EP4110341A2 - Dreifache pharmazeutische kombination mit dabrafenib, einem erk-inhibitor und einem raf-inhibitor - Google Patents

Dreifache pharmazeutische kombination mit dabrafenib, einem erk-inhibitor und einem raf-inhibitor

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Publication number
EP4110341A2
EP4110341A2 EP21739775.1A EP21739775A EP4110341A2 EP 4110341 A2 EP4110341 A2 EP 4110341A2 EP 21739775 A EP21739775 A EP 21739775A EP 4110341 A2 EP4110341 A2 EP 4110341A2
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EP
European Patent Office
Prior art keywords
cancer
compound
braf
dabrafenib
crc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP21739775.1A
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English (en)
French (fr)
Inventor
Vesselina COOKE
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Novartis AG
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Novartis AG
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Publication date
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Publication of EP4110341A2 publication Critical patent/EP4110341A2/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical combination comprising:
  • (ERKi) such as 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N- ((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (“Compound A” or “compound A”), or a pharmaceutically acceptable salt thereof, and a RAF inhibitor such as N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)- isonicotinamide (“Compound C”) or a pharmaceutically acceptable salt thereof; or [0003] (ii). dabrafenib, or a pharmaceutically acceptable salt thereof, an Erk inhibitor
  • ERPi such as 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N- ((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (“Compound A” or “compound A”), or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor such as Spartalizumab; and pharmaceutical compositions comprising the same; commercial packages comprising the same; and methods of using such combinations and compositions in the treatment or prevention of conditions in which MAPK pathway inhibition is beneficial, for example, in the treatment of cancers.
  • the present invention also povides such combinations for use in the treatments of such conditions or cancers, including colorectal cancer (CRC) such as BRAF gain of function colorectal cancer.
  • CRC colorectal cancer
  • the MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of this pathway underlies many instances of tumorigenesis. Aberrant signaling or inappropriate activation of the MAPK pathway has been shown in multiple tumor types and can occur through several distinct mechanisms, including activating mutations in RAS and BRAF.
  • the MAPK pathway is frequently mutated in human cancer with KRAS and BRAF mutations being among the most frequent (approximately 30%).
  • RAS mutations, particularly gain of function mutations have been detected in 9-30% of all cancers, with KRAS mutations having the highest prevalence (86%).
  • the extracellular signal-regulated kinases are one class of signaling kinases that are involved in conveying extracellular signals into cells and subcellular organelles.
  • ERK1 and ERK2 are involved in regulating a wide range of activities and dysregulation of the ERK1/2 cascade is known to cause a variety of pathologies including neurodegenerative diseases, developmental diseases, diabetes and cancer.
  • the role of ERK1/2 in cancer is of special interest because activating mutations upstream of ERK1/2 in its signaling cascade are believed to be responsible for more than half of all cancers.
  • ERK1/2 signaling plays a role in carcinogenesis even in cancers without mutational activations.
  • the ERK pathway has also been shown to control tumor cell migration and invasion, and thus may be associated with metastasis.
  • the Programmed Death 1 (PD-1) protein is an inhibitory member of the extended
  • CD28/CTLA-4 family of T cell regulators Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD-L2 (B7-DC), that have been shown to downregulate T cell activation upon binding to PD-1.
  • PD-L1 is abundant in a variety of human cancers.
  • PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals.
  • the interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, for example, a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells.
  • Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.
  • the triple combinations of the present invention can be used as therapies for the treatment of diseases or disorders resulting from the aberrant activity of the MAPK pathway including, but not limited to, breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.
  • triple combinations of dabrafenib, an Erk-inhibitor such as Compound A, and a RAF-inhibitor such as compound C, or dabrafenib, an Erk-inhibitor such as Compound A, and a PD-1 inhibitor such as Spartalizumab, are particularly useful in the treatment of colorectal cancer (CRC), including advanced or metastatic colorectal cancer, which is BRAF gain of function or BRAFV600E/D/K mutants.
  • CRC colorectal cancer
  • advanced or metastatic colorectal cancer which is BRAF gain of function or BRAFV600E/D/K mutants.
  • the present invention provides a pharmaceutical combination comprising:
  • the present invention provides a pharmaceutical combination comprising:
  • the PD-1 inhibitor is chosen from PDR001
  • the PD-1 inhibitor is PDR001 (spartalizumab).
  • a combination of the invention for use in the treatment of cancer e.g for use in a cancer which is selected from breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.
  • a PD-1 inhibitor such as spartaluzimab, e.g for use in a cancer which is selected from breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.
  • dabrafenib or a pharmaceutically acceptable salt thereof
  • Compound A or a pharmaceutically acceptable salt thereof
  • Compound C or a pharmaceutically acceptable salt thereof
  • dabrafenib or a pharmaceutically acceptable salt thereof
  • Compound A or a pharmaceutically acceptable salt thereof
  • Compound C or a pharmaceutically acceptable salt thereof
  • the combination of the invention is for simultaneous or sequential (in any order) administration.
  • the present invention provides a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the combination of the invention.
  • the cancer is selected from breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.
  • the present invention provides a combination of the invention for use in the manufacture of a medicament for treating a cancer selected from breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non small cell lung cancer, ovarian cancer and thyroid cancer.
  • compositions or commercial package comprising the combination of the invention.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
  • Figure 1 Mice were randomized into treatment groups on Day 26 following
  • ANOVA One-Way Analysis of variance
  • Figure 2 Mice were randomized into treatment groups on Day 28 following
  • ANOVA One-Way Analysis of variance
  • Figure 3 Mice were randomized into treatment groups on Day 12 following
  • HCOX1329 tumor implantation Treatments were initiated on Day 12 and continued until Day 38 (vehicle), Day 62 (dabrafenib+ Compound A+trametinib), or Day 67 (dabrafenib+trametinib and dabrafenib+trametinib+cetuximab) post tumor implantation. Tumor dimensions and body weights were collected at the time of randomization and twice weekly thereafter for the study duration. Tumor volumes (A) or percent body weight change (B) from initial of treatment groups vs. days post randomization are graphed.
  • “Dabrafenib” is N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2- fluorophenyl)-2,6-difluorobenzenesulfonamide, a selective inhibitor of mutated BRAF at V600 capable of inhibiting BRAF(V600E), BRAF(V600K) and BRAF(V600G) mutations, (also known as: N- ⁇ 3 -[5 -(2-Amino-4-pyrimidinyl)-2-( 1 , 1 -dimethylethyl)- 1 ,3 -thiazol-4-yl] -2- fluorophenyl ⁇ -2,6-difluorobenzenesulfonamide; Tafinlar ® ; & N- ⁇ 3[5-(2-Amino-4- pyrimidinyl)-2-( 1 , 1 -dimethyl
  • Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer.
  • Cetuximab is an epidermal growth factor receptor-targetedlgGl monoclonal antibody that is approved for use in combination with irinotecan or as monotherapy in the treatment of metastatic CRC.
  • Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion.
  • Compound A is an inhibitor of extracellular signal-regulated kinases (ERK)
  • Compound A is 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2- yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide.
  • a particularly preferred salt of Compound A is the hydrochloride salt thereof.
  • Compound C N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide, is an ATP competitive inhibitor of the BRAF and CRAF protein kinases.
  • PDR001 is also known as spartalizumab, an anti-PD-1 antibody molecule described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof,” incorporated by reference in its entirety.
  • anti-PD-1 antibody molecules include the following:
  • Nivolumab (Bristol-Myers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®.
  • Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in US 8,008,449 and WO 2006/121168, incorporated by reference in their entirety;
  • Pembrolizumab (Merck & Co), also known as Lambrolizumab, MK-3475, MK03475,
  • Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8,354,509, and WO 2009/114335, incorporated by reference in their entirety;
  • Pidilizumab (CureTech), also known as CT-011.
  • Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J. et al. (2011) J Immunotherapy 34(5): 409-18, US 7,695,715, US 7,332,582, and US 8,686,119, incorporated by reference in their entirety;
  • MEDI0680 Medimmune
  • AMP-514 also known as AMP-514.
  • MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205, 148 and WO 2012/145493, incorporated by reference in their entirety;
  • AMP-224 (B7-DCIg (Amplimmune), e.g. , disclosed in WO 2010/027827 and WO
  • REGN2810 (Regeneron); PF-06801591 (Pfizer); BGB-A317 orBGB-108 (Beigene); INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210; TSR-042 (Tesaro), also known as ANB011; and further known anti-PD-1 antibodies including those described, e.g., in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, incorporated by reference in their entirety.
  • subject or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer.
  • subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non- human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers.
  • treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • a therapeutic agent in these combinations can be administered concurrently with, prior to, or subsequent to, one or more other additional therapies or therapeutic agents.
  • the therapeutic agents or therapeutic protocol can be administered in any order.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutic agent utilized in this combination may be administered together in a single composition or administered separately in different compositions.
  • it is expected that additional therapeutic agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized as single-agent therapeutics.
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub population of cells in an animal (including a human) at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the combinations of the invention, dabrafenib, compound A and compound C or spartalizumab, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have one or more atoms replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into dabrafenib, compound A and Compound C or spartalizumab include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 C1, 123 I, 124 I, 125 I respectively.
  • the invention includes isotopically labeled dabrafenib, compound A and compound C or spartalizumab, for example into which radioactive isotopes, such as 3 H and 14 C, or non-radioactive isotopes, such as 2 H and 13 C, are present.
  • Isotopically labelled dabrafenib, compound A and compound C or spartalizumab are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • dabrafenib, compound A or compound C or spartalizumab labeled with 18 F may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagents.
  • substitution with heavier isotopes may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index.
  • deuterium in this context is regarded as a substituent of either dabrafenib, compound A or compound C or spartalizumab.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent dabrafenib, compound A or compound C or spartalizumab is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Dabrafenib is an orally bioavailable small molecule with RAF inhibitory activity.
  • Compound A is an orally bioavailable small molecule with ERK inhibitory activity. It is an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK 1/2).
  • Compound C is an orally bioavailable small molecule with B/C-RAF inhibitory activity.
  • Spartalizumab is a high-affinity, ligand-blocking, humanized anti-programmed death- 1 (PD-1) IgG4 antibody that blocks the binding of Programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) to PD- 1.
  • a pharmaceutical combination comprising: N-(3-(5-(2-aminopyrimidin-4-yl)-2- (tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib), or a pharmaceutically acceptable salt thereof; 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)- 2-fluorobenzamide (compound A), or a pharmaceutically acceptable salt thereof; and N-(3-(2- (2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)
  • N-(3-(5-(2- aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6- difluorobenzenesulfonamide (dabrafenib) is in an oral dosage form.
  • N-(3-(2-(2- hydroxyethoxy)-6-morphobnopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)- isonicotinamide (compound C) is in an oral dosage form.
  • a pharmaceutical composition or a commercial package comprising the pharmaceutical combination (as described in any of the embodiments above) and at least one pharmaceutically acceptable carrier.
  • the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer (CRC), melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.
  • CRC colorectal cancer
  • the cancer is advanced or metastatic colorectal cancer.
  • the cancer is BRAF gain of function CRC or BRAF
  • V600E, V600D or V600K CRC V600E, V600D or V600K CRC.
  • the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer, optionally wherein the cancer is advanced or metastatic colorectal cancer, optionally wherein the cancer is BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC.
  • In another embodiment is a method of treating a cancer selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer comprising administrating to a patient in need thereof a pharmaceutical combination or commercial package according to any one of the above embodiemnts or the pharmaceutical composition according to the above embodiments.
  • the colorectal cancer is advanced or metastatic colorectal cancer.
  • the colorectal cancer is BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC.
  • N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert- butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib) is administered orally at a dose of about from about 1 to about 150 mg per day (for example, 1, 2, 5, 10, 50, 100 or 150 mg per day).
  • N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert- butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide is administered orally at a dose of 75mg BID.
  • 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)- 2-fluorobenzamide is administered orally at a dose of from about 50 to about 200 mg per day (for example, at a dose of about 50, 75, 100, 125, 150, 175 or 200 mg per day).
  • N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4- yl)-4-methylphenyl)-2-(trifluoromethyl)-isonicotinamide (compound C) is adminstered orally at a dose of from about 100 mg per day, or 200 mg per day, or 300 mg per day to about 400 mg per day.
  • N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4- yl)-4-methylphenyl)-2-(trifluoromethyl)-isonicotinamide (compound C) is adminstered orally at a dose of 200mg BID.
  • a pharmaceutical combination comprising: N-(3-(5-(2-aminopyrimidin-4-yl)-2- (tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib), or a pharmaceutically acceptable salt thereof; 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)- 2-fluorobenzamide (compound A), or a pharmaceutically acceptable salt thereof; and a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the PD-1 inhibitor is an anti-PD-1 antibody molecule.
  • the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof,” incorporated by reference in its entirety.
  • the anti-PD-1 antibody molecule is BAP049-Clone E or B AP049-Clone B.
  • the anti-PD-1 antibody molecule is Spartalizumab
  • the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 (e.g., from the heavy and light chain variable region sequences of BAP049-Clone-E or BAP049-Clone-B disclosed in Table 1), or encoded by a nucleotide sequence shown in Table 1.
  • CDRs complementarity determining regions
  • the CDRs are according to the Kabat definition (e.g., as set out in Table 1). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 1). In some embodiments, the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 1). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541).
  • one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.
  • the anti -PD- 1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 501, a VHCDR2 amino acid sequence of SEQ ID NO: 502, and a VHCDR3 amino acid sequence of SEQ ID NO: 503; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 510, a VLCDR2 amino acid sequence of SEQ ID NO: 511, and a VLCDR3 amino acid sequence of SEQ ID NO: 512, each disclosed in Table 1.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody molecule comprises a VH comprising a
  • the anti -PD- 1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 506.
  • the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 520.
  • the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 516.
  • the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 516. [0085] In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 507.
  • the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 521 or 517. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.
  • the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 508. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 508.
  • the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 518.
  • the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 522.
  • the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 509.
  • the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 523 or 519.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.
  • the antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0210769, incorporated by reference in its entirety. Table 1. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules
  • N-(3-(5-(2- aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6- difluorobenzenesulfonamide (dabrafenib) is in an oral dosage form.
  • compositions or a commercial package comprising the pharmaceutical combination (as described in any of the embodiments above) and at least one pharmaceutically acceptable carrier.
  • the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer (CRC), melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.
  • the cancer is advanced or metastatic colorectal cancer.
  • the cancer is BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC.
  • the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer, optionally wherein the cancer is advanced or metastatic colorectal cancer, optionally wherein the cancer is BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC.
  • In another embodiment is a method of treating a cancer selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer comprising administrating to a patient in need thereof a pharmaceutical combination or commercial package according to any one of the above embodiemnts or the pharmaceutical composition according to the above embodiments.
  • the colorectal cancer is advanced or metastatic colorectal cancer.
  • the colorectal cancer is BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC.
  • N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert- butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide is administered orally at a dose of about from about 1 to about 150 mg per day (for example, 1, 2, 5, 10, 50, 100 or 150 mg per day).
  • 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)- 2-fluorobenzamide is administered orally at a dose of from about 50 to about 200 mg per day (for example, at a dose of about 50, 75, 100, 125, 150, 175 or 200 mg per day).
  • the PD-f inhibitor is administered at a dose of about 300-
  • the PD-f inhibitor is administered once every 3 weeks or once every 4 weeks.
  • the PD-f inhibitor is administered at a dose of about 300 mg once every 3 weeks.
  • the PD-f inhibitor is administered at a dose of about 400 mg once every 4 weeks.
  • the RAS/RAF/MEK/ERK or mitogen activated protein kinase (MAPK) pathway is a key signaling cascade that integrates upstream cellular signals, such as from growth factor receptor tyrosine kinases, to orchestrate cell proliferation, differentiation, and survival.
  • the MAPK signaling pathway is frequently dysregulated in human cancers, most commonly through mutation of members of the RAS family of genes. These mutations promote the GTP-bound state resulting in RAS activity leading in turn to activation of RAF, MEK, and ERK proteins.
  • RAS mutations are found in multiple cancer types, including colorectal, lung, and pancreatic cancers.
  • RAF Rapidly Accelerated Fibrosarcoma
  • ARAF ARAF, BRAF, CRAF
  • Activated GTP-bound RAS recruits cytosolic inactive RAF monomers to the plasma membrane where RAF binds to GTP-RAS thereby promoting homo- and heterodimerization of RAF.
  • the dimerization of RAF facilitates conformational changes that lead to catalytically activated RAF.
  • Activated RAF dimers phosphorylate and activate MEK1/2 (also known as mitogen-activated protein kinase) proteins, which subsequently phosphorylate and activate extracellular signal-regulated kinases (ERK1/2).
  • MEK1/2 also known as mitogen-activated protein kinase
  • ERKs phosphorylate a variety of substrates, including multiple transcription factors, thereby regulating several key cellular activities, including proliferation, metabolism, migration, and survival.
  • the role of ERK1/2 in cancer is of special interest because activating mutations upstream of ERK1/2 in its signaling cascade are believed to be responsible for more than half of all cancers.
  • Dysregulated activation at any step in the MAPK pathway contributes to tumorigenesis.
  • Activating BRAF mutations can be found in approximately 7% of cancers, with V600E accounting for greater than 90% of observed mutations in BRAF.
  • the V600E mutation encodes a valine to glutamic acid substitution that exposes the active site of BRAF, enabling its constitutive activation as monomers or dimers independent of RAS.
  • Inhibitors of active RAF such as vemurafenib, dabrafenib, and encorafenib, have demonstrated dramatic activity in BRAF V600E metastatic melanoma with overall response rates (ORR) of 50-70%.
  • inhibitors in V600E melanoma derives from the ability to bind to and inhibit the mutant monomeric form of RAF that is the oncogenic driver in cancer cells.
  • inhibitors such as vemurafenib paradoxically activate RAF signaling.
  • the complexity of MAPK pathway signaling in the presence of monomeric RAF inhibitors is highlighted in patients whose BRAF V600E-dependent melanoma cells die while normal epidermal cells containing wild-type BRAF hyperproliferate. This paradoxical activation of RAF in wild-type cells is precipitated by the inhibitor’s binding to one protomer of a RAF dimer.
  • Intrinsic resistance to RAF inhibition manifests because drugs such as vemurafenib or dabrafenib effectively inhibit BRAF V600E signaling through MEK to ERK; however, this in turn releases ERK-dependent negative feedback into RAS signaling. Therefore, upstream signals are able to activate RAS, leading to the induction of BRAF V600E and wild-type homo- and heterodimers.
  • BRAF and MEK inhibition in BRAF V600E CRC acquired resistance quickly develops. For instance, in an analysis of nine tumor samples from eight patients experiencing disease progression after MAPK inhibition, genetic alterations leading to MAPK reactivation were uncovered. These included activating mutations in KRAS or NRAS, amplification of wild-type (WT) NRAS or KRAS or mutant BRAFN 600E, and an intragenic deletion in BRAF V600E. Acquired genetic alterations have also been reported, leading to reactivation of ERK signaling in the face of MAPK inhibitors. Acquired resistance may also arise through complementary signaling in the tumor microenvironment.
  • CRC is generally unresponsive to PD-1 blockade with the exception of tumors possessing micro satellite instability.
  • MAPK pathway inhibitors such as BRAF and MEK inhibitors, could improve lymphocyte homing and function by increasing tumor infiltrating lymphocytes in tumors.
  • RAF and MEK inhibitors may modulate the immune response to tumors, and the combination of such agents with checkpoint blockade may increase the susceptibility of “immune cold” tumors such as CRC to PD-1 inhibition.
  • CRC cancer-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor-derived tumor .
  • MSI-H genetic micro satellite instability
  • single-agent anti-PD-1 therapy has been associated with response rates of 30-50%.
  • targeted MAPK inhibition in tumor immune cells may complement the mechanism of action of anti-PD-1 antibodies in microsatellite stable and mismatch-repair deficient CRC, thereby potentially increasing anti-cancer immunomoduclation.
  • Lung cancer is a common type of cancer that affects men and women around the globe.
  • NSCLC is the most common type (roughly 85%) of lung cancer with approximately 70% of these patients presenting with advanced disease (Stage IIIB or Stage IV) at the time of diagnosis.
  • About 30% of NSCLC tumors contain activating KRAS mutations, and these mutations are associated with resistance to EGFR tyrosine kinase inhibitors (TKIs).
  • TKIs EGFR tyrosine kinase inhibitors
  • Activating KRAS mutations are also frequently found in melanoma, pancreatic cancer and ovarian cancer.
  • BRAF mutations have been observed in up to 3 % of NSCLC and have also been described as a resistance mechanism in EGFR mutation positive NSCLC.
  • CRC is a common disease with more than 1.8 million new cases estimated worldwide in 2018, along with >800,000 deaths (World Health Organization, Globocan 2018). Mutations in genes encoding components of the MAPK pathway are common, with RAS mutations occurring in approximately 50% of CRC. Activating mutations in the gene encoding BRAF V600E are present in approximately 10-15% of CRC patients, and mutated BRAFconfers a poor prognosis. The V600E mutation occurs in approximately 90% of BRAF-mutant CRC, though others, for example, V600D or V600K mutations are also seen.
  • Dabrafenib (Tafinlar®) is an orally bioavailable, potent and selective inhibitor of
  • RAF kinases whose mechanism of action of is consistent with competitive inhibition of adenosine triphosphate (ATP) binding.
  • ATP adenosine triphosphate
  • dabrafenib to inhibit some mutated forms of BRAF kinases is concentration dependent, with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively.
  • Inhibition of wild-type BRAF and CRAF kinases requires higher concentrations, with IC50 values of 3.2 and 5.0 nM, respectively.
  • Other kinases such as SIK1, NEK11, and LIMK1 may also be inhibited at higher concentrations.
  • Dabrafenib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.
  • Dabrafenib was first approved by the FDA in 2013 as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with the BRAF ⁇ 600 mutation and is approved in various other countries for the same indication. Dabrafenib in combination with trametinib is also approved in multiple countries for the following indications (approved indications vary by country): treatment of patients with unresectable or metastatic melanoma with a BRAFV600 mutation; the adjuvant treatment of patients with Stage III melanoma with a BRAFV600 mutation, following complete resection; treatment of patients with advanced nonsmall cell lung cancer (NSCLC) with a BRAFV600 mutation; and treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with a BRAFV600E mutation.
  • the recommended dose of dabrafenib is 150 mg BID (corresponding to a total daily dose of 300 mg).
  • Compound A is a potent, selective and orally bioavailable ATP-competitive
  • ERK1/2 kinase inhibitor that exhibits physical chemical properties enabling combinations with RAF and MEK inhibitors, or other targeted therapeutic agents.
  • Compound A effectively inhibits pERK signaling and has demonstrated tumor growth inhibition in multiple MAPK-activated cancer cells and xenograft models.
  • compound A demonstrated broad efficacy targeting multiple known mechanisms of resistance to BRAF and MEK inhibitors, including RAS mutations, BRAF splice variants and MEK1/2 mutations, as shown in engineered cell line models.
  • Compound A has been dosed in patients between 45 mg and 450 mg QD.
  • Preclinical models of RAS, RAF, or MEK resistance mutations engineered into a BRAF V600E cell line supported this concept. While the parental BRAF V600E cell line was sensitive to combinations of BRAF, MEK, EGFR, and/or ERK inhibitors, the introduction of KRAS, NRAS, MEK1, or MEK2 resistance mutations resulted in decreased sensitivity of engineered BRAF V600E cells to all inhibitor combinations, except for those containing an ERK inhibitor. Furthermore, the outgrowth of pre-existing, low-frequency pooled resistant clones in mouse xenografts was suppressed more effectively by treatment with drug combinations containing BRAF and ERK inhibitors, as compared to BRAF and MEK inhibitors.
  • Dabrafenib + Compound A was tested in vivo in the BRAF mutant human cell line xenograft HT29. Mice treated with Dabrafenib + Compound A achieved similar anti-tumor response as compared to Dabrafenib +Trametinib at clinically relevant doses (36% T/C vs 28% T/C, respectively). Single agent treatment led to progressive disease, whereby compound A achieved 54% T/C, Dabrafenib achieved 59% T/C, and Trametinib achieved 48% T/C. All regimens were tolerated as judged by lack of significant body weight loss. These data suggest that the combination of Dabrafenib + Compound A may achieve similar anti-tumor activity to Dabrafenib + Trametinib in patients with BRAF mutant colorectal cancer, and provides rationale for its use in the clinic.
  • BRAF-selective inhibitors are effective against constitutively activated monomeric BRAF V600; however, intrinsic and acquired resistance to RAF inhibitors develop at multiple levels of the MAPK pathway. Under steady-state conditions, activated MAPK signaling through BRAF V600E leads to ERK-dependent negative feedback on signals generated through activated RAS. In BRAF V600 CRC, intrinsic resistance to RAF inhibition manifests because drugs such as dabrafenib effectively inhibit monomeric BRAF V600E signaling through MEK to ERK; however, this in turn releases ERK-dependent negative feedback into RAS signaling.
  • upstream signals such as through the epidermal growth factor receptor (EGFR) are able to activate RAS.
  • EGFR epidermal growth factor receptor
  • BRAF V600E and wild-type homo- and heterodimers including homodimers and heterodimers of WT and BRAF-V600E, CRAF and BRAF-V600E and ARAF and BRAF-V600E that signal to MEK.
  • RAF inhibitors such as dabrafenib allosterically promote the homo- and hetero- dimerization of RAF family members such that inhibitor binds to only one RAF partner while the other unbound dimer partner is catalytically active in stimulating downstream signaling.
  • RAF inhibitors such as Compound C, that potently inhibit the activity of CRAF and BRAF can be effective in blocking BRAF- mutant tumors and RAS-driven adaptive MAPK activation.
  • targeted small molecule inhibitors may modulate the immune microenvironment.
  • MAPK pathway inhibitors could improve lymphocyte homing and function by increasing tumor infiltrating lymphocytes in tumors, decreasing upregulated immunosuppressive cytokines, and generally counteracting immune tolerance of cancer.
  • BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. Therefore, RAF and MEK inhibitors can modulate the immune response to tumors, and the combination of such agents with checkpoint blockade can even increase the susceptibility of “immune cold” tumors, such as microsatellite stable CRC, to PD-1 inhibition.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of dabrafenib, compound A and compound C, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, for example, drenches (aqueous or non- aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transport
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum, such
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non- toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methane sulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically -acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically -acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • a particularly preferred salt of dabrafenib is the mesylate salt thereof.
  • a particularly preferred solvate of compound A is the hydrochloride salt thereof.
  • a particularly preferred form of compound C is the free base crystalline form.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution, suspension or solid dispersion in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically -acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants,
  • pharmaceutically -acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fdlers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface -active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the compounds of the present invention and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of the combination of the invention will be that amount of each compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • Dabrafenib is synthesized according to example 58a of WO2009/137391.
  • Compound A is synthesized according to example 184 of WO2015/066188.
  • Compound C is synthesized according to example 1156 of WO2014/151616.
  • WO2009/137391, WO2015/066188 and WO2014/151616 are herein incorporated by reference in their entirety.
  • the utility of a combination of Dabrafenib, Compound A and Compound C described herein can be evidenced by testing in the following examples.
  • Dabrafenib (DRB436): selective inhibitor of mutated BRAF at V600 capable of inhibiting BRAF(V600E), BRAF(V600K) and BRAF(V600G) mutations.
  • Compound A selective ATP-competitive ERK1 and ERK2 kinase inhibitor.
  • Compound C an ATP competitive inhibitor of BRAF and CRAF.
  • Dabrafenib was dosed p.o. in vehicle: 0.5% HPMC + 0.2% Tween 80 in pH 8 DI water.
  • Compound A was dosed p.o. in vehicle: 0.5% HPC / 0.5% Pluronic F127 in a pH 7.4 phosphate buffer, adjusted to pH 4.0 with acid.
  • Compound C free base crystalline form, in powder form) was dosed p.o. in MEPC4 vehicle (45% Cremophor RH40 + 27% PEG400 +
  • the HT29 human colorectal cancer (CRC) tumor cell line was purchased from
  • the cells were maintained in EMEM (Lonza #12-61 IF) plus 10% FBS (Gibco #26140-079) (56°C for 30 min. inactivated), at 37°C in a humidified atmosphere containing 5% carbon dioxide.
  • Cells were harvested at 80-95% confluence with 0.25% trypsin-EDTA (Gibco #25200-056), neutralized with growth medium, after centrifugation for 5 min at 1200 rpm, followed by resuspension of the cell pellet in cold HBSS (Gibco #14175-095) and then mixed with an equal volume of MatrigelTM Matrix (Coming #354234) to prepare a final concentration of 10x10 6 cells/mL.
  • mice 200m1 (2 x 10 6 cells) was implanted subcutaneously into the right flank of female nude mice.
  • Mice were monitored for tumor growth and body weight twice/week. Animal well-being and behavior, including grooming and ambulation, were monitored twice weekly. General health of mice was monitored daily.
  • the HCOX1329 CRC patient-derived tumor xenograft was propagated by serial passage of tumor slurry in nude mice. Briefly, fragments of fresh tumor from a previous passage were homogenized using gentleMACS Dissociator (MACS (Miltenyi Biotec, #120-005- 331), passed through a tissue grinder (Chemglass lifeSciences # CLS-5020-085), and diluted in PBS. Then 4c10 ⁇ 6 cells in 100 ⁇ I of tumor slurry was implanted subcutaneously into the right flank of female nude mice as passage 7.
  • MCS gentleMACS Dissociator
  • Test agents were dosed at dose volume of 10 mL/kg, which was adjusted according to body weight. Tumor dimensions and body weights were collected at the time of randomization and twice weekly thereafter for the study duration.
  • Table 3 p.o.: per os (oral gavage); i.p.: intraperitoneal; qd: once a day; bid: twice a day; biw: twice a week.
  • the percent change in body weight was calculated as (BW Current - BW initial )/(BW initial ) x 100%. Data was presented as mean percent body weight change from the day of treatment initiation ⁇ SEM.
  • ⁇ T mean tumor volume of the drug-treated group on the final day of the study - mean tumor volume of the drug-treated group on initial day of dosing;
  • T initial mean tumor volume of the drug-treated group on initial day of dosing
  • Anti-tumor activity was determined by assessing %T/C or % regression on day 39 post implant (13 days post treatment initiation). Anti-tumor activity, mean change in tumor volume, mean change in body weight and survival 13 days post treatment initiation is reported in Table 3. Tumor volume and body weight change post treatment are plotted on Figure 1. Daily single agent treatment with Compound A, dabrafenib or trametinib achieved 54%T/C, 59%T/C, or 48%T/C, respectively, when compared to the vehicle treated group.
  • mice BRAF mutant patient-derived CRC xenograft model HCOX1329 in athymic nude mice. Mice were treated with vehicle or combinations of MAPK pathway inhibitors as described in Table 3 until vehicle-treated tumors achieved a volume >1000 mm 3 , or 62-67 days post MAPK pathway inhibitor treatment initiation.
  • Anti-tumor activity was determined by assessing %T/C or % regression on day 38 post implant (26 days post treatment initiation), at which point mice treated with vehicle were sacrificed and mice treated with MAPK pathway inhibitors were treated for an additional 24-29 days and were sacrificed on day 62 (dabrafenib+Compound A+trametinib) or day 67 (dabrafenib+trametinib and dabrafenib+trametinib+cetuximab) post implant.
  • Anti-tumor activity, mean change in tumor volume, mean change in body weight and survival 26 days post treatment initiation is reported in Table 4. Tumor volume and body weight change post 26-55 days of treatment are plotted on Figure 3.
  • A+trametinib was also significantly more active than the combination of dabrafenib+trametinib and dabrafenib+trametinib+cetuximab. Collectively, these data indicate that the triple combinations of dabrafenib+Compound A+trametinib or dabrafenib+Compound A+Compound C can achieve greater and more durable responses in BRAF mutant CRC patients.

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