Therapeutic compositions, combinations, and methods of use

Abstract

To provide methods useful for treating abnormal cell growth, such as cancer, in a subject, such as a human.SOLUTION: Provided is a method comprising the step of administering a FAK inhibitor (e.g., VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766).SELECTED DRAWING: None

Description

background

[0001] Compelling evidence suggests that focal adhesion kinase (FAK), or PTK2, a cytoplasmic nonreceptor tyrosine kinase, plays an essential role in cell-matrix signaling pathways (Clark and Brugge 1995, Science 268:233-239) and that aberrant activation of PTK2 is associated with increased metastatic potential of tumors (Owens et al., 1995, Cancer Research 55:2752-2755). FAK was initially identified as a 125 kDa protein that was highly tyrosine-phosphorylated in v-Src-transformed cells. In humans, FAK is encoded by the PTK2 gene. FAK was subsequently found to be a tyrosine kinase that localizes to focal adhesions, which are contact points between cultured cells and their underlying matrix and are sites of intense tyrosine phosphorylation. FAK is phosphorylated in response to the binding of extracellular matrix (ECM) to integrins, resulting in activation. Recently, studies have shown that increased FAK mRNA levels are associated with invasive transformation of tumors, and attenuation of FAK expression (by using antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al., 1996, Cell Growth and Diff. 7:413-418). In addition to being expressed in most tissue types, FAK is found at elevated levels in most human cancers, including thyroid, prostate, cervical, colon, rectal, oral epithelial, ovarian and breast cancers, for example in highly invasive metastases. Thus, compounds, combinations of compounds, compositions, and methods for inhibiting FAK in a subject are desired.

[0002] Components of the RAS / RAF / MEK / ERK signaling pathway also represent opportunities for the treatment of abnormal cell growth, such as cancer.

[0003] WO 2015 / 120289 discloses a method of treating a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of a FAK inhibitor (e.g., VS-6063) in combination with a MEK inhibitor (e.g., GDC-0623, cobimetinib, trametinib, pimasertib, AZD6244), thereby treating the subject.

[0004] WO 2014 / 059095 and Br J Cancer. 2019 May;120(10):975-981 relate to the use of a combination comprising a specific FAK inhibitor and a specific MEK inhibitor (trametinib) in the treatment of cancer.

[0005] The combination of a FAK inhibitor (e.g., VS-6063) with a RAF / MEK dual inhibitor (e.g., CH5126766) can enhance the generation and potency of tumor-specific cytotoxic lymphocytes, providing a promising approach to more effectively treat a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer described herein)). VS-6063, or a pharma- ceutically acceptable salt thereof (FAK inhibitor), can be used in combination with CH5126766, or a pharma-ceutically acceptable salt thereof (RAF / MEK dual inhibitor), to treat a disease or disorder described herein, e.g., abnormal cell growth (e.g., cancer described herein).

[0006] Thus, provided herein are certain combinations (e.g., combinations described herein (e.g., a FAK inhibitor in combination with a RAF / MEK dual inhibitor)) that can be used, for example, to treat abnormal cell growth, e.g., cancer (e.g., a cancer with a RAS mutation), in a subject (e.g., a human).

[0007] Described herein are methods of treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of VS-6063, or a pharma- ceutically acceptable salt thereof (a FAK inhibitor), in combination with CH5126766, or a pharma- ceutically acceptable salt thereof (a RAF / MEK dual inhibitor), thereby treating the subject, wherein the cancer is a cancer with a RAS mutation. In some embodiments, the RAS mutation is a KRAS mutation or an NRAS mutation.

[0008] Described herein is a method of treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of VS-6063 or a pharma- ceutically acceptable salt thereof in combination with a RAF / MEK dual inhibitor, wherein the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutically acceptable salt thereof. In some embodiments, the cancer is caused by a mutation in RAS, BRAF, or NF-1. In some embodiments, the cancer is a cancer with a RAS mutation. In other aspects, the cancer has a KRAS mutation or an NRAS mutation.

[0009] Described herein is the use of VS-6063 or a pharma- ceutically acceptable salt thereof in combination with a RAF / MEK dual inhibitor to treat cancer, wherein the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutically acceptable salt thereof. In some embodiments, the cancer is caused by a mutation in RAS, BRAF, or NF-1. In some embodiments, the cancer has a RAS mutation. In other aspects, the cancer has a KRAS mutation or a NRAS mutation.

[0010] Described herein is a method of treating a subject with cancer, comprising administering to the subject a therapeutically effective amount of CH5126766 or a pharma- ceutically acceptable salt thereof in combination with a FAK inhibitor, wherein the FAK inhibitor is VS-6063 or a pharma-ceutically acceptable salt thereof. In some embodiments, the cancer is caused by a mutation in RAS, BRAF, or NF-1. In some embodiments, the cancer has a RAS mutation. In other aspects, the cancer has a KRAS mutation or a NRAS mutation.

[0011] The use of CH5126766 or its pharmacologic acceptable salt in combination with a FAK inhibitor to treat cancer is described herein, wherein the FAK inhibitor is VS-6063 or its pharmacologic acceptable salt. In some embodiments, the cancer is caused by a mutation in RAS, BRAF or NF-1. In some embodiments, the cancer has a RAS mutation. In other aspects, the cancer has a KRAS mutation or a NRAS mutation.

[0012] Described herein are methods of treating a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of a RAF / MEK dual inhibitor in combination with a FAK inhibitor, wherein the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutical acceptable salt thereof, and the FAK inhibitor is VS-6063 or a pharma- ceutical acceptable salt thereof.

[0013] Described herein is the use of a RAF / MEK dual inhibitor in combination with a FAK inhibitor to treat cancer, wherein the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutically acceptable salt thereof, and the FAK inhibitor is VS-6063 or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, the cancer is caused by a mutation in RAS, BRAF, or NF-1.

[0015] In some embodiments, the cancer is selected from ovarian cancer, lung cancer, colon cancer, and pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is low-grade serous ovarian cancer. In some embodiments, the cancer is lung cancer. In other embodiments, the cancer is colon cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is selected from low-grade serous ovarian cancer, lung cancer, colon cancer, and pancreatic cancer.

[0016] In some aspects, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered twice weekly. In some aspects, the FAK inhibitor (e.g., VS-6063) is administered twice daily. In other aspects, the FAK inhibitor (e.g., VS-6063) is administered once daily. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) and the FAK inhibitor (e.g., VS-6063) are administered for at least three weeks. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) and the FAK inhibitor (e.g., VS-6063) are administered independently in cycles of three weeks on followed by one week off. In some embodiments, both the RAF / MEK dual inhibitor (e.g., CH5126766) and the FAK inhibitor (e.g., VS-6063) are administered simultaneously in cycles of three weeks on followed by one week off.

[0017] In some aspects, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 0.5 mg to about 10 mg. In further embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 4 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 3.2 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 100 mg to about 400 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 100 mg to about 500 mg. In further embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 200 mg to about 500 mg. In other embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 200 mg to about 600 mg. In some aspects, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 0.5 mg to about 10 mg, and the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 100 mg to about 400 mg. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 4 mg twice weekly, and the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 200 mg twice daily. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 3.2 mg twice weekly, and the FAK inhibitor (e.g., VS-6063) is administered at a dose of 200 mg twice daily. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 4 mg twice weekly and the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 400 mg twice daily. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 3.2 mg twice weekly and the FAK inhibitor (e.g., VS-6063) is administered at a dose of 400 mg twice daily. DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

[0018] Specifically described herein is a method for treating abnormal cell growth, e.g., cancer, comprising administering a FAK inhibitor and a RAF / MEK dual inhibitor, wherein the FAK inhibitor is VS-6063 or a pharma- ceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutically acceptable salt thereof.

[0019] Methods of Treatment and Administration The methods described herein relate to treating a subject (e.g., a human subject) suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)) with a FAK inhibitor in combination with a RAF / MEK dual inhibitor, where the FAK inhibitor is VS-6063 or a pharma- ceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharma-ceutically acceptable salt thereof. As used herein, administered in combination means that two (or more) different treatments are delivered to a subject while the subject is suffering from a disorder, e.g., two or more treatments are delivered after the subject has been diagnosed with a disorder and before the disorder is cured or eliminated or the treatments are terminated for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second treatment begins, so there is an overlap in terms of administration. This may be referred to herein as "simultaneous" or "concurrent delivery." In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments in either case, the combined administration makes the treatment more effective. For example, the second treatment is more effective than would be seen when administered in the absence of the first treatment, for example, the equivalent effect is seen with the second treatment but to a lesser extent, or the second treatment relieves symptoms to a greater extent, or a similar situation is seen with respect to the first treatment. In some embodiments, the delivery is such that the relief of symptoms, or other parameters related to the disorder, is greater than would be observed with the other treatment delivered in the absence of the other treatment. The effect of the two treatments is slightly additive, completely additive, or greater than additive. The delivery can be such that the effect of the first treatment delivered is still detectable when the second treatment is delivered.

[0020] In some embodiments, the method includes administration of a FAK inhibitor (e.g., VS-6063) prior to administration of a RAF / MEK dual inhibitor (e.g., CH5126766). In some embodiments, the method includes administration of a FAK inhibitor (e.g., VS-6063) following administration of a RAF / MEK dual inhibitor (e.g., CH5126766). In some embodiments, the method includes administration of a FAK inhibitor (e.g., VS-6063) in parallel with administration of a RAF / MEK dual inhibitor (e.g., CH5126766). In some embodiments, the FAK inhibitor is VS-6063 (PF-04554878, defactinib) or a pharma- ceutically acceptable salt thereof. In some embodiments, the RAF / MEK dual inhibitor is CH5126766 or a pharma-ceutically acceptable salt thereof.

[0021] Tumor microenvironment The combination of compounds described herein is also directed to a method of modulating or regulating the tumor microenvironment in a subject (e.g., a subject with a cancer described herein). As used herein, "tumor microenvironment" refers to the cellular environment in which a tumor resides, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signaling molecules, and extracellular matrix (ECM). Tumors and the surrounding microenvironment are closely related and constantly interact. Tumors can affect the microenvironment by releasing extracellular signals, promoting tumor angiogenesis, and inducing peripheral immune tolerance, while immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

[0022] As used herein, the term "immunosuppressive cells" refers to cells that contribute to or promote an immunosuppressive tumor microenvironment. The presence of a population of immunosuppressive cells in the tumor microenvironment, also referred to herein as "tumor-associated immunosuppressive cells", increases the resistance of the tumor to immune responses, resulting in tumor protection, tumor evasion, and / or tumor metastasis. Unless countered in some way, tumor-associated immunosuppressive cells can reduce the effectiveness of immune-mediated anticancer treatments. There are numerous tumor-associated immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells.

[0023] In some embodiments, the combination of compounds described herein enhances the efficacy of tumor-specific cytotoxic lymphocytes or anti-tumor cytotoxic T cells. In some embodiments, the FAK inhibitors described herein (e.g., VS-6063) target immunosuppressive cells in the tumor microenvironment. In some embodiments, the FAK inhibitors described herein (e.g., VS-6063) act as a barrier to T cell infiltration via tumor-stroma regulation of dense desmoplastic stroma and / or FAK-regulated proinflammatory and / or profibrotic cytokine secretion. In some embodiments, BRAF inhibition activates stromal cells (e.g., cancer-activated fibroblasts, cell adhesion factors) that result in FAK-dependent cancer survival signaling (e.g., in melanoma).

[0024] Abnormal cell growth The methods described herein are directed to the treatment of abnormal cell growth in a subject (e.g., a human subject). As used herein, abnormal cell growth refers to cell growth that is not dependent on normal control mechanisms (e.g., loss of contact inhibition), unless otherwise indicated. This includes the abnormal growth of the following cells: (1) tumor cells (tumors) that grow, for example, by expressing mutant tyrosine kinases or overexpressing receptor tyrosine kinases; (2) benign and malignant cells of other proliferative diseases, for example, where abnormal tyrosine kinase activation occurs; (3) any tumor that grows, for example, by receptor tyrosine kinases; (4) any tumor that grows, for example, by abnormal serine / threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases, for example, where abnormal serine / threonine kinase activation occurs. Abnormal cell growth can refer to cell growth in epithelial (e.g., carcinoma, adenocarcinoma); mesenchymal (e.g., sarcoma (e.g., leiomyosarcoma, Ewing's sarcoma)); hematopoietic (e.g., lymphoma, leukemia, myelodysplasia (e.g., precancerous)); or other (e.g., mesothelioma and other tumors of unknown origin) cells.

[0025] In some embodiments, the method is effective in treating non-hematologic malignancies. In some embodiments, the method is effective in treating pancreatic, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), mesothelioma, breast cancer, and ovarian cancer. In some embodiments, the breast cancer is triple-negative breast cancer (e.g., breast cancer that does not express genes for estrogen receptor, progesterone receptor, and Her2 / neu). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), e.g., KRAS-mutated NSCLC. In some embodiments, the ovarian cancer is advanced ovarian cancer (e.g., advanced ovarian cancer or metastatic ovarian cancer). In some embodiments, the ovarian cancer is low-grade serous ovarian cancer. In some embodiments, the low-grade serous ovarian cancer is KRAS-mutated low-grade serous ovarian cancer. In some embodiments, the method is effective in treating mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma). In some embodiments, the cancer is pancreatic cancer.

[0026] Neoplastic diseases Abnormal cell growth can refer to a neoplastic disease. A "neoplastic disease" is a disease or disorder characterized by cells capable of autonomous growth or replication, e.g., an abnormal condition characterized by proliferative cell growth. An abnormal mass of tissue, or "neoplasm," resulting from abnormal cell growth or division can be benign, precancerous (carcinoma in situ) or malignant (cancer).

[0027] Exemplary neoplastic diseases include carcinomas, sarcomas, metastatic diseases (e.g., tumors arising from prostate, colon, lung, breast, and liver origins), hematopoietic neoplastic diseases such as leukemia, metastatic tumors. Treatment with the compound can be in an amount effective to ameliorate at least one symptom of the neoplastic disease, e.g., inhibit cell proliferation, reduce tumor burden, etc.

[0028] cancer In some embodiments, the methods of the present invention may be useful for treating cancers, including, for example, solid tumors, soft tissue tumors, and their metastases. In some embodiments, the methods of the present invention may be useful for treating cancers in which the MEK-ERK pathway is activated. The disclosed methods are also useful for treating non-solid cancers. Exemplary solid tumors include malignancies of various organ systems (e.g., sarcomas, adenocarcinomas, and carcinomas), such as lung, breast, lymphatic, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular), pharyngeal, prostate, and ovarian malignancies. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma), non-small cell carcinoma of the lung, pancreas (e.g., metastatic pancreatic adenocarcinoma), and small intestine cancer.

[0029] Cancers can also include uterine cancer (such as endometrial cancer, uterine tumors, and cervical cancer), biliary cancer, and biliary tract cancer (such as cholangiocarcinoma, bile duct cancer, and gallbladder cancer).

[0030] The cancer may be a primary tumor, i.e., located at the anatomical site of tumor growth initiation. The cancer may also be metastatic, i.e., appear at at least one second anatomical site other than the anatomical site of tumor growth initiation. The cancer may also be a recurrent cancer, i.e., a cancer that reoccurs after a period of time following treatment in which the cancer was undetectable. The recurrent cancer may be anatomically located in the same place as the original tumor, e.g., anatomically near the original tumor, or in the same region as the original tumor, e.g., in lymph nodes located near the original tumor, or at a distance from the original tumor, e.g., in a region anatomically distant from the original tumor.

[0031] The cancer may also have a RAS mutation, meaning that the cancer is caused by a mutation in the RAS gene (HRAS, NRAS, or KRAS). The cancer may also have a KRAS mutation, meaning that the cancer is caused by a mutation in the KRAS gene. The cancer may also have an NRAS mutation, meaning that the cancer is caused by a mutation in the NRAS gene. In some embodiments, the cancer is ovarian cancer caused by a mutation in the RAS gene (e.g., the KRAS gene). In some embodiments, the cancer is low-grade ovarian cancer or mucinous ovarian cancer, both of which are caused by a mutation in the RAS gene (e.g., the KRAS gene). In some embodiments, the cancer is lung cancer caused by a mutation in the RAS gene (e.g., the KRAS gene). In some embodiments, the cancer is colon cancer caused by a mutation in the RAS gene (e.g., the KRAS gene or the NRAS gene). In some embodiments, the cancer is pancreatic cancer caused by a mutation in the RAS gene (e.g., the KRAS gene).

[0032] Cancers can also include, for example, epithelial cancer, breast, lung, pancreatic, colorectal (e.g., metastatic colorectal, e.g., KRAS-mutated metastatic), prostate, head and neck, melanoma, acute myeloid leukemia, and glioblastoma. Exemplary breast cancers include triple-negative breast cancer, basal-like breast cancer, claudin-low breast cancer, treatment-resistant invasive, inflammatory, metaplastic, and advanced Her-2-positive or ER-positive cancers.

[0033] Examples of genes mutated in cancer also include EGFR, FGFR, ALK, ROS1, PI3K, NF-1, BRAF, HRAS, KRAS, and NRAS. The cancer is preferably a KRAS mutated and / or NRAS mutated cancer, more preferably a KRAS mutated or NRAS mutated colon cancer, or a KRAS mutated solid cancer (preferably ovarian cancer, lung cancer (particularly non-small cell lung cancer), colon cancer, and pancreatic cancer).

[0034] Other cancers include brain, abdominal, esophageal, gastrointestinal, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovarian, retinoblastoma, Wilms' tumor, multiple myeloma, skin, lymphoma, blood and bone marrow cancers (e.g., advanced hematological malignancies, leukemias, e.g., acute myeloid leukemia (e.g., primary or secondary), acute lymphoblastic leukemia, acute lymphocytic leukemia, T-cell leukemia, hematological malignancies, advanced myeloproliferative disorders, myelodysplastic syndromes, relapsed or refractory multiple myeloma, advanced myeloproliferative disorders), retina, bladder, cervix, kidney, endometrium, meningioma, lymphoma, skin, uterus, lung, non-small cell lung, nasopharyngeal carcinoma, neuroblastoma, solid tumors, hematological malignancies, squamous cell carcinoma, testicular, thyroid, mesothelioma, brain These include vulvar, sarcoma, intestinal, oral, endocrine, salivary, spermatocytic seminoma, sporadic medullary thyroid carcinoma, non-proliferating testicular cell, malignant mast cell-associated carcinoma, non-Hodgkin's lymphoma, and diffuse large B-cell lymphoma.

[0035] Exemplary cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, astrocytoma, cholangiocarcinoma, extrahepatic, bladder cancer; bone cancer, osteosarcoma / malignant fibrous histiocytoma, brain stem glioma, brain tumor, brain stem glioma, cerebellar astrocytoma, brain astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic tract and hypothalamic glioma; breast cancer; bronchial adenoma / carcinoid, carcinoid tumor, carcinoid tumor, gastrointestinal; carcinoma, adrenal cortical; carcinoma, islet cell; carcinoma of unknown primary; central nervous system lymphoma, primary ;cerebellar astrocytoma, brain astrocytoma / malignant glioma, cervical cancer;chronic lymphocytic leukemia;chronic myelogenous leukemia;chronic myeloproliferative disorders;clear cell sarcoma of tendon sheath;colon cancer;colorectal cancer;cutaneous T-cell lymphoma;endometrial cancer;ependymoma, epithelial carcinoma, ovary;esophageal cancer;esophageal cancer, Ewing family tumors;extracranial germ cell tumors, extragonadal germ cell tumors;extrahepatic bile duct cancer;eye cancer, retinoblastoma;gallbladder cancer;gastric cancer;gastric cancer;gastrointestinal carcinoid tumors;germ cell tumors, extracranial;germ cell tumors, extragonadal;germ cell tumors, ovary;gestational trophoblastic tumor;glioma, glioma, optic tract and hypothalamus;hairy cell white Hematologic malignancies;Head and neck cancer;Hepatocellular (liver) cancer;Hodgkin's lymphoma;Hodgkin's lymphoma;Hodgkin's lymphoma during pregnancy;Hypopharyngeal cancer;Hypothalamic and optic tract glioma;Islet cell carcinoma (pancreatic endocrine);Kaposi's sarcoma;Kidney cancer;Pharyngeal cancer;Pharyngeal cancer;Leukemia, acute lymphoblastic;Leukemia, acute lymphoblastic;Leukemia, acute myeloid;Leukemia, acute myeloid;Leukemia, chronic lymphocytic;Leukemia, chronic myeloid;Leukemia, hairy cell;Lip and oral cavity cancer;Liver cancer;Lung cancer, non-small cell;Lung cancer, small cell;Lymphoblastic leukemia, lymphocytic leukemia, chronic;Lymphoma, AIDS-related;Lymphoma, central nervous system (primary);lymphoma, cutaneous T-cell;lymphoma, Hodgkin;lymphoma, Hodgkin;lymphoma, Hodgkin, pregnancy;lymphoma, non-Hodgkin;lymphoma, non-Hodgkin;non-Hodgkin, pregnancy;lymphoma, primary central nervous system;macroglobulinemia, Waldenstrom;male breast cancer;malignant mesothelioma, adult;malignant mesothelioma;malignant thymoma;medulloblastoma, Merkel cell carcinoma;mesothelioma, malignant;metastatic squamous neck cancer of unknown primary;multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm;mycosis fungoides;myelodysplastic syndrome;myeloid leukemia, chronic;myeloid leukemia, myeloma, multiple;Myeloproliferative disorders, chronic;nasal and paranasal sinus cancer;nasopharyngeal cancer;nasopharyngeal carcinoma;neuroblastoma;non-Hodgkin's lymphoma, non-Hodgkin's lymphoma during pregnancy;non-small cell lung cancer;cancer of the mouth;cancer of the oral cavity and lip;oropharyngeal cancer;osteosarcoma / malignant fibrous histiocytoma of bone;ovarian cancer;ovarian epithelial cancer;ovarian germ cell tumors;ovarian low malignant potential tumors;pancreatic cancer;pancreatic cancer;pancreatic cancer, islet cell;sinoasal and nasal sinus cancer;parathyroid cancer; Penile cancer;pheochromocytoma;pineal and supratentorial primitive neuroectodermal tumors;pituitary tumors;plasma cell neoplasms / multiple myeloma;pleuropulmonary blastoma;pregnancy and breast cancer;pregnancy and Hodgkin's lymphoma;pregnancy and non-Hodgkin's lymphoma;primary central nervous system lymphoma;primary liver cancer;primary liver cancer;prostate cancer;rectal cancer;renal cell (kidney) cancer;renal cell carcinoma;renal pelvis and ureter, transitional cell carcinoma;retinoblastoma;striated muscle Sarcoma;Salivary gland cancer;Salivary gland cancer;Sarcoma, Ewing family tumor;Sarcoma, Kaposi;Sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone;Sarcoma, rhabdomyosarcoma;Sarcoma, soft tissue;Sarcoma, soft tissue;Sezary syndrome;Skin cancer;Skin cancer;Skin cancer (melanoma);Skin cancer, Merkel cell;Small cell lung cancer;Small intestine cancer;Soft tissue sarcoma;Soft tissue sarcoma;Squamous neck cancer of unknown primary, metastatic;Gastric cancer;Gastric cancer;Te These include: epithelial primitive neuroectodermal tumors; T-cell lymphoma, skin; testicular cancer; thymoma; thymoma, malignant; thyroid cancer; thyroid cancer; transitional cell carcinoma of the renal pelvis and ureter; trophoblastic tumor, gestational; carcinoma of unknown primary site; ureter and renal pelvis, transitional cell carcinoma; urethral cancer; uterine sarcoma; vaginal cancer; optic tract and hypothalamic glioma; vulvar cancer; Waldenstrom's macroglobulinemia; and Wilms' tumor. Metastases of the above cancers can also be treated according to the methods described herein.

[0036] In some embodiments, the tumor is a tumor of the hematopoietic and lymphoid tissues or a tumor affecting the blood, bone marrow, lymph, and lymphatic systems. Hematological malignancies include acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute monocytic leukemia, other leukemias, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0037] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is refractory (e.g., resistant) to standard treatments.

[0038] The methods described herein can reduce, ameliorate, or completely eliminate the disorder and / or symptoms associated with the disorder, preventing it from becoming worse, slowing its rate of progression, or minimizing the rate of recurrence of the disorder (i.e., avoiding relapse) if it is initially eliminated. Suitable doses and treatment regimens can vary depending on the specific compounds and / or pharmaceutical compositions used and the mode of delivery of the compounds and / or pharmaceutical compositions. In some embodiments, the methods statistically significantly increase the mean survival time, statistically significantly increase the mean progression-free survival, and / or statistically significantly reduce the rate of recurrence of subjects treated with the combinations described herein.

[0039] In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutated NSCLC; metastatic cancer), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer (e.g., unresectable low-grade ovarian cancer, advanced or metastatic ovarian cancer), rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., breast cancer that does not express genes for estrogen receptor, progesterone receptor, and Her2 / neu)), uterine cancer, , carcinoma of the fallopian tube, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney (e.g., Wilms' tumor, rhabdoid tumor; nephroma (e.g., mesoblastic nephroma)) or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), or a combination of one or more of the foregoing cancers. In some embodiments, the cancer is ovarian cancer, pancreatic cancer, non-small cell lung cancer, head and neck cancer. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (e.g., the subject has a locally recurrent disease, e.g., cancer).

[0040] The methods of the present invention contemplate single and multiple administrations of a therapeutically effective amount of a FAK inhibitor in combination with a RAF / MEK dual inhibitor, where the FAK inhibitor is VS-6063 or a pharma- ceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutically acceptable salt thereof. Combinations, such as those described herein, for example, a FAK inhibitor (e.g., VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766), can be administered at regular intervals depending on the nature, severity and extent of the subject's condition. In some embodiments, combinations described herein, for example, a FAK inhibitor in combination with a RAF / MEK dual inhibitor, are administered in a single dose, where the FAK inhibitor is VS-6063 or a pharma- ceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutically acceptable salt thereof. In some embodiments, a combination described herein, e.g., a FAK inhibitor in combination with a RAF / MEK dual inhibitor, is administered in multiple doses, where the FAK inhibitor is VS-6063 or a pharma- ceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutically acceptable salt thereof. In some embodiments, a therapeutically effective amount of a combination described herein, e.g., a FAK inhibitor (e.g., VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766), may be orally administered periodically at regular intervals (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times every 1, 2, 3, 4, 5, 6, 7, 8, 9 days, or every 1, 2, 3, 4, 5, 6, 7, 8, 9 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9 months or more). In some embodiments, a therapeutically effective amount of a combination described herein, for example, a FAK inhibitor (e.g., VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766), which may be administered orally on a regular basis (e.g., twice a day), may be administered orally.In some embodiments, a therapeutically effective amount of a combination described herein, for example, a FAK inhibitor (e.g., VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766) that may be orally administered on a regular basis (e.g., twice a week) may be orally administered once a day. In some embodiments, a therapeutically effective amount of a combination described herein, for example, a FAK inhibitor (e.g., VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766) that may be orally administered on a regular basis (e.g., three times a week) may be orally administered twice a day. VS-6063 and CH5126766 may each be in the form of a pharma- ceutically acceptable salt.

[0041] In some embodiments, a combination as described herein, e.g., a FAK inhibitor (VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766) administered orally at predetermined intervals (e.g., twice a week), is administered orally on a regular schedule (e.g., twice daily) for three weeks, followed by a one-week rest period (or interval during which neither the FAK inhibitor (e.g., VS-6063) nor the RAF / MEK dual inhibitor (e.g., CH5126766) is administered), and then repeated periodically (e.g., three weeks on, one week off, three weeks on, one week off, etc.). In some embodiments, CH5126766 or a pharma- ceutically acceptable salt thereof and VS-6063 or a pharma-ceutically acceptable salt thereof are each administered for at least three weeks. In some embodiments, CH5126766 or a pharma-ceutically acceptable salt thereof and VS-6063 or a pharma-ceutically acceptable salt thereof are each administered for at least four weeks. In some embodiments, CH5126766 or a pharma- ceutically acceptable salt thereof and VS-6063 or a pharma-ceutically acceptable salt thereof are each administered for at least 5 weeks. In some embodiments, CH5126766 or a pharma-ceutically acceptable salt thereof and VS-6063 or a pharma-ceutically acceptable salt thereof are each administered in cycles of 4 weeks on, followed by at least 1 week of rest. In other embodiments, CH5126766 or a pharma-ceutically acceptable salt thereof and VS-6063 or a pharma-ceutically acceptable salt thereof are each administered in cycles of 5 or 6 weeks on, followed by 1 or 2 weeks of rest.

[0042] The timing of the one-week off of VS-6063 or a pharma- ceutically acceptable salt thereof and the timing of the one-week off of CH5126766 or a pharma- ceutically acceptable salt thereof may be simultaneous or different. In a preferred embodiment, the timing of the one-week off of VS-6063 or a pharma- ceutically acceptable salt thereof and the timing of the one-week off of CH5126766 or a pharma- ceutically acceptable salt thereof are simultaneous.

[0043] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is orally administered once a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is orally administered twice a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is orally administered three times a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is orally administered four times a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is orally administered five times a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is orally administered once a day. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is orally administered twice a day. CH5126766 can also be in the form of a pharma- ceutically acceptable salt.

[0044] In some embodiments, the FAK inhibitor (e.g., VS-6063) is orally administered twice a day. In some embodiments, the FAK inhibitor (e.g., VS-6063) is orally administered once a day. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 100 mg to about 400 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 100 mg to about 500 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 200 mg to about 500 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 200 mg to about 600 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 200 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dose of about 400 mg. It should be understood that the FAK inhibitor (e.g., VS-6063) can be administered at a dose and at any regular time period described herein.For example, the FAK inhibitor (e.g., VS-6063) can be administered at a dose of about 200 mg twice a day.The FAK inhibitor (VS-6063) can be administered at a dose of about 400 mg twice a day.

[0045] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 0.5 mg to about 10 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 0.5 mg to about 7 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 0.5 mg to about 5 mg. In other embodiments, the RAF / MEK dual inhibitor is administered at a dose of about 1 mg to about 10 mg. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of about 4 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 3.2 mg. It should be understood that the RAF / MEK dual inhibitor (e.g., CH5126766) may be administered at any regular time frame described herein. For example, the RAF / MEK dual inhibitor (e.g., CH5126766) may be administered at a dose of about 0.5 mg to about 10 mg twice a week. The RAF / MEK dual inhibitor (e.g., CH5126766) may be administered at a dose of about 4 mg twice a week. The RAF / MEK dual inhibitor (e.g., CH5126766) may be administered at a dose of 3.2 mg twice a week. CH5126766 may be in the form of a pharma- ceutical acceptable salt.

[0046] As described herein, a FAK inhibitor (e.g., VS-6063) may be administered with a RAF / MEK dual inhibitor (e.g., CH5126766). For example, CH5126766 or a pharma- ceutically acceptable salt thereof may be administered at a dose of about 0.5 mg to about 10 mg, and VS-6063 or a pharma-ceutically acceptable salt thereof may be administered at a dose of about 100 mg to about 400 mg. CH5126766 or a pharma-ceutically acceptable salt thereof may be administered at a dose of about 3 mg to about 5 mg, and VS-6063 or a pharma-ceutically acceptable salt thereof may be administered at a dose of about 100 mg to about 400 mg. CH5126766 or a pharma-ceutically acceptable salt thereof may be administered at a dose of about 3 mg to about 5 mg twice a week, and VS-6063 or a pharma-ceutically acceptable salt thereof may be administered at a dose of about 100 mg to about 400 mg twice a day. CH5126766 or a pharma- ceutically acceptable salt thereof may be administered at a dose of about 4.0 mg twice weekly, and VS-6063 or a pharma- ceutically acceptable salt thereof may be administered at a dose of about 200 mg twice daily. CH5126766 or a pharma- ceutically acceptable salt thereof may be administered at a dose of about 3.2 mg twice weekly, and VS-6063 or a pharma- ceutically acceptable salt thereof may be administered at a dose of about 200 mg twice daily. CH5126766 or a pharma- ceutically acceptable salt thereof may be administered at a dose of about 3.2 mg twice weekly, and VS-6063 or a pharma- ceutically acceptable salt thereof may be administered at a dose of about 400 mg twice daily.

[0047] In some embodiments, the dual RAF / MEK inhibitor (eg, CH5126766) is administered according to the following steps. (a) RAF / MEK dual inhibitor administered twice weekly for 3 weeks; (b) then withdrawing administration of the compound or salt for one week; (c) Thereafter, steps (a) and (b) are repeated at least once.

[0048] In some embodiments, the dual RAF / MEK inhibitor (eg, CH5126766) is administered by methods (R1) or (R2) below. (R1) (A1) (A1a) A RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 4 mg twice weekly for three weeks; (A1b) The RAF / MEK dual inhibitor (e.g., CH5126766) is then discontinued for one week (i.e., on a 3-week on / 1-week off basis, for a total of 4 weeks in one cycle), (A1c) Steps (A1a) and (A1b) are then repeated at least once. (R2) (A2) First, (A2a) A RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 4 mg twice weekly for three weeks; (A2b) The administration of a RAF / MEK dual inhibitor (e.g., CH5126766) is then suspended for one week. (A2c) steps (A2a) and (A2b) are then repeated at least once, (B2) After that, (B2a) A RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 3.2 mg twice weekly for three weeks; (B2b) The administration of the RAF / MEK dual inhibitor (e.g., CH5126766) is then suspended for one week. (B2c) Steps (B2a) and (B2b) are then repeated at least once.

[0049] In some embodiments, (i) a 4-week cycle consisting of steps (a) and (b), and (ii) a 4-week cycle consisting of steps (A1a) and (A1b) are repeated, for example, 2 times (8 weeks) to 90 times (approximately 6 years and 11 months), more specifically, for example, 8 times (32 weeks) to 18 times (72 weeks). Even if the number of cycles to be repeated is predetermined, it may be changed based on the judgment of a physician or veterinarian, for example, depending on the condition of the subject. Furthermore, administration may be discontinued midway through a cycle, for example, based on the judgment of a physician or veterinarian, depending on the condition of the subject.

[0050] In some embodiments, the 4-week cycle consisting of steps (A2a) and (A2b) is repeated, for example, 2 times (8 weeks) to 45 times (approximately 3 years and 5 months), more specifically, for example, 8 times (32 weeks) to 18 times (72 weeks). Even if the number of cycles to be repeated is predetermined, it may be changed based on the judgment of a physician or veterinarian, for example, depending on the condition of the subject. Furthermore, administration may be discontinued midway through the cycle, for example, based on the judgment of a physician or veterinarian, depending on the condition of the subject.

[0051] In some embodiments, the 4-week cycle consisting of steps (B2a) and (B2b) is repeated, for example, 2 times (8 weeks) to 45 times (approximately 3 years and 5 months), more specifically, for example, 8 times (32 weeks) to 18 times (72 weeks). Even if the number of cycles to be repeated is predetermined, it may be changed based on the judgment of a physician or veterinarian, for example, depending on the condition of the subject. Furthermore, administration may be discontinued midway through the cycle, for example, based on the judgment of a physician or veterinarian, depending on the condition of the subject.

[0052] In some embodiments, the dose of the RAF / MEK dual inhibitor (e.g., CH5126766) per administration is preferably 3.2 mg or 4 mg. More preferably, it is 4 mg, and can be reduced to 3.2 mg. The dose of the FAK inhibitor (e.g., VS-6063) per administration is preferably 200 mg or 400 mg. More preferably, it is 200 mg, and can be increased to 400 mg.

[0053] The period during which the RAF / MEK dual inhibitor (e.g., CH5126766) is used in combination with the FAK inhibitor (e.g., VS-6063) can be determined based on the judgment of a physician or veterinarian, for example, depending on the condition of the subject. Also, administration of either or both of the RAF / MEK dual inhibitor (e.g., CH5126766) and the FAK inhibitor (e.g., VS-6063) can be discontinued based on the judgment of a physician or veterinarian, for example, depending on the condition of the subject.

[0054] compound The methods described herein include, inter alia, administering to a subject having cancer a FAK inhibitor in combination with a RAF / MEK dual inhibitor, where the FAK inhibitor is VS-6063 or a pharma- ceutical acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharma- ceutical acceptable salt thereof.

[0055] VS-6063 Exemplary FAK inhibitors include VS-6063 or a pharma- ceutically acceptable salt thereof (e.g., VS-6063 hydrochloride).VS-6063 and related compounds are also disclosed, for example, in U.S. Patent No. 7,928,109, the contents of which are incorporated herein by reference.VS-6063 is also known as defactinib and PF-04554878, and has the following structure: [ka] has.

[0056] In some embodiments, VS-6063 may form a pharma- ceutically acceptable salt (e.g., VS-6063 hydrochloride). In some embodiments, VS-6063 or a pharma- ceutically acceptable salt thereof is present in the composition in an amount of 5, 10, 11, 12, 12.5, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60% w / w, or more. In some embodiments, VS-6063 or a pharma- ceutically acceptable salt thereof is present in the composition in an amount of about 5 to about 60% w / w, about 5 to about 50% w / w, about 10 to about 50% w / w, or about 10 to about 40% w / w.

[0057] CH5126766 CH5126766 is a dual RAF / MEK inhibitor, also known as RO5126766. Methods of using CH5126766 or a pharma- ceutically acceptable salt thereof are included herein. CH5126766 (free base) has the following formula: [ka] It is represented by:

[0058] The CH5126766 or a pharma- ceutically acceptable salt thereof used in the present invention is preferably a potassium salt of CH5126766. The potassium salt of CH5126766 is preferably, for example, represented by the following formula: [ka] It is a salt represented by:

[0059] For example, CH5126766 and its pharma- ceutically acceptable salts are disclosed in WO 2007 / 091736 and WO 2009 / 014100 and can be prepared according to the methods described in these publications.

[0060] Cancer Combination Therapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) are administered with an additional therapy (e.g., cancer treatment). In one embodiment, a mixture of one or more compounds or pharmaceutical compositions may be administered with the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof). In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) may be administered with the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) for the treatment of various diseases, including, for example, cancer.

[0061] In various embodiments, a combination therapy comprising a compound or pharmaceutical composition described herein can refer to (1) a pharmaceutical composition comprising one or more compounds in combination with a combination described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof), and (2) the co-administration of one or more compounds or pharmaceutical compositions described herein with a combination described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof), where the compounds or pharmaceutical compositions described herein are not formulated in the same composition. In some embodiments, a combination described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) is administered with an additional treatment (e.g., an additional cancer treatment). In some embodiments, the additional treatment (e.g., an additional cancer treatment) can be administered simultaneously (e.g., at the same time) or sequentially in the same or separate compositions. Sequential administration refers to administration of one treatment prior to (e.g., immediately before, less than 5 minutes, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 hours or more; 4, 5, 6, 7, 8, 9 days or more; 1, 2, 3, 4, 5, 6, 7, 8 weeks or more) administration of an additional treatment (e.g., compound or therapy). The order of administration of the first and second compound or therapy can also be reversed. In some embodiments, the FAK inhibitor (e.g., VS-6063) and the RAF / MEK dual inhibitor (e.g., CH5126766) are administered at different regular time intervals. For example, dual RAF / MEK inhibitors (e.g., CH5126766) may be administered twice weekly, once weekly, or every 3 or 4 days, whereas FAK inhibitors (e.g., VS-6063) may be administered once daily or twice daily.

[0062] The method of the present invention can be used or administered in combination with one or more additional therapies (e.g., cancer treatment, e.g., surgical treatment, additional drugs or therapeutic agents) for the treatment of the disorders / diseases mentioned. The additional therapies (e.g., cancer treatment, e.g., drugs or therapeutic agents described herein) can be administered in the same formulation or in separate formulations. When administered in separate formulations, the compound of the present invention can be administered sequentially or simultaneously with the other drugs.

[0063] In addition to being able to be administered in combination with one or more additional therapies (e.g., cancer treatments, e.g., surgical procedures, additional drugs or therapeutic agents), the methods of the invention may be administered simultaneously or sequentially (as a combined preparation) to achieve the desired effect. This is particularly desirable when the therapeutic profile of each compound is different, such that the combined effect of the two drugs provides an improved therapeutic outcome.

[0064] Exemplary cancer treatments include, for example, chemotherapy, targeted therapies such as antibody therapy, immunotherapy, and hormonal therapy. Examples for each of these treatments are provided below.

[0065] chemotherapy In some embodiments, the combination described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) is administered with chemotherapy. Chemotherapy is the treatment of cancer with drugs capable of destroying cancer cells. "Chemotherapy" generally refers to cytotoxic drugs that affect rapidly dividing cells in general, in contrast to targeted therapy. Chemotherapy drugs disrupt cell division by a variety of possible means, for example, DNA duplication or separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some specificity may arise from the fact that normal cells are generally able to repair DNA damage, whereas many cancer cells cannot.

[0066] Examples of chemotherapeutic agents used in cancer chemotherapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkylsulfonates, hydrazines, triazenes, aziridines, spindle poisons, cytotoxic agents, topoisomerase inhibitors, etc.). Exemplary agents include aclarubicin, actinomycin, alitretinoin, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquone, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, Cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demecolcine, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, etoglucide, etoposide, floxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, Gliadel implant (Gliadelimplant), hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucantone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednisolone Mustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagene seradenovec, strataplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurin, thioguanine, tipifarnib, topotecan, trabectedin, triazicon, triethylenemelamine, triplatin, tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, zorubicin, and other cytostatic or cytotoxic agents described herein.

[0067] Since some drugs work better together than alone, two or more drugs are often given simultaneously or sequentially. Often, two or more chemotherapeutic agents are used as combination chemotherapy. In some embodiments, chemotherapeutic agents (including combination chemotherapy) can be used in combination with the combinations described herein (e.g., FAK inhibitors combined with RAF / MEK dual inhibitors).

[0068] Targeted therapy In some embodiments, the combination described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) is administered with targeted therapy. Targeted therapy constitutes the use of drugs specific to deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains of mutated, overexpressed, or otherwise important proteins in cancer cells. Well-known examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, and cyclin-dependent kinase inhibitors such as alvocidib and seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells. Examples include the anti-HER2 / neu antibody trastuzumab (HERCEPTIN®), typically used in breast cancer, and the anti-CD20 antibodies rituximab and tositumomab, typically used in various B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin diftitox. Targeted therapies may also include small peptides as "homing devices" that can bind to cell surface receptors or to the extracellular matrix surrounding affected tumors. Radionuclides (e.g., RGD) bound to these peptides ultimately kill cancer cells when they disintegrate in the vicinity of the cells. An example of such a therapy includes BEXXAR®.

[0069] immunotherapy In some embodiments, the combination described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma-ceutically acceptable salt thereof) is administered with immunotherapy. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight tumors. Modern methods for generating immune responses against tumors include the use of IL-2 and intravesical BCG immunotherapy for bladder cancer, and the use of interferon and other cytokines to induce immune responses in subjects with renal cell carcinoma, melanoma, multiple myeloma, chronic myelogenous leukemia, and hairy cell leukemia.

[0070] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, as donor immune cells can often attack tumors in a graft-versus-tumor effect. In some embodiments, immunotherapeutic agents can be used in combination with the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma-ceutically acceptable salt thereof).

[0071] In some embodiments, the immunotherapeutic agent is a compound (e.g., ligand, antibody) that inhibits immune checkpoint blockade pathways. Cancer immunotherapy refers to the use of the immune system to treat cancer. Three major groups of immunotherapies used to treat cancer include cell-based therapy, antibody-based therapy, and cytokine therapy. All groups use the display by cancer cells of slightly different structures (e.g., molecular structures, antigens, proteins, molecules, carbohydrates) on the cancer cell surface that can be detected by the immune system. Cancer immunotherapy (i.e., anti-tumor immunotherapy or anti-tumor immunotherapy drugs) includes immune checkpoint antibodies (e.g., PD-1 antibody, PD-L1 antibody, PD-L2 antibody, CTLA-4 antibody, TIM3 antibody, LAG3 antibody, TIGIT antibody), and cancer vaccines (i.e., anti-tumor vaccines).

[0072] In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (e.g., ipilimumab, tremelimumab), anti-TIM3, anti-LAG3, or anti-TIGIT. In some embodiments, the immunotherapeutic agent is an anti-PD-1 ligand (e.g., PD-L1 (e.g., B7-H1 or CD274) or PD-L2 (e.g., B7-DC or CD273)). In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody (e.g., anti-PD-1 or anti-PD-L1) (e.g., nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538), CT-011, AMP-224, pembrolizumab, pidilizumab, or MK-3475). In some embodiments, the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559 (i.e., MDX-1105), MEDI4736, MSB0010718C (avelumab), or MPDL-3280A). In some embodiments, the immunotherapeutic agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy. In some embodiments, the immunotherapeutic agent is a costimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40). In some embodiments, the method further comprises administering an additional chemotherapeutic agent or radiation therapy. In some embodiments, the method further comprises administering a cytotoxic agent. In some embodiments, the cytotoxic agent is gemcitabine or paclitaxel (e.g., nab-paclitaxel). In some embodiments, the immunotherapeutic agent is a costimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0073] Anti-inflammatory agents In some embodiments, the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) can be administered with an anti-inflammatory agent. Anti-inflammatory agents include nonsteroidal anti-inflammatory agents (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoformaldehyde, naphthalene ... oxicam), fenamic acid derivatives (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (celecoxib), sulfonanilides (nimesulide), steroids (e.g., hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone).

[0074] Painkillers In some embodiments, the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) can be administered with an analgesic, including opiates (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetamol, and nonsteroidal anti-inflammatory drugs (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprozin, valproate ... fen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (fenamic acid series) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), and sulfonanilide drugs (nimesulide).

[0075] Antiemetics In some embodiments, the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) can be administered with an antiemetic. Antiemetics include 5-HT3 receptor antagonists (dolasetron (Anzemet), granisetron (Kytril, Thankuso), ondansetron (Zofran), tropisetron (Navoban), palonosetron (Aloxi), mirtazapine (Remeron)), dopamine antagonists (domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide (Reglan), alizapride, prochlorperazine (Compazine), , Stemidine, Bukkastem, Stemethyl, Phenotil), NK1 receptor antagonists (Aprepitant (Emend), antihistamines (cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Gravol, Dramamine), meclozine (Bonin, Antivert), promethazine (Pentazin, Phenergan, Promacot), hydroxyzine), benzodiazapines (lorazepam, midazolam), anticholinergics (hyoscine), and steroids (dexamethasone).

[0076] Hormone therapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma-ceutically acceptable salt thereof) are administered with hormone therapy. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancer. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens, can be therapeutically beneficial. In some embodiments, hormone therapy agents can be used in combination with the combinations described herein (e.g., VS-6063 or a pharma-ceutically acceptable salt thereof in combination with CH5126766 or a pharma-ceutically acceptable salt thereof).

[0077] Radiation therapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) can be used in combination with directed energy or particle or radioisotope treatment, e.g., radiation therapy, e.g., radiation oncology, for the treatment of proliferative diseases, e.g., cancer, e.g., cancer associated with cancer stem cells. The methods of the invention can be administered to a subject simultaneously or sequentially with directed energy or particle or radioisotope treatment. For example, the methods of the invention can be administered before, during or after directed energy or particle or radioisotope treatment, or combinations thereof. Directed energy or particle therapy can include total body irradiation, localized irradiation, or point irradiation. Directed energy or particles can originate from accelerators, synchrotrons, nuclear reactions, vacuum tubes, lasers, or from radioisotopes. Therapy can include external beam radiotherapy, teletherapy, brachytherapy, sealed source radiotherapy, total body radioisotope therapy, or unsealed source radiotherapy. Therapy may include ingestion or close placement of a radioisotope, e.g., radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon. External beam radiation may include directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio, millimeter wave, microwave, infrared, visible, ultraviolet, x-ray, or gamma ray photons). Radiation may be directed to any part of the subject requiring treatment.

[0078] Surgical procedure In some embodiments, the combinations described herein (e.g., VS-6063 or a pharma- ceutically acceptable salt thereof in combination with CH5126766 or a pharma- ceutically acceptable salt thereof) can be used in combination with a surgical procedure, e.g., surgical exploration, intervention, biopsy, for the treatment of a proliferative disease, e.g., cancer, e.g., cancer associated with cancer stem cells. The methods of the present invention can be administered to a subject simultaneously or sequentially with a surgical procedure. For example, the methods of the present invention can be administered before (pre-op), during or after (post-op) a surgical procedure, or a combination thereof. A FAK inhibitor (e.g., VS-6063) can be administered before (pre-op) a surgical procedure, and a RAF / MEK dual inhibitor (e.g., CH5126766) can be administered during or after (post-op) a surgical procedure. Alternatively, a RAF / MEK dual inhibitor (e.g., CH5126766) may be administered before (pre-op) the surgical procedure, and a FAK inhibitor (e.g., VS-6063) may be administered during or after (post-op) the surgical procedure. The surgical procedure may be a biopsy in which one or more cells are collected for further analysis. The biopsy may be performed, for example, with a scalpel, needle, catheter, endoscope, spatula, or scissors. The biopsy may be an excision biopsy, an incision biopsy, a core biopsy, or a needle biopsy, for example, a needle aspiration biopsy. The surgical procedure may involve the removal of localized tissue suspected or identified as cancerous. For example, the surgery may involve the removal of a cancerous lesion, a lump, a polyp, or a mole. The surgery may involve the removal of a larger amount of tissue, for example, breast, bone, skin, fat, or muscle. The surgery may involve removal of part or all of an organ or node, such as the lung, throat, tongue, bladder, cervix, ovaries, testes, lymph nodes, liver, pancreas, brain, eye, kidney, gallbladder, stomach, colon, rectum, or intestine. In one embodiment, the cancer is breast cancer, such as triple negative breast cancer, and the surgical procedure is a mastectomy or partial mastectomy.

[0079] First-line therapy In some embodiments, methods are described herein for treating a human subject with cancer, where the subject has failed (e.g., relapsed, was insensitive, or received little or no benefit from) a first-line treatment (e.g., a first-line therapy for cancer). The present invention also provides a method for treating a human subject with cancer, where the method of the present invention is administered in conjunction with an additional agent. In some embodiments, the additional agent is a first-line therapy for cancer.

[0080] First-line therapy is typically the first treatment given for a disease (e.g., cancer as described herein). First-line therapy is often part of a set of standard treatments, such as surgery followed by chemotherapy and radiation. When used alone, first-line therapy is the therapy that is generally considered to be the best treatment. If first-line therapy does not cure the disease or causes severe side effects, other treatments can be added or used instead. First-line therapy is also referred to as induction therapy, primary therapy, and primary treatment.

[0081] For example, first line therapies, e.g., first line therapies for Hodgkin's lymphoma, include Adcetris (brentuximab vedotin), Adriamycin PFS (doxorubicin hydrochloride), Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), Ambochlorin (chlorambucil), Blenoxane (bleomycin), bleomycin, brentuximab vedotin, chlorambucil, Clafen (cyclophosphamide), cyclophosphamide, Cytoxa These may include vinblastine, doxorubicin hydrochloride, DTIC Dohme (dacarbazine), Leukeran (chlorambucil), lympholidine (chlorambucil), lomustine, matulan (procarbazine hydrochloride), Neosal (cyclophosphamide), procarbazine hydrochloride, Velban (vinblastine sulfate), Belsal (vinblastine sulfate), vinblastine sulfate, Vincasal PFS (vincristine sulfate), and vincristine sulfate.

[0082] In some embodiments, the first line therapy, for example for Hodgkin's lymphoma, comprises the administration of a combination of therapeutic agents, for example, therapeutic agents described herein. For example, the combination may comprise doxorubicin hydrochloride (adriamycin), bleomycin, vinblastine sulfate, and dacarbazine (i.e., ABVD). As another example, the combination may comprise doxorubicin hydrochloride (adriamycin), bleomycin, vinblastine sulfate, and etoposide (i.e., ABVE). In some embodiments, the combination comprises doxorubicin hydrochloride (adriamycin), bleomycin, vinblastine sulfate, etoposide, prednisone, and cyclophosphamide (i.e., ABVE-PC). In some embodiments, the combination comprises vincristine sulfate, doxorubicin hydrochloride (adriamycin), methotrexate, and prednisone (i.e., VAMP).

[0083] Approved therapeutic agents and combinations for various types of cancer can be found on the National Cancer Institute's cancer website at the National Institutes of Health, http: / / www.cancer.gov / cancertopics / druginfo / drug-page-index.

[0084] Second-line therapy In some embodiments, methods of treating a human subject with cancer are described herein, where the subject has failed (e.g., relapsed, was insensitive, or received no or little benefit from) a second-line treatment or subsequent treatment (e.g., a second-line therapy for cancer or a third-line therapy for cancer). The present invention also provides methods of treating a human subject with cancer, where the method of the present invention is administered with an additional agent. In some embodiments, the additional agent is a first- or second-line therapy for cancer. Second-line therapy generally refers to a treatment given when an earlier treatment (e.g., a first-line therapy) does not achieve the desired results, e.g., is ineffective, ineffective, or becomes ineffective. Second-line therapy is typically considered or given when a subject does not respond to or acquires resistance to an earlier treatment (e.g., a first-line therapy). For example, second-line therapy is typically considered or given for subjects with relapsed or refractory disease.

[0085] Administration and Dosage The combinations of the present invention may be administered orally, parenterally, topically, rectally, or via an implanted reservoir, preferably by oral administration or injection. In some cases, the pH of a composition (e.g., a pharmaceutical composition) may be adjusted with pharma- ceutical acceptable acids, bases, or buffers to enhance the stability or effectiveness of the composition.

[0086] In some embodiments, the subject is orally administered the composition (e.g., pharmaceutical composition). In some embodiments, the composition (e.g., pharmaceutical composition) is orally administered in any orally acceptable dosage form, including liqui-gel, tablet or capsule, syrup, emulsion, and aqueous suspension. Liqui-gel may contain gelatin, plasticizer, and / or opacifier as necessary to obtain a suitable viscosity, and liqui-gel may be coated with an enteric coating approved for use, such as shellac. When used as an oral dosage form, additional thickening agents, such as gums, e.g., xanthan gum, starch, e.g., corn starch, or gluten, may be added to obtain the desired viscosity of the composition (e.g., pharmaceutical composition). If desired, certain sweeteners and / or flavorings and / or colorings may be added.

[0087] In some embodiments, the subject is administered the composition (e.g., pharmaceutical composition) in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions. The composition (e.g., pharmaceutical composition) may be in a unit dosage form suitable for single administration of a precise dose. The pharmaceutical composition may include a pharma- ceutically acceptable carrier in addition to the compounds described herein (e.g., FAK inhibitors (e.g., VS-6063), RAF / MEK dual inhibitors (e.g., CH5126766)), and may optionally further include one or more pharma- ceutically acceptable additives, such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, emulsifiers, and the like. In addition, the tablet may include other medicinal or pharmaceutical agents, carriers, and / or adjuvants.

[0088] Examples of excipients include starches (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium hydrogen phosphate.

[0089] Examples of lubricants (coating agents) include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, shellac, talc, carnauba wax, and paraffin.

[0090] Examples of binders include polyvinylpyrrolidone and macrogols, as well as the same compounds mentioned for the excipients.

[0091] Examples of disintegrants include chemically modified starches and celluloses, such as croscarmellose sodium, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone, as well as the same compounds mentioned with respect to excipients.

[0092] Examples of stabilizers include paraoxybenzoates, such as methylparaben and propylparaben; benzalkonium chloride; phenols, such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0093] Examples of flavoring agents include commonly used sweeteners, acidulants and fragrances.

[0094] Examples of bases include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; lanolin; petrolatum; paraffin; bentonite; glycerin; and glycolic oils.

[0095] Examples of dispersing agents include cellulose derivatives (such as gum arabic, tragacanth, methylcellulose), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.

[0096] Examples of solvents and diluents in liquid formulations include phenol, chlorocresol, purified water, and distilled water.

[0097] Examples of surfactants and emulsifiers include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

[0098] The preferred content of the RAF / MEK inhibitor (eg, CH5126766) or FAK inhibitor (eg, VS-6063) in the formulation may vary depending on the dosage form, but is generally 0.01% by weight to 100% by weight based on the total weight of the formulation.

[0099] The content of the RAF / MEK inhibitor (e.g., CH5126766) in the formulation can be appropriately set according to the predetermined dose. The preferred content is, for example, 0.01 mg to 10 mg, and in the case of a capsule, it can be, for example, 0.1 mg to 4 mg. The more preferred content is, for example, 0.8 mg.

[0100] Exemplary pharmaceutical compositions include, for example, compressed tablets (eg, direct compressed tablets) containing a FAK inhibitor (eg, VS-6063) or a dual RAF / MEK inhibitor (eg, CH5126766).

[0101] Tablets containing an active ingredient or therapeutic ingredient (e.g., a compound described herein (e.g., a FAK inhibitor (e.g., VS-6063) and a RAF / MEK dual inhibitor (e.g., CH5126766))) are also provided. In addition to the active ingredient or therapeutic ingredient, the tablet may contain several inert materials, such as carriers. Pharmaceutically acceptable carriers can be sterile liquids, such as water, and oils, such as oils of petroleum, vegetable, or synthetic origin, such as peanut oil, sesame oil, and the like. Saline and aqueous dextrose can also be used as liquid carriers. Thus, oral dosage forms for use according to the present invention can be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers, including additives and adjuvants that facilitate processing of the active ingredient into a pharma- ceutically usable preparation.

[0102] Additives can impart good powder flow and compression properties to the material being compressed. Examples of additives are described, for example, in Handbook of Pharmaceutical Excipients (5th Edition), Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen, eds.; Publisher: Pharmaceutical Press.

[0103] For oral administration, the active ingredient, e.g., the compound described herein (e.g., FAK inhibitor (e.g., VS-6063), RAF / MEK dual inhibitor (e.g., CH5126766)) can be easily formulated by combining with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the active ingredient of the present invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in water or non-aqueous media, etc., for oral ingestion by a subject. Pharmacological preparations for oral use can be made using solid additives. The resulting mixture is optionally milled, and the mixture of granules can be processed, for example, to obtain tablets, after appropriate addition of suitable auxiliary agents. Suitable additives such as diluents, binders or disintegrants are sometimes desirable. Also, the FAK inhibitor (e.g., VS-6063) and the RAF / MEK dual inhibitor (e.g., CH5126766) can be formulated separately according to the methods described above.

[0104] Dosages can vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by the individual physician in consideration of the patient's condition (see, for example, Fingl et al., 1975, "The Pharmacological Basis of Therapeutics"). Lower or higher dosages than those mentioned above may be required. The specific dosage and treatment regimen for any particular subject may depend on a variety of factors, including the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of symptoms, condition or symptoms, subject's predisposition to disease, condition or symptoms, and the judgment of the treating physician. A course of treatment may include one or more separate administrations of the compounds described herein (e.g., VS-6063 or a pharmacologic acceptable salt thereof and / or CH5126766 or a pharmacologic acceptable salt thereof).

[0105] The oral dosage form may be provided as a package or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient, if desired. The package may, for example, comprise metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for administration. The package or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting the approval by the agency of the form of the composition or administration to humans or animals. Such notice may, for example, be of the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or of the approved product insert.

[0106] The dosing regimen used in the present invention allows for the long-term administration of a RAF / MEK dual inhibitor (e.g., CH5126766) in combination with a FAK inhibitor (e.g., VS-6063) while minimizing side effects and maintaining the efficacy of the drug. In addition, the dosing regimen and combination allow for the treatment or prevention of cell proliferative diseases, particularly cancer, while minimizing the burden on the patient.

[0107] definition As used herein, the articles "a" and "an" refer to one or to more than one (eg, to at least one) of the grammatical object of the article.

[0108] As used herein, "about" and "approximately" refer to an acceptable degree of error for the quantity measured, given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0109] As used herein, an amount of a compound effective in treating a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), i.e., an "effective amount" or an "effective course", refers to an amount of a compound that, upon single or multiple administration to a subject, is more effective in treating the subject, or in curing, ameliorating, alleviating or ameliorating a subject having a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), than would be expected in the absence of such treatment (e.g., placebo treatment).

[0110] As used herein, the term "pharmaceutical acceptable" refers to a compound or carrier (e.g., an excipient) that can be administered to a subject together with a compound described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and / or CH5126766 or a pharmaceutically acceptable salt thereof), does not destroy the pharmacological activity of the compound, and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0111] As used herein, the term "pharmaceutical acceptable salt" refers to derivatives of the compounds described herein (e.g., VS-6063 or a pharmaceutical acceptable salt thereof and / or CH5126766 or a pharmaceutical acceptable salt thereof), where the compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutical acceptable salts include mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the compounds described herein, for example, formed from non-toxic inorganic or organic acids. The pharmaceutical acceptable salts of the present disclosure can be synthesized from the compounds described herein (e.g., VS-6063 or a pharmaceutical acceptable salt thereof and / or CH5126766 or a pharmaceutical acceptable salt thereof) that contain a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of water and an organic solvent. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A listing of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. Examples of pharma- ceutically acceptable salts also include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.; sulfonate salts such as methanesulfonate, benzenesulfonate, toluenesulfonate, etc.; carboxylate salts such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, glutarate, etc.; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, rubidium salt, etc.; alkaline earth metal salts such as magnesium salt, calcium salt, etc.; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc.

[0112] As used herein, the term "oral dosage form" refers to a composition or vehicle used to administer a drug, e.g., a therapeutic agent, e.g., a compound described herein, to a subject. Typically, oral dosage forms are administered via the mouth, but "oral dosage form" is intended to include any substance administered to a subject and absorbed through a membrane, e.g., a mucosa, of the digestive tract, e.g., the mouth, esophagus, stomach, small intestine, large intestine, and colon. For example, "oral dosage form" includes a solution administered to the stomach via a feeding tube.

[0113] As used herein, the term "treat" or "treatment" refers to the application or administration of a compound, alone or in combination with an additional agent, to a subject, e.g., a subject having a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), or suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), a symptom of a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), or a predisposition to a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), for the purpose of curing, healing, mitigating, alleviating, altering, curing, ameliorating, ameliorating, or affecting such disease or disorder (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)).

[0114] The phrases "in combination with" or "in combination with," as well as the terms "co-administration," "co-administering," or "co-providing," as used herein in the context of administration of a compound described herein or a therapy described herein, mean that two (or more) different compounds or therapies are delivered to a subject while the subject is suffering from a disease or disorder (e.g., cancer), for example, that two (or more) different compounds or therapies are delivered to a subject after the subject has been diagnosed with a disease or disorder (e.g., a disease or disorder described herein, e.g., cancer) and before the disease or disorder is cured or eliminated or treatment is terminated for other reasons. The combination can achieve synergistic results, i.e., results that are greater than additive, e.g., at least 20, 50, 70, or 100% greater than additive.

[0115] As used herein, the phrase "synergistic effect" refers to a greater than additive effect (e.g., therapeutic effect) of two or more compounds or compositions. An exemplary synergistic effect includes the administration of an amount of a FAK inhibitor (e.g., VS-6063) used (e.g., administered) in combination with an amount of a RAF / MEK dual inhibitor (e.g., CH5126766) that results in a therapeutic effect that is greater than the additive therapeutic effect of each inhibitor used alone.

[0116] As used herein, a "course of treatment" includes one or more separate administrations of a therapeutic agent. A course of treatment can include one or more cycles of a therapeutic agent.

[0117] "Cycle," as used herein in the context of administration of a cycle of a drug, refers to a period of time during which the drug is administered to a patient. Preferably, a cycle is equal to 4 weeks.

[0118] Many ranges are provided herein, e.g., ranges relating to the amount of drug administered per day. In some embodiments, the ranges include both endpoints. In other embodiments, the ranges exclude one or both endpoints. By way of example, a range may exclude the lower endpoint. Thus, in such embodiments, a range of 100 to 400 mg / day, excluding the lower endpoint, would include amounts greater than 100 mg / day and less than or equal to 400 mg / day.

[0119] As used herein, the term "subject" is intended to include humans and non-human animals. In some embodiments, the subject is a human. Exemplary human subjects include a human subject having or suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancers described herein)). The term "non-human animal" of the present invention includes all vertebrates, e.g., non-mammals (e.g., chickens, amphibians, reptiles), as well as mammals, e.g., non-human primates, domestic animals, and / or agriculturally useful animals, e.g., sheep, dogs, cats, cows, pigs, etc.

[0120] The phrase "twice a week" means that the RAF / MEK dual inhibitor (e.g., CH5126766) is administered twice within a one-week period. The administration may be twice on the same day, or once a day on different days (which may be consecutive days), but is preferably on different days. More preferably, the administration is performed, for example, on the first and fourth days or the second and fifth days of the period, so that the RAF / MEK dual inhibitor (e.g., CH5126766) is administered with as uniform an interval between administrations as possible, i.e., an interval between administrations of 3 to 4 days. The one-week period may start, for example, on a Monday, or may start, for example, on a Tuesday. If the two administrations are administered on different days, each administration may be administered at any time, but is preferably administered at the same time of day (e.g., after breakfast). EXAMPLES

[0121] The following representative examples are intended to help illustrate the present invention and are not intended, nor should they be construed, to limit the scope of the invention.

[0122] In the following Examples 1 and 2 and Tables 1 to 4, "CH5126766" means the potassium salt of CH5126766, and "VS-6063" means VS-6063 hydrochloride.

[0123] Example 1. Phase I Study of the Combination of VS-6063 (FAK Inhibitor) and CH5126766 (RAF / MEK Dual Inhibitor) in Patients with Advanced Solid Tumors [NCT03875820] method: The study explored dose escalation, mandatory biopsy, and expansion cohorts. CH5126766 was administered twice weekly and VS-6063 was administered twice daily (BD). Each cycle consisted of administering both drugs on a 3-week on / 1-week off (1 cycle = 4 weeks) basis. Three dose levels were explored in the dose escalation cohort. Dose level 1 included a schedule of 3.2 mg CH5126766 + 200 mg BD VS-6063, dose level 2A included a schedule of 4 mg CH5126766 + 200 mg BD VS-6063, and dose level 2B included a schedule of 3.2 mg CH5126766 + 400 mg BD VS-6063. The maximum dose at which no more than one patient among six patients at the same dose level experienced a protocol-specified drug-related toxicity (DLT) was determined. The safety and toxicity profiles of CH5126766 and VS-6063 were evaluated. The causality and graded severity of each adverse event according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 were determined. Disease response according to RECIST version 1.1 was examined every two cycles. Serum tumor markers were also examined for eligible patients. Data related to progression-free survival were also collected.

[0124] Findings: The most common side effects in dose escalation were rash, as well as non-dose limiting nausea and hyperbilirubinemia. No DLTs were observed in either cohort 1 or 2A. A grade 2 DLT of rash requiring dose interruption or dose reduction in the first cycle was observed in cohort 2B (corresponding to dose level 2B), which resulted in cohort 2A (corresponding to dose level 2A) being the recommended phase 2 dose (R2PD). KRAS-mutated ovarian cancer (3 low-grade serous and 1 mucinous adenocarcinoma), KRAS-mutated lung cancer evaluable for response had a partial response. Two NRAS-mutated colon / rectal cancers were treated and showed a reduction in CEA levels of more than 50% and showed stable disease. Pancreatic cancer with KRAS mutations showed a minor response (-19%, -14% and -11% in cycles 2, 4 and 6, respectively) with a reduction in CA19-9 levels of more than 50%.

[0125] Representative results obtained so far regarding disease response, serum tumor markers and duration of treatment are shown in Example 2.

[0126] Conclusion: In patients with ovarian cancer and other tumors harboring KRAS and / or NRAS mutations, the combination of CH5126766 and VS-6063 is well tolerated and highly active.

[0127] Example 2. Combination of CH5126766 and VS-6063 in Patients with Advanced Solid Tumors In Tables 1-4 below, "CH" stands for the potassium salt of CH5126766 and "VS" stands for VS-6063 hydrochloride. The potassium salt of CH5126766 was administered twice weekly and VS-6063 hydrochloride was administered twice daily (BID). Each cycle consisted of administering both drugs on a 3-week on / 1-week off (1 cycle = 4 weeks) basis. "PR" stands for Partial Response, "SD" stands for Stable Disease, and "N / A" stands for Not Available.

[0128]

Table 1

[0129]

Table 2

[0130]

Table 3

[0131]

Table 4

Claims

1. 1. A method of treating a subject having cancer, comprising the step of administering to the subject a therapeutically effective amount of VS-6063, or a pharma- ceutically acceptable salt thereof, in combination with CH5126766, or a pharma- ceutically acceptable salt thereof, thereby treating the subject, wherein the cancer is a RAS mutated cancer.

2. 2. The method of claim 1, wherein the CH5126766 or a pharma- ceutically acceptable salt thereof is the potassium salt of CH5126766.

3. 3. The method of claim 1 or 2, wherein the cancer is selected from the group consisting of ovarian cancer, lung cancer, colon cancer and pancreatic cancer.

4. The method of any one of claims 1 to 3, wherein the cancer is ovarian cancer.

5. 5. The method of claim 4, wherein the ovarian cancer is low-grade serous ovarian cancer.

6. The method according to any one of claims 1 to 3, wherein the cancer is lung cancer.

7. The method of any one of claims 1 to 3, wherein the cancer is colon cancer.

8. The method according to any one of claims 1 to 3, wherein the cancer is pancreatic cancer.

9. 9. The method of any one of claims 1 to 8, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered twice weekly.

10. The method of any one of claims 1 to 9, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered twice daily.

11. The method of any one of claims 1 to 9, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered once daily.

12. The method of any one of claims 1 to 11, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, and VS-6063, or a pharma- ceutically acceptable salt thereof, are administered for at least 3 weeks.

13. 13. The method of any one of claims 1 to 12, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, and VS-6063, or a pharma- ceutically acceptable salt thereof, are administered independently in a cycle of three weeks on, followed by one week off.

14. 13. The method of any one of claims 1 to 12, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, and VS-6063, or a pharma- ceutically acceptable salt thereof, are administered simultaneously in a cycle of three weeks on, followed by one week off.

15. 15. The method of any one of claims 1 to 14, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 0.5 mg to about 10 mg.

16. 15. The method of any one of claims 1 to 14, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 4 mg.

17. 15. The method of any one of claims 1 to 14, wherein CH5126766 or a pharma- ceutically acceptable salt thereof is administered at a dose of 3.2 mg.

18. The method of any one of claims 1 to 17, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 100 mg to about 400 mg.

19. The method of any one of claims 1 to 17, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 100 mg to about 500 mg.

20. The method of any one of claims 1 to 17, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 200 mg to about 500 mg.

21. The method of any one of claims 1 to 17, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 200 mg to about 600 mg.

22. 15. The method of any one of claims 1-14, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 0.5 mg to about 10 mg, and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 100 mg to about 400 mg.

23. 15. The method of any one of claims 1-14, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 4 mg twice weekly and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 200 mg twice daily.

24. 15. The method of any one of claims 1 to 14, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 3.2 mg twice weekly and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 200 mg twice daily.

25. 15. The method of any one of claims 1-14, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 4 mg twice weekly and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 400 mg twice daily.

26. 15. The method of any one of claims 1 to 14, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 3.2 mg twice weekly and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 400 mg twice daily.

27. 1. A method of treating a subject having cancer, comprising the step of administering to the subject a therapeutically effective amount of CH5126766, or a pharma- ceutically acceptable salt thereof, in combination with VS-6063, or a pharma- ceutically acceptable salt thereof.

28. 28. The method of claim 27, wherein the cancer is selected from the group consisting of ovarian cancer, lung cancer, colon cancer and pancreatic cancer.

29. 29. The method of claim 27 or 28, wherein the cancer is ovarian cancer.

30. 30. The method of claim 29, wherein the ovarian cancer is low-grade serous ovarian cancer.

31. 29. The method of claim 27 or 28, wherein the cancer is lung cancer.

32. 29. The method of claim 27 or 28, wherein the cancer is colon cancer.

33. 29. The method of claim 27 or 28, wherein the cancer is pancreatic cancer.

34. 34. The method of any one of claims 27 to 33, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered twice weekly.

35. The method of any one of claims 27 to 34, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered twice daily.

36. The method of any one of claims 27 to 34, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered once daily.

37. The method of any one of claims 27 to 36, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, and VS-6063, or a pharma- ceutically acceptable salt thereof, are administered for at least 3 weeks.

38. 38. The method of any one of claims 27 to 37, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, and VS-6063, or a pharma- ceutically acceptable salt thereof, are administered independently in a cycle of three weeks on, followed by one week off.

39. 38. The method of any one of claims 27 to 37, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, and VS-6063, or a pharma- ceutically acceptable salt thereof, are administered simultaneously in a cycle of three weeks on, followed by one week off.

40. 40. The method of any one of claims 27 to 39, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 0.5 mg to about 10 mg.

41. 40. The method of any one of claims 27 to 39, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 4 mg.

42. 40. The method of any one of claims 27 to 39, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 3.2 mg.

43. 43. The method of any one of claims 27 to 42, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 100 mg to about 400 mg.

44. 43. The method of any one of claims 27 to 42, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 100 mg to about 500 mg.

45. 43. The method of any one of claims 27 to 42, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 200 mg to about 500 mg.

46. 43. The method of any one of claims 27 to 42, wherein VS-6063, or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 200 mg to about 600 mg.

47. 40. The method of any one of claims 27 to 39, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 0.5 mg to about 10 mg, and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 100 mg to about 400 mg.

48. 40. The method of any one of claims 27-39, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 4 mg twice weekly, and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 200 mg twice daily.

49. 40. The method of any one of claims 27 to 39, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 3.2 mg twice weekly and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 200 mg twice daily.

50. 40. The method of any one of claims 27-39, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 4.0 mg twice weekly, and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 400 mg twice daily.

51. 40. The method of any one of claims 27 to 39, wherein CH5126766, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 3.2 mg twice weekly and VS-6063, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 400 mg twice daily.

52. The method of any one of claims 27 to 51, wherein the cancer is caused by a mutation in RAS or BRAF.

53. The method of any one of claims 27 to 51, wherein the cancer is caused by a KRAS mutation or an NRAS mutation.

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