WO2018222135A1 - Cancérothérapie - Google Patents

Cancérothérapie Download PDF

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WO2018222135A1
WO2018222135A1 PCT/SG2018/050210 SG2018050210W WO2018222135A1 WO 2018222135 A1 WO2018222135 A1 WO 2018222135A1 SG 2018050210 W SG2018050210 W SG 2018050210W WO 2018222135 A1 WO2018222135 A1 WO 2018222135A1
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inhibitor
cancer
treatment according
therapy
treatment
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PCT/SG2018/050210
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English (en)
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Mark Thomas Mchale
Bertil Lindmark
Ann Gee Lisa OOI
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Aslan Pharmaceuticals Pte Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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

  • the present disclosure relates to a method of treating cancer which is PTEN mutated with a therapy comprising a DHODH inhibitor or a pharmaceutically acceptable salt thereof.
  • Phosphatase and tensin homolog deleted on chromosome 10 is one of the most frequently mutated tumor suppressor genes in human cancers. PTEN deficiency is caused by inherited germline mutations, somatic mutations, epigenetic and transcriptional silencing, post- translational modifications, and protein-protein interactions.
  • PTEN phosphatidylinositol 3 -kinase
  • PI3K phosphatidylinositol 3 -kinase
  • PTEN mutations occur most frequently in three types of human cancer: glioblastoma, endometrial and prostate cancer but also occur in liver cancer (such as hepatocellular carcinoma] and colorectal cancer. Given the high frequency of PTEN deficiency across cancer subtypes, therapeutic approaches that address PTEN loss of function may provide useful cancer treatments.
  • DHODH inhibitors Dihydroorotate dehydrogenase inhibitors
  • Known DHODH inhibitors include leflunomide or teriflunomide.
  • the present inventors believe that the DHODH inhibitor 2-(3,5-difluoro- 3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof is also useful in the treatment of cancers in which PTEN is mutated, for example glioblastoma, endometrial cancer, melanoma, liver cancer, colorectal cancer, breast cancer and prostate cancer.
  • the present disclosure provides a method of treating a cancer patient characterised in that the cancer is PTEN mutated, said treatment comprising administering a therapeutically effective amount of a DHODH inhibitor 2-(3,5-difluoro-3'methoxybiphenyl-4- ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof.
  • the cancer is glioblastoma, endometrial cancer, melanoma, liver cancer, colorectal cancer, biliary duct cancer, gastric cancer, breast cancer and prostate cancer.
  • the PTEN mutated haematological cancer for CML, AML, CLL, or ALL.
  • the cancer is a PTEN mutated myeloid malignancy.
  • the haematological cancer is selected from myeloma, lymphoma, leukaemia, such as acute myeloid leukaemia (AML], chronic myeloproliferative disease, monoclonal gammopathy of uncertain significance, myelodysplasia syndrome and amyloidosis.
  • the myeloma is selected from multiple myeloma, amyloidosis and plasmacytoma.
  • the myeloma is selected from monoclonal gammopathy of undetermined significance, asymoptomatic myeloman, symptomatic myeloma and Kahler's disease.
  • the lymphoma is selected from anaplastic large cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, and Waldenstrom's macroglobulinaemia.
  • the chronic myeloproliferative disease is selected from essential thrombocythaemia, chronic idiopathic myelofibrosis, and polycythaemia rubra vera.
  • the leukaemia is selected from acute myeloid leukaemia (AML], hairy cell leukaemia, acute lymphoblastic leukaemia, and chronic lymphoblastic leukaemia.
  • AML acute myeloid leukaemia
  • hairy cell leukaemia hairy cell leukaemia
  • acute lymphoblastic leukaemia acute lymphoblastic leukaemia
  • chronic lymphoblastic leukaemia chronic lymphoblastic leukaemia
  • the haematological cancer is acute myeloid leukaemia.
  • the DHODH inhibitor provides anticancer efficacy via induction of p53.
  • the DHODH inhibitor is administered orally, for example once daily, or bi-daily.
  • the DHODH inhibitor is administered at a dose of 50 to 500 mg/kg, for example 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg/kg.
  • the DHODH inhibitor is administered at a dose of 100 mg/kg.
  • the DHODH inhibitor is administered at a dose of 100 mg/kg, once daily.
  • 2-(3,5-difluoro-3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer, in particular a PTEN mutated cancer, for example as disclosed herein.
  • a DHODH inhibitor 2-(3,5-difluoro- 3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt in the manufacture of a therapy for the treatment of a cancer, in particular a PTEN mutated cancer, for example as disclosed herein.
  • DHODH inhibitor 2-(3,5-difluoro-3'methoxybiphenyl-4- ylamino]nicotinic acid or a pharmaceutically acceptable salt in the treatment of patient population characterised in that they have PTEN mutation in a cancer, for example where a patient has been identified as part of the relevant population before treatment with said DHODH inhibitor.
  • the DHODH inhibitor is employed in a combination therapy with a second therapy, in particular a second cancer therapy.
  • a DHODH inhibitor 2-(3,5-difluoro- 3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt for use in a combination therapy for the treatment of a cancer, in particular a PTEN mutated cancer, for example as disclosed herein.
  • a DHODH inhibitor 2-(3,5-difluoro- 3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt in the manufacture of a combination therapy for the treatment of a cancer, in particular a PTEN mutated cancer, for example as disclosed herein.
  • the second therapy is an inhibitor of DNA repair.
  • the inhibitor is a small molecule therapy or biological therapy.
  • inhibitor mechanism is via the base excision repair pathway.
  • the inhibitor's target is independently selected from APE1, Pol ⁇ , FEN1, and PARP.
  • the inhibitor is selected from TRC102, (2E]-2-[(4,5-Dimethoxy-2- methyl-3,6-dioxo-l,4-cyclohexadien-l-yl]methylene]-undecanoic acid [also known as E3330], NCS- 666715 and NSC-124854, 8-oxoguamine, tanespirmycin, luminespib, alvespimycin, genetespib, retaspimycin, 6-Amino-8- [(6-iodo-l,3-benzodioxol-5-yl]thio]-N-(l-methylethyl]-9H-purine-9- propanamine (PU-H71], 4-[2-carbamoyl-5- [6,6-dimethyl-4-oxo-3-(trifluoromethyl]-5,7- dihydroindazol-l-yl]anilino]cyclohexyl] 2-amin
  • the inhibitor is a PARP inhibitor, such as a PARP-1 and/or PARP-2 inhibitor.
  • the PARP inhibitor is independently selected from olaparib, rucaparib, niraparib, iniparib, talazoparib, veliparib, CEP9722, E7016, BGB-290, AZD-2461, 3-aminobenzamide and combinations thereof.
  • the inhibitor mechanism is via the mismatch repair pathway.
  • the inhibitor mechanism is via the nucleotide excision pathway.
  • the inhibitor is independently selected from 7-hydroxystaurosporine [UCN-01], trabectedin, MCI13E, NERI01 and combinations of two or more of the same.
  • the inhibitor mechanism is via the double stranded break repair pathway.
  • the inhibitor mechanism is via the non-homologous end joining pathway.
  • the inhibitor mechanism is via the homologous recombination pathway.
  • the second therapy is a topoisomerase inhibitor, such as topoisomerase I and/or II inhibitor.
  • the topoisomerase inhibitor is independently selected from irinotecan, topotecan, camptothecin lamellarin D and combinations thereof.
  • the topoisomerase inhibitor is independently selected from etoposide (VP- 16], teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, 3-Hydroxy-2-[(li?]-6-isopropenyl-3-methyl-cyclohex-2-en-l-yl]-5-pentyl- 1,4-benzoquinone (HU-331] and combinations thereof.
  • the topoisomerase inhibitor is doxorubicin.
  • the therapy further comprises a pan-HER inhibitor (i?]-N4-[3-Chloro-4- (thiazol2-ylmethoxy]-phenyl]-N6-(4-methyl-4,5,-dihydro-oxazol-2-yl]-quinazoline-4,6-diamine (also known as Varlitinib] or a pharmaceutically acceptable salt thereof.
  • pan-HER inhibitor is administered parenterally.
  • pan-HER inhibitor is administered orally, for example is administered bi-daily.
  • each dose of pan-HER inhibitor is in the range 100 to 900mg, such as 100, 200, 300, 400, 500, 600, 700, 800 or 900 mg, for example wherein each dose is in the range 300 to 500mg, for example each dose is in the range 300 to 500mg.
  • the disclosure also extends to a combination therapy comprising a DHODH inhibitor 2- (3,5- difluoro-3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof and a second therapy (for example an-HER inhibitor (such as (i?]-N4- [3-Chloro-4-(thiazol2- ylmethoxy]-phenyl]-N6-(4-methyl-4,5,-dihydro-oxazol-2-yl]-quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof)]]]]]]]]]] for use in the treatment of a PTEN mutated cancer, for example as disclosed herein.
  • a DHODH inhibitor 2- (3,5- difluoro-3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof
  • a second therapy for example an-HER inhibitor (such as (i?]-N
  • a DHODH inhibitor 2-(3,5-difluoro-3'methoxybiphenyl-4- ylamino]nicotinic acid or a pharmaceutically acceptable salt and a second therapy for example pan- HER inhibitor (such as fl]-N4- [3-Chloro-4-(thiazol2-ylmethoxy]-phenyl]-N6-(4-methyl-4,5,- dihydro-oxazol-2-yl]-quinazoline-4,6-diamine or a pharmaceutically acceptable saltthereof]] in the manufacture of a combination therapy for the treatment of a cancer, in particular a PTEN mutated cancer, for example as disclosed herein.
  • a second therapy for example pan- HER inhibitor (such as fl]-N4- [3-Chloro-4-(thiazol2-ylmethoxy]-phenyl]-N6-(4-methyl-4,5,- dihydro-oxazol-2-yl]-quinazoline
  • a 2-(3,5-difluoro-3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable saltthereof for use in the treatment of a PTEN mutated cancer, in particular a PTEN mutated cancer which is negative for a marker selected from ER, PR, HER 2 and a combination of two or more of the same, such as ER & PR, ER & HER2, PR & HER2 or ER, PR & HER2 (triple negative]. as disclosed herein.
  • a DHODH inhibitor 2-(3,5-difluoro- 3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt in the manufacture of a combination therapy for the treatment of a PTEN mutated cancer, in particular a PTEN mutated cancer which is negative for a marker selected from ER, PR, HER 2 and a combination of two or more of the same, such as ER & PR, ER & HER2, PR & HER2 or ER, PR & HER2 (triple negative].
  • a marker selected from ER, PR, HER 2 and a combination of two or more of the same, such as ER & PR, ER & HER2, PR & HER2 or ER, PR & HER2 (triple negative].
  • the therapy of the present disclosure continues for 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, 53, 54, 55, 56, 57, 58, 59, 60 months or more.
  • dosing of the second therapy continues for 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, 53, 54, 55, 56, 57, 58, 59, 60 months or more.
  • a pan-HER inhibitor such as Varlitinib
  • Varlitinib is administered in a 28-day cycle.
  • the patient is a human.
  • a method of treating a cancer patient characterised in that the cancer is PTEN mutated comprising administering a therapeutically effective amount of a DHODH inhibitor 2-(3,5-difluoro-3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof.
  • inhibitor's target is independently selected from APE1, Pol ⁇ , FEN1, and PARP.
  • the PARP inhibitor is independently selected from olaparib, rucaparib, niraparib, iniparib, talazoparib, veliparib, CEP9722, E7016, BGB-290, AZD-2461, 3-aminobenzamide and combinations thereof.
  • topoisomerase inhibitor is independently selected from irinotecan, topotecan, camptothecin lamellarin D and combinations thereof.
  • topoisomerase inhibitor is independently selected from etoposide (VP- 16], teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, 3-Hydroxy-2- [(li?]-6- isopropenyl-3-methyl-cyclohex-2-en- l-yl]-5-pentyl-l,4-benzoquinone (HU-331] and combinations thereof.
  • etoposide teniposide
  • doxorubicin doxorubicin
  • daunorubicin daunorubicin
  • mitoxantrone amsacrine
  • ellipticines aurintricarboxylic acid
  • the therapy further comprises a pan-HER inhibitor, for example (i?]-N4- [3-Chloro-4- (thiazol2-ylmethoxy]-phenyl]-N6-(4- methyl-4,5,-dihydro-oxazol-2-yl]-quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof.
  • a pan-HER inhibitor for example (i?]-N4- [3-Chloro-4- (thiazol2-ylmethoxy]-phenyl]-N6-(4- methyl-4,5,-dihydro-oxazol-2-yl]-quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof.
  • a DHODH inhibitor 2-(3,5-difluoro-3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt in the manufacture of a combination therapy for the treatment of a PTEN mutated cancer, which in negative for a marker selected from ER, PR, HER 2 and a combination of two or more of the same (such as ER & PR, ER & HER2, PR & HER2 or triple negative].
  • cancer is selected from the group consisting of glioblastoma, endometrial cancer, melanoma, breast cancer and prostate cancer.
  • PTEN mutated cancer refers to any type of cancer where there is a genetic mutation in the PTEN gene.
  • PTEN mutations include inherited germ line mutations as well as somatic mutations. Examples of mutations include but are not limited to insertions, deletions, frameshifts, in-frame deletions, truncations, missense mutations, nonsense mutations, repeat expansions and point mutations. Generally, in the context of cancer or cancer- facilitating diseases the mutation is reduction or loss of PTEN activity.
  • DHODH is a key enzyme in the production of uridine, which is a central building block in the cell. Whilst not wishing to be bound by theory, it may be that the DHODH inhibitor is able to upregulate p53 based apoptosis.
  • the up-regulation of p53 (which may lead to cell cycle arrest and at higher levels of p 53, to apoptosis] is likely to occur via mechanisms sensing the levels of intracellular uridine, and then setting forth a series of reactions leading to stabilisation of p53, and increasing its concentration (also referred to herein as p53 induction].
  • DHODH inhibitors such as -(3,5-difluoro- 3'methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof are particularly advantageous for use in the treatment of PTEN mutated cancers because they kill the cancer cells via apoptosis, which does not involve necrotic cell death.
  • Necrosis a form of cell injury which results in premature death of cells in living tissue by autolysis (i.e. destruction of the cell through the action of its own enzymes]. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma which result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death.
  • necrotic cell death does not follow the apoptotic signal transduction pathway, but rather various receptors are activated, and result in the loss of cell membrane integrity and an uncontrolled release of products of cell death into the extracellular space.
  • necrosis results in a build-up of decomposing dead tissue and cell debris at or near the site of the cell death.
  • a classic example is gangrene. For this reason, it is often necessary to remove necrotic tissue surgically, a procedure known as debridement.
  • First generation DHODH inhibitors such as leflunomide and teriflunomide are thought to kill cells by necrotic mechanisms.
  • the DHODH inhibitor herein may be beneficial in the therapy according to the present disclosure because the biological effects are stronger than those of "first generation" DHODH inhibitors, such as leflunomide and teriflunomide.
  • the DHODH inhibitor of the present disclosure may have less toxicity (off target effects] than the so-called "first generations” inhibitors, such as leflunomide and teriflunomide.
  • the ability to treat PTEN mutated cancers with DHODH inhibitor that causes apoptotic cell death is likely to lead to less side effects and an overall better therapeutic outcome.
  • Employing the DHODH inhibitor as a combination therapy, for example wherein the second therapy is an inhibitor of the DNA repair or a pan-HER inhibitor may be particular beneficial to minimises the cancers ability to resist treatment, in particular by "attacking" the cancer cells by two or more mechanisms with the combination therapy.
  • an inhibitor of DNA repair for example, the sensitivity of a tumor cell to DNA damage caused by anti-cancer agents and thus DNA damage-induced cell death is enhanced. Thus it may also be desirable to use this combination therapy with chemotherapy.
  • ABT-737 a PARP-1 and PARP-2 inhibitor
  • Topoisomerase inhibitors which may be employed in a method of the present disclosure include type I topoisomerase inhibitors, type II topoisomerase inhibitors and type II topoisomerase poisons.
  • Type I inhibitors include topotecan, irinotecan, indotecan and indimitecan.
  • Type II inhibitors include genistein and ICRF 193 which has the following structure:
  • Type II poisons include amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin and fluoroquinolones.
  • the DHODH inhibitor of the present disclosure (alone as a combination therapy] is employed in a combination therapy comprising chemotherapy, in particular a described herein.
  • a method of treating a patient comprising administering a therapeutically effective amount of an inhibitor of at least HER2 and a therapeutically effective amount of DHODH inhibitor.
  • the pan-HER inhibitor is an inhibitor of at least two HER receptors. In one embodiment at least one of the HER receptors inhibited is HER2.
  • the pan-HER inhibitor is an organic chemistry molecule, for example with a molecular weight of 500 or less.
  • pan-HER inhibitor has a molecular formula of formula (I]:
  • the pan-HER inhibitor is an inhibitor of one or more HER receptors independently selected from HER1, HER2, HER3, HER4.
  • the biological therapeutic agent is administered parenterally.
  • Varlitinib is employed as a free base. Varlitinib at an appropriate dose is capable of inhibiting HERl, HER2 and HER4 directly and thought to be capable of inhibiting HER3 indirectly.
  • the compound of formula (I] (including formula (la] and Varlitinib] at least inhibits the activity of HERl and HER2, HERl and HER4 or HER2 and HER4.
  • the compound of formula (I] (including formula (la] and Varlitinib] at least inhibits the activity of HERl, HER2 and HER4, for example directly inhibits the activity of HERl, HER2 and HER4.
  • the compound of formula (I] (including formula (la] and Varlitinib] inhibits the activity of HERl, HER2, HER3 and HER4, for example directly inhibits the activity of HERl, HER2, and HER4, and indirectly inhibits the activity of HER3
  • each dose of the compound of formula (I], (including formula (la] and Varlitinib] is in the range 100 to 900mg, for example each dose is in the range of 300 to 500mg, such as 400mg, for example administered once or twice daily, such as twice daily.
  • patients may benefit from having the initial dose reduced to 300mg or 200mg bi-daily.
  • Other patients may benefit from receiving the compound of formula (I], such as Varlitinib for example in a regime which is non-continuous, such as taking medication on alternate days instead of each day or taking medication for four sequential days followed by one, two or three days without medication.
  • a regime which is non-continuous such as taking medication on alternate days instead of each day or taking medication for four sequential days followed by one, two or three days without medication.
  • the compound of formula (I], (including formula (la] and Varlitinib] is administered orally.
  • the HER inhibitor is a combination of HER inhibitors, for example a combination of Varlitinib and Herceptin (trastuzumab] and/or pertuzumab.
  • a combination of Varlitinib and Herceptin show more therapeutic activity than either entity alone.
  • the DHODH inhibitor is 2- (3, 5-difluoro-3'-methoxybiphenyl-4-ylamino] nicotinic acid (referred to herein as ASLAN003] has the structure:
  • the DHODH inhibitor is administered daily, for example once daily. In one embodiment the DHODH inhibitor is administered orally. In one embodiment the DHODH inhibitor and the second therapy (for example pan-HER inhibitor such as particular Varlitinib or chemotherapy] are administered sequentially in a treatment regimen, for example are administered on the same day.
  • the second therapy for example pan-HER inhibitor such as particular Varlitinib or chemotherapy
  • the second therapy (for example the pan-HER inhibitor such as Varlitinib or chemotherapy] is administered twice daily, for example a dose in the range disclosed herein.
  • the DHODH inhibitor and the second therapy are administered simultaneously, at approximately the same time.
  • the DHODH inhibitor is administered in regimen that is daily or weekly for a continuous period of time for example 1 to 60 months or more, and the second therapy (for example HER2 inhibitor or pan-HER inhibitor or chemotherapy is administered intermittently during this period, for example Varlitinib] may be administered in a one or more 28 days cycles.
  • the second therapy for example a pan-HER inhibitor] comprises an antibody molecule, such as Herceptin then the administration protocol is likely to be very different to that of small molecule inhibitors.
  • Herceptin for example may be administered (in particular in combination with cytotoxic chemotherapy] in a regime as follows: 1] First administration 4mg/Kg over 90 minute; 2] Weekly administrations of 2mg/Kg over 30 minutes for the next 12 weeks; and 3] One week post 2] initiation of 6mg/Kg over 30-90 minutes every three weeks.
  • the second therapy (for example the pan-HER inhibitor or chemotherapy] is administered in regimen that is daily or weekly for a continuous period of time, for example 1 to 60 months or more, and the DHODH inhibitor is administered intermittently during this period.
  • Administered intermittently as employed herein refers to a period wherein the therapy is administered and then stopped with the option of starting the therapy again at some point in the future, for example in accordance with a treatment plan.
  • the DHODH inhibitor is administered in regimen that is daily or weekly for a continuous period of time, for example 1 to 60 months or more
  • the second therapy for example pan-HER inhibitor or chemotherapy] is administered in regimen that is daily or weekly for a continuous period of time, for example 1 to 60 months or more.
  • the DHODH inhibitor is administered in regimen that is daily or weekly for intermittent periods over for example 1 to 60 months or more
  • the second therapy for example pan-HER inhibitor or chemotherapy
  • the DHODH inhibitor and the second therapy are co-formulated.
  • the DHODH inhibitor is administered orally.
  • the second therapy (for example HER inhibitor] is administered orally, parenterally or both, in particular orally.
  • the second therapy for example HER inhibitor, such as HER2 inhibitor
  • the second therapy is administered orally or parenterally, for example intravenously.
  • the second therapy for example HER inhibitor, such as pan-HER inhibitor
  • the DHODH inhibitor and the second therapy are both administered orally.
  • the therapy of the present disclosure is, for example beneficial in that it provides augmented therapeutic activity in comparison to monotherapy comprising one of the components.
  • Augmented activity may be any beneficial therapeutic effect of employing the combination of the present disclosure, for example an increase in anti-tumor activity and/or a reduced propensity for the cancer to become resistant
  • Other benefits may be therapeutic effect in patients who have failed one or more lines of therapy.
  • the patient population has a cancer that is resistant or refractory to known therapies, such as cytotoxic chemotherapy.
  • Combination therapy as employed herein refers to two or more modes of therapy being employing over the same treatment period, i.e. the opposite of sequential therapy.
  • Two or more modes of therapy as employed herein refers to at least two therapies which have different modes of action and/or different activities and/or different routes of administration.
  • combination therapy refers to where a medicament according to the present disclosure is administered in a treatment regimen along with at least one further therapeutic agent.
  • the regime may be separate formulations administered at the same time or different times or co-formulations of the two or more therapeutic agents.
  • the "first" medicament employed in the combination therapy according to the present disclosure may be administered; prior to the further therapeutic agent or agents, concomitant with the further therapeutic agent or agents, or after the further therapeutic agent or agents.
  • therapeutic agent or agents such as an anti-cancer therapy are employed in combination with the therapy of the present disclosure.
  • the therapeutic agent is a chemotherapeutic agent
  • Chemotherapeutic agent as employed herein is intended to refer to specific antineoplastic chemical agents or drugs that are destructive to malignant cells and tissues, including alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumour agents.
  • Specific examples of chemotherapy include doxorubicin, 5-fluorouracil (5-FU], paclitaxel (for example abraxane or docetaxel], capecitabine, irinotecan, and platins, such as cisplatin and oxaliplatin or a combination thereof.
  • a suitable dose may be chosen by the practitioner based on the nature of the cancer being treated and the patient
  • Co-administered as employed herein refers to administration of the DHODH inhibitor and the "second therapy" at the same time or approximately the same time (including where the actives are administered by the same or different routes].
  • Inhibitor refers to the reduction of a relevant biological activity, for example by 5, 10, 15, 20, 25, 30, 35, 40, 5, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100%, such as when measured in a relevant in vitro assay.
  • Direct inhibition is where the inhibitor binds directly to or physically blocks a binding interaction to inhibit a biological activity, or when the inhibitor inhibits the activation through phosphorylation of the target molecule.
  • Indirect inhibition as employed herein refers to where the biological activity in question is inhibited as a result of directly inhibiting a target that is other than the entity that is indirectly inhibited.
  • Dihydroorotate dehydrogenase is the enzyme that catalyzes the fourth step in the pyrimidine biosynthetic pathway namely the conversion of dihydroorotate to orotate concomitantly with an electron transfer to ubiquinone (cofactor Q] via a flavin mononucleotide intermediate (Loffler Mol Cell Biochem, 1997].
  • DHODH Dihydroorotate dehydrogenase
  • mitochondrial cytochrome bcl a component of the electron transport chain complex III
  • DHODH dihydroorotate dehydrogenase
  • the p53 activation has been shown to be triggered by the impairment of the de novo pyrimidine 15 biosynthesis due to the suppression of DHODH.
  • a DHODH inhibitor as employed herein refers to a compound which inhibits the activity of dihydroorotate dehydrogenase, in particular in vivo.
  • Asian 003 is disclosed in WO2008/077639, incorporated herein by reference.
  • a biological therapeutic is one based on a protein, for example an antibody or binding fragment thereof, including fusion proteins and biological molecules, for example conjugated to a polymer, toxin or similar payload.
  • a “drug” as employed herein refers to a chemical entity, organic chemistry molecule with pharmacological activity.
  • the HER2 inhibitor is a HER dimerization inhibitor, for example pertuzumab disclosed in WO01/00244 and WOO 1/100245 incorporated herein by reference.
  • Examples of pharmaceutically acceptable salts include but are not limited to acid addition 40 salts of strong mineral acids such as HC1 and HBr salts and addition salts of strong organic acids, such as a methansulfonic acid salt, tosylates, furoates and the like, including di, tri salts thereof, such as ditosylates.
  • the combination therapy according to the present disclosure further comprises a RON inhibitor, for example as disclosed WO2008/058229, incorporated herein by reference.
  • the combination therapy of the present disclosure comprises a checkpoint inhibitor, such as a CTLA4 inhibitor, a PD-1 inhibitor or a PD-Ll inhibitor, in particular an antibody or binding fragment thereof.
  • a checkpoint inhibitor such as a CTLA4 inhibitor, a PD-1 inhibitor or a PD-Ll inhibitor, in particular an antibody or binding fragment thereof.
  • the combination therapy of the present disclosure further comprises a chemotherapeutic agent
  • the therapy of the present disclosure may be employed in combination with a further cancer therapy, for example chemotherapy.
  • Chemotherapeutic agent and chemotherapy or cytotoxic agent are employed interchangeably herein unless the context indicates otherwise.
  • alkylating agents which may be employed in the method of the present disclosure include an alkylating agent nitrogen mustards, nitrosoureas, tetrazines, aziridines, platins and derivatives, and non-classical alkylating agents.
  • platinum containing chemotherapeutic agent examples include cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin and lipoplatin (a 25 liposomal version of cisplatin], in particular cisplatin, carboplatin and oxaliplatin.
  • the dose for cisplatin ranges from about 20 to about 270 mg/m 2 depending on the exact cancer. Often the dose is in the range about 70 to about 100mg/m 2 .
  • Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan.
  • Nitrosoureas include N-Nitroso-N-methylurea (MNU], carmustine (BCNU], lomustine (CCNU] and semustine (MeCCNU], fotemustine and streptozotocin.
  • Tetrazines include dacarbazine, mitozolomide and temozolomide.
  • Aziridines include thiotepa, mytomycin and diaziquone (AZOJ.
  • antimetabolites examples include anti-folates (for example methotrexate and pemetrexed], purine analogues (for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fludarabine (including the phosphate form], pentostatin and cladribine], pyrimidine analogues (for example fluoropyrimidines, such as 5-fluorouracil and prodrugs thereof such as capecitabine [Xeloda®]], floxuridine, gemcitabine, cytarabine, decitabine, raltitrexed(tomudex] hydrochloride, cladribine 40 and 6-azauracil.
  • anti-folates for example methotrexate and pemetrexed
  • purine analogues for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fludarabine (including the phosphate form
  • anthracyclines examples include daunorubicin (Daunomycin], daunorubicin (liposomal], doxorubicin (Adriamycin], doxorubicin (liposomal], epirubicin, idarubicin, valrubicin currenlty used only to treat bladder cancer and mitoxantrone an anthracycline analog, in particular doxorubicin.
  • anti-microtubule agents examples include vinca alkaloids and taxanes.
  • Vinca alkaloids include completely natural chemicals for example vincristine and vinblastine and also semi-synthetic vinca alkaloids, for example vinorelbine, vindesine, and vinflunine
  • Taxanes include paclitaxel, docetaxel, abraxane, carbazitaxel and derivatives of thereof.
  • Derivatives of taxanes as employed herein includes reformulations of taxanes like taxol, for example in a micelluar formulaitons, derivatives also include chemical derivatives wherein synthetic chemistry is employed to modify a starting material which is a taxane.
  • Topoisomerase inhibitors are described above.
  • a combination of chemotherapeutic agents employed is, for example a platin and 5-FU or a prodrug thereof, for example cisplatin or oxaplatin and capecitabine or gemcitabine, such as FOLFOX.
  • the chemotherapy comprises a combination of chemotherapy agents, in particular cytotoxic chemotherapeutic agents.
  • the chemotherapy combination comprises a platin, such as cisplatin and fluorouracil or capecitabine.
  • the chemotherapy combination in capecitabine and oxaliplatin (Xelox].
  • the chemotherapy is a combination of folinic acid and 5-FU, optionally in combination with oxaliplatin.
  • the chemotherapy is a combination of folinic acid, 5-FU and irinotecan (FOLFIRI], optionally in combination with oxaliplatin (FOLFIRINOX].
  • the regimen may for example consists of: irinotecan (180 mg/m 2 IV over 90 minutes] concurrently with folinic acid (400 mg/m 2 [or 2 x 250 mg/m 2 ] IV over 120 minutes]; followed by fluorouracil (400-500 mg/m 2 IV bolus] then fluorouracil (2400-3000 mg/m 2 intravenous infusion over 46 hours]. This cycle is typically repeated every two weeks.
  • the dosages shown above may vary from cycle to cycle.
  • the chemotherapy combination employs a microtubule inhibitor, for example vincristine sulphate, epothilone A, N- [2-[(4-Hydroxyphenyl]amino]-3-pyridinyl]- 4methoxybenzenesulfonamide (ABT-751], a taxol derived chemotherapeutic agent, for example paclitaxel, abraxane, or docetaxel or a combination thereof.
  • a microtubule inhibitor for example vincristine sulphate, epothilone A, N- [2-[(4-Hydroxyphenyl]amino]-3-pyridinyl]- 4methoxybenzenesulfonamide (ABT-751]
  • ABT-751 N- [2-[(4-Hydroxyphenyl]amino]-3-pyridinyl]- 4methoxybenzenesulfonamide
  • the chemotherapy combination employs an mTor inhibitor.
  • mTor inhibitors include: everolimus (RAD001], WYE-354, KU-0063794, papamycin (Sirolimus], Temsirolimus, Deforolimus(MK-8669], AZD8055 and BEZ235(NVP-BEZ235].
  • the chemotherapy combination employs a MEK inhibitor.
  • MEK inhibitors include: AS703026, CI-1040 (PD184352], AZD6244 (Selumetinib], PD318088, PD0325901, AZD8330, PD98059, U0126-EtOH, BIX 02189 or BIX 02188.
  • the chemotherapy combination employs an AKT inhibitor.
  • AKT inhibitors include: MK-2206 and AT7867.
  • the combination employs an aurora kinase inhibitor.
  • aurora kinase inhibitors include: Aurora A Inhibitor I, VX-680, AZD1152-HQPA (Barasertib], SNS314 Mesylate, PHA-680632, ZM-447439, CCT129202 and Hesperadin.
  • the chemotherapy combination employs a p38 inhibitor, for example as disclosed in WO2010/038086, such as iV- [4-( ⁇ 4-[3-(3-tert-Butyl-l-p-tolyl-lH-pyrazol- 5yl]ureido]naphthalen-l-yloxy ⁇ methyl]pyridin-2-yl]-2-methoxyacetamide.
  • a p38 inhibitor for example as disclosed in WO2010/038086, such as iV- [4-( ⁇ 4-[3-(3-tert-Butyl-l-p-tolyl-lH-pyrazol- 5yl]ureido]naphthalen-l-yloxy ⁇ methyl]pyridin-2-yl]-2-methoxyacetamide.
  • the combination employs a Bcl-2 inhibitor.
  • Bcl-2 inhibitors include: obatoclax mesylate, ABT-737, ABT-263 (navitoclax] and TW-37.
  • the chemotherapy combination comprises an antimetabolite such as capecitabine (xeloda], fludarabine phosphate, fludarabine (fludara], decitabine, raltitrexed (tomudex], gemcitabine hydrochloride and cladribine.
  • an antimetabolite such as capecitabine (xeloda], fludarabine phosphate, fludarabine (fludara], decitabine, raltitrexed (tomudex], gemcitabine hydrochloride and cladribine.
  • the chemotherapy combination comprises ganciclovir, which may assist in controlling immune responses and/or tumour vasculation.
  • the chemotherapy includes a PARP inhibitor.
  • one or more therapies employed in the method herein are metronomic, that is a continuous or frequent treatment with low doses of anticancer drugs, often given concomitant with other methods of therapy.
  • the therapy of the present disclosure is employed after chemotherapy.
  • the therapy of the present disclosure is employed before chemotherapy.
  • the dose of chemotherapy employed in the therapy of the present disclosure is lower than the dose of chemotherapy employed in "monotherapy" (where monotherapy may include the dose of chemotherapy employed when combinations of chemotherapy agents are employed].
  • the medicament is administered in combination with therapy complimentary to the cancer therapy, for example a treatment for cachexia, such as cancer cachexia, for example S-pindolol, S-mepindolol or S-bopindolol.
  • a treatment for cachexia such as cancer cachexia, for example S-pindolol, S-mepindolol or S-bopindolol.
  • Suitable doses may be in the range of 2.5mg to lOOmg, such as 2.5mgto 50mgper day provided a single dose or multiple doses given as multiple doses administered during the day.
  • Treatment as employed herein refers to where the patient has a disease or disorder, for example cancer and the medicament according to the present disclosure is administered to stabilise the disease, delay the disease, amelorate the disease, send the disease into remission, maintain the disease in remission or cure the disease.
  • Treating as employed herein includes administration of a medicament according to the present disclosure for treatment or prophylaxis.
  • the present disclosure is explained in the context of a method of treating a patient.
  • the disclosure extends to use of the combination therapy as described herein for use in treatment, in particular for the treatment of cancer, such as a cancer described herein.
  • Also provided is use of the combination of compounds as described herein for the manufacture of a medicament for the treatment of cancer, in particular a cancer described herein.
  • the combination therapy according to the present disclosure is employed as cancer adjuvant therapy, for example after surgery to remove some or all of the cancerous cells.
  • a therapeutically effective dose (such as a daily dose] of a DHODH inhibitor is in the range lOmgto lOOOmg, for example 50 to 500mg, such as 100, 150, 200, 250, 300, 350, 400, 450, 500mg, in particular administered once a day.
  • the DHODH inhibitor for example 2-(3,5-difluoro-3'methoxybiphenyl-4- ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof is administered bi-daily, such as at a dose in the range lOOmgto 900mgon each occasion, in particular 300mg, or 400mgor 500mg each dose.
  • active ingredients employed in the therapy of the present disclosure will be provided in the form of a pharmaceutical formulation comprising one or more excipients, diluents or carriers.
  • the DHODH inhibitor for example 2-(3,5-difluoro-3'methoxybiphenyl- 4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof is administered as pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients.
  • Embodiments of the invention comprising certain features/elements are also intended to extend to alternative embodiments "consisting" or “consisting essentially” of the relevant elements/features.
  • ASLAN003 is a small molecule inhibitor of Dihydroorotate Dehydrogenase (DHODH].
  • DHODH Dihydroorotate Dehydrogenase
  • ASLAN003 alone (lOOmg/Kg daily, oral gavage], doxorubicin alone (1 or 10 mg/kg once per week, intravenous], and the combination of ASLAN003 and doxorubicin treatments for their ability to affect orthotopic growth of tumors in the mammary fat pad, using four human breast cancer PDX lines in NRG mice.
  • the PDX lines were all triple negative breast cancers and were selected to have varying TP53 and PTEN mutation status.
  • ASLAN003 Prepared fresh every day: 10 mg/mL in 30% PEG300+30% Captisol, sonicated for 1.5 hrs before use.
  • Doxorubicin 1 OX stock (Selleck Chemical Cat# SI 208]: 20mg/ml in H 2 0. Stored at -80C in 0.5mL aliquots. Working solution prepared fresh by diluting 1:10 in H2O (for high dose] or 1:100 in
  • Frozen tissue fragments ( ⁇ 4x2x2 mm] were thawed by placing the vial in a 37 ° C water bath and removed before the medium completely melted.
  • mice were randomized into 1 of 4 treatment groups:

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Abstract

L'invention concerne une méthode de traitement du cancer à PTEN mutant, avec une thérapie comprenant un inhibiteur de DHODH ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/SG2018/050210 2017-06-02 2018-04-30 Cancérothérapie WO2018222135A1 (fr)

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US11382903B2 (en) 2017-03-02 2022-07-12 Aslan Pharmaceuticals Pte. Ltd. Cancer therapy

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US11382903B2 (en) 2017-03-02 2022-07-12 Aslan Pharmaceuticals Pte. Ltd. Cancer therapy

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