expressed as “about” that value is the absolute value (e.g., a preferred embodiment of “about 1%” is “1%”).
  • to “consume” or “ingest” food encompasses the administering of food I nutrition to a subject where the subject is unable to ingest the food orally - for example administration of food I nutrition via enteral or parenteral routes.
  • the AXL-related disease is cancer.
  • Most preferred AXL-related diseases include lung cancer, such as non small cell lung cancer, and AML.
  • the AXL-related disease is cancer and the AXLi is bemcentinib.
  • the loading dose is administered on days 1 and 2 of the dosage regimen, and the maintenance dose is administered on day 3 and each subsequent day until treatment with the AXLi is stopped.
  • the loading dose is about 200 mg and the maintenance dose is about 100 mg.
  • the loading dose is about 150 mg and the maintenance dose is about 75 mg.
  • a constant dose of AXLi is administered on day 1 and on each subsequent day of the dosage regimen.
  • the constant dose is about 150 mg.
  • the constant dose is about 125 mg.
  • a constant dose of AXLi is administered on day 1 and on each subsequent day of the dosage regimen.
  • a most preferred constant dose of AXLi is about 100 mg.
  • the AXLi may preferably be administered in combination with one or more further treatment and I or therapeutic agent, as described more fully elsewhere herein - such as pembrolizumab, or carboplatin, pemetrexed, and pembrolizumab.
  • the cancer is preferably non small cell lung cancer.
  • the AXLi is administered to the subject under fed conditions.
  • Bemcentinib for use in a method of the disclosure.
  • a chemotherapeutic agent for use in a method of the disclosure is a chemotherapeutic agent for use in a method of the disclosure.
  • An ICM for use in a method of the disclosure is provided.
  • chemotherapeutic agent in the manufacture of a medicament for use in a method of the disclosure.
  • a method for treating an AXL-related disease in a subject comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose.
  • AXLi an inhibitor of AXL activity or expression
  • any positive patient outcome selected from: prolonged survival, progression-free survival, hematologic improvement, bone marrow response, hematologic recovery, tumour shrinkage, reduction in tumour burden, slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, negative response for a genetic marker, improved quality of life, and any other positive patient outcome;
  • the loading dose is about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg.
  • the maintenance dose is about 45-55%, such as about 46-54%, about 47-53%, about 48-52%, or about 49-51% of the loading dose.
  • administering the AXLi under fed conditions comprises administering the AXLi to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes of the subject consuming food.
  • administering the AXLi under fed conditions comprises administering the AXLi to the subject less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed food.
  • administering the AXLi under fed conditions comprises administering the AXLi to the subject administering the AXLi to the subject not more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes before the subject has consumed, or will consume, food.
  • administering the AXLi under fed conditions comprises administering the AXLi to the subject within about 0-240 minutes, such as about 30-240 minutes, 60-240 minutes, 90-240 minutes, 120-240 minutes, 150-240 minutes, 180-240 minutes, or 210-240 minutes of the subject consuming food, or such as about 0-210 minutes, 0-180, 0-150, 0-120, 0-90, 0-60, or 0-30 minutes of the subject consuming food.
  • AXL-related disease is cancer, a fibrotic disorder, or neurofibromatosis.
  • the cancer is selected from the group consisting of: lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma.
  • AML acute myeloid leukemia
  • NSCLC non-small-cell lung cancer
  • R 2 and R 3 are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R 9 -OR 8 , -R 9 -O-R 10 -OR 8 , -R 9 -O-R 10 -O-R 10 -OR 8 , -R 9 -O-R 10 -CN, -R 9 -O-R 10 -C(O) OR 8 , -R 9 -O-R 10 -C(O)N(R 6 )R 7 , -R 9 -O-R
  • AXLi is selected from the group consisting of: 1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/ ⁇ / 3 -(7-(pyrrolidin-1-yl)-6,7,8,9- tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
  • AXLi is administered in combination with: one or more immune checkpoint modulator (ICM); and I or one or more chemotherapeutic agent and I or radiotherapy.
  • ICM immune checkpoint modulator
  • one or more immune checkpoint modulating antibody is selected from the group consisting of: anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-4-1 BB antibodies, anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti-CD28 antibodies, anti-CD40 antibodies, anti-LAG3 antibodies, anti-ICOS antibodies, anti-TWEAKR antibodies, anti-HVEM antibodies, anti-TIM-1 antibodies, anti-TIM-3 antibodies, anti-VISTA antibodies, and anti-TIGIT antibodies;
  • one or more immune checkpoint modulating antibody is selected from the group consisting of: anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-4-1 BB antibodies, anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti-CD40 antibodies, and anti-LAG3 antibodies; or
  • one or more immune checkpoint modulating antibody is selected from the group consisting of: anti-CTLA-4 antibodies, anti-PD-1 antibodies, and anti-PD-L1 antibodies. 157. The method according to any one of statements 154-156, wherein the one or more immune checkpoint modulator includes:
  • T-cell co-stimulatory agonist one or more T-cell co-stimulatory agonist; and I or one or more dendritic cell costimulatory receptor agonist;
  • an anti-CTLA-4 antibody an anti-PD-1 antibody and I or an anti-PD-L1 antibody.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab;
  • the anti-PD-1 antibody is pembrolizumab or nivolumab; and I or
  • the anti-PD-L1 antibody is atezolizumab (CAS number 1380723-44-3), avelumab (CAS number 1537032-82-8), or durvalumab (CAS number 1428935-60-7).
  • the immune checkpoint modulator includes, or is: pembrolizumab; ipilimumab; ipilimumab and nivolumab; ipilimumab and pembrolizumab; tremelilumab and durvalumab.
  • chemotherapeutic agent is a chemotherapeutic agent which:
  • an antifolate chemotherapeutic preferably pemetrexed
  • a platinum-based chemotherapeutic and an antifolate chemotherapeutic preferably carboplatin and pemetrexed;
  • the dose of the anti-PD1 antibody is about 200mg
  • the anti-PD1 antibody is administered in a Q3W (once every 3 weeks) dosage regimen; and I or
  • the anti-PD1 antibody is administered concurrently with the AXLi.
  • the AXL-related disease is characterised by the presence of cells having modified STK11 activity or expression; and I or
  • the subject has been selected for treatment on the basis that the AXL-related disease is characterised by the presence of cells having decreased STK11 activity or expression.
  • modified STK11 activity or expression is assessed by determining the presence or absence of a STK11 mutation and / or a STK111 P mutation.
  • the method improves subject survival or provides clinical benefit to the subject: optionally wherein the clinical benefit may be one or more of: prolonged survival, partial or complete disease remission, slowing or absence of disease progression, improved quality of life, tumour shrinkage, reduction in tumour burden, slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, hematologic improvement, bone marrow response, hematologic recovery, negative response for a genetic marker, or any other positive patient outcome.
  • the dosage regimen reduces the toxicity and I or side effects associated with administration of an AXLi to a subject; and I or increases the efficacy of treatment associated with administration of an AXLi to a subject.
  • the dosage regimen improves subject survival or clinical benefit to the subject, optionally wherein the clinical benefit may be one or more of: prolonged survival, partial or complete disease remission, slowing or absence of disease progression, improved quality of life, tumour shrinkage, reduction in tumour burden, slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, hematologic improvement, bone marrow response, hematologic recovery, negative response for a genetic marker, or any other positive patient outcome.
  • AXLi AXL activity or expression
  • a packaged pharmaceutical product comprising an AXLi as defined in any one of statements 146 to 150, in combination with a label or insert advising that the AXLi should be administered according to the method of any one of statements 1 to 174.
  • a kit comprising: a first medicament comprising an AXLi as defined in any one of statements 146 to 150; optionally, one or more immune checkpoint modulator (ICM) and I or one or more chemotherapeutic agent ; and a package insert or label comprising instructions for administration of the AXLi according to the method of any one of statements 1 to 174.
  • ICM immune checkpoint modulator
  • kit according to statement 302 wherein the one or more immune checkpoint modulator (ICM) and I or one or more chemotherapeutic agent are as defined in any one of statements 155 to 169.
  • ICM immune checkpoint modulator
  • a method for treating an AXL-related disease in a subject comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose; wherein the loading dose is administered on days 1 and 2 of the dosage regimen, and the maintenance dose is administered on day 3 and on each subsequent day of the dosage regimen; and wherein the AXLi is a compound of formula (I): wherein:
  • R 2 and R 3 are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R 9 -OR 8 , -R 9 -O-R 10 -OR 8 , -R 9 -O-R 10 -O-R 10 -OR 8 , -R 9 -O-R 10 -CN, -R 9 -O-R 10 -C(O) OR 8 , -R 9 -O-R 10 -C(O)N(R 6 )R 7 , -R 9 -O-R
  • AXLi is 1-(6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulene-2-yl)-1 H-1 ,2,4-triazole-3,5-diamine, or a pharmaceutically acceptable salt thereof.
  • AXL-related disease is cancer, a fibrotic disorder, or neurofibromatosis.
  • the cancer is selected from the group consisting of: lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma.
  • the cancer is (i) acute myeloid leukemia (AML); and I or (ii) lung cancer, preferably non-small-cell lung cancer (NSCLC).
  • AML acute myeloid leukemia
  • NSCLC non-small-cell lung cancer
  • a packaged pharmaceutical product comprising an AXLi, in combination with a label or insert advising that the AXLi should be administered according to the method of any one of statements 501 to 522.
  • Example 1 Development of an optimal dosing regimen for the AXL inhibitor bemcentinib based on PKPD modelling
  • PK samples were taken along with ECG measurements to understand the relationship between bemcentinib exposure with response (clinical efficacy as well as safety).
  • a population PK model was first developed with data from the phase 1 BGBC001 healthy volunteer trial, to which the data from the Phase 2 BGBC020 study were added. During this portion of the modelling it was noticed that there seemed to be around 70% of the patients in the study who had a 2-3 fold difference in the exposure of bemcentinib within the Phase 2 study. Following examination of the data it was determined that these patients received protein pump inhibitors (PPIs) as a result of the use of the Gl disturbances caused by the extensive use of corticosteroids as part of the SOC for treatment of SARS-CoV-2 infection. It was believed that the extensive use of the PPIs was increasing the pH in the stomach and as a result was reducing the solubility of bemcentinib and its subsequent absorption.
  • PPIs protein pump inhibitors
  • PKPD model outputs required clinical consideration of the additional risk of ECG change due to bemcentinib as a relative risk increase compared to the dynamic risk observed in the standard of care arm.
  • the doses selected and their timing required careful judgement of early added risk during the loading dose period (and the shortening of its duration by 33%), against the need to maintain the efficacy onset which is apparent from the clinical data within the first two days of the study.
  • the later maintenance dose selected for each administration case was tuned to balance the overall risk of for chronic / long-term dosing.
  • the doses selected and their timing required careful judgement in the context of other drugs that will be administered in combination with bemcentinib (e.g. other oncology treatments in the oncology setting).
  • Phase 1b Previously untreated locally advanced (stage II Ib/I llc)/metastatic (stage IV) non- squamous NSCLC without actionable mutations (for phase 1 b)
  • Phase 2a Previously untreated locally advanced (stage lllb/lllc)/metastatic (stage IV) non- squamous NSCLC having a serine/threonine kinase 11 (STK11) mutation as identified by Next Generation Sequencing (NGS) and without actionable mutations
  • NSCLC is a life-threatening condition with a clear unmet need, particularly for subjects diagnosed with advanced or metastatic non-squamous NSCLC without a driver mutation, who remain the majority of NSCLC patients. Despite advances in therapeutic regimens, the 5-year survival of NSCLC is still approximately 20-30%. (Min et al., 2021). Current developments for first-line (1 L) treatment of NSCLC define a widening role for chemo-immunotherapy regardless of programmed death-ligand 1 (PD-L1) status, with approval for the combination of platinum, pemetrexed, and pembrolizumab in 1 L, which has become the standard of care (SOC). However, despite an initial improvement in response rates and survival, the emergence of chemoresistance poses a significant obstacle to the management of NSCLC and highlights the unmet medical need in these patients (Min et al., 2021).
  • P-L1 programmed death-ligand 1
  • Bemcentinib is a potent and highly selective, orally bioavailable, inhibitor of AXL tyrosine kinase. Bemcentinib potentiates the anti-tumorigenic activity of innate immune cells through regulation of myeloid suppressor activation, prevents and reverses aggressive EMT driven phenotypes in NSCLC cells, therefore potentiating the immune therapy through tumor EMT modulation, enhanced Type 1 IFN response and modulation of the immune cell landscape.
  • Phase 1b Previously untreated locally advanced (stage 11 Ib/ll lc)/metastatic (stage IV) non-squamous NSCLC without actionable mutations.
  • Phase 2a Previously untreated locally advanced (stage 11 Ib/ll lc)/metastatic (stage IV) non-squamous NSCLC having a serine/threonine kinase 11 (STK11) mutation as identified by Next Generation Sequencing (NGS) and without actionable mutations.
  • stage 11 Ib/ll lc Previously untreated locally advanced (stage 11 Ib/ll lc)/metastatic (stage IV) non-squamous NSCLC having a serine/threonine kinase 11 (STK11) mutation as identified by Next Generation Sequencing (NGS) and without actionable mutations.
  • STK11 serine/threonine kinase 11
  • An independent data safety monitoring board (DSMB) will be responsible for reviewing the safety data from each cohort at the end of the DLT assessment period of each cohort and will provide recommendations to the Sponsor on progressive dose cohort management. Further, based on overall clinical tolerability, the DSMB will recommend the bemcentinib dose(s) for the phase 2a expansion cohort(s).
  • Subjects will take bemcentinib capsules daily and will continue until a reason for discontinuation has been met or for up to 2 years, whichever comes first. Subjects will receive CIT on Day 1 of each 21-day cycle for a maximum of 4 cycles. After completion of the 4 cycles of CIT, subjects will receive maintenance bemcentinib, pembrolizumab, and pemetrexed for up to 2 years.
  • Both Phase 1 b and 2a of the clinical study consists of a screening period (up to 28 days), a treatment period (up to 24 months), and a post treatment safety follow up period (30 days).
  • the primary endpoint for phase 1 b will be assessed after the first 21 days from C1 D1 for each subject.
  • the DLT evaluable population includes all enrolled subjects in phase 1 b who received a full dose of bemcentinib and completed evaluation for DLT in Cycle 1 or received a partial dose of study drug and developed DLT during Cycle 1.
  • the primary endpoint for phase 2ab is measured at regular intervals over the whole duration of the clinical study, for up to 24 months. In the phase 2a expansion there will be an interim analysis after 20 subjects have completed 2 cycles (no earlier than day 42) with the purpose of identifying potential early efficacy signals.
  • the safety assessments include AEs, safety laboratory parameters, vital signs, and ECG changes based on CTCAE v5.0.
  • Efficacy assessments will all be based on tumor assessment scan evaluation by RECIST 1.1. Assessments will be performed using contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) assessments of chest, abdomen, and pelvis. Additionally, x-ray and bone scans will be used as appropriate.
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • phase 1 b of the clinical study 9 to 24 subjects will be enrolled.
  • phase 2a of the clinical study 40 subjects will be enrolled.
  • the analysis will be primarily descriptive in nature and the clinical study is not statistically powered.
  • the primary endpoint for phase 1b will be analyzed on the DLT evaluable population set, using only phase 1b data.
  • phase 2a clinical study will be analyzed on the per-protocol analysis set, using only phase 2a data. Analysis of ORR will occur in a Bayesian framework.
  • the expected duration of the clinical study for each subject will be no more than 26 months.
  • An independent data safety monitoring board (DSMB) will be responsible for reviewing the safety data from each cohort at the end of the DLT assessment period of each cohort and will provide recommendations to the Sponsor on the dose cohort management. Further, based on overall clinical tolerability, the DSMB will recommend the bemcentinib dose(s) for the phase 2a expansion cohort(s).
  • PK pharmacokinetics

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Abstract

This disclosure relates to compositions and methods for treating AXL-related diseases, such as cancer, in a subject. In particular, the present disclosure relates to novel dosage regimens for the treatment of AXL-related diseases, such as cancer, with inhibitors of AXL activity or expression (AXLi).

Description

DOSAGE REGIMEN FOR AXL INHIBITOR
FIELD
This disclosure relates to compositions and methods for treating AXL-related diseases, such as cancer, in a subject. In particular, the present disclosure relates to administration of inhibitors of AXL activity or expression (AXLi).
BACKGROUND
AXL
All of the protein kinases that have been identified to date in the human genome share a highly conserved catalytic domain of around 300 amino acids. This domain folds into a bi obed structure in which resides ATP-binding and catalytic sites. The complexity of protein kinase regulation allows many potential mechanisms of inhibition including competition with activating ligands, modulation of positive and negative regulators, interference with protein dimerization, and allosteric or competitive inhibition at the substrate or ATP binding sites.
AXL (also known as UFO, ARK, and Tyro7; nucleotide accession numbers NM_021913, NM_001699, NM_001278599; protein accession numbers NP_068713, NP_001690, NP_001265528) is a receptor protein tyrosine kinase (RTK) that comprises a C-terminal extracellular ligand binding domain and N-terminal cytoplasmic region containing the catalytic domain. The extracellular domain of AXL has a unique structure that juxtaposes immunoglobulin and fibronectin Type III repeats and is reminiscent of the structure of neural cell adhesion molecules. AXL and its two close relatives, Mer /Nyk and Sky (Tyro3 I Rse I Dtk), collectively known as the Tyro3 family of RTK's, all bind and are stimulated to varying degrees by the same ligand, GAS6 (growth arrest specific-6), a ~76kDa secreted protein with significant homology to the coagulation cascade regulator, Protein S. In addition to binding to ligands, the AXL extracellular domain has been shown to undergo homophilic interactions that mediate cell aggregation, suggesting that one important function of AXL may be to mediate cell-cell adhesion.
AXL is predominantly expressed in the vasculature in both endothelial cells (EC's) and vascular smooth muscle cells (VSMC's) and in cells of the myeloid lineage and is also detected in breast epithelial cells, chondrocytes, Sertoli cells and neurons. Several functions including protection from apoptosis induced by serum starvation, TNF-a or the viral protein E1 A, as well as migration and cell differentiation have been ascribed to AXL signalling in cell culture. AXL has been found to serve as a key checkpoint for interferon (IFN) signalling (Rothlin et al, 2007; Huang et al, 2015); in the context of viral responses, the Zika virus has been found to antagonize the IFN action by interacting with AXL (Chen et al, 2018). However, Axl-/- mice exhibit no overt developmental phenotype and the physiological function of AXL in vivo is not clearly established in the literature.
AXL pathology
The overexpression of AXL and/or its ligand has also been reported in a wide variety of solid tumor types including, but not limited to, breast, renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, and uveal melanoma as well as in myeloid leukemias. Furthermore, it possesses transforming activity in NIH3T3 and 32D cells. It has been demonstrated that loss of Axl expression in tumor cells blocks the growth of solid human neoplasms in an in vivo MDA-MB-231 breast carcinoma xenograft model. Taken together, these data suggest AXL signalling can independently regulate EC angiogenesis and tumor growth and thus represents a novel target class for tumor therapeutic development.
The expression of AXL and GAS6 proteins is upregulated in a variety of other disease states including endometriosis, vascular injury and kidney disease and AXL signalling is functionally implicated in the latter two indications. AXL-GAS6 signalling amplifies platelet responses and is implicated in thrombus formation. AXL may thus potentially represent a therapeutic target for a number of diverse pathological conditions including solid tumors, including, but not limited to, breast, renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma and uveal melanoma; liquid tumors, including but not limited to, leukemias (particularly myeloid leukemias) and lymphomas; endometriosis, vascular disease I injury (including but not limited to restenosis, atherosclerosis and thrombosis), psoriasis; visual impairment due to macular degeneration; diabetic retinopathy and retinopathy of prematurity; kidney disease (including but not limited to glomerulonephritis, diabetic nephropathy, renal disease due to hypertension, and renal transplant rejection), rheumatoid arthritis; osteoporosis, osteoarthritis and cataracts.
AXL inhibitors
In view of the role played by AXL in numerous pathological conditions, the development of safe and effective AXL inhibitors has been a topic of interest in recent years. Different groups of AXL inhibitors are discussed in, inter alia, US20070213375, US 20080153815, US20080188454, US20080176847, US20080188455, US20080182862, US20080188474, US20080117789, US20090111816, WG2007/0030680, WG2008/045978, WG2008/083353, WG2008/0083357, WG2008/083354, WG2008/083356, WG2008/080134, WG2009/054864, and WG/2008/083367.
Combination therapies using AXL inhibitors
The combination of one or more of the above cited AXL inhibitors with one or more other agents is discussed in, for example, WO/2010/083465 and WO/2016/193680, with WO/2016/193680 focussing on combinations of AXL inhibitors with agents having immune- regulatory or modulatory activity. For example, inhibition of AXL with the small molecule Bemcentinib (BGB324 I R428) was found to enhance the efficacy of immune checkpoint inhibitor treatment with anti PD1 and/or anti CTLA4. Combination of AXL inhibitors with immune checkpoint inhibitor treatment and chemotherapy and I or radiotherapy is discussed in, for example, WO/2021/191197.
Research continues to further improve the efficacy, tolerability, and clinical utility of AXL inhibitor treatments. To this end, the present authors have identified clinically advantageous dosage regimens for the administration of an inhibitor of AXL activity or expression (AXLi) to patients with an AXL-related disease, such as cancer. SUMMARY
Through treatment of subjects with the AXL inhibitor bemcentinib and modelling of pharmacokinetics data obtained from two phase 1 studies and one phase 2 study the present authors have developed dosage regimens that allow for improved efficacy, efficiency, and I or tolerability of AXLi therapies when used in the treatment of AXL-related diseases.
Interestingly, it was found that the parameters required for optimal treatment efficacy, efficiency, and I or tolerability is different for different indications, and is influenced by factors including food effects and concomitant use of other therapeutics.
Accordingly, the present disclosure provides a method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose.
In some embodiments, the loading dose is administered on days 1 , 2, and / or 3 of the dosage regimen. Preferably the loading dose is administered on days 1 and 2 of the dosage regimen. The loading dose may be about 100 to 300 mg, such as about 150 to 250 mg, about 175 to 225 mg, or about 190 to 210 mg. In some preferred embodiments, the loading dose is about 200 mg. The loading dose may be about 50 to 250 mg, such as about 100 to 200 mg, about 125 to 175 mg, or about 140 to 160 mg. In some preferred embodiments, the loading dose is about 150 mg. The loading dose may be about 50 to 150 mg, such as about 75 to 125 mg, or about 90 to 110 mg. In some preferred embodiments, the loading dose is about 100 mg. In some embodiments, the loading dose may be about 200 mg, about 150 mg, or about 100 mg administered to the subject once daily. In some preferred embodiments, the loading dose is about 200 mg, about 150 mg, or about 100 mg administered to the subject once daily on days 1 and 2 of the dosage regimen.
In some embodiments, the maintenance dose is administered beginning on day 2, 3, or 4 of the dosage regimen. Preferably the maintenance dose is administered beginning on day 3 of the dosage regimen. The maintenance dose may be administered on day 2, 3, or 4 and on each subsequent day of the dosage regimen. Preferably the maintenance dose may be administered on day 3 and on each subsequent day of the dosage regimen. The maintenance dose may be administered to the subject once daily, for example once daily on day 3 and on each subsequent day of the dosage regimen.
The maintenance dose may be about 50% of the loading dose. The maintenance dose may be about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg, or may be about 60 to 90 mg, about 65 to 85 mg, or about 70 to 80 mg. Preferably the maintenance dose may be about 100 mg or about 75 mg. The maintenance dose may be about 100 mg or about 75 mg administered to the subject once daily, for example once daily on day 3 and on each subsequent day of the dosage regimen.
The maintenance dose may be the same as the loading dose. In some such embodiments, the loading and maintenance dose may be about 100 mg, about 125 mg, or about 150 mg. In some such embodiments, the loading and maintenance dose may be about 100 mg, about 125 mg, or about 150 mg administered to the subject once daily, for example once daily on day 3 and on each subsequent day of the dosage regimen.
The present disclosure also provides a method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosing regimen comprising administering a constant dose of AXLi on day 1 and on each subsequent day of the dosage regimen. The constant dose may be about 125 mg or about 150 mg. The constant dose may be about 125 mg or about 150 mg administered to the subject once daily, for example once daily on day 1 and on each subsequent day of the dosage regimen. The constant dose may be about 75 mg, about 100 mg, or about 150 mg. The constant dose may be about 75 mg, about 100 mg, or about 150 mg administered to the subject once daily, for example once daily on day 1 and on each subsequent day of the dosage regimen. Preferably, the constant dose may be about 100 mg administered to the subject once daily, for example once daily on day 1 and on each subsequent day of the dosage regimen.
The maintenance dose or constant dose may be administered to the subject daily until treatment with the AXLi is stopped. The maintenance dose or constant dose may be administered to the subject once daily until treatment with the AXLi is stopped. T reatment with the AXLi may be stopped when a treatment endpoint is reached for the subject. The treatment endpoint may be one or more of: partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status); disease progression (progressive disease [PD] status) prompting treatment withdrawal; and toxicity and I or incidence of adverse events requiring treatment withdrawal.
In some embodiments, the AXLi is administered to the subject under fed conditions. That is, the AXLi may be administered to the subject before, at the same time, or after food, for example, within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes of the subject consuming I ingesting food. The food is preferably a meal, such as a high fat and I or high protein meal.
In some embodiments, the AXL-related disease is cancer, a fibrotic disorder, or neurofibromatosis.
Preferably, the AXL-related disease is cancer. The cancer may be selected from the group consisting of: lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma. In some preferred embodiments, the cancer is acute myeloid leukemia (AML) and I or lung cancer, preferably non-small-cell lung cancer (NSCLC).
In some embodiments, the AXLi is administered in combination with: one or more immune checkpoint modulator (ICM); and I or one or more chemotherapeutic agent and I or radiotherapy. In some embodiments, the AXLi is administered in combination with an anti-PD-1 antibody. Preferably the anti-PD1 antibody is pembrolizumab
In some embodiments, the AXLi is administered in combination with an anthracycline. Preferably the anthracycline is doxorubicin. In some embodiments, the AXLi is administered in combination with an ICM and an anthracycline. Preferably the anthracycline is doxorubicin
In some embodiments, the AXLi is administered in combination with a platinum-based chemotherapeutic. Preferably, the platinum-based chemotherapeutic is carboplatin or cisplatin.
In some embodiments, the AXLi is administered in combination with an antifolate chemotherapeutic. Preferably, the antifolate chemotherapeutic is pemetrexed.
In some embodiments, the AXLi is administered in combination with a platinum-based chemotherapeutic, an antifolate chemotherapeutic, and an anti-PD-1 antibody. In some most preferred embodiments, the AXLi may be administered in combination with carboplatin, pemetrexed, and pembrolizumab
The AXLi may be a compound of formula (I): as decribed in more detail elsewhere herein.
Figure imgf000006_0001
In preferred embodiments the AXLi is bemcentinib.
SUMMARY OF THE FIGURES
Figure 1. Overlay of individual pharmacokinetic concentration-time profiles (bemcentinib and total radioactivity) for a single oral dose of 200 mg 14C-bemcentinib following administration in a fed state to 6 healthy volunteers. Figure 1A: axis scale (x-y): linear-linear. Figure 1 B axis scale (x-y): linear-logarithmic. Shown is plasma bemcentinib (ng/mL) with time postdose (h). Dashed horizontal line represents the lower limit of quantification (2.00 ng/mL). Following a single oral administration of 14C-bemcentinib in a fed state the geometric mean Cmax was 55.8 ng/mL (23.5%) and the AUCo-t 5590 ng.h/mL (13.3%). The coefficient of variation between patients was 23.5% for Cmax and 13.3% for AUCo-t.
DETAILED DESCRIPTION Aspects and embodiments of the present disclosure will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art.
As described in more detail below, through treatment of subjects with the AXL inhibitor bemcentinib and modelling of pharmacokinetics data obtained from two phase 1 studies and one phase 2 study the present authors have developed dosage regimens that have improved efficacy and/or reduced toxicity as compared to other AXLi dosage regimens.
Accordingly, the present disclosure provides a method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi). In the disclosed methods the AXLi is: administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose; is administered to the subject in a dosage regimen in which a constant dose level is administered to the subject; and I or is administered to the subject under fed conditions.
AXL inhibitors
Different groups of AXL inhibitors are discussed in, inter alia, US20070213375, US 20080153815, US20080188454, US20080176847, US20080188455, US20080182862, US20080188474, US20080117789, US20090111816, W02007/0030680, W02008/045978, W02008/083353, W02008/0083357, W02008/083354, W02008/083356, W02008/080134, W02009/054864, and WO/2008/083367.
Small molecule AXL inhibitors
General formula
In some embodiments the AXL inhibitor is a compound of formula (I):
Figure imgf000007_0001
wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, -C(O)R8, -C(O)N(R6)R7, and -C(=NR6)N(R6)R7;
R2 and R3 are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R9-OR8, -R9-O-R10-OR8, -R9-O-R10-O-R10-OR8, -R9-O-R10-CN, -R9-O-R10-C(O) OR8, -R9-O-R10-C(O)N(R6)R7, -R9-O-R10-S(O)PR8 (where p is 0, 1 or
2), -R9-O-R10-N(R6)R7, -R9-O-R10-C(NR11)N(R11)H, -R9-OC(O)-R8, -R9-N(R6)R7, -R9-C(O)R8, - R9-C(O)OR8, -R9-C(O)N(R6)R7, -R9-N(R6)C(O)OR8, -R9-N(R6)C(O)R8, -R9-N(R6)S(O)tR8 (where t is 1 or 2), -R9-S(O)tOR8 (where t is 1 or 2), -R9-S(O)PR8 (where p is 0, 1 or 2), and -R9-S(O)tN(R6)R7 (where t is 1 or 2); or R2 is a polycyclic heteroaryl containing more than 14 ring atoms as described above and R3 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R13-OR12, -R13-OC(O)-R12, -R13-O-R14-N(R12)2, -R13-N(R12)-R14-N(R12)2, -R 13-N(R12)-R14-N(R12)2, -R13-N(R12)2, -R13-C(O)R12, -R13-C(O)OR12, -R13-C(O)N(R12)2, -R13-C(0 )N(R12)-R14-N(R12)R13, -R13-C(O)N(R12)-R14-OR12, -R13-N(R12)C(O)OR12, -R13-N(R12)C(O)R12, -R13-N(R12)S(O)tR12 (where t is 1 or 2), -R13-S(O)tOR12 (where t is 1 or 2), -R13-S(O)PR12 (where p is 0, 1 or 2), and -R13-S(O)tN(R12)2 (where t is 1 or 2); or R3 is a polycyclic heteroaryl containing more than 14 ring atoms as described above, and R2 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R13-OR12, -R13-OC(O)-R12, -R13-O-R14-N(R12)2, -R13-N(R12)-R14-N(R12)2, -R 13-N(R12)-R14-N(R12)2, -R13-N(R12)2, -R13-C(O)R12, -R13-C(O)OR12, -R13-C(O)N(R12)2, -R13-C(0 )N(R12)-R14-N(R12)R13, -R13-C(O)N(R12)-R14-OR12, -R13-N(R12)C(O)OR12, -R13-N(R12)C(O)R12, -R13-N(R12)S(O)tR12 (where t is 1 or 2), -R13-S(O)tOR12 (where t is 1 or 2), -R13-S(O)PR12 (where p is 0, 1 or 2), and -R13-S(O)tN(R12)2 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R10-OR8, -R10-CN, -R10-NO2, -R10-N(R8)2, -R10-C(O)OR8 and -R10-C(O)N(R8)2, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted /V- heterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl; each R9 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R10 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R11 is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR8; each R12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl , optionally substituted heteroarylalkyl, -R10-OR8, -R10-CN, -R10-NO2, -R10-N(R8)2, -R10-C(O)OR8 and -R10-C(O)N(R8)2, or two R12s, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl; each R13 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; and each R14 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof.
Some embodiments
In some embodiments, the AXLi is a compound of formula (I) as defined in WO 2021/204713 A1 at 12 line 11 to page 49 line 14. In some embodiments, the compound of formula (I) is selected from the group consisting of:
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(pyrrolidin-1-yl)-
6.7.8.9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7-(S)-pyrrolidin-1- yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7-(R)-pyrrolidin-1- yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(3-fluoro-4-(4- (pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/5-(7-(pyrrolidin-1-yl)-
6.7.8.9-tetrahydro-5/7-benzo[7]annulene-1-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/5-(7-(S)-pyrrolidin-1-yl-
6.7.8.9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine; 1 -(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-A/3-((7S)-7-(f- butoxycarbonylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(acetamido)-
6.7.8.9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-((2/?)-2- (methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4,4- difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7- ((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7- 1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-((2/?)-2- (carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4- (ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4- (carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7- ((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4- (ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7- 1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4- (carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(pyrrolidin-1-yl)-
6.7.8.9-tetrahydro-5/7-benzo[7]annulene-1-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-amino-
6.7.8.9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7s)-7- (di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((2- methylpropyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- ((propyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (dipropylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine; 1 -(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-A/3-((7S)-7- (diethylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (cyclohexylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (cyclopentylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((1- cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(2- propylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((3,3- dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- ((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-
3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-
3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((5- chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((2- carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((3- bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-
3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (dimethylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (cyclobutylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(3- pentylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((2,2- dimethylpropyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine; 1 -(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-A/3-((7S)-7- ((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole- 3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)- 1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- ((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)- 1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(3- methylbutylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(di(3- methylbutyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(2- ethylbutylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(but-2- enylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(butyl(but-2- enyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/5-((7S)-7-(f- butoxycarbonylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-amino- 6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (dimethylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (diethylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (dipropylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(di(3- methylbutyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (cyclobutylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (cyclohexylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine; 1 -(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/V3-((7S)-7- ((methylethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (cyclopentylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine; and
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(2- butylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine; or pharmaceutically acceptable salts thereof.
Preferred embodiments
In some preferred embodiments, the AXLi is selected from the group consisting of:
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-y1)-N3-((7-pyrrolidin-l-y1)- 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y1)-1 H-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7-(S)-pyrrolidin-1- yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-y1)-N3-((7-(R)-pyrrolidin-l- y1)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y1)-1 H-1 ,2,4-triazole-3,5-diamine; and
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-y1)-N3-((7-(8)-pyrrolidin-l- y1)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y1)-1 H-1 ,2,4-triazole-3,5-diamine; or pharmaceutically acceptable salts thereof.
Preferably, the AXL inhibitor is 1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)- /V3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole- 3,5-diamine.
The most preferred AXL inhibitor is bemcentinib (CAS No. 1037624-75-1 ; UNII 0ICW2LX8AS)
Other embodiments
In some other embodiments the AXLi is selected from the group consisting of:
- Dubermatinib (CAS No.1341200-45-0 ; UNII 14D65TV20J);
- Gilteritinib (CAS No. 1254053-43-4 ; UNII 66D92MGC8M);
- Cabozantinib (CAS No. 849217-68-1 ; UNII 1C39JW444G);
- SGI7079 (CAS No. 1239875-86-5);
- Merestinib (CAS No. 1206799-15-6 ; UNII 5OGS5K699E);
- Amuvatinib (CAS No. 850879-09-3 ; UNII SO9S6QZB4R);
- Bosutinib (CAS No. 380843-75-4 ; UNII 5018V4AEZ0);
- XL092 from Exelixis (CAS No. 2367004-54-2);
- Sitravatinib (CAS No. 1123837-84-2 ; UNII CWG62Q1VTB);
- Glesatinib (CAS No. 936694-12-1 ; UNII 7Q29OXD98N); and
- foretinib (CAS No. 849217-64-7; UNII 81 FH7VK1C4).
Definitions
As used herein, unless specified to the contrary, the following terms have the meaning indicated:
"Amino" refers to the -NH2 radical. "Carboxy" refers to the -C(O)OH radical.
"Cyano" refers to the -CN radical.
"Nitro" refers to the -NO2 radical.
"Oxa" refers to the -O- radical.
"Oxo" refers to the =0 radical.
"Thioxo" refers to the =S radical.
"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1 -methylethyl (/so-propyl), n-butyl, n-pentyl, 1 ,1 -dimethylethyl (f-butyl), 3-methylhexyl, 2-methylhexyl, and the like. For purposes of this disclosure, the term "lower alkyl" refers to an alkyl radical having one to six carbon atoms.
"Optionally substituted alkyl" refers to an alkyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR20, -OC(O)-R20, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O )OR20, -N(R20)C(O)R20, -N(R20)S(O)2R20, -S(O)tOR20 (where t is 1 or 2), -S(O)PR20 (where p is 0, 1 or 2), and -S(O)2N(R20)2 where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl.
"Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, for example, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, and penta-1 , 4-dienyl.
"Optionally substituted alkenyl" refers to an alkenyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR20, -OC(O)-R20, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O )OR20, -N(R20)C(O)R20, -N(R20)S(O)2R20, -S(O)tOR20 (where t is 1 or 2), -S(O)PR20 (where p is 0, 1 or 2), and -S(O)2N(R20)2 where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl.
"Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, optionally containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
"Optionally substituted alkynyl" refers to an alkynyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR20, -OC(O)-R20, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O )OR20, -N(R20)C(O)R20, -N(R20)S(O)2R20, -S(O)tOR20 (where t is 1 or 2), -S(O)PR20 (where p is 0, 1 or 2), and -S(O)2N(R20)2 where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl.
"Straight or branched alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, and n-butylene. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain.
"Optionally substituted straight or branched alkylene chain" refers to an alkylene chain, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR20, -OC(O)-R20, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O )OR20, -N(R20)C(O)R20, -N(R20)S(O)2R20, -S(O)tOR20 (where t is 1 or 2), -S(O)PR20 (where p is 0, 1 or 2), and -S(O)2N(R20)2 where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl.
"Straight or branched alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, and n-butenylene. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
"Optionally substituted straight or branched alkenylene chain" refers to an alkenylene chain, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR20, -OC(O)-R20, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O )OR20, -N(R20)C(O)R20, -N(R20)S(O)2R20, -S(O)tOR20 (where t is 1 or 2), -S(O)PR20 (where p is 0, 1 or 2), and -S(O)2N(R20)2 where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl.
"Straight or branched alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms, for example, propynylene, and n-butynylene. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
"Optionally substituted straight or branched alkynylene chain" refers to an alkynylene chain, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR20, -OC(O)-R20, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O )OR20, -N(R20)C(O)R20, -N(R20)S(O)2R20, -S(O)tOR20 (where t is 1 or 2), -S(O)PR20 (where p is 0, 1 or 2), and -S(O)2N(R20)2 where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl.
"Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 14 carbon atoms and at least one aromatic ring. For purposes of this disclosure, the aryl radical may be a monocyclic, bicyclic, or tricyclic system and which may include spiro ring systems. An aryl radical is commonly, but not necessarily, attached to the parent molecule via an aromatic ring of the aryl radical. For purposes of this disclosure, an "aryl" radical as defined herein can not contain rings having more than 7 members and cannot contain rings wherein two non-adjacent ring atoms thereof are connected through an atom or a group of atoms (/.e., a bridged ring system). Aryl radicals include, but are not limited to, aryl radicals derived from acenaphthylene, anthracene, azulene, benzene, 6,7,8,9-tetrahydro-5/7-benzo[7]annulene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, and phenanthrene.
"Optionally substituted aryl" refers to an aryl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R21-OR20, -R21-OC(O)-R20, -R21-N(R20)2, -R21-C(O)R20, -R21-C(O)OR20, -R2 1-C(O)N(R20)2, -R21-O-R22-C(O)N(R20)2, -R21-N(R20)C(O)OR20, -R21-N(R20)C(O)R20, -R21-N(R20 )S(O)2R20 , -R21-C(=NR20)N(R20)2, -R21-S(O)tOR20 (where t is 1 or 2), -R21-S(O)PR20 (where p is 0, 1 or 2), and -R21-S(O)2N(R20)2, where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl, each R21 is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R22 is a straight or branched alkylene or alkenylene chain. "Aralkyl" refers to a radical of the formula -Rb-Rc where Rb is an alkylene chain as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl and diphenylmethyl.
"Optionally substituted aralkyl" refers to an aralkyl radical, as defined above, wherein the alkylene chain of the aralkyl radical is an optionally substituted alkylene chain, as defined above, and each aryl radical of the aralkyl radical is an optionally substituted aryl radical, as defined above.
"Aralkenyl" refers to a radical of the formula -Rd-Rc where Rd is an alkenylene chain as defined above and Rc is one or more aryl radicals as defined above.
"Optionally substituted aralkenyl" refers to an aralkenyl radical, as defined above, wherein the alkenylene chain of the aralkenyl radical is an optionally substituted alkenylene chain, as defined above, and each aryl radical of the aralkenyl radical is an optionally substituted aryl radical, as defined above.
"Aralkynyl" refers to a radical of the formula -ReRc where Re is an alkynylene chain as defined above and Rc is one or more aryl radicals as defined above.
"Optionally substituted aralkynyl" refers to an aralkynyl radical, as defined above, wherein the alkynylene chain of the aralkynyl radical is an optionally substituted alkynylene chain, as defined above, and each aryl radical of the aralkynyl radical is an optionally substituted aryl radical, as defined above.
"Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, spiro or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, more preferably from five to seven carbons and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. For purposes of this disclosure, a bridged ring system is a system wherein two non-adjacent ring atoms thereof are connected through an atom or a group of atoms, wherein the atom or the group of atoms are the bridging element. An example of a bridged cycloalkyl (monovalent) radical is norbornanyl (also called bicyclo[2.2.1]heptanyl). For purposes of this disclosure, a non-bridged ring system is a system which does not contain a bridging element, as described above. For purposes of this disclosure, a fused ring system is a system wherein two adjacent ring atoms thereof are connected through an atom or a group of atoms. An example of a fused cycloalkyl (monovalent) radical is decahydronaphthalenyl (also called decalinyl). For purposes of this disclosure, a spiro ring system is a system wherein two rings are joined via a single carbon (quaternary) atom. An example of a spiro cycloalkyl (monovalent) radical is spiro[5.5]undecanyl. Monocyclic cycloalkyl radicals do not include spiro, fused or bridged cycloalkyl radicals, but do include for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include fused, spiro or bridged cycloalkyl radicals, for example, C10 radicals such as adamantanyl (bridged) and decalinyl (fused), and C7 radicals such as bicyclo[3.2.0]heptanyl (fused), norbornanyl and norbornenyl (bridged), as well as substituted polycyclic radicals, for example, substituted C7 radicals such as 7,7-dimethylbicyclo[2.2.1]heptanyl (bridged).
"Optionally substituted cycloalkyl" refers to a cycloalkyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R21-OR20, -R21-OC(O)-R20, -R21-N(R20)2, -R21-C(O)R20, -R21-C(O)OR20, -R2 1-C(O)N(R20)2, -R21-N(R20)C(O)OR20, -R21-N(R20)C(O)R20, -R21-N(R20)S(O)2R20, -R21-C(=NR20 )N(R20)2, -R21-S(O)tOR20 (where t is 1 or 2), -R21-S(O)PR20 (where p is 0, 1 or 2), and -R21-S(O)2N(R20)2, where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl, and each R21 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
"Cycloalkylalkyl" refers to a radical of the formula -RbRg where Rb is an alkylene chain as defined above and Rg is a cycloalkyl radical as defined above.
"Optionally substituted cycloalkylalkyl" refers to a cycloalkylalkyl radical, as defined above, wherein the alkylene chain of the cycloalkylalkyl radical is an optionally substituted alkylene chain, as defined above, and the cycloalkyl radical of the cycloalkylalkyl radical is an optionally substituted cycloalkyl radical, as defined above.
"Cycloalkylalkenyl" refers to a radical of the formula -RdRg where Rd is an alkenylene chain as defined above and Rg is a cycloalkyl radical as defined above.
"Optionally substituted cycloalkylalkenyl" refers to a cycloalkylalkenyl radical, as defined above, wherein the alkenylene chain of the cycloalkylalkenyl radical is an optionally substituted alkenylene chain, as defined above, and the cycloalkyl radical of the cycloalkylalkenyl radical is an optionally substituted cycloalkyl radical as defined above.
"Cycloalkylalkynyl" refers to a radical of the formula -ReRg where Re is an alkynylene radical as defined above and Rg is a cycloalkyl radical as defined above.
"Optionally substituted cycloalkylalkynyl" refers to a cycloalkylalkynyl radical, as defined above, wherein the alkynylene chain of the cycloalkylalkynyl radical is an optionally substituted alkynylene chain, as defined above, and the cycloalkyl radical of the cycloalkylalkynyl radical is an optionally substituted cycloalkyl radical as defined above. "Halo" refers to bromo, chloro, fluoro or iodo.
"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, and
1-bromomethyl-2-bromoethyl.
"Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
"Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
"Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring system radical which comprises one to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include spiro or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of a bridged heterocyclyl include, but are not limited to, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.3.1]nonanyl, diazabicyclo[3.2.2]nonanyl and oxazabicyclo[2.2.1]heptanyl. A "bridged /V-heterocyclyl" is a bridged heterocyclyl containing at least one nitrogen, but which optionally contains up to four additional heteroatoms selected from O, N and S. For purposes of this disclosure, a non-bridged ring system is a system wherein no two non-adjacent ring atoms thereof are connected through an atom or a group of atoms. Examples of heterocyclyl radicals include, but are not limited to, dioxolanyl, 1 ,4-diazepanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, octahydro-1/7-pyrrolo[3,2-c]pyridinyl, octahydro-1 /7-pyrrolo[2, 3- c]pyridinyl, octahydro-1/7-pyrrolo[2,3-b]pyridinyl, octahydro-1/7-pyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1 /7-py rido[ 1 ,2-a]pyrazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, 3,7-diazabicyclo[3.3.1]nonan-3-yl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, thienyl[1 ,3]dithianyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1 ,1-dioxo-thiomorpholinyl, azetidinyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, decahydroprazino[1 ,2- a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl, and 2,7-diazaspiro[4.4]nonanyl.
"Optionally substituted heterocyclyl" refers to a heterocyclyl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R21-OR20, -R21-OC(O)-R20, -R21-N(R20)2, -R21-C(O)R20, -R21-C(O)OR20, -R2 1-C(O)N(R20)2, -R21-N(R20)C(O)OR20, -R21-N(R20)C(O)R20, -R21-N(R20)S(O)2R20, -R— -C(=NR20 )N(R20)2, -R21-S(O)tOR20 (where t is 1 or 2), -R21-S(O)PR20 (where p is 0, 1 or 2), and -R21-S(O)2N(R20)2, where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl, and each R21 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
"/V-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the /V-heterocyclyl radical to the rest of the molecule may be through a nitrogen atom in the /V-heterocyclyl radical or through a carbon in the /V-heterocyclyl radical.
"Optionally substituted /V-heterocyclyl" refers to an /V-heterocyclyl, as defined above, which is optionally substituted by one or more substituents as defined above for optionally substituted heterocyclyl.
"Heterocyclylalkyl" refers to a radical of the formula -RbRh where Rb is an alkylene chain as defined above and Rh is a heterocyclyl radical as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkylene chain at the nitrogen atom.
"Optionally substituted heterocyclylalkyl" refers to a heterocyclylalkyl radical, as defined above, wherein the alkylene chain of the heterocyclylalkyl radical is an optionally substituted alkylene chain, as defined above, and the heterocyclyl radical of the heterocyclylalkyl radical is an optionally substituted heterocyclyl radical, as defined above.
"Heterocyclylalkenyl" refers to a radical of the formula -RdRh where Rd is an alkenylene chain as defined above and Rh is a heterocyclyl radical as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkenylene chain at the nitrogen atom.
"Optionally substituted heterocyclylalkenyl" refers to a heterocyclylalkenyl radical, as defined above, wherein the alkenylene chain of the heterocyclylalkenyl radical is an optionally substituted alkenylene chain, as defined above, and the heterocyclyl radical of the heterocyclylalkenyl radical is an optionally substituted heterocyclyl radical, as defined above. "Heterocyclylalkynyl" refers to a radical of the formula -ReRh where Re is an alkynylene chain as defined above and Rh is a heterocyclyl radical as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkynylene chain at the nitrogen atom.
"Optionally substituted heterocyclylalkynyl" refers to a heterocyclylalkynyl radical, as defined above, wherein the alkynylene chain of the heterocyclylalkynyl radical is an optionally substituted alkynylene chain, as defined above, and the heterocyclyl radical of the heterocyclylalkynyl radical is an optionally substituted heterocyclyl radical, as defined above. "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. A heteroaryl radical is commonly, but not necessarily, attached to the parent molecule via an aromatic ring of the heteroaryl radical. For purposes of this disclosure, the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include spiro or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. For purposes of this disclosure, the aromatic ring of the heteroaryl radical need not contain a heteroatom, as long as one ring of the heteroaryl radical contains a heteroatom. For example benzo-fused heterocyclyls such as 1 , 2,3,4- tetrahydroisoquinolin-7-yl are considered a "heteroaryl" for the purposes of this disclosure. Except for the polycyclic heteroaryls containing more than 14 ring atoms, as defined below, a "heteroaryl" radical as defined herein can not contain rings having more than 7 members and cannot contain rings wherein two non-adjacent members thereof are connected through an atom or a group of atoms (/.e., a bridged ring system). Examples of heteroaryl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1 ,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1 ,4]dioxepinyl, benzo[b][1 ,4]oxazinyl, benzo[b]azepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-c(]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1 ,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 3,4-dihydro-2/7-benzo[b][1 ,4]dioxepinyl, cyclopenta[4,5]thieno[2,3-c(]pyrimidinyl such as
6.7-dihydro-5/7-cyclopenta[4,5]thieno[2,3-c(]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 3,4- dihydro-2/7-benzo[b][1 ,4]thiazinyl, 5,6-dihydrobenzo[/7]cinnolinyl,
7',8'-dihydro-5'/7-spiro[[1 ,3]dioxolane-2,6'-quinoline]-3'-yl,
6.7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazinyl, 2,3-dihydro-1/7-pyrido[2,3- b][1 ,4]oxazinyl, 3',4'-dihydrospiro[cyclobutane-1 ,2'-pyrido[3,2-b][1 ,4]oxazinyl, dihydropyridooxazinyl such as 3,4-dihydro-2/7-pyrido[3,2-b][1 ,4]oxazinyl, dihydropyridothiazinyl such as 3,4-dihydro-2/7-pyrido[3,2-b][1 ,4]thiazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, furopyrimidinyl, furopyridazinyl, furopyrazinyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl, imidazo[1 ,2-a]pyridinyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl (isoquinolyl), indolizinyl, isoxazolyl, naphthyridinyl, 1 ,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 3'-oxo-3',4'-dihydrospiro[cyclobutane- 1 ,2'-pyrido[3,2-b][1 ,4]oxazine]yl, 7-oxo-5,6,7,8-tetrahydro-1 ,8-naphthyridinyl,
1 -phenyl- 1/7-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phenanthridinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-c(]pyrimidinyl, pyridinyl (pyridyl), pyrido[3,2-d]pyrimidinyl, pyrido[3,4-c/]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl (pyridazyl), pyrrolyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, 2/7-pyrido[3,2- b][1 ,4]oxazinonyl, 1/7-pyrido[2,3-b][1 ,4]oxazinonyl, pyrrolopyridinyl such as 1/7-pyrrolo[2,3- b]pyridinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, tetrahydroquinolinyl,
5.6.7.8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl,
6.7.8.9-tetrahydro-5/7-cyclohepta[b]pyridinyl, 6,7,8,9-tetrahydro-5/7-pyrido[3,2-c]azepinyl,
5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-c(]pyrimidinyl,
6.7.8.9-tetrahydro-5/7-cyclohepta[4,5]thieno[2,3-c(]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, 1 ,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl, thieno[2,3-c/]pyrimidinyl, thienopyrimidinyl (e.g., thieno[3,2-c/]pyrimidinyl), thieno[2,3-c]pyridinyl, thienopyridazinyl, thienopyrazinyl, and thiophenyl (thienyl). "Optionally substituted heteroaryl" refers to a heteroaryl radical, as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R21-OR20, -R21-OC(O)-R20, -R21-N(R20)2, -R21-C(O)R20, -R21-C(O)OR20, -R2 1-C(O)N(R20)2, -R21-N(R20)C(O)OR20, -R21-N(R20)C(O)R20, -R21-N(R20)S(O)2R202, -R21-C(=NR2 °)N(R20)2, -R21-S(O)tOR20 (where t is 1 or 2), -R21-S(O)PR20 (where p is 0, 1 or 2), and -R21-S(O)2N(R20)2, where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl, and each R21 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
"/V-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the /V-heteroaryl radical to the rest of the molecule may be through a nitrogen atom in the /V-heteroaryl radical or through a carbon atom in the /V- heteroaryl radical.
"Optionally substituted /V-heteroaryl" refers to an /V-heteroaryl, as defined above, which is optionally substituted by one or more substituents as defined above for optionally substituted heteroaryl.
"Polycyclic heteroaryl containing more than 14 ring atoms" refers to a 15- to 20-membered ring system radical comprising hydrogen atoms, one to fourteen carbon atoms, one to eight heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. A "polycyclic heteroaryl containing more than 14 ring atoms" radical is commonly, but not necessarily, attached to the parent molecule via an aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms" radical. For purposes of this disclosure, the "polycyclic heteroaryl containing more than 14 ring atoms" radical may be a bicyclic, tricyclic or tetracyclic ring system, which may include fused or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the "polycyclic heteroaryl containing more than 14 ring atoms" radical may be optionally oxidized and the nitrogen atom may also be optionally quaternized. For purposes of this disclosure, the aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms" radical need not contain a heteroatom, as long as one ring of the "polycyclic heteroaryl containing more than 14 ring atoms" radical contains a heteroatom. Examples of "polycyclic heteroaryl containing more than 14 ring atoms" radicals include, but are not limited to, 6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl, 6,7- dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl, 6,7,8,9-tetrahydro-5/7- cyclohepta[4,5]thieno[2,3-c(]pyrimidin-4-yl, 6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2- c/]pyrimidin-4-yl, 6,7-dihydro-5/7-benzo[2,3]azepino[4,5-c]pyridazin-3-yl, (Z)- dibenzo[£>,f][1 ,4]thiazepin-11-yl, 6,7-dihydro-5/7-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl, 6,7-dihydro-5/7-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl, spiro[chromeno[4,3-c]pyridazine-5,1'- cyclopentane]-3-yl, 6,8,9, 10-tetrahydro-5/7-spiro[cycloocta[b]pyridine-7,2'-[1 ,3]dioxolane]-3- yl, 5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1 ,3]dioxolane]-3-yl, 5, 7,8,9- tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1 ,3]dioxolane]-3-yl, 6,7-dihydro-5/7- benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, 6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-d]pyrimidin- 2-yl, 5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1 ,3]dioxolane]-3-yl, 6,8,9,10- tetrahydro-5/7-spiro[cycloocta[b]pyridine-7,2'-[1 ,3]dioxane]-3-yl and 6,7-dihydro-5/7- benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl.
"Optionally substituted polycyclic heteroaryl containing more than 14 ring atoms" is meant to include "polycyclic heteroaryl containing more than 14 ring atoms" radicals, as defined above, which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R21-OR20, -R21-OC(O)-R20, -R21-N(R20)2, -R21-C(O)R20, -R21-C(O)OR20, -R2 1-C(O)N(R20)2, -R21-N(R20)C(O)OR20, -R21-N(R20)C(O)R20, -R21-N(R20)S(O)tR20 (where t is 1 or 2), -R21-S(O)tOR20 (where t is 1 or 2), -R21-S(O)PR20 (where p is 0, 1 or 2), and -R21-S(O)tN(R20)2 (where t is 1 or 2), where each R20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R20's, together with the common nitrogen to which they are both attached, may optionally form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl, and each R21 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
"Heteroarylalkyl" refers to a radical of the formula -RbRi where Rb is an alkylene chain as defined above and Rj is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkylene chain at the nitrogen atom.
"Optionally substituted heteroarylalkyl" refers to a heteroarylalkyl radical, as defined above, wherein the alkylene chain of the heteroarylalkyl radical is an optionally substituted alkylene chain, as defined above, and the heteroaryl radical of the heteroarylalkyl radical is an optionally substituted heteroaryl radical, as defined above.
"Heteroarylalkenyl" refers to a radical of the formula -RdRi where Rd is an alkenylene chain as defined above and Rj is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkenylene chain at the nitrogen atom.
"Optionally substituted heteroarylalkenyl" refers to a heteroarylalkenyl radical, as defined above, wherein the alkenylene chain of the heteroarylalkenyl radical is an optionally substituted alkenylene chain, as defined above, and the heteroaryl radical of the heteroarylalkenyl radical is an optionally substituted heteroaryl radical, as defined above.
"Heteroarylalkynyl" refers to a radical of the formula -ReRj where Re is an alkynylene chain as defined above and Rj is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkynylene chain at the nitrogen atom.
"Optionally substituted heteroarylalkynyl" refers to a heteroarylalkynyl radical, as defined above, wherein the alkynylene chain of the heteroarylalkynyl radical is an optionally substituted alkynylene chain, as defined above, and the heteroaryl radical of the heteroarylalkynyl radical is an optionally substituted heteroaryl radical, as defined above.
"Hydroxyalkyl" refers to an alkyl radical as defined above which is substituted by one or more hydroxy radicals (-OH).
Certain chemical groups named herein may be preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example; C7-C12 alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, and C4-Ci2cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
The compounds of formula (I), or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any said compounds.
"Atropisomers" are stereoisomers resulting from hindered rotation about single bonds where the barrier to rotation is high enough to allow for the isolation of the conformers (Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994; Chapter 14). Atropisomerism is significant because it introduces an element of chirality in the absence of stereogenic atoms. The disclosure is meant to encompass atropisomers, for example in cases of limited rotation around the single bonds emanating from the core triazole structure, atropisomers are also possible and are also specifically included in the compounds of the disclosure.
The chemical naming protocol and structure diagrams used herein are a modified form of the IIIPAC nomenclature system wherein the compounds of formula (I) are named herein as derivatives of the central core structure, i.e., the triazole structure. For complex chemical names employed herein, a substituent group is named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent. In chemical structure diagrams, all bonds are identified, except for some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.
For purposes of this disclosure, the depiction of the bond attaching the R3 substituent to the parent triazole moiety in formula (I), as shown below:
Figure imgf000025_0001
is intended to include only the two regioisomers shown below, /.e., compounds of formula (la) and (lb):
Figure imgf000025_0002
The numbering system of the ring atoms in compounds of formula (la) is shown below:
Figure imgf000025_0003
For example, a compound of formula (la) wherein R1, R4 and R5 are each hydrogen, R2 is 4- (2-(pyrrolidin-1-yl)ethoxy)phenyl and R3 is 6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2- c]pyridazin-3-yl; i.e., a compound of the following formula:
Figure imgf000026_0001
is named herein as 1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(4-(2- (pyrrolidin-1-yl)ethoxy)phenyl)-1/7-1 ,2,4-triazole-3,5-diamine.
The numbering system of the ring atoms in compounds of formula (lb) is shown below:
Figure imgf000026_0002
Compounds of formula (lb) are similarly named herein.
In the methods of the disclosure the AXLi is preferably administered orally, for example as as an oral capsule. The AXLi may may be administered via installation through a feeding tube. The AXLi may be administered by other suitable administration routes as described elsewhere herein.
AXL-related disease
As referred to herein, an AXL-related disease is one which in which dysfunction of Axl expression or activity is a contributing factor. For example, the AXL-related disease may be one in which overexpression of AXL is a contributing factor. Overexpression of AXL and/or its ligand has been reported in a wide variety of solid tumor types, as well as in other disease states including vascular injury and kidney disease. Alternatively, or in addition, the AXL- related disease may be one in which tissue infiltration with AXL+ve cells, such as AXL+ve immune suppressive dendritic cells, NK cells, or macrophages is a contributing factor. Thus, for example, the AXL-related disease may be a cancer, or a fibrotic disorder, characterised by expression or overexpression of AXL. For example, the AXL-related disease may be a cancer, or a fibrotic disorder, characterised by tissue infiltration with AXL+ve cells, such as AXL+ve immune suppressive dendritic cells, NK cells, or macrophages. The AXL-related disease may be selected from: Immune disorders, cardiovascular disorders, thrombosis, diabetes, immune checkpoint disorders, neurofibromatosis, fibrotic disorders (fibrosis), or proliferative diseases such as cancer, particularly metastatic cancer. Furthermore, Axl is known to play a role in many cancers of epithelial origin.
In some embodiments of the disclosure the AXL-related disease is a proliferative disease. A proliferative disease in one in which excessive proliferation of cells contributes to the pathogenesis of the disease. Exemplary proliferative diseases include: cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, and cirrhosis of the liver.
In some embodiments of the disclosure the AXL-related disease is a neoplastic disease. A neoplastic disease is one in which abnormal and excessive growth (termed neoplasia) of cells I tissue occurs. Neoplasia is the abnormal growth and proliferation of abnormal cells or abnormal amounts of cells, which can be due to a benign or malignant process. Exemplary neoplastic diseases include: myeloproliferative diseases, myelodysplastic syndromes (MDS), and acute myeloid leukemias (AML).
Cancer
In some preferred embodiments of the disclosure, the AXL-related disease is a solid tumour. In other preferred embodiments, the AXL-related disease is a liquid tumour (which may also be referred to as a hematologic cancer, or hematologic malignancy). In some preferred embodiments of the disclosure, the AXL-related disease is cancer.
In some embodiments, the cancer may be one or more of the following cancers: Leukemias such as but not limited to acute myelocytic leukemias (AMLs) such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome, acute leukemia, acute lymphocytic leukemia, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, nonHodgkin's disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone and connective tissue sarcomas such as but not limited to bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to papillary, nodular, and diffuse; lung cancers such as non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; genital cancers such as penile cancer; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/or ureter); Wilms' tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.
The cancer may be selected from the group consisting of: lung cancer, small-cell lung cancer, non-small-cell lung cancer, histocytoma, glioma, astrocyoma, osteoma, gastrointestinal cancer, bowel cancer, colon cancer, breast cancer, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, urothelial carcinoma, bladder cancer, pancreas cancer, brain cancer, glioblastoma, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma, mesothelioma, lymphomas, and leukemias. The cancer may be selected from lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, prostate cancer, ovarian cancer, colorectal cancer, glioma cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma. The cancer may be metastatic. The cancer may be one or more solid cancer tumors, including, but not limited to, lung cancer, non-small cell lung carcinoma, breast, renal, endometrial, ovarian, thyroid, and, melanoma, prostate carcinoma, sarcoma, gastric cancer and uveal melanoma.
The cancer may be one or more liquid tumors, including but not limited to, leukemias (particularly myeloid leukemias) and lymphomas. The cancer may be one or more leukaemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myelocytic leukaemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukaemia leukaemias and myelodysplastic syndrome, chronic leukaemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera. The cancer may be one or more lymphomas such as but not limited to Hodgkin's disease, non-Hodgkin's disease.
In some particularly preferred embodiments, the AXL-related disease may be a leukemia, such as acute myeloid leukemia (AML).
In some other particularly preferred embodiments, the AXL-related disease may be a lung cancer, such as non-small-cell lung cancer.
Fibrotic disorders
In some embodiments of the disclosure, the AXL-related disease may be fibrosis (including but not limited to lung fibrosis and liver fibrosis) or a fibrotic disorder. Fibrotic disorders of interest include strabismus, scleroderma, keloid, Nephrogenic systemic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), systemic sclerosis, cardiac fibrosis, non-alcoholic steatohepatitis (NASH), and other types of liver fibrosis, primary biliary cirrhosis, renal fibrosis, cancer, and atherosclerosis. In these diseases, the chronic development of fibrosis in tissue leads to marked alterations in the architecture of the affected organs and subsequently cause defective organ function.
Neurofibromatosis
In some embodiments of the disclosure, the AXL-related disease may be neurofibromatosis. Neurofibromatoses are a group of genetic disorders that cause tumours to form on nerve tissue. Tumours in these disorders are usually noncancerous (benign) but can become cancerous (malignant). There are three types of neurofibromatosis: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. Thus, in some embodiments of this disclosure the AXL-related disease may be neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and I or schwannomatosis. The AXL-related disease may be a neurofibroma and / or a schwannoma.
Other AXL-related diseases
In some embodiments of the disclosure, the AXL-related disease may be selected from: endometriosis, vascular disease I injury (including but not limited to restenosis, atherosclerosis and thrombosis), psoriasis; visual impairment due to macular degeneration; diabetic retinopathy and retinopathy of prematurity; kidney disease (including but not limited to glomerulonephritis, diabetic nephropathy and renal transplant rejection), rheumatoid arthritis; osteoarthritis, osteoporosis and cataracts.
In some embodiments of the disclosure, the AXL-related disease may be an immune checkpoint disorder. Immune checkpoint disorders of interest include: Chronic viral infections, Melanoma, Colorectal cancer, Breast cancer, Ovarian cancer, Non-small cell lung cancer (NSCLC), Prostate cancer, Renal cell cancer, Pancreatic cancer, Esophagus cancer, Bladder cancer, Myeloma, Kidney cancer, Bladder cancer, Brain tumor, and Lymphoma.
Dosage regimens
In some embodiments of the methods for treating an AXL-related disease according to this disclosure, the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose. In other embodiments of the methods of the disclosure, the AXLi is administered to the subject in a dosage regimen in which a constant dose level is administered to the subject. The present authors have discovered that these dosage regimens have improved efficacy and/or reduced toxicity as compared to other AXLi dosage regimens when used in the treatment of AXL-related diseases.
As is described more fully below, a “loading dose” is an initial higher dose of AXLi given for a “loading period” at the beginning of a course of treatment, before the dose is reduced to a maintenance level (“maintenance dose”). The loading dose serves to allow the AXLi to reach a desired steady-state concentration in the body at which the AXLi has a desired therapeutic effect, while the maintenance dose serves to maintain the desired steady-state concentration of AXLi in the body. A regimen comprising a “constant dose level” is one which the same dose is administered to the subject throughout the dosing regimen (that is, one where in effect the “loading dose” and “maintenance dose” are the same).
In the methods of the disclosure the AXLi may be administered to the subject QD (quaque die; every day). That is, the AXLi may be administered to the subject daily (on each day of the dosage regimen). In some preferred embodiments, the AXLi may be administered to the subject once daily.
Loading dose
As used herein, the term "loading dose" refers to an initial higher dose of AXLi given at the beginning of a course of treatment. That is, a “loading dose" is a dose that is initially administered to a subject during a course of treatment, and may also be referred to, for example, as an “initial dose”, “starting dose”, “first dose”, or “first dose level”. The loading dose is administered over a loading period, to allow the AXLi to reach a desired steady-state concentration in the body at which the AXLi has a desired therapeutic effect.
In some embodiments, the loading dose of AXLi may be about 50 to 150 mg, about 60 to 140 mg, about 70 to 130 mg, about 75 to 125 mg, about 80 to 120 mg, about 85 to 115 mg, about 90 to 110 mg, about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg. In some embodiments, the loading dose of AXLi may be about about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg. In some preferred embodiments, the loading dose of AXLi may be about 100 mg.
In some embodiments, the loading dose of AXLi may be about 50 to 250 mg, about 100 to 200 mg, about 110 to 190 mg, about 120 to 180 mg, about 125 to 175 mg, about 130 to 170 mg, about 135 to 165 mg, about 140 to 160 mg, about 145 to 155 mg, about 146 to 154 mg, about 147 to 153 mg, about 148 to 152 mg, or about 149 to 151 mg. In some preferred embodiments, the loading dose of AXLi may be about about 145 to 155 mg, about 146 to 154 mg, about 147 to 153 mg, about 148 to 152 mg, or about 149 to 151 mg. In some particularly preferred embodiments, the loading dose of AXLi may be about 150 mg.
In some embodiments, the loading dose of AXLi may be about 100 to 300 mg, about 150 to 250 mg, about 160 to 240 mg, about 170 to 230 mg, about 175 to 225 mg, about 180 to 220 mg, about 185 to 215 mg, about 190 to 210 mg, about 195 to 205 mg, about 196 to 204 mg, about 197 to 203 mg, about 198 to 202 mg, or about 199 to 201 mg. In some preferred embodiments, the loading dose of AXLi may be about about 195 to 205 mg, about 196 to 204 mg, about 197 to 203 mg, about 198 to 202 mg, or about 199 to 201 mg. In some particularly preferred embodiments, the loading dose of AXLi may be about 200 mg.
The loading period is the period over which the loading dose is administered to the subject, for example, a period of 1 , 2, 3, 4, 5, 6, or 7 days at the beginning of a course of treatment. In the methods of the disclosure the loading period may preferably be 1 , 2, or 3 days, such as days 1 , 2, and 3 of the dosage regimen. In some most preferred embodiments the loading period may be 2 days, such as days 1 and 2 of the dosage regimen.
That is, in the methods of the disclosure the loading dose may be administered on days 1 , 2, 3, and / or 4 of the dosage regimen, such as on days 1 , 2, 3, and 4 of the dosage regimen. In some preferred embodiments, the loading dose may be administered on days 1 , 2, and I or 3, of the dosage regimen, such as on days 1 , 2, and 3 of the dosage regimen, or on day 1 of the dosage regimen. In particularly preferred embodiments, the loading dose may be administered on days 1 and 2 of the dosage regimen.
In some embodiments, the loading dose may be about 100 mg administered on days 1 , 2, and I or 3, of the dosage regimen, such as on days 1 , 2, and 3 of the dosage regimen, or on day 1 of the dosage regimen. In some embodiments, the loading dose may be about 100 mg administered on days 1 and 2 of the dosage regimen.
In some preferred embodiments, the loading dose is about 150 mg administered on days 1 , 2, and I or 3, of the dosage regimen, such as on days 1 , 2, and 3 of the dosage regimen, or on day 1 of the dosage regimen. In some preferred embodiments, the loading dose is about 150 mg administered on days 1 and 2 of the dosage regimen.
In some most preferred embodiments, the loading dose is about 200 mg administered on days 1 , 2, and I or 3, of the dosage regimen, such as on days 1 , 2, and 3 of the dosage regimen, or on day 1 of the dosage regimen. In some most preferred embodiments, the loading dose is about 200 mg administered on days 1 and 2 of the dosage regimen. Maintenance dose
As used herein, the term "maintenance dose" refers to a dose of AXLi given to a subject following the loading period. The maintenance dose is typically a reduced dose as compared to the loading dose, and may also be referred to, for example, as a “subsequent dose”, “reduced dose”, “second dose”, or “second dose level”. The maintenance dose is administered over a maintenance period, to maintain a desired steady-state concentration of AXLi in the body.
In some embodiments, the maintenance dose of AXLi may be about 30 to 120 mg, about 35 to 115 mg, about 45 to 105 mg, about 50 to 100 mg, about 55 to 95 mg, about 60 to 90 mg, about 65 to 85 mg, about 70 to 80 mg, about 71 to 79 mg, about 72 to 78 mg, about 73 to 77 mg, or about 74 to 76 mg. In some preferred embodiments, the maintenance dose of AXLi may be about about 70 to 80 mg, about 71 to 79 mg, about 72 to 78 mg, about 73 to 77 mg, or about 74 to 76 mg. In some particularly preferred embodiments, the maintenance dose of AXLi may be about 75 mg. In some such preferred embodiments, the loading dose of AXLi may be about 150 mg and the maintenance dose of AXLi may be about 75 mg.
In some embodiments, the maintenance dose of AXLi may be about 50 to 150 mg, about 60 to 140 mg, about 70 to 130 mg, about 75 to 125 mg, about 80 to 120 mg, about 85 to 115 mg, about 90 to 110 mg, about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg. In some preferred embodiments, the maintenance dose of AXLi may be about about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg. In some particularly preferred embodiments, the maintenance dose of AXLi may be about 100 mg. In some such preferred embodiments, the loading dose of AXLi may be about 200 mg and the maintenance dose of AXLi may be about 75 mg.
In some embodiments in which the AXL-related disease is cancer, it is most preferred that the loading dose of AXLi may be about 200 mg administered on days 1 and 2 of the dosage regimen, and the maintenance dose of AXLi may be about 100 mg administered on day 3 and each subsequent day of the dosage regimen.
In some embodiments, the maintenance dose may be about 45-55%, such as about 46-54%, about 47-53%, about 48-52%, or about 49-51% of the loading dose. In some such embodiments, the maintenance dose may be about 50% of the loading dose.
In some preferred embodiments, the maintenance dose may be about 50% of the loading dose. That is, the loading dose may be reduced by about 50% to determine the maintenance dose. By way of example, the loading dose may be about 200 mg and the maintenance dose may be about 50% of the loading dose (100 mg), or the loading dose may be about 150 mg and the maintenance dose may be about 50% of the loading dose (75 mg).
In some embodiments, the maintenance dose may be about 95-100%, such as about 96- 100%, about 97-100%, about 98-100%, or about 99-100% of the loading dose. In some such embodiments, the maintenance dose may be about 100% of the loading dose. In some preferred embodiments, the maintenance dose may be about 100% of the loading dose. That is, in some embodiments the maintenance dose may the same as the loading dose. By way of example, the loading dose may be about 200 mg and the maintenance dose may be about 100% of the loading dose (200 mg), or the loading dose may be about 150 mg and the maintenance dose may be about 100% of the loading dose (150 mg). Similalry, the loading dose may be about 100 mg and the maintenance dose may be about 100% of the loading dose (100 mg).
Regimens in which the maintenance dose is the same as the loading dose may also be referred to as regimens in which a constant dose level is administered to the subject, as described more fully elsewhere herein. Such regimens may be preferred in methods of the disclosure in which the AXLi is administered in combination with one or more further treatment and I or therapeutic agent, as described more fully elsewhere herein.
The maintenance period is the period over which the maintenance dose is administered to the subject following the loading period described above, for example, a period of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days following the loading period. That is, for a dosage regimen of a given duration, the maintenance period is the duration of the dosage regimen as described elsewhere herein, minus the loading period as described elsewhere herein. The maintenance period may be the day following the last day of the loading period (for example day 3 where a loading dose is administered on days 1 and 2) and each subsequent day of the dosage regimen, which may be until treatment with the AXLi is stopped, for example when a treatment endpoint as described more fully elsewhere herein is reached for the subject.
By way of non-limiting example, the maintenance period may be 11 , 12, or 13 days, such as days 2-14, days 3-14, or days 4-14 of a 14 day dosage regimen. In a 14 day dosage regimen in which the loading period is 2 days, the maintenance period may be 12 days, such as days 3-14 of the dosage regimen. By way of non-limiting example, the maintenance period may be 18, 19, or 20 days, such as days 2-21 , days 3-21 , or days 4-21 of a 21 day dosage regimen. In a 21 day dosage regimen in which the loading period is 2 days, the maintenance period may be 19 days, such as days 3-21 of the dosage regimen.
That is, in the methods of the disclosure the maintenance dose may be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, and I or 31 of the dosage regimen. The maintenance dose may be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, and I or each subsequent day of the dosage regimen. This is illustrated in the following non-limiting examples. For example, in some embodiments for which the duration of the dosage regimen is 7 days, the maintenance dose may be administered on days 2, 3, 4, 5, 6, and / or 7 of the dosage regimen. In a 7 day dosage regimen in which the loading period is 2 days, the maintenance dose may be administered on days 3, 4, 5, 6, and / or 7 of the dosage regimen, such as days 3, 4, 5, 6, and 7 of the dosage regimen. For example, in some embodiments for which the duration of the dosage regimen is 14 days, the maintenance dose may be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and I or 14 of the dosage regimen. In a 14 day dosage regimen in which the loading period is 2 days, the maintenance dose may be administered on days 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and I or 14 of the dosage regimen, such as on days 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and 14 of the dosage regimen. For example, in some embodiments for which the duration of the dosage regimen is 21 days, the maintenance dose may be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and I or 21 of the dosage regimen. In a 21 day dosage regimen in which the loading period is 2 days, the maintenance dose may be administered on days 3, 4, 5, 6,
7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and I or 21 of the dosage regimen, such as on days 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 of the dosage regimen.
Stated alternatively, in the methods of the disclosure, the maintenance dose may be administered beginning on day 2, 3, or 4 of the dosage regimen. In some preferred embodiments, the maintenance dose may be administered beginning on day 3 of the dosage regimen.
The maintenance dose may be administered on day 2, 3, or 4 and on each subsequent day of the dosage regimen. Preferably, the maintenance dose may be administered on day 3 and on each subsequent day of the dosage regimen such as on day 3 of the dosage regimen, and on each subsequent day until treatment with the AXLi is stopped.
By way of non-limiting example, in embodiments for which the duration of the dosage regimen is 7 days, the maintenance dose may be administered on days 3, 4, 5, 6, and 7 of the dosage regimen. For example, in embodiments for which the duration of the dosage regimen is 14 days, the maintenance dose may be administered on days 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and 14 of the dosage regimen. For example, in embodiments for which the duration of the dosage regimen is 21 days, the maintenance dose may be administered on days 3, 4, 5, 6, 7,
8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 of the dosage regimen.
In some preferred embodiments, the maintenance dose is about 75 mg administered on day 3 of the dosage regimen and on each subsequent day until treatment with the AXLi is stopped. In some such embodiments, the loading dose is preferably about 150 mg administered on days 1 and 2 of the dosage regimen.
In some other preferred embodiments, the maintenance dose is about 100 mg administered on day 3 of the dosage regimen and on each subsequent day until treatment with the AXLi is stopped. In some such embodiments, the loading dose is preferably about 200 mg administered on days 1 and 2 of the dosage regimen.
In some preferred embodiments, the method comprises administering the loading dose of the AXLi on days 1 and 2 of the dosage regimen, and thereafter administering the maintenance dose of the AXLi. In some preferred embodiments, the method comprises administering the loading dose of the AXLi on days 1 and 2 of the dosage regimen, and administereing the maintenance dose on day 3 and on each subsequent day of the dosage regimen. Constant dose
Embodiments of the methods of the disclosure include those in which an AXLi is administered to the subject in a dosage regimen in which a constant AXLi dose level is administered to the subject. A regimen comprising a “constant dose level” is one in which the same dose is administered to the subject throughout the dosing regimen (that is, one where in effect the “loading dose” and “maintenance dose” are the same). Such regimens may be preferred in methods of the disclosure in which the AXLi is administered in combination with one or more further treatment and I or therapeutic agent, as described more fully elsewhere herein.
In some embodiments, the constant dose level of AXLi may be about 30 to 120 mg, about 35 to 115 mg, about 45 to 105 mg, about 50 to 100 mg, about 55 to 95 mg, about 60 to 90 mg, about 65 to 85 mg, about 70 to 80 mg, about 71 to 79 mg, about 72 to 78 mg, about 73 to 77 mg, or about 74 to 76 mg. In some preferred embodiments, the constant dose level of AXLi may be about about 70 to 80 mg, about 71 to 79 mg, about 72 to 78 mg, about 73 to 77 mg, or about 74 to 76 mg. In some particularly preferred embodiments, the constant dose level of AXLi may be about 75 mg.
In some embodiments, the constant dose level of AXLi may be about 50 to 150 mg, about 60 to 140 mg, about 70 to 130 mg, about 75 to 125 mg, about 80 to 120 mg, about 85 to 115 mg, about 90 to 110 mg, about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg. In some preferred embodiments, the constant dose level of AXLi may be about about 95 to 105 mg, about 96 to 104 mg, about 97 to 103 mg, about 98 to 102 mg, or about 99 to 101 mg. In some particularly preferred embodiments, the constant dose level of AXLi may be about 100 mg. In a most preferred regimen comprising a “constant dose level” the constant dose level of AXLi is about 100 mg.
In some embodiments, the constant dose level of AXLi may be about 75 to 175 mg, about 90 to 155 mg, about 95 to 155 mg, about 100 to 150 mg, about 105 to 145 mg, about 110 to 140 mg, about 115 to 135 mg, 120 to 130 mg, about 121 to 129 mg, about 122 to 128 mg, about 123 to 127 mg, or about 124 to 126 mg. In some preferred embodiments, the constant dose level of AXLi may be about about 120 to 130 mg, about 121 to 129 mg, about 122 to 128 mg, about 123 to 127 mg, or about 124 to 126 mg. In some particularly preferred embodiments, the constant dose level of AXLi may be about 125 mg.
In some embodiments, the constant dose level of AXLi may be about 50 to 250 mg, about 100 to 200 mg, about 110 to 190 mg, about 120 to 180 mg, about 125 to 175 mg, about 130 to 170 mg, about 135 to 165 mg, about 140 to 160 mg, about 145 to 155 mg, about 146 to 154 mg, about 147 to 153 mg, about 148 to 152 mg, or about 149 to 151 mg. In some preferred embodiments, the constant dose level of AXLi may be about about 145 to 155 mg, about 146 to 154 mg, about 147 to 153 mg, about 148 to 152 mg, or about 149 to 151 mg. In some particularly preferred embodiments, the constant dose level of AXLi may be about 150 mg.
The constant dose of AXLi may be administered to the subject daily for the duration of the dosage regimen, such as on day 1 and on each subsequent day of the dosage regimen, which may be until treatment with the AXLi is stopped, for example when a treatment endpoint as described more fully elsewhere herein is reached for the subject. By way of non-limiting example, in the methods of the disclosure the constant dose may be administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, and I or 31 of the dosage regimen. For example, in some embodiments for which the duration of the dosage regimen is 7 days, the constant dose may be administered on days 1 , 2, 3, 4, 5, 6, and / or 7 of the dosage regimen, preferably days 1 ,
2, 3, 4, 5, 6, and 7 of the dosage regimen. For example, in some embodiments for which the duration of the dosage regimen is 14 days, the constant dose may be administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and / or 14 of the dosage regimen, preferably days 1 , 2,
3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and 14 of the dosage regimen. For example, in some embodiments for which the duration of the dosage regimen is 21 days, the constant dose may be administered on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and I or 21 of the dosage regimen, preferably on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 of the dosage regimen.
In some preferred embodiments, the constant dose is about 150 mg administered on day 1 of the dosage regimen and on each subsequent day until treatment with the AXLi is stopped.
Regimen duration
In some embodiments, the duration of the dosage regimen may be about 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days, or more. In some embodiments, the duration of the dosage regimen may be about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52 weeks, or more. In some embodiments, the duration of the dosage regimen may be about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 months, or more.
In some embodiments, the duration of the dosage regimen may be about 24, 48, 72 or 96 weeks.
It is anticipated that treatment with the AXLi will continue until a clinically relevant endpoint for completion or discontinuation of treatment is reached. Thus, the duration of the dosage regimen may be any length of time until treatment with the AXLi is stopped (which may also be referred to as “withdrawn”, or “discontinued”), for example when a treatment endpoint is reached for the subject. Treatment endpoints for completion I discontinuation of AXLi treatment may be based on futility in terms of efficacy, or intolerability I toxicity in terms of safety. Treatment endpoints for completion I discontinuation of AXLi treatment may also be based on utility in terms of efficacy, such as partial or complete disease remission.
That is, the methods of the disclosure may comprise administering the maintenance dose of AXLi beginning, for example, on day 3 of the dosage regimen, and continuing to administer the maintenance dose to the subject daily until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject. Similarly, the methods of the disclosure may comprise administering the constant dose of AXLi beginning on day 1 of the dosage regimen, and continuing to administer the constant dose to the subject daily until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject. Treatment endpoints which may result in treatment with the AXLi being stopped (“withdrawn”, or “discontinued”) include, for example:
Partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status), as may be assessed, for example, by % bone marrow myeloblasts, normal maturation of cell lines, reduction in tumour burden, and I or absence of detectable tumours.
Slowing or absence of disease progression (attaining stable disease [SD] status), as may be assessed, for example, by changes in % bone marrow myeloblasts, slowing or absence of tumour enlargement, and I or slowing or absence of increase in tumour burden.
Any positive patient outcome selected from: prolonged survival, progression-free survival, hematologic improvement (as may be assessed, for example, by increased blood haemoglobin, platelet count, and I or neutrophil count), bone marrow response (as may be assessed, for example, by: bone marrow with < 5% myeloblasts; 30%, 40%, 50% or more reduction in bone marrow myeloblasts; absence of circulating myeloblasts and myeloblasts with Auer rods; absence of extramedullary disease), hematologic recovery (as may be assessed, for example, by: >11 g/dL haemoglobin, >100x109/L platelets, and I or >1x109/L neutrophils in peripheral blood), tumour shrinkage (for example, a reduction in tumour volume of 5, 10, 20, 30, 40% or more), reduction in tumour burden (for example, a reduction in tumour burden of 5, 10, 20, 30, 40% or more), slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, negative response for a genetic marker, improved quality of life (as may be assessed, for example, using a health-related quality of life questionnaire such as a Functional Assessment of Cancer Therapy (FACT) questionnaire) or other quality of life questionnaires, and any other positive patient outcome.
Disease progression (progressive disease [PD] status) prompting treatment withdrawal.
Toxicity and I or incidence of adverse events requiring treatment withdrawal, including death.
Suitable methods for determining the above clinical endpoints are well known to the person skilled in the art. Similarly, methods of determing tumour volume I burden are well known to the skilled person, for example, using: computed tomography (CT), or magnetic resonance imaging (MRI)imaging technologies; X-ray imaging, for example, mammography; ultrasound imaging; nuclear imaging, for example positron emission tomography (PET), PET/CT scans, bone scans, gallium scans, or metaiodobenzylguanidine (MIBG) scans; bioluminescence imaging (BLI); fluorescence imaging (FLI); BD ToF (infrared-based 3D Time-of-Flight camera) imaging.
Preferred treatment endpoints which may result in treatment with the AXLi being stopped (“withdrawn”, or “discontinued”) include:
Complete disease remission (attaining complete remission I complete response [CR] status). In some embodiments, AXLi treatment may be continued for a period after first determination if this is deemed to be due to AXLi effect and there are no tolerability concerns. Thus, a treatment endpoint which may result in treatment with the AXLi being stopped is 1 , 2, 3, 4, 5, 6 or more months of CR status.
Disease progression (progressive disease [PD] status).
Incidence of toxicity and I or adverse events requiring treatment withdrawal (as may be determined, for example, by NCI-CTCAE Version 5.0 (v5.0, published November 27, 2017).
As used herein, references to treatment being “stopped” mean that treatment with the therapeutic agent, such as AXLi, is ceased. Alternative terms such as “withdrawn”, “discontinued”, etc. may be used interchangeably with “stopped”. Similarly, references to “treatment withdrawal” mean treatment of the subject with the therapeutic agent, such as AXLi, is ceased. Alternative terms such as “treatment discontinuation”, “treatment to be stopped”, etc. may be used interchangeably.
The AXLi may be administered to the subject QD (quaque die; every day).
In some embodiments, the AXLi may be administered to the subject daily. That is, the AXLi may be administered to the subject on each day of the dosage regimen, which may include days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14 , 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and beyond until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject. By way of non-limiting example, if the duration of the dosage regimen is about 7 days, the AXLi may be administered to the subject on days 1 , 2, 3, 4, 5, 6, and 7 of the dosage regimen. Similarly, if the duration of the dosage regimen is about 14 days, the AXLi may be administered to the subject on days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, and 14 of the dosage regimen.
The AXLi may be administered to the subject once daily. That is, the AXLi may be administered to the subject once on each day of the dosage regimen, which may be once on each of days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, 14 , 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and beyond until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject. By way of non-limiting example, if the duration of the dosage regimen is about 7 days, the AXLi may be administered to the subject once on each of days 1 , 2, 3, 4, 5, 6, and 7 of the dosage regimen. Similarly, if the duration of the dosage regimen is about 14 days, the AXLi may be administered to the subject once on each of days 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 ,13, and 14 of the dosage regimen.
In some embodiments, the dosage regimen may comprise multiple treatment cycles of the AXLi. As used herein a “treatment cycle” refers to a period of treatment that is repeated on a regular schedule. For example, a course of treatment given for one week, two weeks, or three weeks may be referred to as one treatment cycle. This cycle may be repeated to make up a course of treatment - i.e. a course of treatment comprising multiple treatment cycles. Thus, in some embodiments the dosage regimen may represent a course of treatment comprising multiple treatment cycles. In these embodiments in which the dosage regimen comprises cycles of treatment with the AXLi, the length of each treatment cycle may be about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks. For example, the length of each treatment cycle may be about 3 weeks.
In embodiments in which the dosage regimen represents a course of treatment comprising multiple treatment cycles, the first treatment cycle may comprise administering a loading dose and maintenance dose of the AXLi as described more fully elsewhere herein - for example the first treatment cycle may comprise administering a loading dose of about 200 mg on days
1 and 2 of the cycle, and administering a maintenance dose of about 100 mg on day 3 and each subsequent day of the cycle (for example on days 3-21 of a 3 week treatment cycle). In these embodiments, the second and subsequent treatment cycle may comprise administering a maintenance dose of the AXLi as described more fully elsewhere herein - for example the second and subsequent treatment cycles may comprise administering a maintenance dose of about 100 mg on day 1 and each subsequent day of the second and subsequent treatment cycles (for example on days 1-21 of subsequent 3-week treatment cycles).
In other embodiments in which the dosage regimen represents a course of treatment comprising multiple treatment cycles, the first and subsequent treatment cycles may comprise administering a constant dose of the AXLi as described more fully elsewhere herein - for example the first and subsequent treatment cycles may comprise administering a constant dose of about 150 mg on each day of each cycle (for example on days 1-21 of 3-week treatment cycles).
Some embodiments
In some embodiments, the AXL-related disease is cancer. In some other embodiments, the AXL-related disease is a fibrotic disorder. Some specifically contemplated embodiments of the methods of the disclosure include:
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 200 mg administered on days 1 and
2 of the dosage regimen; and, the maintenance dose is about 100 mg administered on day 3 and each subsequent day of the dosage regimen.
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 200 mg administered on day 1 of the dosage regimen; and, the maintenance dose is about 100 mg on day 2 and each subsequent day of the dosage regimen.
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 200 mg administered on days 1 , 2, and 3 of the dosage regimen; and, the maintenance dose is about 100 mg administered on day 4 and each subsequent day of the dosage regimen. A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 150 mg administered on days 1 and 2 of the dosage regimen; and, the maintenance dose is about 75 mg administered on day 3 and each subsequent day of the dosage regimen.
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 150 mg administered on day 1 of the dosage regimen; and, the maintenance dose is about 75 mg on day 2 and each subsequent day of the dosage regimen.
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising a loading dose and a maintenance dose; wherein the loading dose is about 150 mg administered on days 1 , 2, and 3 of the dosage regimen; and, the maintenance dose is about 75 mg administered on day 4 and each subsequent day of the dosage regimen.
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising administering a constant dose of about 75 mg of AXLi on day 1 and each subsequent day of the dosage regimen.
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising administering a constant dose of about 100 mg of AXLi on day 1 and each subsequent day of the dosage regimen.
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising administering a constant dose of about 125 mg of AXLi on day 1 and each subsequent day of the dosage regimen.
A method for treating cancer in a subject, the method comprising administering an AXLi, such as bemcentinib, to the subject once daily in a dosing regimen comprising administering a constant dose of about 150 mg of AXLi on day 1 and each subsequent day of the dosage regimen.
In these embodiments, the AXLi, which may be bemcentinib, is preferably administered to the subject under fed conditions, as described more fully elsewhere herein.
Therapeutic agents that increase gastric pH or decrease gastric acid production
The present authors have discovered that concomitant administration of AXLi with a therapeutic agent that alters gastric pH or alters gastric acid production (as described in more detail below) can influence absorption and subsequent subject exposure to the AXLi. Without being bound by theory, it is believed that use of therapeutic agents that alter gastric pH, such as proton pump inhibitors, result in increased pH in the stomach and therefore a reduction in the solubility of bemcentinib and its subsequent absorption.
Accordingly, in the methods of the disclosure the level of the loading and I or maintenance dose of AXLi may differ dependent on whether the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production. Similarly, in the methods of the disclosure the level of the constant dose of AXLi may differ dependent on whether the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production. In these embodiments, the loading, maintenance dose, and I or constant dose of AXLi may be increased by about 100% if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production, such as a therapeutic agent that increases gastric pH or decreases gastric acid production. The skilled person is readily able to determine the increased dose levels based on the loading, maintenance, and constant doses described elsewhere herein. By way of example:
In some embodiments, the loading and I or maintenance dose of AXLi may be increased by about 100% of the loading or maintenance doses detailed elsewhere herein if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production, such as a therapeutic agent that increases gastric pH or decreases gastric acid production. For example, a loading dose of about 200 mg may be increased to about 400 mg if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production. For example, a maintenance dose of about 100 mg may be increased to about 200 mg if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production.
In some embodiments, the constant dose of AXLi may be increased by about 100% of the constant doses detailed elsewhere herein if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production, such as a therapeutic agent that increases gastric pH or decreases gastric acid production. For example, a constant dose of about 150 mg may be increased to about 300 mg if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production. For example, a constant dose of about 100 mg may be increased to about 200 mg if the subject has been or is being administered a therapeutic agent that alters gastric pH or alters gastric acid production.
In some embodiments, if the subject is administered a therapeutic agent that alters gastric pH or alters gastric acid production, such as a therapeutic agent that increases gastric pH or decreases gastric acid production, during the course of the dosage regimen then the loading and I or maintenance dose, or constant dose, may be increased to a level in accordance with the above embodiments - e.g. increased by about 100%. In these embodiments, the increased dose may be administered to the subject at the increased level for the remainder of the duration of the dosage regimen. By way of example, if the subject is administered a therapeutic agent that alters gastric pH or alters gastric acid production on day 4 of a dosage regimen in which the loading dose of AXLi is 200 mg and the maintenance dose of AXLi is 100 mg, then the maintenance dose may be increased to about 200 mg for day 4 and each subsequent day of the dosage regimen. By way of example, if the subject is administered a therapeutic agent that alters gastric pH or alters gastric acid production on day 4 of a dosage regimen in which the constant dose of AXLi is 150 mg, then the constant dose may be increased to about 300 mg for day 4 and each subsequent day of the dosage regimen.
The therapeutic agent that alters gastric pH or alters gastric acid production may be any therapeutic intervention that is administered to modulate gastric pH or gastric acid production. For example, the therapeutic agent that alters gastric pH or alters gastric acid production may be a drug for treatment of acid related disorders. Such drugs for acid related disorders are categorised in the World Health Organization’s (WHO) Anatomical Therapeutic Chemical Classification System under ATC code A02 and are categorised in the Medical Dictionary for Regulatory Activities (MedDRA) under code A02. A subcategory of these is drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD; ATC A02B). As such, the skilled person would be well aware of which agents can be considered agents that alter gastric pH or alter gastric acid production, and which agents can be considered drugs for acid related disorders.
The therapeutic agent that alters gastric pH or alters gastric acid production may be a therapeutic agent that increases gastric pH or decreases gastric acid production. The therapeutic agent that alters gastric pH or alters gastric acid production may be a gastroprotective agent, a gastric acid synthesis inhibitor, or an agent that neutralises gastric acid. Such agents include:
Proton pump inhibitors (PPI; ATC A02BC), which inhibit the stomach's H+/K+ ATPase proton pump thereby reducing gastric acid production. In some embodiments the PPI may be: omeprazole, lansoprazole, dexlansoprazole, dexrabeprazole, vonoprazan, tegoprazan, esomeprazole, pantoprazole, rabeprazole, and I or ilaprazole.
H2 receptor antagonists (H2RA; ATC A02BA), which block the action of histamine at H2 receptors of parietal cells in the stomach thereby reducing gastric acid production. In some embodiments the H2 antagonist may be cimetidine, ranitidine, famotidine, nizatidine, roxatidine, ranitidine bismuth citrate, lafutidine, lavoltidine, and I or niperotidine.
Antacids (ATC A02A), which contain alkaline ions that chemically neutralise gastric acid. In some embodiments, the antacid may be an aluminium salt, a calcium salt, a magnesium salt, and / or a sodium salt. In some embodiments, the antacid may be aluminium hydroxide, algeldrate, aluminium phosphate, dihydroxialumini sodium carbonate, aluminium acetoacetate, aloglutamol, aluminium glycinate, calcium carbonate, calcium silicate, magnesium carbonate, magnesium oxide, magnesium peroxide, magnesium silicate, magnesium trisilicate, magnesium hydroxide, sodium bicarbonate, magaldrate, almagate, hydrotalcite, almasilate, and I or bismuth subsalicylate.
Prostaglandins (ATC A02BB) such as misoprostol and I or enprostil.
Other drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD; ATC A02BX) such as carbenoxolone, sucralfate, pirenzepine, methiosulfonium chloride, bismuth subcitrate, proglumide, gefarnate, sulglicotide, acetoxoIone, zolimidine, troxipide, bismuth subnitrate, alginic acid, and I or rebamipide.
The therapeutic agent that alters gastric pH or alters gastric acid production may be a therapeutic agent that increases gastric pH above pH 2,0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. In some embodiments, the therapeutic agent may increase gastric pH above pH 3.5, such as above pH 3.6, 3.7, 3.8, 3.9, or 4.0. The therapeutic agent that alters gastric pH or alters gastric acid production may be a therapeutic agent that increases gastric pH out of the range of pH 1.5 to 4.0, such as out of the range of pH 1.5 to pH 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. In some embodiments, the therapeutic agent may increase gastric pH out of the range of pH 2.0 to 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. In some embodiments, the therapeutic agent may increase gastric pH out of the range of pH 3.0 to 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. As outlined elsewhere herein, these effecs on gastric pH may be via reduction of gastric acid secretion and I or neutraliseation of gastric acid.
Fed state dosing
The consumption of food can result in a number of physiological changes influencing the pharmacokinetics of drug compounds, including, for example, changes in gastric and intestinal pH, delayed gastric emptying, increased bile secretion, and increased splanchnic and hepatic blood flow. The present authors have unexpectedly discovered that administration of AXLi to subjects under fed conditions is associated with both increased exposure to the AXLi, and reduced variability in exposure between subjects. Without being bound by theory, it is speculated that the reduced PK variability and increased exposure with food could be a result of the inhibition of efflux transporters within the Gl tract, or increased amount of transport through the lymphatic system due to the increased lipid content within the Gl tract due to the addition of food. The surprising decrease in variability observed with fed state doses allows the dose of AXLi to be reduced, which will in turn reduce the incidence of adverse effects associated with AXLi administration.
Accordingly, the methods of the disclosure may comprise administering the AXLi to the subject under fed conditions. That is, the AXLi may be administered to the subject pc (post cibum; after meals).
In preferred embodiments of the methods of the disclosure, the AXLi is administered to the subject under fed conditions.
As used herein, drug administration under “fed conditions” means drug administration such that administration and I or absorption of the drug occurs while the subject is the prandial absorptive phase - that is, in the period following ingestion of food when the body is digesting the food and absorbing nutrients (and in which catabolism exceeds anabolism). Drug administration under “fed conditions” also encompasses scenarios in which subjects receive nutrition in liquid form (for example, an enteral nutrition feed, composition comprising blended foodstuffs, or other processed food replacement) which may be via enteral or parenteral administration routes. In such cases, drug administration (such as AXLi administration) may still be administered orally, or via installation through a feeding tube. Thus, drug administration under “fed conditions” means drug administration concomitant with food consumption I ingestion, which may be food consumption I ingestion before, at the same time, and I or after drug administration. In some embodiments, drug administration may occur before or during a bolus or infusion feed period (for example to allow for gastro-intestinal and digestive and metabolic “rest” from feeding). Administration under “fed conditions” may also be referred to as e.g. administration in a “fed state”, administration “with food”, etc. By way of comparison, drug administration under “fasted conditions” or in a “fasted state” means administration in a period in which no food is consumed by the subject - as is described more fully below.
In some embodiments, administering the AXLi under fed conditions may comprise administering the AXLi to the subject before, at the same time, and I or after food consumption I ingestion.
In some embedments, administering the AXLi under fed conditions may comprise administering the AXLi to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes of the subject consuming I ingesting food. Preferably, the AXLi is administered to the subject within about 240 minutes of the subject consuming I ingesting food. In this context, within about 240 minutes of consuming I ingesting food means within the window of time of 240 minutes before or after consuming I ingesting food.
In some embodiments, administering the AXLi under fed conditions may comprise administering the AXLi to the subject less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed I ingested food. Preferably, the AXLi is administered to the subject less than about 240 minutes after the subject has consumed I ingested food.
In some embodiments, administering the AXLi under fed conditions may comprise administering the AXLi to the subject not more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes before the subject has consumed I ingested, or will consume I ingest, food. Preferably, the AXLi is administered to the subject not more than about 240 minutes before the subject has consumed I ingested, or will consume I ingest, food.
In some embodiments, administering the AXLi under fed conditions may comprise administering the AXLi to the subject at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed I ingested food.
In some embodiments, administering the AXLi under fed conditions comprises administering the AXLi to the subject within about 0-240 minutes, such as about 30-240 minutes, 60-240 minutes, 90-240 minutes, 120-240 minutes, 150-240 minutes, 180-240 minutes, or 210-240 minutes of the subject consuming I ingesting food, or such as about 0-210 minutes, 0-180, 0- 150, 0-120, 0-90, 0-60, or 0-30 minutes of the subject consuming I ingesting food. In some embodiments, administering the AXLi under fed conditions comprises administering the AXLi to the subject within about 5-60 minutes, such as about 10-50 minutes, or about 20-40 minutes of the subject consuming I ingesting food. In this context, within about 0-240 minutes of consuming I ingesting food means within the window of time of 0-240 minutes before or after consuming / ingesting food. Preferably, administering the AXLi under fed conditions may comprise administering the AXLi to the subject within 240 minutes of the subject consuming I ingesting food. That is, administering the AXLi to the subject not more than about 240 minutes before the subject has consumed I ingested, or will consume I ingest, food and less than about 240 minutes after the subject has consumed I ingested food.
In some embodiments, the food may comprise or may be a meal, such as a high-fat and I or high-protein meal. In some embodiments, the food may comprise, or may be, oral nutritional supplements (ONS). In some embodiments, the food may comprise, or may be an enteral nutrition feed, such as a high-fat and I or high-protein meal formulated for enteral administration. In some embodiments, the food may comprise, or may be a parenteral nutrition feed, such as a high-fat and I or high-protein meal formulated for parenteral administration.
The food may be consumed I ingested by the oral route. In some embodiments, the food may be consumed I ingested by the enteral route, which may be via the nasogastric (NG), percutaneous endoscopic gastrostomy (PEG), or nasojejunal (NJ) route. In some embodiments, the food may be consumed I ingested by the parenteral route.
The person skilled in the art is aware as part of their common general knowledge of suitable high-fat and I or high protein meals that can be used in the methods of the disclosure - for example a standardised high-fat meal as defined by the European Medicines Agency for use in investigation of drug interactions (see, e.g., the EMA “Guideline on the investigation of drug interactions” at htps://www.erna.europa.eu/en/documents/scientific-quideline/guideline- investigation-drug-interactions-revision-1 en.pdf), or a meal with comparable total caloric content and in which similar amounts of calories come from protein, carbohydrate, and fat. Similarly, the person skilled in the art is aware as part of their common general knowledge of suitable oral nutritional supplements (ONS), and enteral and parenteral nutrition feeds that can be used in the methods of the disclosure.
In some embodiments, a high-fat meal is one which contains about 800-1000 kcal with about 500-600 kcal from fat and 250 kcal from carbohydrates. An example high-fat meal is two eggs fried in butter, two strips of bacon, two slices of toast with butter, 120 ml of hash brown potatoes and 240 ml of whole milk. Substitutions in this example meal can be made provided the meal provides similar amounts of calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity.
That is, in some embodiments a high-fat meal is one which contains between about 700-1100 kcal, between about 750-1050 kcal, or between about 800-1000 kcal, wherein about 45, 50, 55, 60, 65, or 70% of the caloric content comes from fats. In some such embodiments, about 10, 15, 20, 25, 30, or 35 % of the caloric content may come from carbohydrates.
Thus, in some embodiments a high-fat meal is one which more than about 25%, such as more than about 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, or 70% of the total caloric content of the meal comes from fats, either saturated or unsaturated. In some embodiments, a high-fat meal is one in which more than about 35% of the total caloric content of the meal comes from fats, either saturated or unsaturated. In some embodiments, a high- fat meal is one in which more than about 45% of the total caloric content of the meal comes from fats, either saturated or unsaturated. In some preferred embodiments, a high-fat meal is one in which more than about 50% of the total caloric content of the meal comes from fats, either saturated or unsaturated. In some embodiments, a high-fat meal is one in which about 25-65%, such as about 35-65%, 45-65%, 50-65%, or 55-65% of the total caloric content of the meal comes from fats, either saturated or unsaturated.
In some embodiments, a high-protein meal is one in which more than about 15%, such as more than about 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35% of the total caloric content of the meal comes from protein. In some embodiments, a high-protein meal is one which more than about 20% of the total caloric content of the meal comes from protein.
Fasted state dosing
In contrast to the “fed state” I “fed conditions” described above, drug administration under “fasted conditions”, “fasting conditions”, in a “fasted state”, or “fasting conditions” means administration in a period in which no food is consumed by the subject - for example, following an overnight fast and with no food consumed until at least 1 , 2, 3, or 4 hours after drug administration. Administration under “fasted conditions” may also be referred to as e.g. administration in “fasting conditions”, in a “fasted state”, in “fasting conditions”, administration “without food”, etc.
The methods of the disclosure may comprise administering the AXLi to the subject under fasted conditions.
In some embodiments, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject following an overnight fast. In some such embodiments, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject following an overnight fast, and at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject consumes I ingests any food. For example, the AXLi may be administered at least about 1 hour before the subject consumes I ingests any food. An “overnight” fast may be a period of about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours overnight during which the subject does not consume I ingest any food. Preferably an “overnight” fast may be a period of about 4 or more hours overnight during which the subject does not consume I ingest any food, “does not consume food” may mean that the subject does not consume I ingest anything other than water.
In some embodiments, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject on an empty stomach. In some such embodiments, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject on an empty stomach, and at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject consumes I ingests any food. For example, the AXLi may be administered at least about 1 hour before the subject consumes I ingests any food. An “empty stomach” may mean that the subject has not consumed I ingested food for a period of about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours prior to administration of the AXLi. Preferably an “empty stomach” may mean that the subject has not consumed I ingested food for a period of about 4 or more hours prior to administration of the AXLi. “has not consumed food” may mean that the subject has not consumed I ingested anything other than water.
In some embodiments, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject has consumed I ingested, or will consume I ingest, food. The AXLi may be administered to the subject at least about 120 minutes before the subject has consumed I ingested, or will consume I ingest, food. For example, the AXLi may be administered to the subject at least about 60 minutes before the subject has consumed I ingested, or will consume I ingest, food.
In some embodiments, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject at least about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours after the subject last consumed I ingested food. Preferably, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject at least about 4 or more hours after the subject last consumed I ingested food. For example, the AXLi may be administered to the subject at least about 8 hours after the subject last consumed I ingested food.
In some embodiments, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject has consumed I ingested, or will consume I ingest, food, and at least about 1 , 2, 3, or more preferably 4, 5, 6, 7, 8, 9, or 10 hours after the subject last consumed I ingested food. For example, the AXLi may be administered to the subject at least about 60 minutes before the subject has consumed I ingested, or will consume I ingest, food, and at least about 8 hours after the subject last consumed I ingested food. For example, the AXLi may be administered to the subject at least about 240 minutes before the subject has consumed I ingested, or will consume I ingest, food, and at least about 4 hours after the subject last consumed I ingested food.
In some embodiments, administering the AXLi under fasted conditions may comprise administering the AXLi to the subject on an empty stomach, preferably after an overnight fast, and at least about 1 hour before the subject consumes I ingests any food.
The AXLi may be administered with water.
Combination agents
In some embodiments, the AXLi described herein may be administered in combination with one or more further treatment and I or therapeutic agent, either simultaneously or sequentially in any order. Examples of treatments and therapeutic agents include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs, such as chemotherapeutic agents), immunotherapy (the administration of active agents, including, e.g. cell-based therapies or drugs, such as immune checkpoint modulators (ICM)), and I or radiotherapy.
Chemotherapeutic agents
A “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in “targeted therapy”, immuno-oncology drugs such as checkpoint inhibitors, and conventional chemotherapy. In the disclosed methods, the AXLi may be administered in combination with one or more chemotherapeutic agent.
Examples of chemotherapeutic agents which may be used in the disclosed methods include: Lenalidomide (REVLIMID®, Celgene), Vorinostat (ZOLINZA®, Merck), Panobinostat (FARYDAK®, Novartis), Mocetinostat (MGCD0103), Everolimus (ZORTRESS®, CERTICAN®, Novartis), Bendamustine (TREAKISYM®, RIBOMUSTIN®, LEVACT®, TREANDA®, Mundipharma International), erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi- Aventis), 5-Fll (fluorouracil, 5-fluorouracil, CAS No. 51-21- 8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cisdiamine, dichloroplatinum(ll), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide (4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9-carboxamide, CAS No. 85622-93-1 , TEMODAR®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1 ,2-diphenylbut-1-enyl)phenoxy]-N,N- dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD, and rapamycin.
More examples of chemotherapeutic agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH 66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11 , Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™ (Cremophor-free), albumin- engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, II), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271 ; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa and cyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g. calicheamicin, calicheamicin gammal l, calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33:183- 186); dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-Fll); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
Examples of chemotherapeutic agents used in the treatment of anal cancer include: Gardasil, Gardasil 9, Recombinant Human Papillomavirus (HPV) Nonavalent Vaccine, Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine. Examples of chemotherapeutic agents used in the treatment of bladder cancer include: Atezolizumab, Avelumab, Balversa (Erdafitinib), Bavencio (Avelumab), Cisplatin, Doxorubicin Hydrochloride, Durvalumab, Erdafitinib, Imfinzi (Durvalumab), Keytruda (Pembrolizumab), Nivolumab, Opdivo (Nivolumab), Pembrolizumab, Tecentriq (Atezolizumab), Thiotepa, Valrubicin, and Valstar (Valrubicin).
Examples of chemotherapeutic agents used in the treatment of bone cancer include: Cosmegen (Dactinomycin), Dactinomycin, Denosumab, Doxorubicin Hydrochloride, Methotrexate, Trexall (Methotrexate), and Xgeva (Denosumab).
Examples of chemotherapeutic agents used in the treatment of brain tumors include: Afinitor (Everolimus), Afinitor Disperz (Everolimus), Avastin (Bevacizumab), Bevacizumab, BiCNll (Carmustine), Carmustine, Carmustine Implant, Everolimus, Gliadel Wafer (Carmustine Implant), Lomustine, Mvasi (Bevacizumab), Temodar (Temozolomide), and Temozolomide.
Examples of chemotherapeutic agents used in the treatment of breast cancer include: Abemaciclib, Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Ado- Trastuzumab Emtansine, Afinitor (Everolimus), Afinitor Disperz (Everolimus), Alpelisib, Anastrozole, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane), Atezolizumab, Capecitabine, Cyclophosphamide, Docetaxel, Doxorubicin Hydrochloride, Ellence (Epirubicin Hydrochloride), Enhertu (Fam-Trastuzumab Deruxtecan- nxki), Epirubicin Hydrochloride, Eribulin Mesylate, Everolimus, Exemestane, 5-Fll (Fluorouracil Injection), Fam-Trastuzumab Deruxtecan-nxki, Fareston (Toremifene), Faslodex (Fulvestrant), Femara (Letrozole), Fluorouracil Injection, Fulvestrant, Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Goserelin Acetate, Halaven (Eribulin Mesylate), Herceptin Hylecta (Trastuzumab and Hyaluronidase-oysk), Herceptin (Trastuzumab), Ibrance (Palbociclib), Ixabepilone, Ixempra (Ixabepilone), Kadcyla (Ado- Trastuzumab Emtansine), Kisqali (Ribociclib), Lapatinib Ditosylate, Letrozole, Lynparza (Olaparib), Megestrol Acetate, Methotrexate, Neratinib Maleate, Nerlynx (Neratinib Maleate), Olaparib, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation, Palbociclib, Pamidronate Disodium, Perjeta (Pertuzumab), Pertuzumab, Piqray (Alpelisib), Ribociclib, Talazoparib Tosylate, Talzenna (Talazoparib Tosylate), Tamoxifen Citrate, Taxol (Paclitaxel), Taxotere (Docetaxel), Tecentriq (Atezolizumab), Thiotepa, Toremifene, Trastuzumab, Trastuzumab and Hyaluronidase-oysk, Trexall (Methotrexate), Tykerb (Lapatinib Ditosylate), Verzenio (Abemaciclib), Vinblastine Sulfate, Xeloda (Capecitabine), and Zoladex (Goserelin Acetate).
Examples of chemotherapeutic agents used in the treatment of cervical cancer include: Avastin (Bevacizumab), Bevacizumab, Bleomycin Sulfate, Hycamtin (Topotecan Hydrochloride), Keytruda (Pembrolizumab), Mvasi (Bevacizumab), Pembrolizumab, Topotecan Hydrochloride.
Examples of chemotherapeutic agents used in the treatment of colon and rectal cancer include: Avastin (Bevacizumab), Bevacizumab, Camptosar (Irinotecan Hydrochloride), Capecitabine, Cetuximab, Cyramza (Ramucirumab), Eloxatin (Oxaliplatin), Erbitux (Cetuximab), 5-Fll (Fluorouracil Injection), Fluorouracil Injection, Ipilimumab, Irinotecan Hydrochloride, Keytruda (Pembrolizumab), Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil Hydrochloride), Mvasi (Bevacizumab), Nivolumab, Opdivo (Nivolumab), Oxaliplatin, Panitumumab, Pembrolizumab, Ramucirumab, Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Vectibix (Panitumumab), Xeloda (Capecitabine), Yervoy (Ipilimumab), Zaltrap (Ziv-Aflibercept), Ziv-Aflibercept.
Examples of chemotherapeutic agents used in the treatment of ovarian, fallopian tube, or primary peritoneal cancer include: Alkeran (Melphalan), Avastin (Bevacizumab), Bevacizumab, Carboplatin, Cisplatin, Cyclophosphamide, Doxorubicin Hydrochloride, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride Liposome, Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Hycamtin (Topotecan Hydrochloride), Lynparza (Olaparib), Melphalan, Niraparib Tosylate Monohydrate, Olaparib, Paclitaxel, Rubraca (Rucaparib Camsylate), Rucaparib Camsylate, Taxol (Paclitaxel), Thiotepa, Topotecan Hydrochloride, Zejula (Niraparib Tosylate Monohydrate).
Examples of chemotherapeutic agents used in the treatment of non-small cell lung cancer include: Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Afatinib Dimaleate, Afinitor (Everolimus), Afinitor Disperz (Everolimus), Alecensa (Alectinib), Alectinib, Alimta (Pemetrexed Disodium), Alunbrig (Brigatinib), Amivantamab-vmjw, Atezolizumab, Avastin (Bevacizumab), Bevacizumab, Brigatinib, Cabozantinib, Carboplatin, Capmatinib, Cemiplimab-rwlc, Ceritinib, Crizotinib, Cyramza (Ramucirumab), Dabrafenib Mesylate, Dacomitinib, Docetaxel, Doxorubicin Hydrochloride, Durvalumab, Entrectinib, Erlotinib Hydrochloride, Everolimus, Gefitinib, Gilotrif (Afatinib Dimaleate), Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Imfinzi (Durvalumab), Iressa (Gefitinib), Keytruda (Pembrolizumab), Lorbrena (Lorlatinib), Lorlatinib, Mechlorethamine Hydrochloride, Mekinist (Trametinib), Methotrexate, Mobocertinib, Mustargen (Mechlorethamine Hydrochloride), Mvasi (Bevacizumab), Navelbine (Vinorelbine Tartrate), Necitumumab, Nivolumab, Opdivo (Nivolumab), Osimertinib Mesylate, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation, Paraplat (Carboplatin), Paraplatin (Carboplatin), Pembrolizumab, Pemetrexed Disodium, Pralsetinib, Portrazza (Necitumumab), Ramucirumab, Rozlytrek (Entrectinib), Selpercatinib, Tafinlar (Dabrafenib Mesylate), Tagrisso (Osimertinib Mesylate), Tarceva (Erlotinib Hydrochloride), Taxol (Paclitaxel), Taxotere (Docetaxel), Tecentriq (Atezolizumab), Trametinib, Trexall (Methotrexate), Vemurafenib, Vizimpro (Dacomitinib), Vinorelbine Tartrate, Xalkori (Crizotinib), Zykadia (Ceritinib). An example of preferred chemotherapeutic agents for use in treatment of non-small cell lung cancer is carboplatin in combination with pemetrexed. Another example of preferred chemotherapeutic agents for use in treatment of non-small cell lung cancer is carboplatin in combination with pemetrexed and pembrolizumab. Another example of preferred chemotherapeutic agents for use in treatment of non-small cell lung cancer is cisplatin in combination with pemetrexed. Another example of preferred chemotherapeutic agents for use in treatment of non-small cell lung cancer is cisplatin in combination with pemetrexed and pembrolizumab. In methods of the disclosure in which the AXLi is administered in combination with chemotherapeutic agents (such as in combination with pembrolizumab, or in combination with carboplatin, pemetrexed, and pembrolizumab) for treatment of non-small cell lung cancer, dosage regimens in which a constant dose level of AXLi is administered to the subject may be preferred. Examples of chemotherapeutic agents used in the treatment of small cell lung cancer include: Afinitor (Everolimus), Atezolizumab, Bendamustine, Carboplatin, Cisplatin, Cyclophosphamide, Docetaxel, Doxorubicin Hydrochloride, Durvalumab, Etopophos (Etoposide Phosphate), Etoposide, Etoposide Phosphate, Everolimus, Gemcitabine (Gemza), Hycamtin (Topotecan Hydrochloride), Irinotecan, Keytruda (Pembrolizumab), Lurbinectedin, Mechlorethamine Hydrochloride, Methotrexate, Mustargen (Mechlorethamine Hydrochloride), Nivolumab, Opdivo (Nivolumab), Paclitaxel, Pembrolizumab, Tecentriq (Atezolizumab), Topotecan Hydrochloride, Trexall (Methotrexate), Vinorelbine, Vincristine, Zepzelca (Lurbinectedin).
Examples of chemotherapeutic agents used in the treatment of melanoma include: Aldesleukin, Binimetinib, Braftovi (Encorafenib), Cobimetinib, Cotellic (Cobimetinib), Dabrafenib Mesylate, Dacarbazine, Encorafenib, IL-2 (Aldesleukin), Imlygic (Talimogene Laherparepvec), lnterleukin-2 (Aldesleukin), Intron A (Recombinant Interferon Alfa-2b), Ipilimumab, Keytruda (Pembrolizumab), Mekinist (Trametinib), Mektovi (Binimetinib), Nivolumab, Opdivo (Nivolumab), Peginterferon Alfa-2b, PEG-lntron (Peginterferon Alfa-2b), Pembrolizumab, Proleukin (Aldesleukin), Recombinant Interferon Alfa-2b, Sylatron (Peginterferon Alfa-2b), Tafinlar (Dabrafenib Mesylate), Talimogene Laherparepvec, Trametinib, Vemurafenib, Yervoy (Ipilimumab), Zelboraf (Vemurafenib).
Examples of chemotherapeutic agents used in the treatment of mesothelioma include: Alimta (Pemetrexed Disodium), Carboplatin, Cisplatin , Bevacizumab, Nivolumab, Ipilimumab, and Pemetrexed Disodium.
Examples of chemotherapeutic agents used in the treatment of AML include: ATRA, Arsenic Trioxide, Azacitidine, Cerubidine (Daunorubicin Hydrochloride), Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Daunorubicin Hydrochloride, Daunorubicin Hydrochloride and Cytarabine Liposome, Daurismo (Glasdegib Maleate), Decitabine, Dexamethasone, Doxorubicin Hydrochloride, Enasidenib Mesylate, Etoposide, Fludarabine, Gemtuzumab Ozogamicin, Gilteritinib Fumarate, Glasdegib Maleate, Idamycin PFS (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idhifa (Enasidenib Mesylate), Ivosidenib, Midostaurin, Mitoxantrone Hydrochloride, Mylotarg (Gemtuzumab Ozogamicin), Rubidomycin (Daunorubicin Hydrochloride), Rydapt (Midostaurin), Sorafenib, Tabloid (Thioguanine), Thioguanine, Tibsovo (Ivosidenib), Trisenox (Arsenic Trioxide), Venclexta (Venetoclax), Venetoclax, Vincristine Sulfate, Vyxeos (Daunorubicin Hydrochloride and Cytarabine Liposome), andXospata (Gilteritinib Fumarate).
Examples of chemotherapeutic agents used in the treatment of pancreatic cancer include: Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Afinitor (Everolimus), Capecitabine, Cisplatin, Entrectinib, Erlotinib Hydrochloride, Everolimus, 5-FU (Fluorouracil Injection), Fluorouracil Injection, Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Irinotecan Hydrochloride Liposome, Larotrectinib, Lynparza (Olaparib), Mitomycin C, Olaparib, Onivyde (Irinotecan Hydrochloride Liposome), Paclitaxel Albumin- stabilized Nanoparticle Formulation, Pembrolizumab, Rucaparib, Sunitinib Malate, Sutent (Sunitinib Malate), and Tarceva (Erlotinib Hydrochloride). Examples of chemotherapeutic agents used in the treatment of renal cancer include: Afinitor (Everolimus), Afinitor Disperz (Everolimus), Aldesleukin, Axitinib, Avastin (Bevacizumab), Avelumab, Axitinib, Bavencio (Avelumab), Bevacizumab, Cabometyx (Cabozantinib-S- Malate), Cabozantinib-S-Malate, Everolimus, IL-2 (Aldesleukin), Inlyta (Axitinib), lnterleukin-2 (Aldesleukin), Ipilimumab, Keytruda (Pembrolizumab), Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Mvasi (Bevacizumab), Nexavar (Sorafenib Tosylate), Nivolumab, Opdivo (Nivolumab), Pazopanib Hydrochloride, Pembrolizumab, Proleukin (Aldesleukin), Sorafenib Tosylate, Sunitinib Malate, Sutent (Sunitinib Malate), Temsirolimus, Tivozanib, Torisel (Temsirolimus), Votrient (Pazopanib Hydrochloride), and Yervoy (Ipilimumab).
Example of chemotherapeutic agents used to treat solid tumors anywhere in the body include: Entrectinib, Keytruda (Pembrolizumab), Larotrectinib Sulfate, Rozlytrek (Entrecti nib), and Vitrakvi (Larotrectinib Sulfate).
Combination treatments are also included in the definition of “chemotherapeutic agent” used herein. Examples of combination treatments of chemotherapeutic agents include: gemcitabine-cisplatin, MVAC (methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin), PCV (procarbazine hydrochloride, lomustine, vincristine sulfate), AC (doxorubicin hydrochloride, cyclophosphamide), AC-T (doxorubicin hydrochloride, cyclophosphamide, paclitaxel), CAF (cyclophosphamide, doxorubicin hydrochloride, fluorouracil), CMF (cyclophosphamide, methotrexate, fluorouracil), FEC (fluorouracil, epirubicin hydrochloride, cyclophosphamide), TAC (docetaxel, doxorubicin hydrochloride, cyclophosphamide), CAPOX (capecitabine, oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride), FOLFIRI-Bevacizumab, FOLFIRI-Cetuximab, FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin), FU-LV (fluorouracil, leucovorin calcium), XELIRI (capecitabine, irinotecan hydrochloride), XELOX (capecitabine, oxaliplatin), TPF (docetaxelm, cisplatin, fluorouracil), ABVD (doxorubicin hydrochloride, bleomycin, vinblastine sulfate, dacarbazine), ABVE (doxorubicin hydrochloride, bleomycin, vincristine sulfate, etoposide phosphate), ABVE-PC (doxorubicin hydrochloride, bleomycin, vincristine sulfate, etoposide phosphate, prednisone, cyclophosphamide), BEACOPP (bleomycin, etoposide phosphate, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone), COPDAC (cyclophosphamide, vincristine sulfate, prednisone, dacarbazine), COPP cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone), COPP-ABV cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone, doxorubicin hydrochloride, bleomycin, vinblastine sulfate), ICE (ifosfamide, carboplatin, etoposide phosphate), MOPP (mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, prednisone), OEPA (vincristine sulfate, etoposide phosphate, prednisone, doxorubicin hydrochloride), OPPA (vincristine sulfate, procarbazine hydrochloride, prednisone, doxorubicin hydrochloride), STANFORD V (mechlorethamine hydrochloride, doxorubicin hydrochloride, vinblastine sulfate, vincristine sulfate, bleomycin, etoposide phosphate, prednisone), VAMP (vincristine sulfate, doxorubicin hydrochloride, methotrexate, prednisone), hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone), ADE (cytarabine, daunorubicin hydrochloride, etoposide phosphate), chlorambucil-prednisone, CVP (cyclophosphamide, vincristine sulfate, prednisone), carboplatin-taxol, PAD (bortezomib, doxorubicin hydrochloride, dexamethasone), BuMel (busulfan, melphalan hydrochloride), CEM (carboplatin, etoposide phosphate, melphalan hydrochloride), CHP (doxorubicin, prednisone, cyclophosphamide), CHOP (doxorubicin, prednisone, cyclophopsphamide, vincristine), EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) ICE (ifosfamide, carboplatin, etoposide phosphate) R-CHOP (rituximab, doxorubicin, prednisone, cyclophopsphamide, vincristine), R-CVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone) R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride), R-ICE (rituximab, ifosfamide, carboplatin, etoposide phosphate), BEP (bleomycin, etoposide phosphate, cisplatin), JEB (carboplatin, etoposide phosphate, bleomycin), PEB (cisplatin, etoposide phosphate, bleomycin) VAC (vincristine sulfate, dactinomycin, cyclophosphamide), VelP (vinblastine sulfate, ifosfamide, cisplatin), Carboplatin/Doxil, Carboplatin/Gemcitabine, Carboplatin/Topotecan, Taxol/Avastin, FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, oxaliplatin), Gemcitabine-cisplatin, gemcitabine oxaliplatin, OFF (oxaliplatin, fluorouracil, leucovorin calcium), CEV (carboplatin, etoposide phosphate, vincristine sulfate), and VIP (etoposide, ifosfamide, cisplatin).
Also included in the definition of “chemotherapeutic agent” are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, such as oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rlL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (A VASTIN®, Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above.
Also included in the definition of “chemotherapeutic agent” are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), ofatumumab (ARZERRA®, GSK), pertuzumab (PERJETATM, OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), MDX- 060 (Medarex). Also included in the definition of “chemotherapeutic agent” are antibody drug conjugates, in particular AXL antibody drug conjugates. For example, gemtuzumab ozogamicin (MYLOTARG®, Wyeth), enapotamab vedotin (HuMax®-AXL-ADC, Genmab), CAB-AXL-ADC (BioAtla).
Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the conjugates of the disclosure include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
Also included in the definition of “chemotherapeutic agent” are therapeutic immunoconjugates, such as antibody-drug conjugates (ADCs). ADCs are a class of biopharmaceutical drugs designed as targeted therapies, and which comprise an antibody (or functional fragment thereof) linked to a payload or drug. The payload may be a cytotoxic drug, for example one or more of the anti-cancer chemotherapeutic agents described above. The antibody portion of the ADC specifically targets an antigen present on a target cell - for example a tumour antigen on tumour cells - delivering the payload to the target cell. The specific targeting of ADCs limits their side effects and gives a wider therapeutic window than other chemotherapeutic agents.
Accordingly, in some embodiments the chemotherapeutic agent may be an antibody-drug conjugate. The antibody-drug conjugate may comprise as its antibody portion one the antibodies disclosed elsewhere herein. The antibody-drug conjugate may comprise as its payload one or more of the anti-cancer chemotherapeutic agents disclosed elsewhere herein. The antibody-drug conjugate may comprise as its payload an anthracycline, such as doxorubicin, or a taxane, such as docetaxel. The antibody drug conjugate may be gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, or moxetumomab pasudotox.
Certain chemotherapeutic agents are known to influence pathways involved in the immune response. For example, the class of cytotoxic chemotherapeutic agents called anthracyclines are known to induce a Type I Interferon response mimicking immune responses to viruses, and the clinical response to antracycline therapy correlates with a Type I IFN gene signature (Sistigue et al 2014; Zitvogel et al, 2015). As AXL serves as a key checkpoint for interferon (IFN) signaling, stimulating IFN signaling in the context of AXL- inhibition could lead to enhanced anticancer T cell responses during immune checkpoint inhibition. Accordingly, in some embodiments the chemotherapeutic agent may be a chemotherapeutic agent which induces an immune response in the subject. In some embodiments the chemotherapeutic agent may be a chemotherapeutic agent which induces a type I interferon response in the subject.
In some preferred embodiments, the chemotherapeutic agent may be an anthracycline. In some such embodiments the chemotherapeutic agent may be selected from the group consisting of: Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, and Valrubicin. In some particularly preferred embodiments, the chemotherapeutic agent may be doxorubicin.
In some other preferred embodiments, the chemotherapeutic agent may be a platinum-based chemotherapeutic. In some such embodiments the chemotherapeutic agent may be selected from the group consisting of: cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin. In some particularly preferred embodiments, the chemotherapeutic agent may be carboplatin.
In some other preferred embodiments, the chemotherapeutic agent may be an antifolate chemotherapeutic. In some such embodiments the chemotherapeutic agent may be selected from the group consisting of: pemetrexed, methotrexate, pralatrexate, and trimetrexate. In some particularly preferred embodiments, the chemotherapeutic agent may be pemetrexed.
In some other preferred embodiments, the combination chemotherapeutic agent may comprise a platinum-based chemotherapeutic and an antifolate chemotherapeutic. A particularly preferred combination is carboplatin and pemetrexed, which may be used for example in combination with an anti-PD1 antibody such as pembrolizumab. The combination of carboplatin, pemetrexed, and pembrolizumab may be particualry preferred when the AXL- related disease to be treated is non small-cell lung cancer. In such embodiments, dosage regimens in which a constant dose level of AXLi is administered to the subject may be preferred.
In some other preferred embodiments, the combination chemotherapeutic agent may comprise cytarabine. Combination with cytarabine may be particualry preferred when the AXL-related disease to be treated is AML.
In some other preferred embodiments, the combination chemotherapeutic agent may comprise an EGFR targeted therapy, such as an EGFR inhibitor and / or a HER2 targeted therapy, such as a HER2 inhibitor. The EGFR targeted therapy may be selected from the group consisting of: gefitinib, erlotinib, osimertinib, lapatinib, brigatinib, rociletinib, olmutinib, nazartinib, naquotinib, mavelertinib, neratinib, dacomitinib, mobocertinib, and vandetanib. The EGFR targeted therapy may be selected from the group consisting of: cetuximab, panitumumab, necitumumab. The HER2 targeted therapy may be selected from the group consisting of: lapatinib, afatinib, canertinib, pelitinib, neratinib, dacomitinib, and tucatinib. The HER2 targeted therapy may be selected from the group consisting of: trastuzumab, pertuzumab, margetuximab, trastuzumab emtansine, and trastuzumab deruxtecan. Immune checkpoint modulators
Immune checkpoint modulators function to modulate the immune response to diseases, such as the AXL-related diseases of this disclosure. This may be achieved in a number of ways, such as increasing the activity of stimulatory pathways and decreasing the activity of inhibitory pathways.
Immune responses to AXL-related diseases such as cancer are known to be able control tumour growth and in some cases lead to elimination of tumours. Therapeutic targeting of tumor immune regulators has resulted in the development of successful immunotherapeutic approaches for cancer treatment - for example agents blocking the activity of negative regulators of T cell immunity, such as a cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor-1 (PD-1). In the disclosed methods, the AXLi may be administered in combination with one or more ICM.
In some embodiments the immune checkpoint modulator (ICM) may be an immune checkpoint inhibitor (ICI). For example, an agent which acts at T cell co-inhibitory receptors, such as CTLA-4, PD-1 , PD-L1 , BTLA, TIM-3, VISTA, LAG-3, and TIGIT.
In some embodiments the immune checkpoint modulator (ICM) may be a T cell co-stimulatory agonist. For example, an agonist of a T-cell co-stimulatory receptor such as CD28, ICOS, 4- 1 BB, 0X40, GITR, CD27, TWEAKR, HVEM, and TIM-1.
In some embodiments the immune checkpoint modulator (ICM) may act at dendritic cell co- stimulatory receptors, such as CD40 and 4-1 BB.
In some embodiments, the immune checkpoint modulator may be an immune checkpoint modulating antibody. In some embodiments the immune checkpoint modulator may be selected from the group consisting of: anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD- L1 antibodies, anti-4-1 BB antibodies, anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti-CD28 antibodies, anti-CD40 antibodies, anti-LAG3 antibodies, anti-ICOS antibodies, anti-TWEAKR antibodies, anti-HVEM antibodies, anti-TIM-1 antibodies, anti-TIM- 3 antibodies, anti-VISTA antibodies, and anti-TIGIT antibodies.
In some preferred embodiments the immune checkpoint modulator may be selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti- 4-1 BB antibodies, anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti- CD40 antibodies, and anti-LAG3 antibodies. In some particularly preferred embodiments the immune checkpoint modulator may be selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies. In some most preferred embodiments, the immune checkpoint modulator may be an anti-PD-1 antibody. Examples of ICMs suitable for use in the methods described herein include atezolizumab, avelumab, camrelizumab, cemiplimab, dostarlimab, durvalumab, ipilimumab, sintilimab, tislelizumab, toripalimab, tremelimumab, pembrolizumab, nivolumab, and urelumab, and those which can be identified by the drug candidate identifiers AMP-514/MEDI0680 (Medlmmune/AstraZeneca), MPDL3280A (Genentech/Roche), MEDI4736 (Medlmmune/AstraZeneca), MSB0010718C (EMD Serono), BMS-936559 (Bristol-Myers Squibb), PF-05082566 (Pfizer), MEDI6469 (Medlmmune/AstraZeneca), MEDI6383 (rOX40L; Medlmmune / AstraZeneca), MOXR0916 (Genentech/Roche), TRX518 (Tolerx), CDX-1127 (Celldex), CP-870,893 (Genentech/Roche), and BMS-986016 (Bristol-Myers Squibb) (preferably ipilimumab, tremelimumab, pembrolizumab, and nivolumab).
In some embodiments, the anti-PD1 antibody is selected from pembrolizumab, nivolumab, MEDI0680, PDR001 (spartalizumab), Camrelizumab, ALINP12, Pidilizumab Cemiplimab (REGN-2810), AMP 224, BGB-A317 (Tisleizumab), and BGB-108. In some embodiments, the anti-PD-L1 antibody is selected from atezolizumab (Tecentriq), BMS-936559/MDX 1105, durvalumab/MEDI4736, and MSB0010718C (Avelumab). In some embodiments, the anti- CTLA-4 antibody is selected from ipilimumab and Tremelimumab. In some embodiments, the anti-GITR antibody or GITR agonist is selected from MEDI1873, TRX518, GWN323, MK- 1248, MK 4166, BMS-986156 and INCAGN1876. In some embodiments, the anti-OX40 antibody or 0X40 agonist is selected from MEDI0562, MEDI6383, MOXR0916, RG7888, OX40mAb24, INCAGN1949, GSK3174998, and PF-04518600.
In some preferred embodiments of the disclosed methods, two or more immune checkpoint modulators may be administered. Results have shown that an improved synergistic effect can be obtained when at least two different immune checkpoint (activity) modulators are employed, especially when such immune checkpoint (activity) modulators act at different cell receptor sub-types. For example, the combination of at least one immune checkpoint inhibitor and at least one T cell co-stimulatory receptor agonist or dendritic cell co-stimulatory receptor agonist.
Preferably, at least one of the two or more immune checkpoint (activity) modulators is an anti- CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. In particular, the combination of an anti-CTLA-4 antibody and an anti-PD-1 antibody has proven to be particularly effective. For example, in the disclosed methods the TKI may be used in combination with two ICMs, such as nivolumab and ipilimumab. In some cases the TKI is used incombination with three ICMs.
In some preferred embodiments the two or more immune checkpoint (activity) modulators may include: (i) an immune checkpoint inhibitor, and (ii) a T cell co-stimulatory receptor agonist or a dendritic cell co-stimulatory receptor agonist. In some embodiments the two or more immune checkpoint (activity) modulators may include: (i) an anti-CTLA-4 antibody; and/or (ii) either an anti-PD-1 antibody or an anti-PD-L1 antibodies.
In some preferred embodiments the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
In some preferred embodiments the anti-PD-1 antibody is pembrolizumab, nivolumab, spartalizumab Camrelizumab, Pidilizumab, or Cemiplimab. Preferably the anti-PD-1 antibody is pembrolizumab or nivolumab.
In some embodiments the anti-PDL1 antibody is Atezolizumab (CAS number 1380723-44-3), Avelumab (CAS number 1537032-82-8), or Durvalumab (CAS number 1428935-60-7).
In some embodiments the two or more immune checkpoint (activity) modulators may be administered concurrently. In other embodiments the two or more immune checkpoint (activity) modulators may be administered separately and I or sequentially in any order. In some embodiments, the immune checkpoint modulator includes, or is: pembrolizumab; ipilimumab; ipilimumab and nivolumab; ipilimumab and pembrolizumab; tremelilumab and durvalumab. In some preferred embodiments the two or more immune checkpoint (activity) modulators may be ipilimumab and pembrolizumab, or ipilimumab and nivolumab.
In some preferred embodiments the combination ICM may comprise an anti-PD1 antibody, such as pembrolizumab. A particularly preferred ICM is pembrolizumab, which may be used for example in combination with a platinum-based chemotherapeutic and an antifolate chemotherapeutic, such as carboplatin and pemetrexed. The combination of carboplatin, pemetrexed, and pembrolizumab may be particularly preferred when the AXL-related disease to be treated is non small-cell lung cancer.
In some preferred embodiments the ICM may comprise an anti-PD1 antibody, an anti-PDL1 antibody, or an anti-PD1 antibody and anti-CTLA4 antibody. In some preferred embodiments, the ICM may comprise pembrolizumab, atezolizumab, cemiplimab (cemiplimab-rwlc), or nivolumab and ipilimumab. In embodiments in which the ICM comprises pembrolizumab, the ICM may be administered in combination with a platinum-based chemotherapeutic and an antifolate chemotherapeutic, such as carboplatin and pemetrexed. In embodiments in which the ICM comprises atezolizumab, the ICM may be administered in combination with an anti- VEGF-A antibody, such as bevacizumab. In other embodiments in which the ICM comprises atezolizumab, the ICM may be administered in combination with a taxane chemotherapeutic, such as paclitaxel. In other embodiments in which the ICM comprises atezolizumab, the ICM may be administered in combination with a platinum-based chemotherapeutic, such as carboplatin. In some preferred embodiments in which the ICM comprises atezolizumab, the ICM may be administered in combination with a taxane chemotherapeutic and a platinumbased chemotherapeutic, such as paclitaxel and carboplatin. In some other preferred embodiments in which the ICM comprises atezolizumab, the ICM may be administered in combination with an anti-VEGF-A antibody, a taxane chemotherapeutic, and a platinum-based chemotherapeutic, such as bevacizumab, paclitaxel, and carboplatin. In embodiments in which the ICM comprises nivolumab and ipilimumab, the ICM may be administered in combination with a platinum-based chemotherapeutic, such as carboplatin or cisplatin. Such ICMs and combinations may be particualry preferred when the AXL-related disease to be treated is non small-cell lung cancer.
Radiotherapy
The terms "radiation therapy" or "radiotherapy" may refer to the medical use of ionizing radiation as part of cancer treatment to control or eradicate malignant cells. Radiotherapy may be used for curative, adjuvant, or palliative treatment. Suitable types of radiotherapy include conventional external beam radiotherapy, stereotactic radiation therapy (e.g., Axesse, Cyberknife, Gamma Knife, Novalis, Primatom, Synergy, X-Knife, TomoTherapy or Trilogy), Intensity-Modulated Radiation Therapy, particle therapy (e.g., proton therapy), brachytherapy, delivery of radioisotopes, intraoperative radiotherapy, Auger therapy, Volumetric modulated arc therapy (VMAT), Virtual simulation, 3-dimensional conformal radiation therapy, and intensity-modulated radiation therapy.
In some embodiments, radiatiotherapy uses high-energy radiation to shrink tumors and kill cancer cells. The radiation may be, for example, X-rays, gamma rays, or charged particles. Modes of cell killing through radiation include DNA damage either directly or by creating free radicals within cells that in turn damage DNA.
Radiation may be delivered by a machine outside the body (external-beam radiation therapy), or may come from radioactive material placed in the body near cancer cells (internal radiation therapy, also called brachy therapy). In one example of systemic radiation therapy, radioactive substances, such as radioactive iodine, are used which travel in the blood to kill cancer cells.
Preferably, the radiotherapy may be administered in a regimen designed to minimize any immunosuppressive effects of the radiation. For example, preclinical evidence indicates high radiation doses above 12-18 Gy result in an attenuation of tumor immunogenicity (Vanpouille- Box C., et al., Nat Commun 2017; 8: 15618). In addition, it is known that circulating lymphocytes are particularly radiosensitive (see Yovino S., et al., Cancer Invest 2013; 31 : 140-144); this indicates radiotherapy regimens aimed at stimulating an anti-tumour immune response should aim to minimise both (1) the amount of vasculature exposed in each treatment, and (2) the number of exposures in the treatment regimen.
Radiation dosages may be fractionated and administered in sequence; for example, on consecutive days until the total desired radiation dose is delivered.
Some embodiments
Specifically contemplated embodiments of the disclosure include: Methods in which the AXLi is administered in combination with cytarabine.
Methods in which the AXLi is administered in combination with an EGFR targeted therapy, such as an EGFR inhibitor and / or a HER2 targeted therapy, such as a HER2 inhibitor.
Methods in which the AXLi is administered in combination with an anti-PD1 antibody and an anthracycline. Preferably the anti-PD1 antibody is pembrolizumab. Preferably the anthracycline is doxorubicin.
Methods in which the AXLi is administered in combination with an anti-PD1 antibody. Preferably the anti-PD1 antibody is pembrolizumab. The anti-PD1 antibody may be administered to the subject before, concurrently with, or after the AXLi. In some embodiments, the dose of anti-PD1 antibody may be about 200 mg. The anti-PD1 antibody may be administered to the subject by intravenous infusion. The anti-PD1 antibody may be administered to the subject by intravenous infusion over about 30 minutes. In some embodiments, the anti-PD1 antibody may be administered in a Q3W (once every 3 weeks) dosage regimen. Administration of the anti-PD1 antibody may begin on any of day 1 , 2, 3, 4,
5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 of the AXLi dosage regimens described more fully elsewhere herein. Preferably, administration of the anti-PD1 antibody begins on day 1 of the AXLi dosage regimens described more fully elsewhere herein.
Methods in which the AXLi is administered in combination with a platinum-based chemotherapeutic. Preferably the platinum-based chemotherapeutic is carboplatin. The platinum-based chemotherapeutic may be administered to the subject before, concurrently with, or after the AXLi. In some embodiments, the dose of platinum-based chemotherapeutic may be about Area Under the Curve 5 (AUC5) based on the Calvert formula for calculating carboplatin dosing (Calvert et al. J Clin Oncol. 1989;7:1748-1756). The platinum-based chemotherapeutic may be administered to the subject by intravenous infusion. The platinumbased chemotherapeutic may be administered to the subject by intravenous infusion over about 15 minutes or over about 30 minutes. In some embodiments, the platinum-based chemotherapeutic may be administered in a Q3W (once every 3 weeks) dosage regimen. Administration of the platinum-based chemotherapeutic may begin on any of day 1 , 2, 3, 4, 5,
6, 7, 8, 9, 10, 11 , 12, 13, or 14 of the AXLi dosage regimens described more fully elsewhere herein. Preferably, administration of the platinum-based chemotherapeutic begins on day 1 of the AXLi dosage regimens described more fully elsewhere herein.
Methods in which the AXLi is administered in combination with an antifolate chemotherapeutic. Preferably the antifolate chemotherapeutic is pemetrexed. The antifolate chemotherapeutic may be administered to the subject before, concurrently with, or after the AXLi. In some embodiments, the dose of antifolate chemotherapeutic may be about 500 mg/m2. The antifolate chemotherapeutic may be administered to the subject by intravenous infusion. The antifolate chemotherapeutic may be administered to the subject by intravenous infusion over about 10 minutes. In some embodiments, the antifolate chemotherapeutic may be administered in a Q3W (once every 3 weeks) dosage regimen. Administration of the antifolate chemotherapeutic may begin on any of day 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 of the AXLi dosage regimens described more fully elsewhere herein. Preferably, administration of the antifolate chemotherapeutic begins on day 1 of the AXLi dosage regimens described more fully elsewhere herein.
Methods in which the AXLi is administered in combination with an anti-PD1 antibody, a platinum-based chemotherapeutic, and an antifolate chemotherapeutic. Preferably the anti- PD1 antibody is pembrolizumab, the platinum-based chemotherapeutic is carboplatin, and the antifolate chemotherapeutic is pemetrexed. These agents may be administered as outlined above.
Reduced toxicity and improved efficacy
In the methods of the disclosure, the disclosed dosage regimens reduce the toxicity and I or side effects associated with treatment of a subject with an AXLi. Alternatively, or in addition, the disclosed dosage regimens increase the efficacy of treatment associated with administration of an AXLi to a subject.
Thus, the present disclosure provides a method of reducing the toxicity and I or side effects associated with administration of an AXLi to a subject; and I or increasing the efficacy of treatment associated with administration of an AXLi to a subject; the method comprising administering the AXLi in a dosage regimen according to the disclosure.
The reduction in toxicity and I or side effects, or the increase in efficacy, may be measured relative to an alternative, comparator, dosage regimen, for example a regimen employing a different constant AXLi dose level, different loading and I or maintenance dose levels, different loading and I or maintenance periods, and / or a longer or shorter duration of treatment.
As used herein, the term "treatment” or “treating" in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis, prevention) is also included.
In some cases the level of toxicity is measured as the incidence of Treatment Emergent Adverse Events (TEAE) occurring after a period of treatment, such as 21 days of treatment, at a given total dose of AXLi. A treatment-emergent AE (TEAE) is defined as any event not present before exposure to the AXLi or any event already present that worsens in either intensity or frequency after exposure to the AXLi. The incidence of AE with the dosage regimens of the disclosure may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of AE in an alternative, comparator, dosage regimen. Adverse events may be graded according to NCI-CTCAE Version 5.0 (v5.0, published November 27, 2017).
For example, if treatment with an alternative, comparator, dosage regimen in 100 subjects leads to 10 AEs and treatment with a dosage regimen of this disclosure leads to 5 AEs, the incidence of AEs with the dosage regimen of this disclosure is 50% of the incidence of AE in the corresponding comparator dosage regimen.
In some cases the level of toxicity is measured as the incidence of Serious Adverse Events (SAE) occurring after a period of treatment, such as 21 days of treatment, at a given total dose of AXLi. A serious adverse event (SAE) is defined as any event that results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. Hospitalization for elective procedures or for protocol compliance is not considered an SAE. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered SAEs when, based upon appropriate medical judgment, they may jeopardize the patient or may require medical or surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. The incidence of SAE with the dosage regimens of the disclosure may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of SAE in an alternative, comparator, dosage regimen. Adverse events may be graded according to NCI- CTCAE Version 5.0 (v5.0, published November 27, 2017).
In some cases the level of toxicity is measured as the incidence of Dose Limiting Toxicity (DLT) occurring after a period of treatment, such as 21 days of treatment, at a given total dose of AXLi. The incidence of DLT with the dosage regimens of the disclosure may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of DLT in an alternative, comparator, dosage regimen.
For example, if treatment with an alternative, comparator, dosage regimen in 100 subjects leads to 10 DLTs and treatment with a dosage regimen of this disclosure leads to 5 DLTs, the incidence of DLTs with the dosage regimen of this disclosure is 50% of the incidence of DLT in the corresponding comparator dosage regimen.
A DLT as used herein is defined as any of the following events, except those that are clearly due to underlying disease or extraneous causes:
• Grade 4 nonhematologic toxicity (not laboratory).
• Grade 4 hematologic toxicity lasting >7 days, except thrombocytopenia: o Grade 4 thrombocytopenia of any duration o Grade 3 thrombocytopenia associated with clinically significant bleeding
• Any nonhematologic AE >Grade 3 in severity should be considered a DLT, with the following exceptions: o Grade 3 fatigue lasting < 3 days; o Grade 3 diarrhoea, nausea, or vomiting if persistent <7 days with optimum prophylactic medication per standard of care;
• Any Grade 3 or Grade 4 non-hematologic laboratory value if: o Clinically significant medical intervention is required to treat the participant or o The abnormality leads to hospitalization, or o The abnormality persists for >7 days. o The abnormality results in a Drug induced Liver Injury (DILI) o Grade 3 QTcF by CTCAE v5.0 on triplicate ECGs (Average QTc >= 501 ms;
>60 ms change from baseline) o Exceptions: Clinically nonsignificant, treatable, or reversible laboratory abnormalities including liver function tests, uric acid, etc.
• Febrile neutropenia Grade 3 or Grade 4: o Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >38 degrees C (100.4 degrees F) for more than 1 hour o Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >38 degrees C (100.4 degrees F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated.
• Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity.
• Any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1.
• Missing >25% of the partner drug(s) doses as a result of drug-related AE(s) during the first cycle.
• Grade 5 toxicity.
The above adverse events will be graded according to NCI-CTCAE Version 5.0 (v5.0, published November 27, 2017).
In some cases the level of toxicity is measured as the incidence of QT / QTc prolongation. QT I QTc prolongation is a measure of delayed ventricular repolarisation, and excessive QT / QTc prolongation can predispose the myocardium to development of early after-depolarisations, which in turn can trigger re-entrant tachycardias. Prolongation of the QT / QTc interval has been noted with tyrosine kinase inhbiitors, including AXL inihibtors such as bemcentinib. In the dosage regimens of the disclosure, the incidence of QT/QTc adverse events (AEs) may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of QT/QTc AEs in a corresponding comparator dosage regimen. Methods for measuring QT interval and QT / QTc prologation are known to the person skilled in the art, for example using electrocardiography.
In some cases, the dosage regimens of this disclosure may provide for an optimal balance of treatment efficacy (as may be assessed by the outcomes outlined below), toxicity and I or incidence of adverse events (as may be assessed as outlined above). For example, the dosage regimens of this disclosure may provide for an optimal balance of AXLi treatment efficacy and incidence of QT / QTc prolongation, and I or an an optimal balance of AXLi treatment efficacy and incidence of disease-driven QT / QTc prolongation.
In some cases, the dosage regimens of this disclosure elicit a change in QTc of less than about 30 ms, such as less than about 29, 28, 27, 26, 25, 24, 23, 22, 21 , 20, or 19 ms. In some preferred cases, the dosage regimens of this disclosure elicit a change in QTc of less than about 20 ms. Stated alternatively, in some cases, the dosage regimens of this disclosure do not prolong the QTc interval by more than about 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 ms. In some preferred cases, the dosage regimens of this disclosure do not prolong the QTc interval by more than about 20 ms.
In some cases the level of efficacy is measured as the proportion of subjects achieving at least stable disease [SD] after a period of treatment with AXLi (i.e the proportion of subjects achieving either stable disease [SD], a partial response [PR], or a complete response [CR], The proportion of subjects achieving at least SD may be at least 110%, such as at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, of the proportion of subjects achieving at least stable disease [SD] in an alternative, comparator, dosage regimen.
For example, if treatment with an alternative, comparator, dosage regimen in 100 subjects leads to at least SD in 50 subjects and treatment with a dosage regimen of this disclosure leads to at least SD in 80 subjects, the proportion of subjects achieving at least SD with the dosage regimen of this disclosure is 160% of the proportion of subjects achieving at least a partial response [SD] in the corresponding comparator dosage regimen.
The skilled person will be aware as part of their common general knowledge of suitable criteria to be used for assessment of response to treatment with AXLi. Accordingly, assessment of response to treatment with AXLi may be based on any commonly used criteria for assessing response rate - for example, RECIST (or mRECIST, or iRECIST; Response Evaluation Criteria in Solid Tumors) criteria for solid tumours, or Lugano Classification Criteria (using the New “Cheson” Criteria) for lyphoma.
In some cases the level of efficacy is measured as the proportion of subjects achieving one or more of the following outcomes:
• Partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status), as may be assessed, for example, by % bone marrow myeloblasts, normal maturation of cell lines, reduction in tumour burden, and I or absence of detectable tumours.
• Slowing or absence of disease progression (attaining stable disease [SD] status), as may be assessed, for example, by changes in % bone marrow myeloblasts, slowing or absence of tumour enlargement, and I or slowing or absence of increase in tumour burden.
• Any positive patient outcome selected from: prolonged survival, progression-free survival, hematologic improvement (as may be assessed, for example, by increased blood haemoglobin, platelet count, and / or neutrophil count), bone marrow response (as may be assessed, for example, by: bone marrow with < 5% myeloblasts; 30%, 40%, 50% or more reduction in bone marrow myeloblasts; absence of circulating myeloblasts and myeloblasts with Auer rods; absence of extramedullary disease), hematologic recovery (as may be assessed, for example, by: >11 g/dL haemoglobin, >100x109/L platelets, and I or >1x109/L neutrophils in peripheral blood), tumour shrinkage (for example, a reduction in tumour volume of 5, 10, 20, 30, 40% or more), reduction in tumour burden (for example, a reduction in tumour burden of 5, 10, 20, 30, 40% or more), slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, negative response for a genetic marker, improved quality of life (as may be assessed, for example, using a health-related quality of life questionnaire such as a Functional Assessment of Cancer Therapy (FACT) questionnaire), and any other positive patient outcome.
The proportion of subjects achieving one or more of these may be at least 110%, such as at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, of the proportion of subjects achieving the same outcomes with an alternative, comparator, dosage regimen.
The disclosed dosage regimens may also increase AXLi exposure in a subject; and I or reduce variability in AXLi exposure in a subject. Thus, the present disclosure also provides a method of increasing AXLi exposure in a subject; and I or reducing variability in AXLi exposure in a subject; the method comprising administering the AXLi in a dosage regimen according to the disclosure.
As used herein, “exposure” refers to the level of a drug achieved in the body. In pharmacokinetics, drug exposure is most often estimated by area under the curve (AUC) methods, but may also be reported as parameters such as Cmax (maximum concentration) or Tmax (time at maximum concentration), as will be understood and readily derivable by the person skilled in the art. In some cases, the increase in exposure and I or reduction in variability in exposure is measured relative to an alternative, comparator, dosage regimen, for example a regimen in which AXLi is administered to the subject in a fasted state, or a regimen in which fed or fasted state administration is not controlled. In the dosage regimens of the disclosure, the variability in exposure may be less than 95%, such as less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5% of the variability in exposure in a comparator dosage regimen.
Subject Selection
In certain aspects, the subjects are selected as suitable for treatment with the treatments of this disclosure before the treatments are administered.
As used herein, subjects who are considered suitable for treatment are those subjects who are expected to benefit from, or respond to, the treatment. To “benefit from” or “respond to” can refer to any beneficial therapeutic effect observed in the subject to which a treatment was administered. This may be any overall clinical benefit derived from the treatment - for example, prolonged survival, partial or complete disease remission, slowing or absence of disease progression, tumour shrinkage (for example, a reduction in tumour volume of 5, 10, 20, 30, 40% or more), reduction in tumour burden (for example, a reduction in tumour burden of 5, 10, 20, 30, 40% or more), slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, or improved quality of life. To “not benefit from” or “not respond to” refers to the absence of these measures of overall clinical benefit derived from a treatment. “Additional benefit” can refer to the extra overall clinical benefit (for example, as assessed by any of the outcomes described above) derived from additional therapeutic agents when administered in combination (and which may be cumulative or synergistic).
In some cases, subjects may be selected on the basis of the amount or pattern of expression or activity of a marker protein of interest, for example STK11, or STK11IP. In some cases, subjects may be selected based on response I benefit (or lack thereof) derived from a previously administered treatment, for example an immune checkpoint modulator, or a combination treatment comprising one or more chemotherapeutic agent and an immune checkpoint modulator. In some cases subjects may be selected on the basis of both: the amount or pattern of expression or activity of a marker protein of interest; and, response I benefit (or lack thereof) derived from a previously administered treatment.
In some embodiments, subjects may be selected based on identifying subjects having an AXL-related disease characterised by the presence of cells having modified STK11 activity or expression. In some embodiments, the modified STK11 activity or expression is decreased STK11 activity or expression. In some embodiments, subjects may be selected based on identifying subjects that have previously been treated with an immune checkpoint modulator (ICM) and I or chemotherapeutic agent (such as the ICMs and chemotherapeutic agents described in more detail elsewhere herein) and which did not respond to treatment with the ICM and I or chemotherapeutic agent.
Stated alternatively, the AXL-related disease to be treated in the methods of the disclosure may be characterised by the presence of cells having modified STK11 activity or expression, such as decreased STK11 activity or expression.
A subject who “did not respond” to treatment with an ICM and I or chemotherapeutic agent is a subject who did not derive any clinical benefit from said treatment. In some embodiments, this may be a subject in which no slowing or absence of disease progression was observed following said treatment, or no slowing or absence of disease progression was attributable to said treatment. In some embodiments, this may be a subject in which no reduction in tumour volume was observed following said treatment, or no reduction in tumour volume was attributable to said treatment. In some embodiments, this may be a subject in which a less than 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10% reduction in tumor volume was observed following said treatment, or less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% reduction in tumor volume was attributable to said treatment. In some embodiments, this may be a subject in which no reduction in tumour burden was observed following said treatment with the ICM, or in which no reduction in tumour burden was attributable to said treatment. In some embodiments, this may be a subject in which less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% reduction in tumor burden was observed following treatment with said treatment, or less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% reduction in tumor burden was attributable to said treatment.
In some embodiments, subjects may be selected based on the methods described in WO2021/214492.
Assessing increased / decreased expression
The term “expression” as used herein refers to the transcription of a gene’s DNA template to produce the corresponding mRNA and translation of this mRNA to produce the corresponding gene product (i.e. , a peptide, polypeptide, or protein) as well as the “expression” of a protein in one or more forms that may have been modified post translation.
Suitable means for determining or detecting level and patterns of expression, including gene expression, are readily known to those skilled in the art - for example, by microarray analysis, Western blotting or by PCR techniques such as QPCR. Altered expression may also be detected by analysing protein content of samples using methods such as ELISA, PET or SELDI-TOF MS, or by analytical techniques such as 2Dgel electrophoresis.
Techniques such as this can be particularly useful for detecting altered expression in the form of alternative post translationally modified forms of a protein. In some embodiments, modified STK11 activity or expression may be assessed using the experimental methods described in the Examples of WO2021/214492 (whole exome sequence analysis of tumour biopsy material).
In some embodiments, decreased STK11 activity or expression may be assessed by determining the level of activity or expression of STK111P. In some embodiments, increased activity or expression of STK111 P relative to a control is indicative of decreased STK11 activity or expression. In some embodiments, decreased activity or expression of STK111 P relative to a control may be indicative of decreased STK11 activity or expression.
In some embodiments of the disclosure, increased STK11 activity or expression may be assessed by determining the level of activity or expression of STK111 P. In some embodiments, increased activity or expression of STK11 IP relative to a control is indicative of increased STK11 activity or expression. In some embodiments, decreased activity or expression of STK11IP relative to a control may be indicative of increased STK11 activity or expression. In some embodiments of the disclosure, modifed (increased or decreased) expression may be assessed by determining copy number of the gene encoding a protein of interest - for example, STK11 or STK111P - relative to a control sample, wherein an increase in the copy number indicates an increased level of expression and a decrease in the copy number indicates a decreased level of expression. In some embodiments, modified (increased or decreased) expression is assessed by determining the level of a protein or mRNA of interest - for example, STK11 or STK11IP - relative to a control sample.
In some embodiments, modified (increased or decreased) activity or expression may be assessed by determining the presence or absence of a mutation in the nucleotide, mRNA, or amino acid protein sequence of a protein of interest. Suitable means for determining or detecting the presence or absence of such mutations are well known to those skilled in the art - for example, nucleotide sequencing, DNA hybridization, restriction enzyme digestion methods.
In some embodiments of the methods of the disclosure, modified STK11 activity or expression may be assessed by determining the presence or absence of a STK11 mutation and / or a STK11 IP mutation. In some embodiments, the STK11 mutation and I or STK11IP mutation may be a mutation selected from: a mutation in the nucleotide sequence encoding STK11 or STK11IP; a mutation in a regulatory sequence controlling expression of the nucleotide sequence encoding STK11 or STKHIP; or, a mutation in a nucleotide encoding a protein which interacts with the transcription product of the STK11 or STK111 P gene.
In some embodiments, the STK11 mutation and I or STK111 P mutation is a mutation in the translation product of the STK11 or STK111P gene. In some embodiments, the STK11 mutation and I or STK111P mutation is a mutation in the transcription product of the STK11 or STK111P gene. In some embodiments, the STK11 mutation and I or STK111P mutation is a mutation in a miRNA that regulates expression of STK11 and I or STK111P.
In some embodiments, the STK11 mutation may be an inactivating mutation. In some embodiments, the STK11 mutation may be an activating mutation. In some embodiments the STK11IP mutation may be an activating mutation. In some embodiments the STK11IP mutation may be an inactivating mutation. In some embodiments the STK11 mutation may be L160P, LD140PY, or D115V. In some embodiments, the STK11P mutation may be E30V, LG334FW, W162C, or R1065Q.
In some embodiments, the STK11 mutation may result in a reduced level of activity or expression of STK11 protein. In some embodiments, the STK11 mutation may result in an increased level of activity or expression of STK11 protein. In some embodiments, the STK111 P mutation may result in an increased level of activity or expression of STK111 P protein. In some embodiments, the STK111 P mutation may result in a decreased level of activity or expression of STK11IP protein. In some embodiments the STK11IP mutation may result in an altered pattern of activity or expression of STK11 protein, and I or altered subcellular localisation of STK11 protein. For example, increased cytosolic sequestration of STK11 protein and I or reduced localisation of STK11 protein to the nucleus.
As used herein, an “activating” mutation is one which results in the transcription and I or translation product of a gene having increased function (which may be either increased activity or expression). As used herein, an “inactivating” mutation is one which results in the transcription and I or translation product of a gene having reduced or no function (which may be either decreased activity or expression). The mutation may be mutation in a nucleotide, mRNA, or protein sequence.
Samples
In some embodiments of the methods of the disclosure, the increased or decreased activity or expression is determined in a sample derived from a subject. That is, the methods of the disclosure may be performed in vitro or ex vivo on a sample isolated from a subject. The sample may comprise or may be derived from: a quantity of blood; a quantity of serum derived from the subject’s blood which may comprise the fluid portion of the blood obtained after removal of the fibrin clot and blood cells; a quantity of pancreatic juice; a tissue sample or biopsy; a urine sample; or cells isolated from said subject. A sample may be taken from any tissue or bodily fluid. In some embodiments, the sample may include or may be derived from a tissue sample, biopsy, resection or isolated cells from a subject. In some preferred embodiments, the sample may be a tissue sample. The sample may be a sample of tumor tissue, such as neoplastic tumor tissue. The sample may be one that is obtained by a tumor biopsy.
In some embodiments, the sample may be taken from a bodily fluid, more preferably one that circulates through the body. Accordingly, the sample may be a blood sample or lymph sample. In some embodiments, the sample is a urine sample or a saliva sample. In some other embodiments, the sample is a blood sample or blood-derived sample. The blood derived sample may be a selected fraction of a subject’s blood, e.g. a selected cellcontaining fraction or a plasma or serum fraction.
A selected cell-containing fraction may contain cell types of interest which may include white blood cells (WBC), particularly peripheral blood mononuclear cells (PBC) and/or granulocytes, and/or red blood cells (RBC). Accordingly, methods according to the present disclosure may involve detection of a marker polypeptide or nucleic acid in the blood, in white blood cells, peripheral blood mononuclear cells, granulocytes and/or red blood cells. The sample may be fresh or archival. For example, archival tissue may be from the first diagnosis of a subject, or a biopsy at a relapse. In some preferred embodiments, the sample may be a fresh biopsy.
Controls
Increased or decreased activity or expression of a marker protein of interest may be determined relative to a control. Controls are useful to support the validity of staining, and to identify experimental artefacts. In some embodiments, target expression or activity in the subject is compared to target expression or activity in a control. In some cases, the control may be a reference sample or a reference dataset. The reference may be a sample that has been previously obtained from an individual or individuals with a known degree of suitability - for example, from an individual or individuals known to be responsive to the treatments disclosed herein. The reference may be a dataset obtained from analyzing a reference sample.
Controls may be positive controls in which the target molecule is known to be present, or expressed at high level, or may be negative controls in which the target molecule is known to be absent or expressed at low level. Controls may be samples of tissue that are from individuals who are known to benefit from the treatment. The tissue may be of the same type as the sample being tested. For example, a sample of tumor tissue from an individual may be compared to a control sample of tumor tissue from an individual who is known to be suitable for the treatment, such as an individual who has previously responded to the treatment. In some cases the control may be a sample obtained from the same individual as the test sample, but from a tissue known to be healthy. Thus, a sample of cancerous tissue from an individual may be compared to a non-cancerous tissue sample. In some cases, the control is a cell culture sample.
In some cases, the control may be a sample from a comparable AXL-related disease that is not characterized by modified activity or expression of STK11 and I or STK11IP. In some other cases, the control may be a sample of healthy tissue. In some preferred embodiments, the control is of the same sample type as the test sample - for example, a sample of the same tissue type as the AXL-related disease. In some other preferred embodiments, the control is a reference sample or dataset obtained from an individual or individuals known to be responsive to the AXLi or combination therapies disclosed herein.
Subject status
The subject may be an animal, mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human. In preferred embodiments, the subject is a human.
Furthermore, the subject may be any of its forms of development, for example, a foetus.
The terms “subject”, “patient” and “individual” are used interchangeably herein.
In some cases the subject has, is suspected of having, or has received a diagnosis of, an AXL-related disease, such as cancer or fibrosis.
Methods of Treatment
The term “treatment,” as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e. , prophylaxis, prevention) is also included.
Typically, in the methods of treatment described herein the agents (eg. AXLi) are administered in a therapeutically or prophylactically effective amount.
The term “therapeutically-effective amount” or “effective amount” as used herein, pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
Similarly, the term “prophylactically-effective amount,” as used herein, pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
Typically, the subjects treated are in need of the described treatment.
Disclosed herein are methods of therapy. Also provided is a method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of an AXLi. The term “therapeutically effective amount” is an amount sufficient to show benefit to a subject. Such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors. The subject may have been tested to determine their eligibility to receive the treatment according to the methods disclosed herein. The method of treatment may comprise a step of determining whether a subject is eligible for treatment, using a method disclosed herein. The treatment may involve administration of the AXLi alone or in further combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
Compositions according to the present disclosure are preferably pharmaceutical compositions. Pharmaceutical compositions according to the present disclosure, and for use in accordance with the present disclosure, may comprise, in addition to the active ingredient, i.e. a conjugate compound, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.
Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such a gelatin.
For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
In some embodiments of the methods of treatment described herein, the AXLi is comprised in a pharmaceutical composition, optionally further comprising a pharmaceutically acceptable excipient.
In addition to the methods and compositions described above, the present disclosure provides agents and reagents, as well as compositions and kits comprising these agents and reagents, for use in the disclosed methods, and the use such agents and reagents, as well as compositions and kits comprising these agents and reagents, in the manufacture of a medicament for use in the methods of the disclosure.
Dosage
It will be appreciated by one of skill in the art that appropriate dosages of the AXLi and compositions comprising the active element, can vary from subject to subject. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the subject. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
In general, a suitable dose of each active compound is in the range of about 100 ng to about 25 mg (more typically about 1 pg to about 10 mg) per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
Definitions
As used herein, the term “about” refers to any minimal alteration in a stated absolute value (e.g., the dose, concentration, or amount of a therapeutic agent) that does not change the stated efficacy, activity, action, results, etc. In some cases, the term “about” may include ±10% of a specified numerical value. The term “about” includes the stated value (e.g., “about 1%” includes 1 % as well as minimal alterations thereof), and a preferred embodiment of a numerical value expressed as “about” that value is the absolute value (e.g., a preferred embodiment of “about 1%” is “1%”).
As used herein, to “consume” or “ingest” food encompasses the administering of food I nutrition to a subject where the subject is unable to ingest the food orally - for example administration of food I nutrition via enteral or parenteral routes.
SOME EMBODIMENTS
Certain specifically contemplated embodiments of the disclosure are as follows:
In some preferred embodiments, the AXL-related disease is cancer. Most preferred AXL- related diseases include lung cancer, such as non small cell lung cancer, and AML. In some preferred embodiments the AXL-related disease is cancer and the AXLi is bemcentinib.
In some such preferred embodiments, the loading dose is administered on days 1 and 2 of the dosage regimen, and the maintenance dose is administered on day 3 and each subsequent day until treatment with the AXLi is stopped. Preferably, the loading dose is about 200 mg and the maintenance dose is about 100 mg. In other preferred embodiments, the loading dose is about 150 mg and the maintenance dose is about 75 mg. In some other such preferred embodiments, a constant dose of AXLi is administered on day 1 and on each subsequent day of the dosage regimen. Preferably, the constant dose is about 150 mg. In other preferred embodiments, the constant dose is about 125 mg.
In some other such preferred embodiments, a constant dose of AXLi is administered on day 1 and on each subsequent day of the dosage regimen. A most preferred constant dose of AXLi is about 100 mg. In these embodiments, the AXLi may preferably be administered in combination with one or more further treatment and I or therapeutic agent, as described more fully elsewhere herein - such as pembrolizumab, or carboplatin, pemetrexed, and pembrolizumab. In some such embodiments the cancer is preferably non small cell lung cancer.
In most preferred embodiments of these regimens, the AXLi is administered to the subject under fed conditions.
Specifically contemplated embodiments of the disclosure also include:
An AXLi for use in a method of the disclosure.
Bemcentinib for use in a method of the disclosure.
Use of an AXLi in the manufacture of a medicament for use in a method of the disclosure.
Use of bemcentinib in the manufacture of a medicament for use in a method of the disclosure.
A chemotherapeutic agent for use in a method of the disclosure.
An ICM for use in a method of the disclosure.
Use of a chemotherapeutic agent in the manufacture of a medicament for use in a method of the disclosure.
Use of an ICM in the manufacture of a medicament for use in a method of the disclosure.
STATEMENTS OF DISCLOSURE
The following numbered statements, outlining aspects of the present disclosure, are part of the description.
Method of treatment
101. A method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose.
Dose timing
102. The method according to statement 101 , wherein the loading dose is administered on days 1 and 2 of the dosage regimen.
103. The method according to any preceding statement, wherein the maintenance dose is administered beginning on day 3 of the dosage regimen.
104. The method according to any preceding statement, wherein the maintenance dose is administered on day 3 and on each subsequent day of the dosage regimen.
105. The method according to any preceding statement, wherein the method comprises administering the loading dose of the AXLi on days 1 and 2 of the dosage regimen, and thereafter administering the maintenance dose of the AXLi.
106. The method according to any preceding statement, wherein the AXLi is administered to the subject daily.
107. The method according to any preceding statement, wherein the AXLi is administered to the subject once daily.
108. The method according to statement 107, wherein the method comprises administering the loading dose of the AXLi to the subject once daily on days 1 and 2 of the dosage regimen, and thereafter administering the maintenance dose of the AXLi to the subject once daily.
109. The method according to any preceding statement, wherein the maintenance dose is administered beginning on day 3 of the dosage regimen, and is administered to subject daily until treatment with the AXLi is stopped, for example when a treatment endpoint is reached for the subject.
110. The method according to statement 108, wherein the treatment endpoint is one or more of:
(i) partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status);
(ii) slowing or absence of disease progression (attaining stable disease [SD] status);
(iii) any positive patient outcome selected from: prolonged survival, progression-free survival, hematologic improvement, bone marrow response, hematologic recovery, tumour shrinkage, reduction in tumour burden, slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, negative response for a genetic marker, improved quality of life, and any other positive patient outcome;
(iv) disease progression (progressive disease [PD] status) prompting treatment withdrawal; and I or
(v) toxicity and I or incidence of adverse events requiring treatment withdrawal.
Loading dose
111. The method according to any preceding statement, wherein the loading dose is:
(i) about 100 to 300 mg, such as about 150 to 250 mg, about 175 to 225 mg, or about
190 to 210 mg; or
(ii) about 50 to 250 mg, such as about 100 to 200 mg, about 125 to 175 mg, or about 140 to 160 mg.
112. The method according to any preceding statement, wherein the loading dose is:
(i) about 200 mg; or
(ii) about 150 mg.
113. The method according to any preceding statement, wherein the loading dose is:
(i) about 200 mg administered to the subject once daily; or
(ii) about 150 mg administered to the subject once daily.
114. The method according to any preceding statement, wherein the loading dose is about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg.
115. The method according to any preceding statement, wherein the loading dose is about 100 mg.
116. The method according to any preceding statement, wherein the loading dose is about 100 mg administered to the subject once daily.
Maintenance dose
117. The method according to any preceding statement, wherein the maintenance dose is about 45-55%, such as about 46-54%, about 47-53%, about 48-52%, or about 49-51% of the loading dose.
118. The method according to any preceding statement, wherein the maintenance dose is about 50% of the loading dose.
119. The method according to any preceding statement, wherein the maintenance dose is about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg.
120. The method according to any preceding statement, wherein the maintenance dose is about 100 mg. 121. The method according to any preceding statement, wherein the maintenance dose is about 100 mg administered to the subject once daily.
122. The method according to any one of statements 101-118, wherein the maintenance dose is about 50 to 100 mg, about 60 to 90 mg, about 65 to 85 mg, or about 70 to 80 mg.
123. The method according to statement 122, wherein the maintenance dose is about 75 mg.
124. The method according to statement 123, wherein the maintenance dose is about 75 mg administered to the subject once daily.
125. The method according to any one of statements 101-117, wherein the maintenance dose is the same as the loading dose.
126. The method according to statement 125, wherein the maintenance dose is:
(i) about 100 to 300 mg, such as about 150 to 250 mg, about 175 to 225 mg, or about 190 to 210 mg;
(ii) about 200 mg; and I or
(iii) about 200 mg administered to the subject once daily.
127. The method according to statement 125, wherein the maintenance dose is:
(i) about 50 to 250 mg, such as about 100 to 200 mg, about 125 to 175 mg, or about 140 to 160 mg;
(ii) about 150 mg; and I or
(iii) about 150 mg administered to the subject once daily.
128. The method according to statement 125, wherein the loading dose and maintenance dose is:
(i) about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg;
(ii) about 100 mg; or
(iii) about 100 mg administered to the subject once daily; or, wherein the loading dose and maintenance dose is:
(iv) about 50 to 100 mg, about 60 to 90 mg, about 65 to 85 mg, or about 70 to 80 mg;
(v) about 75 mg; or
(vi) about 75 mg administered to the subject once daily; or, wherein the loading dose and maintenance dose is:
(vii) about 125 mg; or
(viii) about 125 mg administered to the subject once daily.
Fed state dosing
129. The method according to any preceding statement, wherein the method comprises administering the AXLi to the subject under fed conditions. 130. The method according to statement 129, wherein administering the AXLi under fed conditions comprises administering the AXLi to the subject before, at the same time, or after food.
131. The method according to statement 129, wherein administering the AXLi under fed conditions comprises administering the AXLi to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes of the subject consuming food.
132. The method according to statement 129, wherein administering the AXLi under fed conditions comprises administering the AXLi to the subject less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed food.
133. The method according to statement 129, wherein administering the AXLi under fed conditions comprises administering the AXLi to the subject administering the AXLi to the subject not more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes before the subject has consumed, or will consume, food.
134. The method according to statement 129, wherein administering the AXLi under fed conditions comprises administering the AXLi to the subject within about 0-240 minutes, such as about 30-240 minutes, 60-240 minutes, 90-240 minutes, 120-240 minutes, 150-240 minutes, 180-240 minutes, or 210-240 minutes of the subject consuming food, or such as about 0-210 minutes, 0-180, 0-150, 0-120, 0-90, 0-60, or 0-30 minutes of the subject consuming food.
135. The method according to any one of statements 130 to 134, wherein the food is a meal, such as a high-fat and I or high protein meal.
AXL related disease
136. The method according to any one of statements 101 to 135, wherein the AXL-related disease is a proliferative disease.
137. The method according to any one of statements 101 to 135, wherein the AXL-related disease is a neoplastic disease.
138. The method according to any one of statements 101 to 137, wherein the AXL-related disease is a solid tumour.
139. The method according to any one of statements 101 to 138, wherein the AXL-related disease is a liquid tumour (hematologic cancer).
140. The method according to any one of statements 101 to 139, wherein the AXL-related disease is cancer, a fibrotic disorder, or neurofibromatosis.
141. The method according to statement 140, wherein the cancer is selected from the group consisting of: lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma.
142. The method according to statement 141 , wherein the cancer is acute myeloid leukemia (AML).
143. The method according to statement 141 , wherein the cancer is lung cancer.
144. The method according to statement 141 , wherein the cancer is non-small-cell lung cancer (NSCLC).
AXLi
145. The method according to any preceding statement, wherein the AXLi is administered orally, for example as an oral capsule.
146. The method according to any preceding statement, wherein the AXLi is a compound of formula (I):
Figure imgf000080_0001
wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, -C(O)R8, -C(O)N(R6)R7, and -C(=NR6)N(R6)R7;
R2 and R3 are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R9-OR8, -R9-O-R10-OR8, -R9-O-R10-O-R10-OR8, -R9-O-R10-CN, -R9-O-R10-C(O) OR8, -R9-O-R10-C(O)N(R6)R7, -R9-O-R10-S(O)PR8 (where p is 0, 1 or
2), -R9-O-R10-N(R6)R7, -R9-O-R10-C(NR11)N(R11)H, -R9-OC(O)-R8, -R9-N(R6)R7, -R9-C(O)R8, - R9-C(O)OR8, -R9-C(O)N(R6)R7, -R9-N(R6)C(O)OR8, -R9-N(R6)C(O)R8, -R9-N(R6)S(O)tR8 (where t is 1 or 2), -R9-S(O)tOR8 (where t is 1 or 2), -R9-S(O)PR8 (where p is 0, 1 or 2), and -R9-S(O)tN(R6)R7 (where t is 1 or 2); or R2 is a polycyclic heteroaryl containing more than 14 ring atoms as described above and R3 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R13-OR12, -R13-OC(O)-R12, -R13-O-R14-N(R12)2, -R13-N(R12)-R14-N(R12)2, -R 13-N(R12)-R14-N(R12)2, -R13-N(R12)2, -R13-C(O)R12, -R13-C(O)OR12, -R13-C(O)N(R12)2, -R13-C(O )N(R12)-R14-N(R12)R13, -R13-C(O)N(R12)-R14-OR12, -R13-N(R12)C(O)OR12, -R13-N(R12)C(O)R12, -R13-N(R12)S(O)tR12 (where t is 1 or 2), -R13-S(O)tOR12 (where t is 1 or 2), -R13-S(O)PR12 (where p is 0, 1 or 2), and -R13-S(O)tN(R12)2 (where t is 1 or 2); or R3 is a polycyclic heteroaryl containing more than 14 ring atoms as described above, and R2 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R13-OR12, -R13-OC(O)-R12, -R13-O-R14-N(R12)2, -R13-N(R12)-R14-N(R12)2, -R 13-N(R12)-R14-N(R12)2, -R13-N(R12)2, -R13-C(O)R12, -R13-C(O)OR12, -R13-C(O)N(R12)2, -R13-C(O )N(R12)-R14-N(R12)R13, -R13-C(O)N(R12)-R14-OR12, -R13-N(R12)C(O)OR12, -R13-N(R12)C(O)R12, -R13-N(R12)S(O)tR12 (where t is 1 or 2), -R13-S(O)tOR12 (where t is 1 or 2), -R13-S(O)PR12 (where p is 0, 1 or 2), and -R13-S(O)tN(R12)2 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R10-OR8, -R10-CN, -R10-NO2, -R10-N(R8)2, -R10-C(O)OR8 and -R10-C(O)N(R8)2, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted /V- heterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl; each R9 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R10 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R11 is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR8; each R12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl , optionally substituted heteroarylalkyl, -R10-OR8, -R10-CN, -R10-NO2, -R10-N(R8)2, -R10-C(O)OR8 and -R10-C(O)N(R8)2, or two R12s, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl; each R13 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; and each R14 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof.
147. The method according to any preceding statement, wherein the AXLi is selected from the group consisting of: 1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(pyrrolidin-1-yl)-6,7,8,9- tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7-(S)-pyrrolidin-1-yl)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7-(R)-pyrrolidin-1-yl)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(3-fluoro-4-(4- (pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/5-(7-(pyrrolidin-1-yl)-6,7,8,9- tetrahydro-5/7-benzo[7]annulene-1-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/5-(7-(S)-pyrrolidin-1-yl-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(t- butoxycarbonylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(acetamido)-6,7,8,9- tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-((2R)-2-
(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4,4-difluoropiperidin-1- yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine; 1 -(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-A/3-(7- ((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7- 1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-((2/?)-2-
(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4-
(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4-(carboxy)piperidin-1- yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-
((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4-
(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-
1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(4-
(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-(7-(pyrrolidin-1-yl)-6,7,8,9- tetrahydro-5/7-benzo[7]annulene-1-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-amino-6,7,8,9- tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7s)-7-
(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((2- methylpropyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((propyl)amino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(dipropylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(diethylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(cyclohexylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(cyclopentylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((1- cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(2-propylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine; 1 -(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/V3-((7S)-7-((3,3-dimethylbut-2- yl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-
3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-
3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((5-chlorothien-2- yl)methyl)amino-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((2- carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((3- bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-
3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(dimethylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(cyclobutylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(3-pentylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((2,2- dimethylpropyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-
3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-
1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-((bicyclo[2.2.1]hept-
2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(3- methylbutylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(di(3- methylbutyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(2-ethylbutylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(but-2-enylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(butyl(but-2- enyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/5-((7S)-7-(t- butoxycarbonylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-amino-6,7,8,9- tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
(dimethylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(diethylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7- (dipropylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4- triazole-3,5-diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(di(3- methylbutyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
(cyclobutylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
(cyclohexylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
((methylethyl)amino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine;
1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-
(cyclopentylamino)-6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5- diamine; and 1-(6,7-dihydro-5/7-pyrido[2',3':6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7S)-7-(2-butylamino)-
6,7,8,9-tetrahydro-5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine; or pharmaceutically acceptable salts thereof.
148. The method according to any preceding statement, wherein the AXLi is 1-(6,7-dihydro- 5/7-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/\/3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro- 5/7-benzo[7]annulene-2-yl)-1/7-1 ,2,4-triazole-3,5-diamine, or a pharmaceutically acceptable salt thereof.
149. The method according to any preceding statement, wherein the AXLi is bemcentinib. 150. The method according to any one of statements 1 to 186, wherein the AXLi is selected from the group consisting of:
- Dubermatinib (CAS No.1341200-45-0 ; UNII 14D65TV20J);
- Gilteritinib (CAS No. 1254053-43-4 ; UNII 66D92MGC8M);
- Cabozantinib (CAS No. 849217-68-1 ; UNII 1C39JW444G);
- SGI7079 (CAS No. 1239875-86-5);
- Merestinib (CAS No. 1206799-15-6 ; UNII 5OGS5K699E);
- Amuvatinib (CAS No. 850879-09-3 ; UNII SO9S6QZB4R);
- Bosutinib (CAS No. 380843-75-4 ; UNII 5018V4AEZ0);
- Sitravatinib (CAS No. 1123837-84-2 ; UNII CWG62Q1VTB);
- XL092 from Exelixis (CAS No. 2367004-54-2);
- Glesatinib (CAS No. 936694-12-1 ; UNII 7Q29OXD98N); and
- foretinib (CAS No. 849217-64-7; UNII 81 FH7VK1C4).
Subject
151. The method according to any preceding statement, wherein the subject is human.
152. The method according to any preceding statement, wherein the subject has, is suspected of having, or has been diagnosed as having the AXL-related disease.
Additional treatment
153. The method according to any preceding statement, wherein the AXLi is administered in combination with another therapeutic agent.
154. The method according to any preceding statement, wherein the AXLi is administered in combination with: one or more immune checkpoint modulator (ICM); and I or one or more chemotherapeutic agent and I or radiotherapy.
155. The method according to statement 154, wherein the one or more immune checkpoint modulator includes:
(i) one or more immune checkpoint inhibitors (I Cl); and I or
(ii) one or more immune checkpoint modulating antibody.
156. The method according to statement 155, wherein:
(i) one or more immune checkpoint modulating antibody is selected from the group consisting of: anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-4-1 BB antibodies, anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti-CD28 antibodies, anti-CD40 antibodies, anti-LAG3 antibodies, anti-ICOS antibodies, anti-TWEAKR antibodies, anti-HVEM antibodies, anti-TIM-1 antibodies, anti-TIM-3 antibodies, anti-VISTA antibodies, and anti-TIGIT antibodies;
(ii) one or more immune checkpoint modulating antibody is selected from the group consisting of: anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-4-1 BB antibodies, anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti-CD40 antibodies, and anti-LAG3 antibodies; or
(iii) one or more immune checkpoint modulating antibody is selected from the group consisting of: anti-CTLA-4 antibodies, anti-PD-1 antibodies, and anti-PD-L1 antibodies. 157. The method according to any one of statements 154-156, wherein the one or more immune checkpoint modulator includes:
(i) one or more T-cell co-stimulatory agonist; and I or one or more dendritic cell costimulatory receptor agonist;
(ii) at least two immune checkpoint modulators;
(iii) an immune checkpoint inhibitor; and a T cell co-stimulatory receptor agonist or a dendritic cell co-stimulatory receptor agonist; and I or
(iv) an anti-CTLA-4 antibody; and, an anti-PD-1 antibody and I or an anti-PD-L1 antibody.
158. The method according to statement 157, wherein:
(i) the anti-CTLA-4 antibody is ipilimumab or tremelimumab;
(ii) the anti-PD-1 antibody is pembrolizumab or nivolumab; and I or
(iii) the anti-PD-L1 antibody is atezolizumab (CAS number 1380723-44-3), avelumab (CAS number 1537032-82-8), or durvalumab (CAS number 1428935-60-7).
159. The method according to any one of statements 154-158, wherein the immune checkpoint modulator includes, or is: pembrolizumab; ipilimumab; ipilimumab and nivolumab; ipilimumab and pembrolizumab; tremelilumab and durvalumab.
160. The method according to statement 154, wherein the chemotherapeutic agent is a chemotherapeutic agent which:
(i) induces immunogenic cell death of cancer cells;
(ii) induces an immune response in the subject; and I or
(iii) induces a type I interferon response in the subject.
161. The method according to any one of statements 160-161, wherein the chemotherapeutic agent is an anthracycline.
162. The method according to statement 161, wherein the anthracycline is:
(i) doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin; or
(ii) doxorubicin.
163. The method according to any preceding statement, wherein the AXLi is administered in combination with an anti-PD-1 antibody, preferably pembrolizumab.
164. The method according to any preceding statement, wherein the AXLi is administered in combination with:
(i) a platinum-based chemotherapeutic, preferably carboplatin;
(ii) an antifolate chemotherapeutic, preferably pemetrexed;
(iii) a platinum-based chemotherapeutic and an antifolate chemotherapeutic, preferably carboplatin and pemetrexed; or
(iv) a platinum-based chemotherapeutic, an antifolate chemotherapeutic, and an anti- PD-1 antibody, preferably carboplatin, pemetrexed, and pembrolizumab. 165. The method according to any one of statement 163-164, wherein:
(i) the dose of the anti-PD1 antibody is about 200mg;
(ii) the anti-PD1 antibody is administered in a Q3W (once every 3 weeks) dosage regimen; and I or
(iii) the anti-PD1 antibody is administered concurrently with the AXLi.
166. The method according to any one of statements 154-165, wherein:
(i) the AXL-related disease is characterised by the presence of cells having modified STK11 activity or expression; and I or
(ii) the subject has been selected for treatment on the basis that the AXL-related disease is characterised by the presence of cells having decreased STK11 activity or expression.
167. The method according to statement 166, wherein:
(i) decreased expression is assessed by determining copy number of the gene encoding STK11 relative to a control sample, wherein a decrease in the copy number indicates a decreased level of expression;
(ii) decreased expression is assessed by determining the level of STK11 protein or mRNA relative to a control sample;
(iii) modified STK11 activity or expression is assessed by determining the presence or absence of a STK11 mutation and / or a STK111 P mutation.
168. The method according to statement 167, wherein the STK11 mutation and I or STK111 P mutation is a mutation selected from:
(i) a mutation in the nucleotide sequence encoding STK11 or STKH IP;
(ii) a mutation in a regulatory sequence controlling expression of the nucleotide sequence encoding STK11 or STK111P;
(iii) a mutation in a nucleotide encoding a protein which interacts with the transcription product of the STK11 or STK111 P gene;
(iv) a mutation in the translation product of the STK11 or STK111 P gene;
(v) a mutation in the transcription product of the STK11 or STK111 P gene;
(vi) a STK11 inactivating mutation; and I or
(vii) a STK11 IP activating mutation.
169. The method according to any preceding statement, wherein the AXLi is administered in combination with cytarabine.
Effects of treatment / regimen
170. The method according to any preceding statement, wherein the method improves subject survival or provides clinical benefit to the subject: optionally wherein the clinical benefit may be one or more of: prolonged survival, partial or complete disease remission, slowing or absence of disease progression, improved quality of life, tumour shrinkage, reduction in tumour burden, slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, hematologic improvement, bone marrow response, hematologic recovery, negative response for a genetic marker, or any other positive patient outcome. 171. The method according to any preceding statement, wherein the dosage regimen: reduces the toxicity and I or side effects associated with administration of an AXLi to a subject; and I or increases the efficacy of treatment associated with administration of an AXLi to a subject.
172. The method according to any preceding statement, wherein the dosage regimen increases AXLi exposure in the subject; and I or reduces variability in AXLi exposure in the subject.
173. The method according to any preceding statement wherein the dosage regimen improves subject survival or clinical benefit to the subject, optionally wherein the clinical benefit may be one or more of: prolonged survival, partial or complete disease remission, slowing or absence of disease progression, improved quality of life, tumour shrinkage, reduction in tumour burden, slowing or absence of tumour enlargement, slowing or absence of increase in tumour burden, hematologic improvement, bone marrow response, hematologic recovery, negative response for a genetic marker, or any other positive patient outcome.
174. The method according to any one of statements 171-173, wherein reduced toxicity, increased efficacy, improved survival, and I or improved clinical benefit is determined as compared to a comparator dosage regimen.
Second medical uses
201. An inhibitor of AXL activity or expression (AXLi) for use in a method for treating an AXL-related disease according to any one of statements 101 to 174.
202. The AXLi for use according to statement 201 , wherein the AXLi is as defined in any one of statements 146 to 150.
203. Use of an inhibitor of AXL activity or expression (AXLi) in the manufacture of a medicament for treating an AXL-related disease in a subject, wherein the treatment comprises a method according to any one of statements 101 to 174.
204. The use according to statement 203, wherein the AXLi is as defined in any one of statements 146 to 150.
Kits
301. A packaged pharmaceutical product comprising an AXLi as defined in any one of statements 146 to 150, in combination with a label or insert advising that the AXLi should be administered according to the method of any one of statements 1 to 174.
302. A kit comprising: a first medicament comprising an AXLi as defined in any one of statements 146 to 150; optionally, one or more immune checkpoint modulator (ICM) and I or one or more chemotherapeutic agent ; and a package insert or label comprising instructions for administration of the AXLi according to the method of any one of statements 1 to 174.
303. The kit according to statement 302, wherein the one or more immune checkpoint modulator (ICM) and I or one or more chemotherapeutic agent are as defined in any one of statements 155 to 169.
Further methods
401. A method of reducing the toxicity and I or side effects associated with administration of an AXLi to a subject; and I or increasing the efficacy of treatment associated with administration of an AXLi to a subject; the method comprising performing the method according to any one of statements 101 to 174.
404. A method of increasing AXLi exposure in a subject; and I or reducing variability in AXLi exposure in a subject, the method comprising performing the method according to any one of statements 101 to 174.
Additional embodiments
501. A method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose; wherein the loading dose is administered on days 1 and 2 of the dosage regimen, and the maintenance dose is administered on day 3 and on each subsequent day of the dosage regimen; and wherein the AXLi is a compound of formula (I):
Figure imgf000090_0001
wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, -C(O)R8, -C(O)N(R6)R7, and -C(=NR6)N(R6)R7;
R2 and R3 are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R9-OR8, -R9-O-R10-OR8, -R9-O-R10-O-R10-OR8, -R9-O-R10-CN, -R9-O-R10-C(O) OR8, -R9-O-R10-C(O)N(R6)R7, -R9-O-R10-S(O)PR8 (where p is 0, 1 or
2), -R9-O-R10-N(R6)R7, -R9-O-R10-C(NR11)N(R11)H, -R9-OC(O)-R8, -R9-N(R6)R7, -R9-C(O)R8, - R9-C(O)OR8, -R9-C(O)N(R6)R7, -R9-N(R6)C(O)OR8, -R9-N(R6)C(O)R8, -R9-N(R6)S(O)tR8 (where t is 1 or 2), -R9-S(O)tOR8 (where t is 1 or 2), -R9-S(O)PR8 (where p is 0, 1 or 2), and -R9-S(O)tN(R6)R7 (where t is 1 or 2); or R2 is a polycyclic heteroaryl containing more than 14 ring atoms as described above and R3 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R13-OR12, -R13-OC(O)-R12, -R13-O-R14-N(R12)2, -R13-N(R12)-R14-N(R12)2, -R 13-N(R12)-R14-N(R12)2, -R13-N(R12)2, -R13-C(O)R12, -R13-C(O)OR12, -R13-C(O)N(R12)2, -R13-C(O )N(R12)-R14-N(R12)R13, -R13-C(O)N(R12)-R14-OR12, -R13-N(R12)C(O)OR12, -R13-N(R12)C(O)R12, -R13-N(R12)S(O)tR12 (where t is 1 or 2), -R13-S(O)tOR12 (where t is 1 or 2), -R13-S(O)PR12 (where p is 0, 1 or 2), and -R13-S(O)tN(R12)2 (where t is 1 or 2); or R3 is a polycyclic heteroaryl containing more than 14 ring atoms as described above, and R2 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R13-OR12, -R13-OC(O)-R12, -R13-O-R14-N(R12)2, -R13-N(R12)-R14-N(R12)2, -R 13-N(R12)-R14-N(R12)2, -R13-N(R12)2, -R13-C(O)R12, -R13-C(O)OR12, -R13-C(O)N(R12)2, -R13-C(O )N(R12)-R14-N(R12)R13, -R13-C(O)N(R12)-R14-OR12, -R13-N(R12)C(O)OR12, -R13-N(R12)C(O)R12, -R13-N(R12)S(O)tR12 (where t is 1 or 2), -R13-S(O)tOR12 (where t is 1 or 2), -R13-S(O)PR12 (where p is 0, 1 or 2), and -R13-S(O)tN(R12)2 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R10-OR8, -R10-CN, -R10-NO2, -R10-N(R8)2, -R10-C(O)OR8 and -R10-C(O)N(R8)2, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted /V- heterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl; each R9 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R10 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R11 is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR8; each R12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl , optionally substituted heteroarylalkyl, -R10-OR8, -R10-CN, -R10-NO2, -R10-N(R8)2, -R10-C(O)OR8 and -R10-C(O)N(R8)2, or two R12s, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl; each R13 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; and each R14 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof.
502. The method of statement 501 , wherein the AXLi is 1-(6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulene-2-yl)-1 H-1 ,2,4-triazole-3,5-diamine, or a pharmaceutically acceptable salt thereof.
503. The method of any one of statements 501-502, wherein the AXLi is bemcentinib.
504. The method of any one of statements 501-503, wherein the AXL-related disease is cancer, a fibrotic disorder, or neurofibromatosis.
505. The method of statement 504, wherein the cancer is selected from the group consisting of: lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma.
506. The method of statement 504, wherein the cancer is (i) acute myeloid leukemia (AML); and I or (ii) lung cancer, preferably non-small-cell lung cancer (NSCLC).
507. The method of any one of statements 501-506, wherein the loading dose is;
(i) about 100 to 300 mg, such as about 150 to 250 mg, about 175 to 225 mg, or about
190 to 210 mg; or
(ii) about 50 to 250 mg, such as about 100 to 200 mg, about 125 to 175 mg, or about 140 to 160 mg.
508. The method of any one of statements 501-507, wherein the loading dose is:
(i) about 200 mg; or
(ii) about 150 mg.
509. The method of any preceding one of statements 501-508, wherein the maintenance dose is about 50% of the loading dose.
510. The method of statement 509, wherein the maintenance dose is:
(i) about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg; or
(ii) about 60 to 90 mg, about 65 to 85 mg, or about 70 to 80 mg.
511. The method of statement 509, wherein the maintenance dose is:
(i) about 100 mg; or
(ii) about 75 mg.
512. The method of any one of statement 501 to 508, wherein the maintenance dose is the same as the loading dose.
513. The method of statement 512, wherein the loading and maintenance dose is:
(i) about 100 mg;
(ii) about 125 mg; or
(ii) about 150 mg.
514. The method of any one of statements 501-513, wherein the maintenance dose is administered to the subject daily until treatment with the AXLi is stopped.
515. The method of statement 514, wherein treatment with the AXLi is stopped when a treatment endpoint is reached for the subject.
516. The method according to statement 515, wherein the treatment endpoint is one or more of:
(i) partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status); (ii) disease progression (progressive disease [PD] status) prompting treatment withdrawal; and I or
(iii) toxicity and I or incidence of adverse events requiring treatment withdrawal.
517. The method of any one of statements 501-516, wherein the method comprises administering the AXLi to the subject under fed conditions.
518. The method of statement 517, wherein administering the AXLi under fed conditions comprises:
(i) administering the AXLi to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or 240 minutes of the subject consuming food;
(ii) administering the AXLi to the subject less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or 240 minutes after the subject has consumed food; and I or
(iii) administering the AXLi to the subject not more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or 240 minutes before the subject has consumed, or will consume, food.
519. The method of any one of statements 501-518, wherein the AXLi is administered in combination with: one or more immune checkpoint modulator (ICM); and I or one or more chemotherapeutic agent and I or radiotherapy.
520. The method of any one of statements 501-519, wherein the subject is human.
521. The method of any one of statements 501-520, wherein the method:
(i) increases AXLi exposure in the subject; and I or
(ii) reduces variability in AXLi exposure in the subject.
522. The method of any one of statements 501-521, wherein the dosage regimen: reduces the toxicity and I or side effects associated with administration of an AXLi to a subject; and I or increases the efficacy of treatment associated with administration of an AXLi to a subject.
523. An inhibitor of AXL activity or expression (AXLi) for use in a method for treating an AXL-related disease according to any one of statements 501 to 522.
524. Use of an inhibitor of AXL activity or expression (AXLi) in the manufacture of a medicament for treating an AXL-related disease in a subject, wherein the treatment comprises a method according to any one of statements 501 to 522.
525. A packaged pharmaceutical product comprising an AXLi, in combination with a label or insert advising that the AXLi should be administered according to the method of any one of statements 501 to 522. EXAMPLES
Example 1 : Development of an optimal dosing regimen for the AXL inhibitor bemcentinib based on PKPD modelling
Investigation of a dosing regimen achieving a free concentration at a target site (e.g. lung) which would provide maximal efficacy (based on achieving 80-90% receptor occupancy and saturation of the pAXL target) with acceptable risk (TKIs are known to increase the QT/QTc interval) was performed to identify an optimal dosing regimen for bemcentinib in various indications, including cancer.
During a Phase 2 SARS-CoV-2 infection clinical trial (BGBC020, described for example in Example 10 of WO 2021/204713; NCT04890509) PK samples were taken along with ECG measurements to understand the relationship between bemcentinib exposure with response (clinical efficacy as well as safety).
A population PK model was first developed with data from the phase 1 BGBC001 healthy volunteer trial, to which the data from the Phase 2 BGBC020 study were added. During this portion of the modelling it was noticed that there seemed to be around 70% of the patients in the study who had a 2-3 fold difference in the exposure of bemcentinib within the Phase 2 study. Following examination of the data it was determined that these patients received protein pump inhibitors (PPIs) as a result of the use of the Gl disturbances caused by the extensive use of corticosteroids as part of the SOC for treatment of SARS-CoV-2 infection. It was believed that the extensive use of the PPIs was increasing the pH in the stomach and as a result was reducing the solubility of bemcentinib and its subsequent absorption.
To further understand the effect of food and PPI usage a separate food and gastric pH study was conducted (BGBC018) where the PK parameters of bemcentinib were determined in the fasted and fed state with and without the use of PPIs. As part of this study an extensive measurement of ECG was also taken to understand the relationship of exposure with QT/QTc prolongation. Data generated from this study was added to the PopPK model described above, which was then used to simulate different dosing regimens to predict Cmax and AUC levels.
Data from the PopPK model indicates that the Cmax and AUC was increased by 60 and 70% when given with food and that the variability in PK exposure between individuals was reduced by 60% providing a coefficient value (CoV) of 30% which was within the normal range of variability, previously the CoV for bemcentinib had been 90-100% when dosed in the fasted state. A possible reason for the reduced PK variability and increased exposure with food could be as a result of the inhibition of efflux transporters within the Gl tract or there was an increased amount of transport through the lymphatic system due to the increased lipid content within the Gl tract due to the addition of food. This surprising decrease in variability provided the unique opportunity to reduce the dose as well as reduce the incidence of QT/QTc prolongation which had been seen in earlier oncology studies where there were incidences of Grade 3 AEs related to QT/QTc change (>500ms or >60ms D-QT/QTc). In order to investigate this opportunity, a separate PKPD model was developed to understand the relationship of bemcentinib exposure (Cmax and AUC) and QT/QTc. As outlined above, development of this PKPD model involved collection of electrocardiographic data, which was done in both the active treatment and standard of care control patients during the early acute phase of their hospital admission. Surprisingly, this data showed prolongation of QTcF (corrected QT interval by Fredericia) in patients treated in the control arm (due to either the disease pathogenesis or administered therapies), which has not previously been reported in a controlled trial. From this PKPD modelling it was determined that by reducing the dose of bemcentinib and dosing with food that the exposure would be the same with around 50% of the dose but that the potential for QT/QTc prolongation because of high variability would be greatly reduced.
As a result of this information a number of different dosing regimens were developed based on the different indications being developed to provide the maximum clinical benefit with acceptable risk. Based on this modelling, optimal doses of bemcentinib for chronic I long-term dosing were determined. In an acute setting the planned doses are as follows:
• 200 mg loading dose for 2 days followed by 100 mg dose maintenance in a fed state;
• 150 mg loading dose for 2 days followed by 75 mg dose maintenance in a fed state;
• 150 mg daily dose in fed state; and
• 100 mg daily dose in fed state.
These doses have been modelled to provide an exposure which will engage and inhibit the biological target as well as reduce the potential for QT/QTc prolongation as a result of accumulation of bemcentinib with chronic dosing. These doses are predicted to provide a change in QTc within the acceptable non-oncology and oncology regulatory limits for QTc - the dose of 200/100 mg is predicted to provide a change in QTc of 19ms (based on 90% Cl), while 150mg daily is predicted to provide a change of 29ms (based on a 90% Cl). The 19ms and 29ms intervals are below the 20ms and 30ms levels which are the acceptable nononcology and oncology regulatory limits for QTc. In settings where bemcentinib is given in combination with other drugs (such as oncology, in combination with other oncology treatments), regimens with no loading dose (e.g. 100 mg daily dose in fed state) may be preferrable.
These dosage regimens will be used in future clinical trials investigating safety and efficacy of bemcentinib, for example a planned Phase 1 b/2a clinical trial of safety and efficacy of bemcentinib + standard of care (SoC) for the treatment of untreated advanced I metastatic non-squamous NSCLC (BGBC016).
Interpretation of the PKPD model outputs required clinical consideration of the additional risk of ECG change due to bemcentinib as a relative risk increase compared to the dynamic risk observed in the standard of care arm. Thus, the doses selected and their timing required careful judgement of early added risk during the loading dose period (and the shortening of its duration by 33%), against the need to maintain the efficacy onset which is apparent from the clinical data within the first two days of the study. The later maintenance dose selected for each administration case was tuned to balance the overall risk of for chronic / long-term dosing. Similarly, the doses selected and their timing required careful judgement in the context of other drugs that will be administered in combination with bemcentinib (e.g. other oncology treatments in the oncology setting).
Example 2: Synopsis of dosing protocol (BGBC016)
Protocol Title:
Phase 1 B/2A safety and tolerability study of bemcentinib with pembrolizumab I carboplatin I pemetrexed in subjects with untreated advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) without I with a STK11 mutation.
Indication:
Phase 1b: Previously untreated locally advanced (stage II Ib/I llc)/metastatic (stage IV) non- squamous NSCLC without actionable mutations (for phase 1 b)
Phase 2a: Previously untreated locally advanced (stage lllb/lllc)/metastatic (stage IV) non- squamous NSCLC having a serine/threonine kinase 11 (STK11) mutation as identified by Next Generation Sequencing (NGS) and without actionable mutations
Rationale:
NSCLC is a life-threatening condition with a clear unmet need, particularly for subjects diagnosed with advanced or metastatic non-squamous NSCLC without a driver mutation, who remain the majority of NSCLC patients. Despite advances in therapeutic regimens, the 5-year survival of NSCLC is still approximately 20-30%. (Min et al., 2021). Current developments for first-line (1 L) treatment of NSCLC define a widening role for chemo-immunotherapy regardless of programmed death-ligand 1 (PD-L1) status, with approval for the combination of platinum, pemetrexed, and pembrolizumab in 1 L, which has become the standard of care (SOC). However, despite an initial improvement in response rates and survival, the emergence of chemoresistance poses a significant obstacle to the management of NSCLC and highlights the unmet medical need in these patients (Min et al., 2021).
Bemcentinib is a potent and highly selective, orally bioavailable, inhibitor of AXL tyrosine kinase. Bemcentinib potentiates the anti-tumorigenic activity of innate immune cells through regulation of myeloid suppressor activation, prevents and reverses aggressive EMT driven phenotypes in NSCLC cells, therefore potentiating the immune therapy through tumor EMT modulation, enhanced Type 1 IFN response and modulation of the immune cell landscape.
Objectives and Endpoints:
Figure imgf000097_0001
Figure imgf000098_0001
Abbreviations: 1L=first line; AE=adverse event; C1 D1=Cycle1 Day1 ; CIT=chemo- immunotherapy (pembrolizumab plus pemetrexed and carboplatin) DCR= disease control rate; DLT=dose limiting toxicity; DOR=duration of response; ORR=objective response rate; OS=overall survival; PFS=progression free survival; RP2D=recommended phase 2 dose.
Overall Design:
This is an open-label, multi-center phase 1 b/2a clinical study to assess the safety, tolerability, and preliminary anti-tumor activity of bemcentinib in combination with chemo-immunotherapy ([CIT] comprising pembrolizumab plus pemetrexed and carboplatin) as 1 L treatment in subjects with locally advanced (stage lllb/lllc) or metastatic (stage IV) non squamous NSCLC without actionable mutations, irrespective of PD-L1 status, with or without STK11 m depending on the study phase.
All subjects will receive bemcentinib once daily in combination with CIT administered on Day 1 of 21 -day treatment cycles.
• Phase 1b: Previously untreated locally advanced (stage 11 Ib/ll lc)/metastatic (stage IV) non-squamous NSCLC without actionable mutations.
• Phase 2a: Previously untreated locally advanced (stage 11 Ib/ll lc)/metastatic (stage IV) non-squamous NSCLC having a serine/threonine kinase 11 (STK11) mutation as identified by Next Generation Sequencing (NGS) and without actionable mutations.
Phase 1 b follows a standard 3+3 design: 3 subjects will receive bemcentinib + CIT at one of 3 dose levels: Cohort 1=75 mg daily dose of bemcentinib; Cohort 2=100 mg daily dose of bemcentinib; or Cohort 3=150 mg daily dose of bemcentinib. An independent data safety monitoring board (DSMB) will be responsible for reviewing the safety data from each cohort at the end of the DLT assessment period of each cohort and will provide recommendations to the Sponsor on progressive dose cohort management. Further, based on overall clinical tolerability, the DSMB will recommend the bemcentinib dose(s) for the phase 2a expansion cohort(s).
Subjects will take bemcentinib capsules daily and will continue until a reason for discontinuation has been met or for up to 2 years, whichever comes first. Subjects will receive CIT on Day 1 of each 21-day cycle for a maximum of 4 cycles. After completion of the 4 cycles of CIT, subjects will receive maintenance bemcentinib, pembrolizumab, and pemetrexed for up to 2 years.
Both Phase 1 b and 2a of the clinical study consists of a screening period (up to 28 days), a treatment period (up to 24 months), and a post treatment safety follow up period (30 days).
The primary endpoint for phase 1 b will be assessed after the first 21 days from C1 D1 for each subject. The DLT evaluable population includes all enrolled subjects in phase 1 b who received a full dose of bemcentinib and completed evaluation for DLT in Cycle 1 or received a partial dose of study drug and developed DLT during Cycle 1. The primary endpoint for phase 2ab is measured at regular intervals over the whole duration of the clinical study, for up to 24 months. In the phase 2a expansion there will be an interim analysis after 20 subjects have completed 2 cycles (no earlier than day 42) with the purpose of identifying potential early efficacy signals.
Main Assessments:
The safety assessments include AEs, safety laboratory parameters, vital signs, and ECG changes based on CTCAE v5.0.
Efficacy assessments will all be based on tumor assessment scan evaluation by RECIST 1.1. Assessments will be performed using contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) assessments of chest, abdomen, and pelvis. Additionally, x-ray and bone scans will be used as appropriate.
Number of subjects:
For phase 1 b of the clinical study, 9 to 24 subjects will be enrolled.
For phase 2a of the clinical study, 40 subjects will be enrolled.
Assuming a 30% screening failure rate, up to 92 subjects will be screened for the maximum of 64 dosed subjects.
Statistical methods:
The analysis will be primarily descriptive in nature and the clinical study is not statistically powered.
The primary endpoint for phase 1b, will be analyzed on the DLT evaluable population set, using only phase 1b data.
The primary endpoint of the phase 2a clinical study will be analyzed on the per-protocol analysis set, using only phase 2a data. Analysis of ORR will occur in a Bayesian framework.
Treatment groups and duration:
The expected duration of the clinical study for each subject will be no more than 26 months.
Data Monitoring Committee:
An independent data safety monitoring board (DSMB) will be responsible for reviewing the safety data from each cohort at the end of the DLT assessment period of each cohort and will provide recommendations to the Sponsor on the dose cohort management. Further, based on overall clinical tolerability, the DSMB will recommend the bemcentinib dose(s) for the phase 2a expansion cohort(s).
Example 3: Human ADME study of bemcentinib (BGBC021)
A Phase 1 , open-label, non-randomized study was conducted to investigate the mass balance recovery and metabolic profile of 14C-bemcentinib following a single oral administration in healthy male subjects. All subjects fasted overnight (at least 8 hours) and consumed a standard high-fat breakfast 30 minutes prior to dosing. All subjects fasted until 4.5 hours postdose. Within the study six subjects received a single oral dose of 14C-bemcentinib (32.8 pCi, 200 mg as two 100 mg capsules).
Blood samples were taken pre-dose, and at 15 and 30 minutes, 1 , 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours following the oral dose. The pharmacokinetics (PK) of total radioactivity and bemcentinib were determined as part of the study using a validated LCMS bioanalytical method.
Following a single oral administration of 14C-bemcentinib in a fed state the geometric mean Cmax was 55.8 ng/mL (23.5%) and the AllCo-t 5590 ng.h/mL (13.3%) (see Table 1). The coefficient of variation between patients was 23.5% for Cmax and 13.3% for ALICo-t as represented in Figure 1. These results were in contrast to data generated in clinical study BGBC001 , a Phase 1 first-in-human study that investigated the safety and pharmacokinetics (PK) of bemcentinib, where bemcentinib was shown to have a high geometric coefficient of variation (CV) of 73.1-81.8% and 59.7-96.7% for Cmax and ALICo-t, respectively, when subjects were dosed in the fasted state (see Table 1).
Table 1
Figure imgf000101_0001
Data from clinical study BGBC021 indicates that the Cmax and AUC exposure of bemcentinib are increased 52% and 72%, respectively. The coefficient of variation between patients was reduced 71% and 78% for Cmax and AUC respectively when bemcentinib was dosed with food as compared to a fasted state. These data were in line with the data that was generated during the BGBC0018 food effect study (described in Example 1 above).

Claims

1 . A method for treating an AXL-related disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or expression (AXLi), wherein the AXLi is administered to the subject in a dosage regimen comprising a loading dose and a maintenance dose; wherein the loading dose is administered on days 1 and 2 of the dosage regimen, and the maintenance dose is administered on day 3 and on each subsequent day of the dosage regimen; and wherein the AXLi is a compound of formula (I):
Figure imgf000102_0001
wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, -C(O)R8, -C(O)N(R6)R7, and -C(=NR6)N(R6)R7;
R2 and R3 are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R9-OR8, -R9-O-R10-OR8, -R9-O-R10-O-R10-OR8, -R9-O-R10-CN, -R9-O-R10-C(O) OR8, -R9-O-R10-C(O)N(R6)R7, -R9-O-R10-S(O)PR8 (where p is 0, 1 or
2), -R9-O-R10-N(R6)R7, -R9-O-R10-C(NR11)N(R11)H, -R9-OC(O)-R8, -R9-N(R6)R7, -R9-C(O)R8, - R9-C(O)OR8, -R9-C(O)N(R6)R7, -R9-N(R6)C(O)OR8, -R9-N(R6)C(O)R8, -R9-N(R6)S(O)tR8 (where t is 1 or 2), -R9-S(O)tOR8 (where t is 1 or 2), -R9-S(O)PR8 (where p is 0, 1 or 2), and -R9-S(O)tN(R6)R7 (where t is 1 or 2); or R2 is a polycyclic heteroaryl containing more than 14 ring atoms as described above and R3 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R13-OR12, -R13-OC(O)-R12, -R13-O-R14-N(R12)2, -R13-N(R12)-R14-N(R12)2, -R 13-N(R12)-R14-N(R12)2, -R13-N(R12)2, -R13-C(O)R12, -R13-C(O)OR12, -R13-C(O)N(R12)2, -R13-C(O )N(R12)-R14-N(R12)R13, -R13-C(O)N(R12)-R14-OR12, -R13-N(R12)C(O)OR12, -R13-N(R12)C(O)R12, -R13-N(R12)S(O)tR12 (where t is 1 or 2), -R13-S(O)tOR12 (where t is 1 or 2), -R13-S(O)PR12 (where p is 0, 1 or 2), and -R13-S(O)tN(R12)2 (where t is 1 or 2); or R3 is a polycyclic heteroaryl containing more than 14 ring atoms as described above, and R2 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R13-OR12, -R13-OC(O)-R12, -R13-O-R14-N(R12)2, -R13-N(R12)-R14-N(R12)2, -R 13-N(R12)-R14-N(R12)2, -R13-N(R12)2, -R13-C(O)R12, -R13-C(O)OR12, -R13-C(O)N(R12)2, -R13-C(0 )N(R12)-R14-N(R12)R13, -R13-C(O)N(R12)-R14-OR12, -R13-N(R12)C(O)OR12, -R13-N(R12)C(O)R12, -R13-N(R12)S(O)tR12 (where t is 1 or 2), -R13-S(O)tOR12 (where t is 1 or 2), -R13-S(O)PR12 (where p is 0, 1 or 2), and -R13-S(O)tN(R12)2 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R10-OR8, -R10-CN, -R10-NO2, -R10-N(R8)2, -R10-C(O)OR8 and -R10-C(O)N(R8)2, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted /V- heterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl; each R9 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R10 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R11 is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR8; each R12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl , optionally substituted heteroarylalkyl, -R10-OR8, -R10-CN, -R10-NO2, -R10-N(R8)2, -R10-C(O)OR8 and -R10-C(O)N(R8)2, or two R12s, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heterocyclyl or an optionally substituted /V-heteroaryl; each R13 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; and each R14 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof.
2. The method of claim 1 , wherein the AXLi is 1-(6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulene-2-yl)-1 H-1 ,2,4-triazole-3,5-diamine, or a pharmaceutically acceptable salt thereof.
3. The method of any preceding claim, wherein the AXLi is bemcentinib.
4. The method of any preceding claim, wherein the AXL-related disease is cancer, a fibrotic disorder, or neurofibromatosis.
5. The method of claim 4, wherein the cancer is selected from the group consisting of: lung cancer, non-small-cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplatic syndrome (MDS), pancreas cancer, kidney cancer, urothelial carcinoma, ovarian cancer, neurofibroma, cranial or spinal meningioma, Schwannoma, ependymoma, and glioblastoma.
6. The method of claim 4, wherein the cancer is (i) acute myeloid leukemia (AML); and I or (ii) lung cancer, preferably non-small-cell lung cancer (NSCLC).
7. The method of any preceding claim, wherein the loading dose is;
(i) about 100 to 300 mg, such as about 150 to 250 mg, about 175 to 225 mg, or about 190 to 210 mg; or
(ii) about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg.
8. The method of any preceding claim, wherein the loading dose is:
(i) about 200 mg; or
(ii) about 100 mg.
9. The method of any preceding claim, wherein the maintenance dose is about 50% of the loading dose.
10. The method of claim 9, wherein the maintenance dose is about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg.
11. The method of claim 9, wherein the maintenance dose is about 100 mg.
12. The method of any one of claims 1 to 8, wherein the maintenance dose is the same as the loading dose.
13. The method of claim 12, wherein the loading and maintenance dose is about 100 mg.
14. The method of any preceding claim, wherein the maintenance dose is administered to the subject daily until treatment with the AXLi is stopped.
15. The method of claim 14, wherein treatment with the AXLi is stopped when a treatment endpoint is reached for the subject.
16. The method according to claim 15, wherein the treatment endpoint is one or more of:
(i) partial or complete disease remission (attaining partial remission [PR] or complete remission [CR] status);
(ii) disease progression (progressive disease [PD] status) prompting treatment withdrawal; and I or
(iii) toxicity and I or incidence of adverse events requiring treatment withdrawal.
17. The method of any preceding claim, wherein the method comprises administering the AXLi to the subject under fed conditions.
18. The method of claim 17, wherein administering the AXLi under fed conditions comprises:
(i) administering the AXLi to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or 240 minutes of the subject consuming food;
(ii) administering the AXLi to the subject less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or 240 minutes after the subject has consumed food; and I or
(iii) administering the AXLi to the subject not more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or 240 minutes before the subject has consumed, or will consume, food.
19. The method of any preceding claim, wherein the AXLi is administered in combination with: one or more immune checkpoint modulator (ICM); and I or one or more chemotherapeutic agent and I or radiotherapy.
20. The method of any preceding claim, wherein the subject is human.
21. The method of any preceding claim, wherein the method:
(i) increases AXLi exposure in the subject; and I or
(ii) reduces variability in AXLi exposure in the subject.
22. The method of any preceding claim, wherein the dosage regimen: reduces the toxicity and I or side effects associated with administration of an AXLi to a subject; and I or increases the efficacy of treatment associated with administration of an AXLi to a subject.
23. An inhibitor of AXL activity or expression (AXLi) for use in a method for treating an
AXL-related disease according to any one of claims 1 to 22.
24. Use of an inhibitor of AXL activity or expression (AXLi) in the manufacture of a medicament for treating an AXL-related disease in a subject, wherein the treatment comprises a method according to any one of claims 1 to 22.
25. A packaged pharmaceutical product comprising an AXLi, in combination with a label or insert advising that the AXLi should be administered according to the method of any one of claims 1 to 22.
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