Combination of VS-6063 and ch5126766 for the treatment of cancer

Abstract

In particular, the present invention relates to methods comprising administering a FAK inhibitor (e.g., VS-6063) in combination with a dual RAF / MEK inhibitor (e.g., CH5 126766) for treating abnormal cell growth, such as cancer, in a subject (e.g., a human).

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: September 11, 2020; application number: 202080063860.3). Background Art

[0002] Reliable evidence indicates that focal adhesion kinase (FAK), also known as PTK2 (a cytoplasmic non-receptor tyrosine kinase), plays an important role in the cell-matrix signal transduction pathway (Clark and Brugge 1995, Science 268:233-239), and its abnormal activation is associated with increased tumor metastasis potential (Owens et al., 1995, Cancer Research 55:2752-2755). FAK was originally identified as a highly tyrosine-phosphorylated 125kDa protein in cells transformed by v-Src. FAK is encoded by the PTK2 gene in humans. It was subsequently discovered that FAK is a tyrosine kinase that is localized to focal adhesions, which are contact points between cultured cells and their underlying matrix and are sites of intense tyrosine phosphorylation. FAK is phosphorylated and thus activated in response to the binding of the extracellular matrix (ECM) to integrins. Recently, studies have shown that increased FAK mRNA levels are associated with aggressive transformation of tumors and attenuation of FAK expression (using antisense oligonucleotides), which induces apoptosis of tumor cells (Xu et al., 1996, Cell Growth and Diff. 7: 413-418). In addition to being expressed in most tissue types, FAK levels are also found to be elevated in most human cancers, such as in highly aggressive metastatic lesions, including thyroid cancer, prostate cancer, cervical cancer, colon cancer, rectal cancer, oral epithelial cancer, ovarian cancer, and breast cancer. Therefore, compounds, combinations of compounds, compositions, and methods for inhibiting FAK in a subject are desirable.

[0003] Components of the RAS / RAF / MEK / ERK signaling pathway also represent opportunities for treating abnormal cell growth, such as cancer.

[0004] WO 2015 / 120289 discloses a method of treating a subject having cancer, 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, pemazertinib, AZD6244), thereby treating the subject.

[0005] WO 2014 / 059095 and Br J Cancer. 2019 May; 120(10): 975-981 relate to the treatment of cancer using a combination comprising a specific FAK inhibitor and a specific MEK inhibitor (trametinib). Summary of the Invention

[0006] The combination of a FAK inhibitor (e.g., VS-6063) and a RAF / MEK dual inhibitor (e.g., CH5126766) can enhance the production and effectiveness of tumor-specific cytotoxic lymphocytes and provide a promising approach for more effectively treating the diseases or conditions described herein (e.g., abnormal cell growth, e.g., cancer (e.g., the cancers described herein)). VS-6063 or a pharmaceutically acceptable salt thereof (FAK inhibitor) can be used in combination with CH5126766 or a pharmaceutically acceptable salt thereof (RAF / MEK dual inhibitor) to treat the diseases or conditions described herein, e.g., abnormal cell growth (e.g., the cancers described herein).

[0007] Thus, provided herein is a particular combination (e.g., a combination described herein (e.g., a combination of a FAK inhibitor and a dual RAF / MEK inhibitor)) that can be used, for example, to treat abnormal cell growth, such as cancer (e.g., a cancer with a RAS mutation), in a subject (e.g., a human).

[0008] Described herein are methods for treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of VS-6063 or a pharmaceutically acceptable salt thereof (FAK inhibitor) in combination with CH5126766 or a pharmaceutically acceptable salt thereof (RAF / MEK dual inhibitor), thereby treating the subject, wherein the cancer is a cancer having a RAS mutation. In some embodiments, the RAS mutation is a KRAS mutation or a NRAS mutation.

[0009] Described herein are methods for treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of VS-6063, or a pharmaceutically acceptable salt thereof, in combination with a RAF / MEK dual inhibitor, wherein the RAF / MEK dual inhibitor is CH5126766, or a pharmaceutically 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 a NRAS mutation.

[0010] Described herein are uses of VS-6063, or a pharmaceutically acceptable salt thereof, in combination with a dual RAF / MEK inhibitor for treating cancer, wherein the dual RAF / MEK inhibitor is CH5126766, or a pharmaceutically 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] Described herein are methods for treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of CH5126766, or a pharmaceutically acceptable salt thereof, in combination with a FAK inhibitor, wherein the FAK inhibitor is VS-6063, or a pharmaceutically 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.

[0012] Described herein are uses of CH5126766, or a pharmaceutically acceptable salt thereof, in combination with a FAK inhibitor for treating cancer, wherein the FAK inhibitor is VS-6063, or a pharmaceutically 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.

[0013] Described herein are methods of treating a subject having cancer, 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 pharmaceutically acceptable salt thereof, and the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof.

[0014] Described herein is the use of a combination of a RAF / MEK dual inhibitor and a FAK inhibitor for treating cancer, wherein the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof, and the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the cancer is caused by a mutation in RAS, BRAF, or NF-1.

[0016] 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.

[0017] In some aspects, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered twice a week. In some aspects, the FAK inhibitor (e.g., VS-6063) is administered twice a day. In other aspects, the FAK inhibitor (e.g., VS-6063) is administered once a day. 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 independently administered periodically, wherein the drug is continuously administered for three weeks and then stopped for one week. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) and the FAK inhibitor (e.g., VS-6063) are administered periodically simultaneously, wherein the drug is continuously administered for three weeks and then stopped for one week.

[0018] In some aspects, RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dosage of about 0.5 mg to about 10 mg. In further embodiments, RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dosage of about 4 mg. In other embodiments, RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dosage of 3.2 mg. In some embodiments, FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 100 mg to about 400 mg. In some embodiments, FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 100 mg to about 500 mg. In further embodiments, FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 200 mg to about 500 mg. In other embodiments, FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 200 mg to about 600 mg. In some aspects, RAF / MEK dual inhibitor (for example, CH5126766) is administered with a dosage of about 0.5mg to about 10mg, and FAK inhibitor (for example, VS-6063) is administered with a dosage of about 100mg to about 400mg. In some embodiments, RAF / MEK dual inhibitor (for example, CH5126766) is administered twice a week with a dosage of about 4mg, and FAK inhibitor (for example, VS-6063) is administered twice a day with a dosage of about 200mg. In some embodiments, RAF / MEK dual inhibitor (for example, CH5126766) is administered twice a week with a dosage of 3.2mg, and FAK inhibitor (for example, VS-6063) is administered twice a day with a dosage of 200mg. In some embodiments, RAF / MEK dual inhibitor (for example, CH5126766) is administered twice a week with a dosage of about 4mg, and FAK inhibitor (for example, VS-6063) is administered twice a day with a dosage of about 400mg. In some embodiments, the dual RAF / MEK inhibitor (eg, CH5126766) is administered at a dose of 3.2 mg twice a week, and the FAK inhibitor (eg, VS-6063) is administered at a dose of 400 mg twice a day. Detailed Description of the Invention

[0019] Described herein, among other things, are methods 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 pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof.

[0020] Treatment and administration methods

[0021] The methods described herein relate to treating subjects (e.g., human subjects) suffering from a disease or condition 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, wherein the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. As used herein, "combination" administration refers to delivering two (or more) different treatments to a subject while the subject is suffering from the disease, e.g., after the subject is diagnosed with the disease and before the condition has been cured or eliminated or treatment has been stopped for other reasons. In some embodiments, the delivery of the first treatment is still ongoing when the second treatment begins delivery, so there is overlap in administration. This is sometimes referred to herein as "simultaneous" or "parallel delivery." In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective due to combined administration. For example, the second treatment is more effective, e.g., the same effect can be observed with less of the second treatment when the combination is administered than when the second treatment is administered without the first treatment, or the second treatment reduces symptoms to a greater extent, or a similar situation is observed for the first treatment. In some embodiments, the delivery of the present invention results in a greater reduction in symptoms or other parameters associated with the condition than when one treatment is delivered in the absence of the other treatment. The effects of the two treatments can be partially additive, fully additive, or greater than additive. The delivery can be such that the effect of the first treatment is still detectable when the second treatment is delivered.

[0022] In some embodiments, the method includes administering a FAK inhibitor (e.g., VS-6063) before administering a RAF / MEK dual inhibitor (e.g., CH5126766). In some embodiments, the method includes administering a FAK inhibitor (e.g., VS-6063) after administering a RAF / MEK dual inhibitor (e.g., CH5126766). In some embodiments, the method includes administering a FAK inhibitor (e.g., VS-6063) while administering a RAF / MEK dual inhibitor (e.g., CH5126766). In some embodiments, the FAK inhibitor is VS-6063 (PF-04554878; defactinib) or a pharmaceutically acceptable salt thereof. In some embodiments, the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof.

[0023] Tumor microenvironment

[0024] The combination of compounds described herein also relates to a method for regulating or conditioning the tumor microenvironment in a subject (e.g., a subject suffering from a cancer described herein). As used herein, "tumor microenvironment" refers to the cellular environment in which a tumor exists, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signaling molecules, and extracellular matrix (ECM). Tumors are closely related to and constantly interact with the surrounding microenvironment. Tumors can affect the microenvironment by releasing extracellular signals, promoting tumor angiogenesis, and inducing peripheral immune tolerance, and immune cells in the microenvironment can affect the growth and evolution of cancer cells.

[0025] As used herein, the term "immunosuppressive cells" refers to cells that contribute to or promote an immunosuppressive tumor microenvironment. The presence of immunosuppressive cell populations in the tumor microenvironment, also referred to herein as "tumor-associated immunosuppressive cells," increases the tumor's resistance to immune responses, leading to tumor protection, tumor escape, and / or tumor metastasis. Unless counteracted in some way, tumor-associated immunosuppressive cells reduce the efficacy of immune-mediated anticancer therapy. There are a large number of tumor-associated immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells.

[0026] In some embodiments, the combination of compounds described herein enhances the effectiveness of tumor-specific cytotoxic lymphocytes or anti-tumor toxic T cells. In some embodiments, FAK inhibitors described herein (e.g., VS-6063) target immunosuppressive cells in the tumor microenvironment. In some embodiments, FAK inhibitors described herein (e.g., VS-6063) regulate the tumor-matrix of dense desmoplastic stroma and / or the pro-inflammatory and / or pro-fibrotic cytokine secretion regulated by FAK as a barrier to T cell infiltration. In some embodiments, BRAF inhibition activates stromal cells (e.g., cancer-activated fibroblasts, cell adhesion factors), resulting in FAK-dependent cancer survival signaling (e.g., in melanoma).

[0027] Abnormal cell growth

[0028] The methods described herein relate to treating abnormal cell growth in a subject (e.g., a human subject). As used herein and unless otherwise indicated, abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes: (1) abnormal growth of tumor cells (tumors), which proliferate by, for example, expressing a mutated tyrosine kinase or overexpressing a receptor tyrosine kinase; (2) abnormal growth of benign and malignant cells of other proliferative diseases, e.g., diseases in which abnormal tyrosine kinase activation occurs; (3) abnormal growth of any tumor, e.g., diseases in which proliferate by receptor tyrosine kinases; (4) abnormal growth of any tumor, e.g., diseases in which proliferate by abnormal serine / threonine kinase activation; (5) abnormal growth of benign and malignant cells of other proliferative diseases, e.g., diseases in which abnormal serine / threonine kinase activation occurs. Abnormal cell growth can refer to epithelial cell growth (e.g., carcinoma, adenocarcinoma); mesenchymal cell growth (e.g., sarcomas (e.g., leiomyosarcoma, Ewing's sarcoma)); hematopoietic cell growth (e.g., lymphoma, leukemia, myelodysplasia (e.g., precancerous lesions)); or other (e.g., mesothelioma and other tumors of unknown origin) cells.

[0029] In some embodiments, the method is effective in treating non-hematological malignancies. In some embodiments, the method can effectively treat pancreatic cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), mesothelioma, breast cancer and ovarian cancer. In one embodiment, breast cancer is triple-negative breast cancer (for example, breast cancer that does not express estrogen receptor, progesterone receptor and Her2 / neu genes). In one embodiment, lung cancer is non-small cell lung cancer (NSCLC), for example, KRAS mutated NSCLC. In one embodiment, ovarian cancer is advanced ovarian cancer (for example, advanced ovarian cancer or metastatic ovarian cancer). In one embodiment, ovarian cancer is low-grade serous ovarian cancer. In one embodiment, low-grade serous ovarian cancer is low-grade serous ovarian cancer that KRAS mutates. In one embodiment, the method can effectively treat mesothelioma (for example, malignant pleural mesothelioma, for example, surgically resectable malignant pleural mesothelioma). In some embodiments, cancer is pancreatic cancer.

[0030] Neoplastic diseases

[0031] Abnormal cell growth can refer to a neoplastic disease. A "neoplastic disease" is a disease or condition characterized by cells that have the ability to grow or replicate autonomously, for example, an abnormal state or condition characterized by proliferative cell growth. The abnormal tissue mass, or "neoplasm," resulting from abnormal cell growth or division can be benign, precancerous (carcinoma in situ), or malignant (cancer).

[0032] Exemplary neoplastic diseases include carcinomas, sarcomas, metastatic diseases (e.g., tumors originating from the prostate, colon, lung, breast, and liver), hematopoietic neoplastic diseases (e.g., leukemia, metastatic tumors). Treatment with the compound can be carried out in an amount effective to ameliorate at least one symptom of the neoplastic disease (e.g., decreased cell proliferation, decreased tumor mass, etc.).

[0033] cancer

[0034] In some embodiments, the method of the present invention can be used to treat cancer, including, for example, solid tumors, soft tissue tumors, and metastases. In some embodiments, the method of the present invention can be used to treat cancers in which the MEK-ERK pathway is activated. The method disclosed in the present invention can also be used to treat non-solid cancers. Exemplary solid tumors include malignant tumors (e.g., sarcomas, adenocarcinomas, and cancers) of various organ systems, such as lung, breast, lymph, gastrointestinal tract (e.g., colon), and urogenital (e.g., kidney, urothelial or testicular tumors) tract, pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma), non-small cell lung cancer, pancreatic cancer (e.g., metastatic pancreatic cancer), and small intestinal cancer.

[0035] Cancer may also include uterine cancer (endometrial cancer, uterine neoplasms, cervical cancer, etc.), biliary cancer, and biliary tract cancer (cholangiocarcinoma, bile duct cancer, gallbladder cancer, etc.).

[0036] Cancer can be a primary tumor, i.e., located at the anatomical site where the tumor growth originated. Cancer can also be metastatic, i.e., appear at at least a second anatomical site different from the anatomical site where the tumor growth originated. Cancer can be a recurrent cancer, i.e., a cancer that comes back after treatment and a period of time in which the cancer has not been detected. Recurrent cancer can be anatomically local to the original tumor, e.g., anatomically near the original tumor; or located in the region of the original tumor, e.g., in a lymph node near the original tumor; or located remotely from the original tumor, e.g., in a region anatomically distant from the original tumor.

[0037] Cancer can also have a RAS mutation, which means that the cancer is caused by a mutation in a RAS gene (HRAS, NRAS or KRAS). Cancer can also have a KRAS mutation, which means that the cancer is caused by a mutation in a KRAS gene. Cancer can also have a NRAS mutation, which means that the cancer is caused by a mutation in a NRAS gene. In some embodiments, the cancer is ovarian cancer caused by a mutation in a RAS gene (e.g., a 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 a RAS gene (e.g., a KRAS gene). In some embodiments, the cancer is lung cancer caused by a mutation in a RAS gene (e.g., a KRAS gene). In some embodiments, the cancer is colon cancer caused by a mutation in a RAS gene (e.g., a KRAS gene or a NRAS gene). In some embodiments, the cancer is pancreatic cancer caused by a mutation in a RAS gene (e.g., a KRAS gene).

[0038] Cancer can also include, for example, epithelial cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer (e.g., metastatic colorectal cancer, e.g., metastatic KRAS mutant colorectal cancer), prostate cancer, head and neck cancer, melanoma, acute myeloid leukemia, and glioblastoma. Exemplary breast cancers include triple-negative breast cancer, basal-like breast cancer, Claudin-low breast cancer, invasive, inflammatory, metaplastic, and advanced Her-2 positive or ER positive cancers that are resistant to treatment.

[0039] 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 cancer in which KRAS is mutated and / or NRAS is mutated, more preferably a colon cancer in which KRAS is mutated or NRAS is mutated, or a solid cancer (preferably ovarian cancer, lung cancer (especially non-small cell lung cancer), colon cancer and pancreatic cancer) in which KRAS is mutated.

[0040] Other cancers include brain cancer, abdominal cancer, esophageal cancer, gastrointestinal cancer, glioma, liver cancer, tongue cancer, neuroblastoma, osteosarcoma, ovarian cancer, retinoblastoma, Wilms' tumor, multiple myeloma, skin cancer, lymphoma, blood and bone marrow cancer (e.g., advanced hematological malignancies, leukemias, such as acute myeloid leukemia (e.g., primary or secondary), acute lymphoblastic leukemia, acute lymphocytic leukemia, T-cell leukemia, hematological malignancies, advanced myeloproliferative disorders, myelodysplastic syndrome, relapsed or refractory multiple myeloma, advanced myeloproliferative disorders), retinal cancer, bladder cancer, cervical cancer, kidney cancer, endometrial cancer, meningioma, lymphoma, skin cancer, uterine cancer, lung cancer, non-small cell lung cancer, nasopharyngeal cancer, neuroblastoma, solid tumors, hematologic malignancies, squamous cell carcinoma, testicular cancer, thyroid cancer, mesothelioma, brain cancer, vulvar cancer, sarcoma, intestinal cancer, oral cancer, endocrine cancer, salivary gland cancer, spermatocytic seminoma, sporadic medullary thyroid cancer, non-proliferative testicular cell cancer, cancers associated with malignant mast cells, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0041] Exemplary cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, astrocytoma, bile duct cancer, extrahepatic cancer, 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, visual pathway and hypothalamic glioma; breast cancer; bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal carcinoid tumor; adrenocortical carcinoma; pancreatic islet cell carcinoma; cancer of unknown primary; primary central nervous system lymphoma; cerebellar astrocytoma, brain astrocytoma / malignant glioma, cervical cancer; chronic myeloid leukemia ... Lymphocytic leukemia; chronic myeloid leukemia; chronic myeloproliferative disorders; clear cell sarcoma of the tendon sheath; colon cancer; colorectal cancer; cutaneous T-cell lymphoma; endometrial cancer; ependymoma, epithelial carcinoma, ovarian cancer; esophageal cancer; Ewing's family of tumors, esophageal cancer; extracranial germ cell tumors, extragonadal germ cell tumors; extrahepatic bile duct cancer; eye cancer, retinoblastoma; gallbladder cancer; stomach (gastric) cancer; stomach (gastric) cancer; gastrointestinal carcinoid tumor; germ cell tumor, extracranial; germ cell tumor, extragonadal; germ cell tumor, ovarian; gestational trophoblastic tumor; glioma; optic pathway and hypothalamic glioma; hairy cell leukemia; head and neck cancer; hepatocellular (liver) cancer; Hodgkin's lymphoma; Hodgkin's lymphoma; gestational Hodgkin's lymphoma; Hypopharyngeal cancer; Gliomas of the hypothalamus and visual pathways; Islet cell carcinoma (endocrine pancreas); Kaposi's sarcoma; Kidney cancer; Laryngeal cancer; Laryngeal cancer; Acute lymphocytic leukemia; Acute lymphocytic leukemia; Acute myeloid leukemia; Acute myeloid leukemia; Chronic lymphocytic leukemia; Chronic myeloid leukemia; Hairy cell leukemia; Lip and oral cancer; Liver cancer; Non-small cell lung cancer; Small cell lung cancer; Lymphoblastic leukemia, lymphocytic leukemia, chronic; AIDS-related lymphoma; Central nervous system (primary) lymphoma; Cutaneous T-cell lymphoma; Hodgkin lymphoma; Hodgkin lymphoma; Pregnancy Hodgkin lymphoma; Non-Hodgkin lymphoma; Non-Hodgkin lymphoma; Pregnancy non-Hodgkin's disease; Primary central nervous system lymphoma; Macroglobulinemia Proteinemia, Waldenstrom's macroglobulinemia; male breast cancer; malignant mesothelioma in adults; malignant mesothelioma; malignant thymoma; medulloblastoma, Merkel cell carcinoma; malignant mesothelioma; occult primary metastatic squamous neck cancer; multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms; mycosis fungoides; myelodysplastic syndrome; chronic myeloid leukemia; myeloid leukemia, multiple myeloma; chronic myeloproliferative disorders; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer; nasopharyngeal cancer; neuroblastoma; non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy; non-small cell lung cancer; oral cavity cancer; oral cavity and lip cancer; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; ovarian cancer; epithelial ovarian cancer;Ovarian germ cell tumor; ovarian low-grade malignant potential tumor; pancreatic cancer; pancreatic cancer; islet cell pancreatic cancer; sinus and nasal cavity 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 lymphoma; pregnancy and non-Hodgkin 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; rhabdomyosarcoma; salivary gland cancer; salivary gland cancer; sarcoma, Ewing family of tumors; Kaposi's sarcoma; sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; sarcoma, rhabdomyosarcoma; soft tissue sarcoma; sarcoma, soft tissue; Sézary syndrome syndrome); skin cancer; skin cancer; skin cancer (melanoma); Merkel cell skin cancer (skin carcinoma); small cell lung cancer; small intestinal cancer; soft tissue sarcoma; soft tissue sarcoma; metastatic occult primary squamous neck cancer; gastric (stomach) cancer; gastric (stomach) cancer; supratentorial primitive neuroectodermal tumor; cutaneous T-cell lymphoma; testicular cancer; thymoma; malignant thymoma; thyroid cancer; thyroid cancer; transitional cell carcinoma of the renal pelvis and ureter; gestational trophoblastic tumor; cancer of unknown primary site; ureteral and renal pelvis, transitional cell carcinoma; urethral cancer; uterine sarcoma; vaginal cancer; optic pathway and hypothalamic glioma; vulvar cancer; Waldenstrom's macroglobulinemia; and Wilms' tumor. Metastases of the above cancers can also be treated using the methods described herein.

[0042] In some embodiments, the tumor is a tumor of hematopoietic and lymphoid tissue or a tumor affecting the blood, bone marrow, lymphatic and lymphatic systems. Hematological malignancies include acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute monocytic leukemia, other leukemias, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0043] 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) after standard treatment.

[0044] The methods described herein can reduce, improve or completely eliminate the disease and / or its associated symptoms to prevent it from worsening, slowing the rate of progression, or minimizing the recurrence rate of the disease after it is initially eliminated (i.e., avoiding recurrence). Suitable dosages and treatment regimens can vary depending on the specific compound and / or pharmaceutical composition used and the delivery mode of the compound and / or pharmaceutical composition. In some embodiments, the method increases the mean survival of subjects treated with the combination described herein in a statistically significant manner, increases the mean length of progression-free survival, and / or reduces the recurrence rate.

[0045] In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC; metastatic cancer), bone cancer, pancreatic cancer, skin cancer, head and 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, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, In some embodiments, the cancer is a prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer (e.g., Wilms' tumor, rhabdomyomas; nephroma (e.g., mesodermal nephroma)) or ureter, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphomas, spinal axis tumors, brain stem gliomas, pituitary adenomas, 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 suffers from a locally recurrent disease, such as cancer).

[0046] The methods of the present invention contemplate single and multiple combined administrations of a therapeutically effective amount of a FAK inhibitor and a RAF / MEK dual inhibitor, wherein the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. Combinations, such as the combinations described herein, such as the combination of a FAK inhibitor (e.g., VS-6063) with a RAF / MEK dual inhibitor (e.g., CH5126766), can be administered regularly depending on the nature, severity, and extent of the subject's condition. In some embodiments, the combination as described herein, such as the combination of a FAK inhibitor with a RAF / MEK dual inhibitor, is administered in a single dose, wherein the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. In some embodiments, a combination as described herein, such as a FAK inhibitor in combination with a RAF / MEK dual inhibitor, is administered in multiple doses, wherein the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutically effective amount of a combination as described herein, such as a FAK inhibitor (e.g., VS-6063) and a RAF / MEK dual inhibitor (e.g., CH5126766) can be administered orally at regular intervals (e.g., every 1, 2, 3, 4, 5, or 6 days, or every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9 months or longer, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times or more). In some embodiments, the combination of therapeutically effective amounts as described herein is, for example, a combination of a FAK inhibitor (e.g., VS-6063) (e.g., twice a day) and a RAF / MEK dual inhibitor (e.g., CH5126766) (e.g., twice a week) administered orally on a regular basis. In some embodiments, the combination as described herein of a therapeutically effective amount is, for example, a FAK inhibitor (e.g., VS-6063) administered orally once a day and a RAF / MEK dual inhibitor (e.g., CH5126766) (e.g., twice a week) administered orally on a regular basis. In some embodiments, the combination of therapeutically effective amounts as described herein is, for example, a FAK inhibitor (e.g., VS-6063) administered orally twice a day and a RAF / MEK dual inhibitor (e.g., CH5126766) (e.g., three times a week) administered orally on a regular basis. VS-6063 and CH5126766 can each be in the form of a pharmaceutically acceptable salt.

[0047] In some embodiments, for the combinations described herein, for example, a FAK inhibitor (e.g., VS-6063) administered orally regularly (e.g., twice a day) and a RAF / MEK dual inhibitor (e.g., CH5126766) administered orally at predetermined time intervals (e.g., twice a week) are administered for three weeks, followed by a one-week break (or an interval in which no FAK inhibitor (e.g., VS-6063) or RAF / MEK dual inhibitor (e.g., CH5126766) is administered), and then the cycle is repeated (e.g., three weeks of administration, one week of rest, three weeks of administration, one week of rest, etc.). In some embodiments, CH5126766 or a pharmaceutically acceptable salt thereof, and VS-6063 or a pharmaceutically acceptable salt thereof are each administered for at least three weeks. In some embodiments, CH5126766 or a pharmaceutically acceptable salt thereof, and VS-6063 or a pharmaceutically acceptable salt thereof are each administered for at least 4 weeks. In some embodiments, CH5126766 or a pharmaceutically acceptable salt thereof, and VS-6063 or a pharmaceutically acceptable salt thereof, are each administered for at least five weeks. In some embodiments, CH5126766 or a pharmaceutically acceptable salt thereof, and VS-6063 or a pharmaceutically acceptable salt thereof, are each administered cyclically in the form of four weeks of administration followed by at least one week of rest. In other embodiments, CH5126766 or a pharmaceutically acceptable salt thereof, and VS-6063 or a pharmaceutically acceptable salt thereof, are each administered cyclically in the form of five or six weeks of administration followed by one or two weeks of rest.

[0048] The one-week discontinuation schedule for VS-6063 or a pharmaceutically acceptable salt thereof and the one-week discontinuation schedule for CH5126766 or a pharmaceutically acceptable salt thereof can be simultaneous or different. In a preferred embodiment, the one-week discontinuation schedule for VS-6063 or a pharmaceutically acceptable salt thereof and the one-week discontinuation schedule for CH5126766 or a pharmaceutically acceptable salt thereof are simultaneous.

[0049] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is taken orally once a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is taken orally twice a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is taken orally three times a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is taken orally four times a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is taken orally five times a week. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is taken orally once a day. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is taken orally twice a day. CH5126766 can be in the form of a pharmaceutically acceptable salt.

[0050] In some embodiments, the FAK inhibitor (e.g., VS-6063) is taken orally twice a day. In some embodiments, the FAK inhibitor (e.g., VS-6063) is taken orally once a day. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 100 mg to about 400 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 100 mg to about 500 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 200 mg to about 500 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 200 mg to about 600 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 200 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered at a dosage of about 400 mg. It should be understood that the FAK inhibitor (e.g., VS-6063) can be administered at a dose at any periodic time period described herein. For example, the FAK inhibitor (e.g., VS-6063) can be administered at a dose of about 200 mg twice daily. The FAK inhibitor (VS-6063) can be administered at a dose of about 400 mg twice daily.

[0051] In some embodiments, RAF / MEK dual inhibitors (e.g., CH5126766) are administered at a dosage of about 0.5 mg to about 10 mg. In other embodiments, RAF / MEK dual inhibitors (e.g., CH5126766) are administered at a dosage of about 0.5 mg to about 7 mg. In other embodiments, RAF / MEK dual inhibitors (e.g., CH5126766) are administered at a dosage of about 0.5 mg to about 5 mg. In other embodiments, RAF / MEK dual inhibitors are administered at a dosage of about 1 mg to about 10 mg. In some embodiments, RAF / MEK dual inhibitors (e.g., CH5126766) are administered at a dosage of about 4 mg. In other embodiments, RAF / MEK dual inhibitors (e.g., CH5126766) are administered at a dosage of 3.2 mg. It should be understood that RAF / MEK dual inhibitors (e.g., CH5126766) can be administered at a certain dosage in any periodic time pattern described herein. For example, a dual RAF / MEK inhibitor (e.g., CH5126766) can be administered at a dose of about 0.5 mg to about 10 mg twice a week. A dual RAF / MEK inhibitor (e.g., CH5126766) can be administered at a dose of about 4 mg twice a week. A dual RAF / MEK inhibitor (e.g., CH5126766) can be administered at a dose of 3.2 mg twice a week. CH5126766 can be in the form of a pharmaceutically acceptable salt.

[0052] As described herein, FAK inhibitors (e.g., VS-6063) can be administered together with RAF / MEK dual inhibitors (e.g., CH5126766). For example, CH5126766 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 0.5 mg to about 10 mg, and VS-6063 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 100 mg to about 400 mg. CH5126766 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 3 mg to about 5 mg, and VS-6063 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 100 mg to about 400 mg. CH5126766 or a pharmaceutically acceptable salt thereof can be administered twice a week at a dose of about 3 mg to about 5 mg, and VS-6063 or a pharmaceutically acceptable salt thereof can be administered twice a day at a dose of about 100 mg to about 400 mg. CH5126766 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 4.0 mg twice a week, and VS-6063 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 200 mg twice a day. CH5126766 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 3.2 mg twice a week, and VS-6063 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 200 mg twice a day. CH5126766 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 3.2 mg twice a week, and VS-6063 or a pharmaceutically acceptable salt thereof can be administered at a dose of about 400 mg twice a day.

[0053] In some embodiments, a dual RAF / MEK inhibitor (e.g., CH5126766) is administered according to the following steps, comprising:

[0054] (a) Administering a dual RAF / MEK inhibitor twice a week for 3 weeks,

[0055] (b) suspending administration of the compound or salt for the next week, and

[0056] (c) then repeating steps (a) and (b) at least once.

[0057] In some embodiments, the dual RAF / MEK inhibitor (eg, CH5126766) is administered as follows (R1) or (R2):

[0058] (R1)

[0059] (A1)

[0060] (A1a) RAF / MEK dual inhibitor (e.g., CH5126766) administered at a dose of 4 mg per administration twice a week for 3 weeks,

[0061] (A1b) Administration of the dual RAF / MEK inhibitor (e.g., CH5126766) is suspended for the next week (i.e., based on a three-week on, one-week off cycle, for a total of four weeks), and

[0062] (A1c) then repeating steps (A1a) and (A1b) at least once; or

[0063] (R2)

[0064] (A2) First:

[0065] (A2a) RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 4 mg per administration twice a week for 3 weeks,

[0066] (A2b) Administration of the RAF / MEK dual inhibitor (e.g., CH5126766) is suspended for the next week, and

[0067] (A2c) then repeating steps (A2a) and (A2b) at least once;

[0068] (B2) The following:

[0069] (B2a) RAF / MEK dual inhibitor (e.g., CH5126766) administered twice a week at a dose of 3.2 mg per administration for 3 weeks,

[0070] (B2b) Administration of the RAF / MEK dual inhibitor (e.g., CH5126766) is suspended for the next week, and

[0071] (B2c) then repeating steps (B2a) and (B2b) at least once;

[0072] In some embodiments, for example, a 4-week cycle consisting of (i) steps (a) and (b), and (ii) a 4-week cycle consisting of steps (A1a) and (A1b) is repeated from two times (8 weeks) to 90 times (approximately 6 years and 11 months), and more specifically, for example, from 8 times (32 weeks) to 18 times (72 weeks). Even if the number of cycles to be repeated is predetermined, the number of cycles can be changed based on the judgment of the physician or veterinarian, for example, based on the condition of the subject. In addition, based on the judgment of the physician or veterinarian, for example, based on the condition of the subject, administration can even be stopped during the cycle.

[0073] In some embodiments, for example, a 4-week cycle consisting of steps (A2a) and (A2b) is repeated from two times (8 weeks) to 45 times (approximately 3 years and 5 months), and more specifically, for example, is repeated from 8 times (32 weeks) to 18 times (72 weeks). Even if the number of cycles to be repeated is predetermined, the number of cycles can be changed based on the judgment of the physician or veterinarian, for example, based on the condition of the subject. In addition, based on the judgment of the physician or veterinarian, for example, based on the condition of the subject, administration can even be stopped during the cycle.

[0074] In some embodiments, for example, a 4-week cycle consisting of steps (B2a) and (B2b) is repeated from two times (8 weeks) to 45 times (approximately 3 years and 5 months), and more specifically, for example, is repeated from 8 times (32 weeks) to 18 times (72 weeks). Even if the number of cycles to be repeated is predetermined, the number of cycles can be changed based on the judgment of the physician or veterinarian, for example, based on the condition of the subject. In addition, the drug can even be discontinued during the cycle based on the judgment of the physician or veterinarian, for example, based on the condition of the subject.

[0075] In some embodiments, the dose of a dual RAF / MEK inhibitor (e.g., CH5126766) is preferably 3.2 mg or 4 mg per administration. A more preferred dose is 4 mg, which can be reduced to 3.2 mg. The dose of a FAK inhibitor (e.g., VS-6063) is preferably 200 mg or 400 mg per administration. A more preferred dose is 200 mg, which can be increased to 400 mg.

[0076] The time period for the combined use of a RAF / MEK dual inhibitor (e.g., CH5126766) and a FAK inhibitor (e.g., VS-6063) can be determined based on the judgment of a physician or veterinarian (e.g., according to the condition of the subject). In addition, at the physician's or veterinarian's discretion, for example, based on the patient's condition, 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.

[0077] Compound

[0078] Among other things, the methods described herein comprise administering to a subject having cancer a FAK inhibitor in combination with a RAF / MEK dual inhibitor, wherein the FAK inhibitor is VS-6063, or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766, or a pharmaceutically acceptable salt thereof.

[0079] VS-6063

[0080] Exemplary FAK inhibitors include VS-6063 or a pharmaceutically 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, also known as defactinib and PF-04554878, has the following structure:

[0081]

[0082] In some embodiments, VS-6063 can form a pharmaceutically acceptable salt (e.g., VS-6063 hydrochloride). In some embodiments, VS-6063 or a pharmaceutically 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 pharmaceutically 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.

[0083] CH5126766

[0084] CH5126766 is a dual RAF / MEK inhibitor, also known as RO5126766. This document includes methods of using CH5126766 or a pharmaceutically acceptable salt thereof. CH5126766 (free base) is represented by the following formula:

[0085]

[0086] The CH5126766 or a pharmaceutically acceptable salt thereof used in the present invention is preferably the potassium salt of CH5126766. The potassium salt of CH5126766 is preferably, for example, a salt represented by the following formula:

[0087]

[0088] For example, CH5126766 and pharmaceutically acceptable salts thereof are disclosed in WO 2007 / 091736 and WO 2009 / 014100 and can be prepared according to the methods described in these publications.

[0089] Cancer combination therapy

[0090] In some embodiments, the combinations described herein (e.g., VS-6063, or a pharmaceutically acceptable salt thereof, in combination with CH5126766, or a pharmaceutically acceptable salt thereof) are administered together with an additional therapy (e.g., cancer treatment). In one embodiment, a mixture of one or more compounds or pharmaceutical compositions can be administered in combination with the combinations described herein (e.g., VS-6063, or a pharmaceutically acceptable salt thereof, and CH5126766, or a pharmaceutically acceptable salt thereof). In another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) can be administered in combination with the combinations described herein (e.g., VS-6063, or a pharmaceutically acceptable salt thereof, and CH5126766, or a pharmaceutically acceptable salt thereof) for the treatment of various diseases, including, for example, cancer.

[0091] In various embodiments, a combination therapy comprising a compound or pharmaceutical composition described herein may refer to (1) a pharmaceutical composition comprising one or more compounds in combination with a combination described herein (e.g., a combination of VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof); and (2) co-administration of one or more compounds or pharmaceutical compositions described herein with a combination described herein (e.g., a combination of VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof), wherein the compounds or pharmaceutical compositions described herein are not formulated in the same composition. In some embodiments, a combination described herein (e.g., a combination of VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof) is administered together with an additional treatment (e.g., an additional cancer treatment). In some embodiments, the additional treatment (e.g., the additional cancer treatment) can be administered simultaneously (e.g., at the same time), in the same or separate compositions, or sequentially. Sequential administration refers to administration of one treatment prior to administration of an additional treatment (e.g., compound or therapy) (e.g., just less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours; 4, 5, 6, 7, 8, 9 or more days; 1, 2, 3, 4, 5, 6, 7, 8 or more weeks). The order of administration of the first and second compounds or therapies may 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 periodic time intervals. For example, the FAK inhibitor (e.g., VS-6063) can be administered once a day or twice a day, while the RAF / MEK dual inhibitor (e.g., CH5126766) is administered twice a week, once a week, or every three or four days.

[0092] The methods of the present invention can be used or administered in combination with one or more additional therapies (e.g., cancer treatments, e.g., surgery, additional drugs or therapeutic agents) to treat the conditions / diseases mentioned. The additional therapies (e.g., cancer treatments, e.g., drugs or therapeutic agents described herein) can be administered in the same formulation or in separate formulations. If administered in separate formulations, the compounds of the present invention can be administered sequentially or simultaneously with the other drugs.

[0093] In addition to being able to be administered in combination with one or more additional therapies (e.g., cancer treatments such as surgery, additional drugs or therapeutic agents), the methods of the present invention can also be administered simultaneously (as a combined preparation) or sequentially to achieve the desired effect. This is especially desirable in cases where the therapeutic properties of each compound are different, such that the combined action of the two drugs provides an improved therapeutic outcome.

[0094] Exemplary cancer treatments include, for example, chemotherapy, targeted therapy such as antibody therapy, immunotherapy, and hormone therapy. Examples of each of these treatments are provided below.

[0095] chemotherapy

[0096] In some embodiments, the combination described herein (e.g., a combination of VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof) is administered together with chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. In contrast to targeted therapy, "chemotherapy" generally refers to cytotoxic drugs that affect rapidly dividing cells. Chemotherapeutic drugs interfere with cell division in various possible ways, for example, by interfering with the replication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although a certain degree of specificity may come from the fact that many cancer cells cannot repair DNA damage, while normal cells usually can.

[0097] 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, platinums, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle toxins, cytotoxic agents, topoisomerase inhibitors, etc.). Exemplary agents include aclarubicin, actinomycin; Alitretinon, hexamethylmelamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine (endamstine), bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquinone, carmofur, carmustine, celecoxib, benzodiazepine, benzophenone ... Nitrogen mustard, nitrogen mustard, cisplatin, cladribine, clofarabine, cretasone, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin, decitabine, demeclocycline, docetaxel, doxorubicin, efamixirol, ilisimol, elsamitrucin, enocitabine, epirubicin, estramustine, etogluconol, etoposide, floxuridine, fludarabine, 5FU, fotemustine, gemcitabine, Gliadel implant Injections, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, ilofofen, ixabepilone, larotrectin, folinate, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucanthone, mannosulfate, masorol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, dibromomannitol , mitoguanzone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacitaxin, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagene

[00135] The invention further comprises the following agents: cefixime, cefixime, ceradenovec, strataplatin, streptozotocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, pentylenetetrate, thiotepa, thiazofurine, thioguanine, tipifarnib, topotecan, trabectedin, triazinon, trotamide, triplatin, tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, zorubicin, and other cytostatic or cytotoxic agents described herein.

[0098] Because some drugs are used in combination and are more effective than when used alone, two or more drugs are usually given simultaneously or sequentially. Typically, two or more chemotherapeutic agents are used as combined chemotherapy. In some embodiments, chemotherapeutic agents (including combined chemotherapy) can be used in combination with a combination as described herein (e.g., a combination of a FAK inhibitor and a RAF / MEK dual inhibitor).

[0099] Targeted therapy

[0100] In some embodiments, the combination described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof, in combination with CH5126766 or a pharmaceutically acceptable salt thereof) is administered together with a targeted therapy. Targeted therapy includes the use of agents that are specific for dysregulated proteins of cancer cells. Small molecule targeted therapy drugs are typically inhibitors of enzyme domains on mutations, overexpression, or other key proteins within cancer cells. Prominent examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semasanib, sorafenib, sunitinib, and vandetanib, as well as cyclin-dependent kinase inhibitors such as avosidic and celecoxib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of a cancer cell. Examples include the anti-HER2 / neu antibody trastuzumab typically used for breast cancer and the anti-CD20 antibodies rituximab and tositumomab, which are typically used for various B-cell malignancies. Other exemplary antibodies include ctuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin-2 (Denileukindiftitox). Targeted therapies can also involve small peptides as "homing devices" that can bind to cell surface receptors or affect the extracellular matrix surrounding the tumor. Radionuclides attached to these peptides (e.g., RGD) will eventually kill the cancer cells if the nuclide decays near the cell. An example of such a therapy includes Immunotherapy

[0101] In some embodiments, the combination described herein (e.g., a combination of VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof) is administered together with immunotherapy. Cancer immunotherapy refers to a variety of treatment 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 intracapsular 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 myeloid leukemia, and hairy cell leukemia.

[0102] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy because the donor's immune cells typically attack the tumor with a graft-versus-tumor effect. In some embodiments, immunotherapeutic agents can be used with the combinations described herein (e.g., a combination of VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof).

[0103] In some embodiments, immunotherapeutic agents are compounds (e.g., ligands, antibodies) that inhibit immune checkpoint blockade pathways. Cancer immunotherapy refers to the use of the immune system to treat cancer. The three main immunotherapies for treating cancer include cell-based, antibody-based, and cytokine therapies. All immunotherapies utilize subtly different structures (e.g., molecular structures, antigens, proteins, molecules, carbohydrates) displayed by cancer cells on their surfaces, which can be detected by the immune system. Cancer immunotherapy (i.e., antitumor immunotherapy or antitumor immunotherapeutic agents) includes immune checkpoint antibodies (e.g., PD-1 antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA-4 antibodies, TIM3 antibodies, LAG3 antibodies, TIGIT antibodies) and cancer vaccines (i.e., antitumor vaccines).

[0104] In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (e.g., ipilimumab, tesilimumab), 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-HI 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 Cell-based therapy. In some embodiments, cell-based therapy is CAR-T therapy. In some embodiments, immunotherapeutic agent is a co-stimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40). In some embodiments, the method also includes administering additional chemotherapeutic agents or radiotherapy. In some embodiments, the method also includes administering a cytotoxic agent. In some embodiments, the cytotoxic agent is gemcitabine or paclitaxel (e.g., albumin-bound paclitaxel). In some embodiments, immunotherapeutic agent is a co-stimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0105] anti-inflammatory agents

[0106] In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically 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, isoxicam), fenamic acid derivatives (fenamic acid class) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), sulfonanilides (nimesulide). Steroids (e.g., hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone).

[0107] analgesics

[0108] In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof) can be administered with an analgesic. Analgesics include opioids (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), acetaminophen, and 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, isoxicam), fenamic acid derivatives (fenamic acid class) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), sulfonanilides (nimesulide).

[0109] antiemetics

[0110] In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof) can be administered with an antiemetic. Antiemetics include 5-HT3 receptor antagonists (dolasetron (Anzemet), granisetron (Kytril, Sancuso), ondansetron (Zofran), tropisetron (Navoban), palonosetron (Aloxi, mirtazapine (Remeron)), dopamine antagonists (domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide (Reglan), alizapril, prochlorperazine (Compazine, Stemzine, Buccaste m, Stemetil, Phenotil)), NK1 receptor antagonists (Aprepitant (Emend), antihistamines (Cyclizine, Diphenhydramine (Benadryl), Dimenhydrinate (Gravol, Dramamine), Meclizine (Bonine, Antivert), Promethazine (Pentazine, Phenergan, Promacot), Hydroxyzine), Benzodiazepines (Lorazepam, Midazolam), Anticholinergics (Scopamine), Steroids (Dexamethasone).

[0111] Hormone therapy

[0112] In some embodiments, the combinations described herein (e.g., a combination of VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof) are administered together 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 cancer and prostate cancer. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, the administration of hormone agonists such as progestins may be beneficial for treatment. In some embodiments, hormone therapy agents may be used in combination with the combinations described herein (e.g., a combination of VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof).

[0113] Radiation therapy

[0114] In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof) can be used in combination with directed energy or particles, or with radioisotope therapy, such as radiation therapy, such as radiation oncology, for the treatment of proliferative diseases, such as cancer, such as cancer associated with cancer stem cells. The methods of the present invention can be administered to a subject simultaneously or sequentially with directed energy or particles, or radioisotope therapy. For example, the methods of the present invention can be administered before, during, or after directed energy or particles, or radioisotope therapy, or a combination thereof. Directed energy or particle therapy can include whole-body irradiation, localized body irradiation, or point irradiation. Directed energy or particles may originate from an accelerator, a synchrotron, a nuclear reaction, a vacuum tube, a laser, or from a radioisotope. The therapy can include external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, whole-body radioisotope therapy, or unsealed source radiation therapy. Treatment can include ingestion or placement in the vicinity of a radioactive isotope, such as radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, or carbon. External beam radiation can include exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio waves, millimeter waves, microwaves, infrared, visible light, ultraviolet light, X-rays, or gamma-ray photons). Radiation can be directed to any part of the subject in need of treatment.

[0115] Operation

[0116] In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and CH5126766 or a pharmaceutically acceptable salt thereof) can be used in conjunction with surgery (e.g., surgical exploration, intervention, biopsy) to treat proliferative diseases, such as cancer, such as cancer associated with cancer stem cells. The methods of the present invention can be administered to a subject simultaneously with or sequentially with surgery. For example, the methods of the present invention can be administered before (preoperative), during, or after (postoperative) surgery, or a combination thereof. A FAK inhibitor (e.g., VS-6063) can be administered before (preoperative), while a RAF / MEK dual inhibitor (e.g., CH5126766) can be administered during or after (postoperative) surgery. Alternatively, a RAF / MEK dual inhibitor (e.g., CH5126766) can be administered before (preoperative), while a FAK inhibitor (e.g., VS-6063) can be administered during or after (postoperative) surgery. Surgery can be a biopsy during which one or more cells are collected for further analysis. Biopsy can be completed, for example, with a scalpel, needle, catheter, endoscope, spatula or scissors. Biopsy can be an excisional biopsy, an incisional biopsy, a core biopsy or a needle biopsy, for example, a needle aspiration biopsy. Surgery may involve excision of a local tissue suspected or determined to be cancerous. For example, the procedure may involve excision of a cancerous lesion, a lump, a polyp or a mole. The process may involve excision of a large amount of tissue, for example, breast, bone, skin, fat or muscle. The procedure may involve removal of part or all of an organ or nodule, for example, a lung, throat, tongue, bladder, cervix uteri, ovary, testicle, lymph node, liver, pancreas, brain, eye, kidney, gall bladder, stomach, colon, rectum or intestinal tract. In one embodiment, the cancer is breast cancer, for example, triple negative breast cancer, and the surgery is mastectomy or lumpectomy.

[0117] First-line treatment

[0118] In some embodiments, described herein is a method of treating a human subject having cancer, wherein the subject has failed (e.g., relapsed, is insensitive to, has received little or no benefit from) a first-line therapy (e.g., a first-line treatment for the cancer). Also described herein are methods of treating a human subject having cancer, wherein the methods of the invention are administered with an additional drug. In some embodiments, the additional drug is a first-line therapy for the cancer.

[0119] First-line therapy is usually the first treatment given for a disease (e.g., cancer as described herein). It is usually part of a group of standard treatments, such as chemotherapy and radiation therapy after surgery. When used alone, first-line therapy is usually the recognized best treatment. If it does not cure the disease or causes serious side effects, other treatments may be used in addition or instead. First-line therapy is also called induction therapy, primary therapy, and primary treatment.

[0120] For example, first-line treatment (e.g., for Hodgkin lymphoma) may include: Adcetris (brentuximab), Adriamycin PFS (doxorubicin hydrochloride), Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), Amboclorin (chlorambucil), Blenoxane (bleomycin), bleomycin, brentuximab, chlorambucil, Clafen (cyclophosphamide), cyclophosphamide, Cytoxan (cyclophosphamide), dacarbazine, doxorubicin hydrochloride, DTIC-Dome (dacarbazine), Leukeran (chlorambucil), Linfolizin (chlorambucil), lomustine, Matulane (procarbazine hydrochloride), Neosar (cyclophosphamide), procarbazine hydrochloride, Velban (vinblastine sulfate), Velsar (vinblastine sulfate), vinblastine sulfate, Vincasar PFS (vincristine sulfate), and vincristine sulfate.

[0121] In some embodiments, the first-line therapy (for example, Hodgkin's lymphoma) includes the combined administration of therapeutic agents, such as therapeutic agents as described herein. For example, the combination can include doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine sulfate, and dacarbazine (i.e., ABVD). As another example, the combination can include doxorubicin hydrochloride (adriamycin), bleomycin, vinblastine sulfate, and etoposide (i.e., ABVE). In some embodiments, the combination includes doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine sulfate, etoposide, prednisone, and cyclophosphamide (i.e., ABVE-PC). In some embodiments, the combination includes vincristine sulfate, doxorubicin hydrochloride (Adriamycin), methotrexate, and prednisone (i.e., VAMP).

[0122] Approved therapeutic agents and combinations for different types of cancer can be found at the National Cancer Institute at the NIH cancer website at http: / / www.cancer.gov / cancertopics / druginfo / drug-page-index.

[0123] Second-line treatment

[0124] In some embodiments, described herein are methods for treating a human subject with cancer, wherein the subject's second-line treatment or more treatments (e.g., second-line cancer treatment or third-line cancer treatment) have failed (e.g., relapsed, insensitive, no or little benefit therefrom). The present invention also describes methods for treating a human subject with cancer, wherein the methods of the present invention are administered together with additional drugs. In some embodiments, the additional drugs are first-line or second-line cancer treatments. Second-line treatment generally refers to treatment given when the initial treatment (e.g., first-line treatment) does not achieve the desired results, such as failure, ineffectiveness, or cessation of effect. When a subject does not respond to or develops resistance to the initial treatment (e.g., first-line treatment), second-line treatment is generally considered or given. For example, second-line treatment is generally considered or given to a subject with a relapsed or refractory disease.

[0125] Administration and dosage

[0126] The combination of the present invention can be administered orally, parenterally, topically, rectally or by implantation of a reservoir, preferably by oral administration or injection. In some cases, the pH of a composition (e.g., a pharmaceutical composition) can be adjusted to enhance the stability or efficacy of the composition with a pharmaceutically acceptable acid, base or buffer.

[0127] In some embodiments, subject's oral administration composition (for example, pharmaceutical composition).In some embodiments, composition (for example pharmaceutical composition) is orally administered with any oral acceptable dosage form, including liquid gel, tablet or capsule, syrup, emulsion and aqueous suspension.Liquid gel may include gelatin, plasticizer, and / or sunscreen, as needed to obtain suitable viscosity, and can be coated with the enteric coating used with approval, for example shellac.When used as oral dose, extra thickening agent can be added, for example glue (for example, xanthan gum), starch (for example, corn starch) or gluten, to realize the required viscosity of composition (for example, pharmaceutical composition).If necessary, some sweetener and / or flavoring and / or coloring agent can be added.

[0128] In some embodiments, the composition (e.g., pharmaceutical composition) is administered to a subject 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) can be a unit dosage form suitable for single administration of precise doses. In addition to compounds as described herein (e.g., FAK inhibitors (e.g., VS-6063); RAF / MEK dual inhibitors (e.g., CH5126766)), the pharmaceutical composition can include a pharmaceutically acceptable carrier, and can optionally further include one or more pharmaceutically acceptable excipients, such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavorings, matrix, dispersants, diluents, surfactants, emulsifiers, etc. In addition, tablets can include other drugs or medicaments, carriers, and / or adjuvants.

[0129] Examples of the excipient include starches (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium hydrogen phosphate.

[0130] Examples of the lubricant (coating agent) include ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin wax.

[0131] Examples of binders include polyvinyl pyrrolidone and polyethylene glycol, and the same compounds as described for the excipients.

[0132] Examples of disintegrants include chemically modified starches and celluloses, such as cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, and cross-linked polyvinyl pyrrolidone, and the same compounds as described for the excipients.

[0133] Examples of the stabilizer include: parabens such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0134] Examples of flavoring agents include common sweeteners, acidulants, and spices.

[0135] Examples of the base include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetyl alcohol; animal oils; lanolin acid; petrolatum; paraffin; bentonite; glycerin; and glycol oils.

[0136] Examples of dispersants include cellulose derivatives (gum arabic, gum tragacanth, methylcellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.

[0137] Examples of solvents and diluents in liquid preparations include phenol, chlorocresol, purified water, and distilled water.

[0138] Examples of surfactants and emulsifiers include polysorbate 80, polyethylene glycol 40 stearate, and lauromacrogol.

[0139] The preferred percentage of RAF / MEK inhibitor (eg, CH5126766) or FAK (eg, VS-6063) inhibitor contained in the formulation will vary depending on the dosage form, but is generally 0.01% to 100% by weight of the total weight of the formulation.

[0140] The amount of the RAF / MEK inhibitor (e.g., CH5126766) in the formulation can be appropriately set based on the intended dose. For example, a preferred amount is 0.01 mg to 10 mg; for example, for capsules, the amount may be 0.1 mg to 4 mg. For example, a more preferred amount is 0.8 mg.

[0141] Exemplary pharmaceutical compositions include compressed tablets (eg, direct compressed tablets), eg, comprising a FAK inhibitor (eg, VS-6063); or a dual RAF / MEK inhibitor (eg, CH5126766).

[0142] Also provided are tablets comprising active or therapeutic ingredients, such as compounds described herein, such as FAK inhibitors (e.g., VS-6063) and dual RAF / MEK inhibitors (e.g., CH5126766). In addition to the active or therapeutic ingredients, the tablets may also contain a number of inert materials, such as carriers. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including oils of petroleum, plant, or synthetic origin, such as peanut oil, sesame oil, and the like. Saline solutions and aqueous glucose solutions can also be used as liquid carriers. Therefore, the oral dosage forms used according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers including excipients and adjuvants to facilitate processing of the active ingredients into pharmaceutically acceptable preparations.

[0143] Excipients can impart good powder flow and compression properties to the compressed material. Examples of excipients are described in, for example, Handbook of Pharmaceutical Excipients (5 th Publisher: Pharmaceutical Press.

[0144] For oral administration, the active ingredient (e.g., a compound described herein (e.g., a FAK inhibitor (e.g., VS-6063); a RAF / MEK dual inhibitor (e.g., CH5126766))) can be readily formulated by combining the active ingredient with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the active ingredient of the invention to be formulated into tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in water or non-aqueous media, and the like for oral ingestion by a subject. Oral pharmaceutical preparations can be prepared using solid excipients, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants as needed to obtain, for example, tablets. Suitable excipients, such as diluents, binders, or disintegrants, may be required. In addition, the FAK inhibitor (e.g., VS-6063) and the RAF / MEK dual inhibitor (e.g., CH5126766) can be formulated separately according to the above methods.

[0145] The dosage can vary depending on the dosage form used and the route of administration adopted. Each physician can choose the exact formulation, route of administration, and dosage in light of the patient's condition. (See, for example, Finglet al., 1975, in "The Pharmacological Basis of Therapeutics"). The required dosage may be lower or higher than the above dosages. The specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health status, sex, diet, time of administration, excretion rate, drug combination, severity and course of the disease, condition or symptom, the subject's tendency to the disease, condition or symptom, and the judgment of the treating physician. A course of treatment may include one or more separate administrations of a compound as described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof, and / or CH5126766 or a pharmaceutically acceptable salt thereof).

[0146] If desired, the oral dosage form can be presented in the form of a package or dispensing device, such as an FDA-approved kit, which can contain one or more unit dosage forms containing the active ingredient. For example, the package can include metal or plastic foil, such as a blister pack. The package or dispensing device can be accompanied by instructions for administration. The package or dispenser can 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, which reflects the agency's approval of the form of the composition or the form for human or veterinary administration. For example, such a notice may be a prescription drug package insert approved by the U.S. Food and Drug Administration or an approved product insert.

[0147] The dosing regimen used in the present invention allows for long-term combined administration of a RAF / MEK dual inhibitor (e.g., CH5126766) with a FAK inhibitor (e.g., VS-6063) while minimizing side effects and maintaining the efficacy of the drugs. Furthermore, the dosing regimen and combination can treat or prevent cell proliferative diseases, particularly cancer, while minimizing the burden on patients.

[0148] definition

[0149] 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.

[0150] As used herein, "about" and "approximately" refer to an acceptable degree of error for the measured value, taking into account the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0151] As used herein, an amount of a compound effective to treat a disease or condition described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), "effective amount," or "effective progression" refers to an amount of a compound that, following single or multiple dose administration to a subject, effectively treats a subject, or cures, alleviates, relieves, or improves a subject suffering from a disease or condition described herein (e.g., abnormal cell growth (e.g., cancer (e.g., a cancer described herein))) over that which would be expected in the absence of such treatment (e.g., placebo treatment).

[0152] As used herein, the term "pharmaceutically acceptable" refers to a compound or carrier (e.g., an excipient) that can be administered to a subject together with the compound described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof, and / or CH5126766 or a pharmaceutically acceptable salt thereof) without destroying its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0153] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound described herein (e.g., VS-6063, or a pharmaceutically acceptable salt thereof, and / or CH5126766 or a pharmaceutically acceptable salt thereof), wherein the compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the compounds described herein, for example, formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from compounds described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof, and / or CH5126766 or a pharmaceutically acceptable salt thereof) containing 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 the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th ed., 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 pharmaceutically acceptable salts also include: inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, and phosphates; sulfonates such as methanesulfonates, benzenesulfonates, and toluenesulfonates; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium, sodium, potassium, cesium, and rubidium; alkaline earth metal salts such as magnesium and calcium; ammonium salts such as ammonium, alkylammonium, dialkylammonium, trialkylammonium, and tetraalkylammonium.

[0154] As used herein, the term "oral dosage form" refers to a composition or medium for administering a pharmaceutical agent (e.g., a therapeutic agent, such as a compound described herein) to a subject. Typically, oral dosage forms are administered through the mouth, however, "oral dosage form" is intended to encompass any substance that is administered to a subject and absorbed through the membranes (e.g., mucosa) of the digestive tract, including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and colon. For example, "oral dosage form" encompasses a solution administered into the stomach through a feeding tube.

[0155] As used herein, the term "treat" or "treating" refers to the application or administration of a compound, alone or in combination with an additional agent, to a subject, e.g., a subject suffering from, afflicted with, having symptoms of, prone to having, a disease or condition described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)), for the purpose of treating, curing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting a disease or condition described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)).

[0156] As used herein in the context of administering a compound described herein or a therapy described herein, the phrase "combination" and the term "co-administering" or "co-providing" means that two (or more) different compounds or therapies are delivered to a subject during the course of the subject's disease or condition (e.g., cancer), for example, after the subject is diagnosed with a disease or condition (e.g., a disease or condition described herein, such as cancer) and before the disease or condition is cured or eliminated or treatment is stopped for other reasons. The combination can achieve a synergistic result, i.e., a greater than additive result, e.g., at least 20, 50, 70, or 100% greater than the additive result.

[0157] As used herein, the phrase "synergistic effect" refers to an effect of two or more compounds or compositions that is greater than the additive effect (e.g., therapeutic effect). Exemplary synergistic effects include administering an amount of a FAK inhibitor (e.g., VS-6063) in combination (e.g., administering) with an amount of a RAF / MEK dual inhibitor (e.g., CH5126766), resulting in a therapeutic effect that is greater than the additive therapeutic effect of each inhibitor alone.

[0158] As referred to herein, a "course of treatment" includes one or more separate administrations of a therapeutic agent. A course of treatment may include one or more cycles of a therapeutic agent.

[0159] As used herein in the context of a drug administration cycle, a "cycle" refers to a period of time during which a drug is to be administered to a patient. Preferably, one cycle is equal to four weeks.

[0160] Many ranges are provided herein, such as ranges for the amount of drug administered per day. In some embodiments, the range includes both endpoints. In other embodiments, the range does not include one or both endpoints. For example, the range may not include the lower endpoint. Therefore, in such embodiments, a range of 100 to 400 mg / day does not include the lower endpoint, which encompasses an amount greater than 100 and less than or equal to 400 mg / day.

[0161] 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 subjects suffering from a disease or condition as described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer as described herein)) or suffering from a disease or condition as described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer as described herein)). The term "non-human animal" of the present invention includes all vertebrates, such as non-mammals (e.g., chickens, amphibians, reptiles) and mammals, such as non-human primates, domestic and / or agriculturally useful animals, such as sheep, dogs, cats, cattle, pigs, etc.

[0162] The phrase "twice a week" refers to that a RAF / MEK dual inhibitor (e.g., CH5126766) is administered twice during a week. Administration can be performed twice on the same day, or once on different days (which may be continuous), but is preferably performed on different days. More preferably, administration is performed, for example, on the 1st and 4th day of the cycle, or on the 2nd and 5th day, so that the RAF / MEK dual inhibitor (e.g., CH5126766) is administered with the dosage interval as uniform as possible, i.e., the dosage interval is 3 to 4 days. For example, a week can start from Monday, or, for example, can start from Tuesday. When twice administration is performed on different days, each administration can be performed at any time of the day, but they are preferably performed at the same time of the day (e.g., after breakfast). Example

[0163] The following representative examples are intended to help illustrate the present invention but are not, and should not be construed as, limiting the scope of the invention.

[0164] In Examples 1 and 2 below and Tables 1 to 4 below, "CH5126766" refers to the potassium salt of CH5126766, and "VS-6063" refers to VS-6063 hydrochloride.

[0165] Example 1 Phase I clinical trial of the combination of VS-6063 (FAK inhibitor) and CH5126766 (RAF / MEK dual inhibitor) in patients with advanced solid tumors [NCT03875820]

[0166] method

[0167] The study explored dose escalation groups, mandatory biopsy groups, and expansion groups. CH5126766 was administered twice a week, and VS-6063 was administered twice a day (BD). Each cycle consisted of a dosing regimen based on 3 weeks of administration of both drugs and 1 week of rest (1 cycle = 4 weeks). Three dose levels were explored in the escalation group. 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 1 of 6 patients at the same dose level experienced drug-related toxicity (DLT) as specified in the protocol was determined. The safety and toxicity profiles of CH5126766 and VS-6063 were evaluated. The causality and severity grade of each adverse event were determined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Disease response according to RECIST, version 1.1, was assessed every two cycles. Serum tumor markers were also assessed in eligible patients. Data related to progression-free survival were also collected.

[0168] Discover

[0169] The most common side effects in dose escalation were rash and non-dose-limiting nausea and hyperbilirubinemia. No DLTs were observed in either cohorts 1 or 2A. A grade 2 rash DLT requiring dose interruption or dose reduction in cycle 1 was observed in cohort 2B (corresponding to dose level 2B), and therefore cohort 2A (corresponding to dose level 2A) was declared the recommended phase 2 dose (R2PD). Partial responses have been achieved in ovarian cancer with KRAS mutations (3 low-grade serous adenocarcinomas and 1 mucinous adenocarcinoma) and response-evaluable KRAS-mutant lung cancers. Two NRAS-mutant colon / rectal cancers have been treated, showing a reduction in CEA levels greater than 50% and stable disease. Pancreatic cancer with KRAS mutants showed minor responses (-19%, -14%, and -11% at cycles 2, 4, and 6, respectively), showing a reduction in CA19-9 levels greater than 50%.

[0170] Representative results of disease response, serum tumor markers, and treatment duration obtained to date are shown in Example 2.

[0171] in conclusion

[0172] The combination of CH5126766 and VS-6063 was tolerable and highly active in patients with ovarian cancer and other tumors harboring KRAS and / or NRAS mutations.

[0173] Example 2 Combination of CH5126766 and VS-6063 in patients with advanced solid tumors

[0174] In Tables 1 to 4 below, "CH" represents the potassium salt of CH5126766, administered twice weekly, and "VS" represents the hydrochloride salt of VS-6063, administered twice daily (BID). Each cycle consists of a dosing regimen based on 3 weeks of both drugs followed by 1 week of rest (1 cycle = 4 weeks). "PR" represents partial response; "SD" represents stable disease; and "N / A" represents not available.

[0175] Table 1: Combination of CH5126766 and VS-6063 administered to patients with ovarian cancer

[0176]

[0177] **Data cutoff date is June 18, 2019

[0178] Table 2 Combination of CH5126766 and VS-6063 administered to NSCLC patients

[0179]

[0180] **Data cutoff date is June 18, 2019

[0181] Table 3 Combination of CH5126766 and VS-6063 administered to patients with colorectal cancer

[0182]

[0183]

[0184] Table 4: Combination of CH5126766 and VS-6063 administered to pancreatic cancer patients

[0185]

[0186] **Data cutoff date is June 18, 2019

[0187] This application involves the following technical solutions:

[0188] 1. A method for treating a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of a combination of VS-6063, or a pharmaceutically acceptable salt thereof, and CH5126766, or a pharmaceutically acceptable salt thereof, thereby treating the subject, wherein the cancer is a cancer having a RAS mutation.

[0189] 2. The method according to 1, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is the potassium salt of CH5126766.

[0190] 3. The method according to 1 or 2, wherein the cancer is selected from the group consisting of ovarian cancer, lung cancer, colon cancer and pancreatic cancer.

[0191] 4. The method according to any one of 1-3, wherein the cancer is ovarian cancer.

[0192] 5. The method according to 4, wherein the ovarian cancer is low-grade serous ovarian cancer.

[0193] 6. The method according to any one of 1-3, wherein the cancer is lung cancer.

[0194] 7. The method according to any one of 1-3, wherein the cancer is colon cancer.

[0195] 8. The method of any one of 1-3, wherein the cancer is pancreatic cancer.

[0196] 9. The method according to any one of 1-8, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered twice a week.

[0197] 10. The method according to any one of 1-9, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered twice a day.

[0198] 11. The method according to any one of 1-9, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered once a day.

[0199] 12. The method according to any one of 1 to 11, wherein the CH5126766 or a pharmaceutically acceptable salt thereof and the VS-6063 or a pharmaceutically acceptable salt thereof are administered for at least three weeks.

[0200] 13. The method according to any one of 1 to 12, wherein the CH5126766 or a pharmaceutically acceptable salt thereof and the VS-6063 or a pharmaceutically acceptable salt thereof are independently administered periodically, wherein the administration is continuous for three weeks and then rested for one week.

[0201] 14. The method according to any one of 1 to 12, wherein the CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are administered simultaneously and periodically, wherein the administration is continuous for three weeks and then rested for one week.

[0202] 15. The method according to any one of 1-14, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 0.5 mg to about 10 mg.

[0203] 16. The method according to any one of 1-14, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 4 mg.

[0204] 17. The method according to any one of 1 to 14, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at 3.2 mg.

[0205] 18. The method of any one of 1-17, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 100 mg to about 400 mg.

[0206] 19. The method of any one of 1-17, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 100 mg to about 500 mg.

[0207] 20. The method of any one of 1-17, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 200 mg to about 500 mg.

[0208] 21. The method of any one of 1-17, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 200 mg to about 600 mg.

[0209] 22. The method according to any one of 1-14, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 0.5 mg to about 10 mg and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 100 mg to about 400 mg.

[0210] 23. The method according to any one of 1-14, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 4 mg twice a week and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 200 mg twice a day.

[0211] 24. The method according to any one of 1-14, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at 3.2 mg twice a week, and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at 200 mg twice a day.

[0212] 25. The method according to any one of 1-14, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 4 mg twice a week, and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 400 mg twice a day.

[0213] 26. The method according to any one of 1-14, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at 3.2 mg twice a week, and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at 400 mg twice a day.

[0214] 27. A method of treating a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof in combination.

[0215] 28. The method of 27, wherein the cancer is selected from the group consisting of ovarian cancer, lung cancer, colon cancer, and pancreatic cancer.

[0216] 29. The method according to 27 or 28, wherein the cancer is ovarian cancer.

[0217] 30. The method of 29, wherein the ovarian cancer is low-grade serous ovarian cancer.

[0218] 31. The method according to 27 or 28, wherein the cancer is lung cancer.

[0219] 32. The method of 27 or 28, wherein the cancer is colon cancer.

[0220] 33. The method according to 27 or 28, wherein the cancer is pancreatic cancer.

[0221] 34. The method according to any one of 27-33, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered twice a week.

[0222] 35. The method of any one of 27-34, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0223] 36. The method according to any one of 27-34, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered once a day.

[0224] 37. The method according to any one of 27-36, wherein the CH5126766 or a pharmaceutically acceptable salt thereof and the VS-6063 or a pharmaceutically acceptable salt thereof are administered for at least three weeks.

[0225] 38. The method according to any one of 27-37, wherein the CH5126766 or a pharmaceutically acceptable salt thereof and the VS-6063 or a pharmaceutically acceptable salt thereof are independently administered periodically, wherein the administration is continuous for three weeks and then rested for one week.

[0226] 39. The method according to any one of 27-37, wherein the CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are administered simultaneously and periodically, wherein the administration is continuous for three weeks and then rested for one week.

[0227] 40. The method according to any one of 27-39, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 0.5 mg to about 10 mg.

[0228] 41. The method according to any one of 27-39, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 4 mg.

[0229] 42. The method according to any one of 27-39, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at 3.2 mg.

[0230] 43. The method of any one of 27-42, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 100 mg to about 400 mg.

[0231] 44. The method of any one of 27-42, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 100 mg to about 500 mg.

[0232] 45. The method of any one of 27-42, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 200 mg to about 500 mg.

[0233] 46. ​​The method of any one of 27-42, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 200 mg to about 600 mg.

[0234] 47. The method according to any one of 27-39, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 0.5 mg to about 10 mg and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 100 mg to about 400 mg.

[0235] 48. The method according to any one of 27-39, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 4 mg twice a week, and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 200 mg twice a day.

[0236] 49. The method according to any one of 27-39, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at 3.2 mg twice a week, and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at 200 mg twice a day.

[0237] 50. The method according to any one of 27-39, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at about 4.0 mg twice a week, and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at about 400 mg twice a day.

[0238] 51. The method according to any one of 27-39, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is administered at 3.2 mg twice a week, and the VS-6063 or a pharmaceutically acceptable salt thereof is administered at 400 mg twice a day.

[0239] 52. The method of any one of 27-51, wherein the cancer is caused by a mutation in RAS or BRAF.

[0240] 53. The method of any one of 27-51, wherein the cancer is caused by a KRAS mutation or a NRAS mutation.

Claims

1. A method for treating a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of a combination of VS-6063, or a pharmaceutically acceptable salt thereof, and CH5126766, or a pharmaceutically acceptable salt thereof, thereby treating the subject, wherein the cancer is a cancer having a RAS mutation.

2. The method according to claim 1, wherein The CH5126766 or a pharmaceutically acceptable salt thereof is the potassium salt of CH5126766.

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

5. The method according to 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 according to 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. The method according to any one of claims 1 to 8, wherein The CH5126766 or a pharmaceutically acceptable salt thereof is administered twice a week.

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

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