Combination therapy including a PKC inhibitor and a C-MET inhibitor

Abstract

Provided herein are combination therapies and methods of using such combination therapies for treating diseases or disorders associated with PKC and c-MET.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 286,345, filed December 6, 2021, U.S. Provisional Application No. 63 / 317,573, filed March 8, 2022, and U.S. Provisional Application No. 63 / 370,056, filed August 1, 2022, the entire contents of which are incorporated by reference herein in their entireties. [Background technology]

[0002] Uveal melanoma is the most common primary intraocular malignant tumor in adults. Several protein kinase inhibitors are described in International Publication Nos. WO02 / 38561 and WO2008 / 106692. One protein kinase C (PKC) inhibitor, sotrastaurin, has been shown to have activity against several PKC isotypes and has recently been shown to selectively inhibit the growth of uveal melanoma cells with GNAQ mutations by targeting the PKC / ERK1 / 2 and PKC / NF-xB pathways (see X.Wu, et al., Mol.Cancer Ther., Vol.11, pages 1905-1914, 2012). However, there remains an unmet need to provide next-generation PKC inhibitors for treating uveal melanoma with improved efficacy, improved potency, hERG activity, absorption, gastrointestinal resistance and kinase selectivity, such that tumor regression is achieved at lower doses. PCT Application No. PCT / IB2015 / 055951 (WO2016 / 020864) discloses a number of potent and selective PKC inhibitors.

[0003] The c-MET receptor has been shown to be expressed in a number of human cancers. c-MET and its ligand, HGF, have also been shown to be co-expressed at high levels in a variety of human cancers, particularly sarcomas. However, because the receptor and ligand are usually expressed in different cell types, c-MET signaling is most commonly regulated by tumor-stroma (tumor-host) interactions. Furthermore, amplification, mutation, and rearrangement of the c-MET gene have been observed in a subset of human cancers. Families with germline mutations that activate c-MET kinase are predisposed to multiple kidney tumors as well as tumors of other tissues. Many studies have shown a correlation between the expression of c-MET and / or HGF / SF and disease progression in various types of cancer, including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovarian, gastric, skin, and bone cancers. Moreover, overexpression of c-MET or HGF has been shown to correlate with poor prognosis and disease outcome in many major human cancers, including lung, liver, gastric, and breast cancer. c-MET has also been directly implicated in cancers lacking effective treatment regimens, such as pancreatic cancer, glioma, and hepatocellular carcinoma. PCT Application No. PCT / IB2005 / 002837 (WO2006 / 021884) discloses a number of potent and selective c-MET inhibitors. Summary of the Invention

[0004] Provided herein is a combination therapy comprising a PKC inhibitor and a c-MET inhibitor. The combination therapy is useful for treating various cancers, including uveal melanoma. The combination therapy is also useful for treating various cancers, including solid tumors with GNAQ and / or GNA11 mutations. The combination therapy is also useful for treating a number of PKC-related and / or c-MET-related diseases.

[0005] Accordingly, in one aspect, provided herein is a method of treating uveal melanoma or solid tumors harboring a GNAQ or GNA11 mutation in a subject in need thereof, comprising administering to the subject a pharma- tically effective amount of Compound 1: [ka] or a pharma- ceutically acceptable salt thereof; A pharma- ceutical effective amount of Compound 2: [ka] or a pharma- ceutically acceptable salt thereof.

[0006] In some embodiments, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutical acceptable salt thereof, and Compound 2, or a pharma-ceutical acceptable salt thereof, wherein: Compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily (BID) at a dose of about 200 mg or about 300 mg, based on the free base equivalent of Compound 1; Compound 2, or a pharma- ceutically acceptable salt thereof, is administered BID at about 200 mg or about 250 mg, equivalent to the free base of Compound 2.

[0007] In some embodiments, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutical acceptable salt thereof, and and administering Compound 2 or a pharma- ceutically acceptable salt thereof, Where: Compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 300 mg, equivalent to the free base of Compound 1; Compound 2, or a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 200 mg, equivalent to the free base amount of Compound 2.

[0008] In another aspect, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutical acceptable salt thereof, and and administering Compound 2 or a pharma- ceutically acceptable salt thereof, Where: Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 400 mg to about 600 mg per day (i.e., total daily dose) in terms of the amount of the free base of Compound 1; In this method, compound 2 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 400 mg to about 500 mg per day, as the amount equivalent to the free base of compound 2.

[0009] In another aspect, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutical acceptable salt thereof, and and administering Compound 2 or a pharma- ceutically acceptable salt thereof, Where: Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 600 mg per day as the free base equivalent of Compound 1; Compound 2, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 400 mg per day, equivalent to the free base amount of Compound 2.

[0010] In some embodiments, the uveal melanoma is metastatic uveal melanoma. The uveal melanoma can be a solid tumor that has a GNAQ mutation or a GNA11 mutation.

[0011] In some embodiments, the solid tumor with a GNAQ mutation or GNA11 mutation being treated is a cutaneous melanoma. In another embodiment, the solid tumor with a GNAQ mutation or GNA11 mutation being treated is a non-small cell lung cancer (NSCLC).

[0012] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of 300 mg. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of 300 mg, as the free base equivalent of Compound 1. In another embodiment, Compound 2 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of 200 mg, as the free base equivalent of Compound 2.

[0013] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of 200 mg, as the free base equivalent of Compound 1, and Compound 2 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of 200 mg, as the free base equivalent of Compound 2.

[0014] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of 300 mg, as the free base equivalent of Compound 1, and Compound 2 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of 250 mg, as the free base equivalent of Compound 2.

[0015] In some embodiments, provided herein is a method for detecting uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject, comprising: (i) at least one first treatment cycle of 7 day administration cycles, in which Compound 1, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered alone at a dose of about 300 mg BID on each day of the first treatment cycle, followed by (ii) at least one second treatment cycle of 7 day dosing cycles, wherein Compound 1, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 300 mg every day of the second treatment cycle, and Compound 2, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 200 mg every day of the second treatment cycle.

[0016] In some embodiments, the method of treating uveal melanoma or a solid tumor with a GNAQ mutation or GNA11 mutation in a subject includes: (i) at least one first treatment cycle of 7 day administration cycles, in which Compound 1, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered alone at a dose of about 300 mg BID on each day of the first treatment cycle, followed by (ii) a second treatment cycle of at least three 7-day treatment cycles, wherein Compound 1, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 300 mg on each day of the second treatment cycle, and Compound 2, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 200 mg on each day of the second treatment cycle.

[0017] In yet another embodiment, a method for treating uveal melanoma or solid tumors harboring a GNAQ mutation or a GNA11 mutation in a subject is according to a dosing schedule comprising at least one 7-day dosing cycle, wherein compound 1, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 300 mg every day of at least one 7-day dosing cycle, and compound 2, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 200 mg every day of at least one 7-day dosing cycle.

[0018] In yet another embodiment, a method for treating uveal melanoma or solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject is according to a dosing schedule comprising at least four 7-day dosing cycles, wherein compound 1, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 300 mg every day for at least four 7-day dosing cycles, and compound 2, or a corresponding amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 200 mg every day for at least four 7-day dosing cycles.

[0019] In yet another embodiment, the method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject is according to a dosing schedule comprising at least one 7-day dosing cycle, wherein Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered alone at a dose of about 300 mg BID.

[0020] In yet another embodiment, administration of Compound 1, or a corresponding amount of a pharma- ceutically acceptable salt thereof, in combination with administration of Compound 2, or a corresponding amount of a pharma- ceutically acceptable salt thereof, continues uninterrupted for a dosing schedule comprising at least one seven-day dosing cycle.

[0021] In some embodiments, Compound 1 and Compound 2 are administered sequentially (ie, continuous treatment until completion).

[0022] Regarding any of the above embodiments, the method of treating uveal melanoma or solid tumors with GNAQ mutation or GNA11 mutation in a subject in need thereof may further comprise continuing to administer compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof without interruption during a dosing schedule comprising at least two or more consecutive 7-day dosing cycles, or preferably at least four or more consecutive 7-day dosing cycles. In a particularly preferred embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof are co-administered without interruption during a dosing schedule comprising at least 8 or more, 12 or more, 24 or more, 48 or more, or 96 or more consecutive 7-day dosing cycles.

[0023] Regarding any of the above embodiments, the method of treating uveal melanoma or solid tumors with GNAQ mutations or GNA11 mutations in a subject in need thereof may further comprise continuing to administer compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof for a dosing schedule comprising at least two or more consecutive 7-day dosing cycles, or preferably at least four or more consecutive 7-day dosing cycles. In a particularly preferred embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof are co-administered without interruption for a dosing schedule comprising at least 8 or more, 12 or more, 24 or more, 48 or more, or 96 or more consecutive 7-day dosing cycles. In particularly preferred embodiments, Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof, and Compound 2, or an equivalent amount of a pharma- ceutically acceptable salt thereof, continue to be co-administered without interruption during a dosing schedule that includes at least 4 or more, 8 or more, 12 or more, 16 or more, 20 or more, 24 or more, 28 or more, 32 or more, 36 or more, 40 or more, 44 or more, 48 or more, or 96 or more consecutive 7-day dosing cycles.

[0024] In another aspect, provided herein is a method for treating a pulmonary circulation disorder comprising: (i) about 300 mg of Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof; (ii) A combination comprising about 200 mg of Compound 2 or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0025] In yet another embodiment, provided herein is a method for treating a pulmonary circulation disorder comprising: (i) about 200 mg to about 300 mg of Compound 1 or an equivalent amount of a pharma- ceutically acceptable salt thereof; (ii) A combination comprising about 200 mg to about 250 mg of Compound 2 or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0026] In one embodiment, the combination comprises Compound 1 as the free base. In another embodiment, the combination comprises Compound 2 as the free base. [Brief description of the drawings]

[0027] [Figure 1] CT scan of a patient with metastatic uveal melanoma (MUM) with diffuse disease in the liver, lungs, lymph nodes, and subcutaneous lesions, and elevated LDH. The patient was administered Compound 1 at 300 mg BID (equivalent to the free base amount of Compound 1) and Compound 2 at 200 mg BID (equivalent to the free base amount of Compound 2). The patient was treated for approximately 23 weeks. [Diagram 2] CT scan of a patient with MUM with multiple liver lesions and normal LDH. The patient was administered Compound 1 at 300 mg BID (equivalent to the free base of Compound 1) and Compound 2 at 200 mg BID (equivalent to the free base of Compound 2). The patient was treated for approximately 12 weeks. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Provided herein is a combination therapy comprising compound 1 or a pharma- ceutically acceptable salt thereof and compound 2 or a pharma- ceutically acceptable salt thereof. The combination therapy is useful for treating various cancers, including uveal melanoma. The combination therapy may also be useful for treating solid tumors with GNAQ or GNA11 mutations. In another aspect, the combination therapy is useful for treating many PKC-related and / or c-MET-related diseases.

[0029] Administering a combination of Compound 1 and Compound 2 can have a beneficial effect on the treatment of a subject's cancer, e.g., uveal melanoma. Such an approach (combination or coadministration of the two agents) can provide uninterrupted treatment to subjects in need of treatment over a clinically relevant treatment period.

[0030] definition Listed below are definitions of various terms used in this specification. These definitions apply to the terms as they are used throughout this specification and claims, unless limited in specific instances either individually or as part of a larger group.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.

[0032] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms such as "include," "includes," and "included" are not limiting.

[0033] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein, the term "about" when referring to a measurable value, such as an amount, length of time, etc., is meant to encompass variations of ±20% or ±10%, e.g., ±5%, ±1%, and ±0.1% from the specified value, such variations being appropriate for carrying out the disclosed methods. For example, a dose of about 300 mg can be understood to mean that the dose can vary between 270 mg and 330 mg.

[0034] As used in the specification and claims, "comprising" can include "consisting of" and "consisting essentially of" embodiments. The terms "comprise(s)", "include(s)", "having", "has", "may", "contain(s)" and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or statements that require the presence of the specified components / steps and permit the presence of other components / steps. However, such statements also shall be construed as describing compositions or processes that "consist of" and "consist essentially of" the recited compounds, which acknowledge that only the specified compounds are present, along with any pharma- ceutically acceptable carriers, and exclude other compounds.

[0035] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in range format herein. It should be understood that such range formats are used for convenience and brevity, and thus should be interpreted flexibly to include not only the numerical values ​​explicitly stated as range limits, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were explicitly stated. By way of example, a dose range of "200 mg to about 600 mg" should be interpreted to include not only the explicitly stated concentration of about 200 mg to about 600 mg, but also the individual doses (e.g., 250 mg, 400 mg, 550 mg) and subranges (e.g., 250 mg to 450 mg) within the specified range. By way of further example, a tumor size reduction of "30% to 50%" should be interpreted to include not only the explicitly stated concentration of about 30% to about 50%, but also the individual percentages (e.g., 35%, 40%, 50%) and subranges (e.g., 35% to 45%) within the specified range. The term "about" can include ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10% of the modified numerical value. In addition, the phrase "about x to y" includes "about x to about y."

[0036] The terms "combination," "therapeutic combination," "pharmaceutical combination," or "combination" as used herein refer to either a fixed combination in one dosage unit form, or a non-fixed combination in separate dosage forms, or a kit of parts for combined administration in which two or more therapeutic agents can be administered simultaneously or separately and independently with an interval of time.

[0037] As used herein, the term "non-fixed combination" means that the active ingredients, e.g., Compound 1 and Compound 2, are both administered to a patient as separate entities, either in parallel, simultaneously or sequentially, such administration providing therapeutically effective levels of the two compounds in the patient's body.

[0038] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses substantially simultaneous co-administration of the therapeutic agents, such as a single formulation having a fixed ratio of active ingredients or separate formulations of each active ingredient (i.e., separate dosage units, e.g., separate tablets, capsules, and / or intravenous formulations). In addition, such administration also encompasses sequential or separate use of the various therapeutic agents at about the same time or at different times. Whether the active ingredients are administered as a single formulation or as separate formulations, the agents are administered to the same patient as part of the same course of treatment. The agents may be administered at the same time as each other or sequentially. The agents may be administered in any order. The agents may be administered separately at different times during the course of treatment, with such time intervals that the combination therapy is effective in treating cancer. In either case, the treatment regimen provides a beneficial effect in treating the condition or disorder described herein.

[0039] As used herein, the term "free base equivalent" refers to the amount of an active agent (e.g., Compound 1 or Compound 2) present in the active agent or a pharma- ceutically acceptable salt thereof. In other words, the term "free base equivalent" means either the amount of the free base of Compound 1 or Compound 2, or the equivalent amount of the free base of Compound 1 or Compound 2 provided by a salt of the compound.

[0040] As used herein, "metastasis" or "metastatic" means that cancer spreads from the primary site to other locations in the body. Cancer cells can break away from the primary tumor, enter lymphatic and blood vessels, circulate in the bloodstream, and grow (metastasize) at distant foci in other normal tissues in the body. Metastasis can be local or distant. Metastasis is a sequential process in which tumor cells break away from the primary tumor, travel in the bloodstream, and lodge at a distant site. At the new site, the cells can grow until they establish a blood supply and form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cells control this behavior, and interactions between tumor cells and host cells at distant sites are also important.

[0041] As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., arresting further development of pathology and / or symptoms) in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, or ameliorating a disease, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms) in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, e.g., reducing the severity of the disease.

[0042] As used herein, the term "prevent" or "prevention" refers to the absence of onset of a disorder or disease if the disorder or disease has not occurred, or the absence of further onset of a disorder or disease if the disorder or disease has already occurred. Also contemplated is the ability to prevent some or all of the symptoms associated with the disorder or disease.

[0043] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, farm animals and pets, such as sheep, cows, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0044] As used herein, the term "first-line MUM patient" refers to a patient who has not received prior systemic therapy in the metastatic setting, including having not received prior embolization, radiation to metastatic sites, or resection of liver lesions.

[0045] As used herein, the term "all-lineage MUM patients" refers to all patients who meet the patient eligibility criteria for the clinical trials disclosed herein. All-lineage MUM patients include (1) first-line MUM patients and (2) patients who have received prior therapy other than the combination (Compound 1 and Compound 2) disclosed herein.

[0046] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to produce a desired biological result. That result can be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0047] As used herein, the term "pharmaceutical acceptable" refers to a substance, such as a carrier or diluent, that does not destroy the biological activity or properties of the compound and is relatively non-toxic, i.e., it may be administered to an individual without causing undesired biological effects or interacting adversely with any of the components of the composition in which it is contained.

[0048] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an acid or base moiety present therein into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines; alkali or organic salts of acidic residues, such as carboxylic acids. The pharmaceutically acceptable salts described herein include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts discussed herein can be synthesized by conventional chemical methods from the parent compound containing a basic or acidic moiety. In general, such salts can be prepared by reacting the free acid or free 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 solvents such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The term "pharmaceutically acceptable salts" is not limited to mono-salts or 1:1 salts. For example, "pharmaceutically acceptable salts" also includes bis-salts, such as dihydrochlorides. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th 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.

[0049] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound and a pharma- ceutical acceptable carrier. The pharmaceutical composition facilitates administration of the composition to a patient or subject. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0050] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, which is involved in carrying or transporting a compound useful to a patient so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound disclosed herein, and not harmful to the patient. Some examples of substances which may function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar, buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations.

[0051] As used herein, "pharmaceutically acceptable carrier" also includes any coating agent, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds disclosed herein and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" can further include pharmaceutically acceptable salts of the compound(s) disclosed herein. Other additional components that can be included in pharmaceutical compositions are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0052] As used herein, "RECIST 1.1" refers to the Response Evaluation Criteria In Solid Tumors (RECIST) guideline version 1.1. See Eisenhauer et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan; 45 (2): 228-47.

[0053] The term "single formulation" as used herein refers to a single carrier or vehicle formulated to deliver effective amounts of both therapeutic agents to a patient. The single vehicle is designed to deliver an effective amount of each agent, along with any pharma- ceutically acceptable carriers or excipients. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

[0054] The term "unit dose" is used herein to mean that both agents are administered simultaneously in one dosage form to a patient to be treated. In some embodiments, the unit dose is a single formulation. The term "unit dose" as used herein may also refer to the administration of both agents separately in two dosage forms simultaneously to a patient to be treated. In certain embodiments, the unit dose comprises one or more vehicles, each of which comprises an effective amount of at least one agent together with pharma- ceutically acceptable carriers and excipients. In some embodiments, the unit dose is one or more tablets, capsules, pills, or patches administered simultaneously to a patient.

[0055] Doses (Compound 1 and Compound 2) are expressed as free base equivalent amounts unless otherwise indicated.

[0056] The combination of agents described herein may exhibit synergistic effects. See, for example, Wagle, MC., et al., Preclinical evaluation of PKC and MET inhibitor combination in primary and metastatic uveal melanoma, AACR Meeting 2021, the entire contents of which are incorporated herein by reference. As used herein, the term "synergistic effect" refers to the action of two agents, e.g., compound 1 and compound 2, in which an effect, e.g., delaying symptomatic progression of cancer or its symptoms, is greater than the simple additive effect of each drug administered alone. Synergistic effects can be calculated using suitable methods, such as, for example, the sigmoid Emax formula (Holford, NHG and Scheiner, LB, Clin. Pharmacokinet. 6:429-453 (1981)), the Loewe additivity formula (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114:313-326 (1926)) and the mean effect formula (Chou, TC and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Each of the above-mentioned formulas can be applied to experimental data to generate corresponding graphs, which can be used to evaluate the combination effect of drugs. The corresponding graphs associated with the above-mentioned formulas are the concentration-effect curve, the isobologram curve and the combination index curve, respectively.

[0057] As used herein, the term "synergy" refers to an effect achieved when the active ingredients, i.e., compound 1 and compound 2, are used together that is greater than the sum of the effects obtained when the compounds are used separately.

[0058] In one embodiment, provided herein is a combination therapy comprising effective amounts of Compound 1 and Compound 2. An "effective amount" of the combination of agents (i.e., Compound 1 and Compound 2) is an amount sufficient to provide an observable improvement over clinically observable baseline signs and symptoms of the disorder being treated with the combination.

[0059] An "oral dosage form" includes a unit dosage form formulated or intended for oral administration.

[0060] Combinations Provided herein is a combination comprising compound 1 or a pharmaceutically acceptable salt thereof and compound 2 or a pharmaceutically acceptable salt thereof. The combination is useful for treating various cancers, including uveal melanoma, for example, uveal melanoma with GNAQ mutation or GNA11 mutation; or metastatic uveal melanoma. The combination may also be useful for treating solid tumors with GNAQ mutation or GNA11 mutation. In another embodiment, the combination is useful for treating many PKC-related diseases and / or c-MET-related diseases. In one embodiment, the combination is useful for treating c-MET-amplified tumors or tumors with high c-MET expression, for example, NSCLC, CRC (colorectal cancer), gastric cancer, HCC (hepatocellular carcinoma). In one embodiment, the present disclosure provides a synergistic combination. In some such embodiments, the disclosure provides a combination comprising (i) compound 1, or a pharma- ceutically acceptable salt thereof, and (ii) compound 2, or a pharma- ceutically acceptable salt thereof, as described herein, for use in treating uveal melanoma or a solid tumor having a GNAQ mutation or a GNA11 mutation in a subject, wherein components (i) and (ii) are synergistic.

[0061] The compound 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (also known as 3-amino-N-[3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinyl]-6-[3-(trifluoromethyl)-2-pyridinyl]-2-pyrazinecarboxamide) has the following structure: [ka] (also known as darovasertib or IDE196), or a pharma- ceutically acceptable salt thereof.

[0062] Compound 1 is a potent and selective inhibitor of protein kinase C. Compound 1, its synthesis, and biological activity against PKC can be found in PCT / IB2015 / 055951 (WO2016020864), which is incorporated by reference in its entirety. The contents of WO2016020864 are incorporated by reference in their entirety herein.

[0063] The compound 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine ("Compound 2") has the following structure: [ka] (known as crizotinib or PF-02341066), or a pharma- ceutically acceptable salt thereof.

[0064] Crizotinib is an inhibitor of anaplastic lymphoma kinase (ALK) and its oncogenic variants (i.e., ALK fusion events and select oncogenic ALK mutations), as well as hepatocyte growth factor receptor (HGFR, c-Met), c-ros oncogene 1 (Ros1) and its oncogenic variants, and Recepteur d'Origine Nantais (RON) receptor tyrosine kinases (RTKs).

[0065] Crizotinib and its pharma- ceutically acceptable salts are described in International Publication Nos. WO2006 / 021884, WO2006 / 021881 and WO2007 / 066185, and U.S. Patent Nos. 7,858,643, 8,217,057 and 8,785,632. The use of crizotinib in the treatment of abnormal cell growth, such as cancer mediated by ALK or c-MET / HGFR, is described in U.S. Patent No. 7,825,137. The use of crizotinib in the treatment of ROS-mediated cancer is described in WO2013 / 017989. The contents of each of the aforementioned patents and applications are incorporated herein by reference in their entirety.

[0066] Thus, in one aspect, provided herein is a method for treating a pulmonary circulation disorder comprising: (i) about 300 mg of Compound 1: [ka] or an equivalent amount of a pharma- ceutically acceptable salt thereof; (ii) about 200 mg of Compound 2: [ka] or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0067] In another aspect, provided herein is (i) about 200 mg to about 600 mg of Compound 1: [ka] or an equivalent amount of a pharma- ceutically acceptable salt thereof; (ii) about 400 mg to about 500 mg of compound 2: [ka] or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0068] In yet another aspect, provided herein is a method for treating a pulmonary circulation disorder comprising: (i) about 200 mg of Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof; (ii) A combination comprising about 200 mg of Compound 2 or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0069] In yet another aspect, provided herein is a method for treating a pulmonary circulation disorder comprising: (i) about 300 mg of Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof; (ii) A combination comprising about 250 mg of Compound 2, or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0070] In one embodiment, the combination provided above comprises about 300 mg of Compound 1 or an equivalent amount of a pharma- ceutically acceptable salt thereof. In another embodiment, the combination comprises about 200 mg of Compound 2 or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0071] In one embodiment, the combination provided above comprises about 300 mg of Compound 1 or an equivalent amount of a pharma- ceutically acceptable salt thereof. In another embodiment, the combination comprises about 250 mg of Compound 2 or an equivalent amount of a pharma- ceutically acceptable salt thereof.

[0072] In another embodiment, the combination comprises Compound 1 as the free base. In yet another embodiment, the combination comprises Compound 2 as the free base.

[0073] In one embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose selected from the group consisting of 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, and 600mg. In another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 200mg. In yet another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 300mg. In yet another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is orally administered as a tablet. In another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is administered twice a day (BID).

[0074] In another embodiment, Compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 200 mg once per day (QD).In yet another embodiment, Compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 300 mg once per day (QD).

[0075] In one embodiment, compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose selected from the group consisting of 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, and 600mg. In another embodiment, compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 200mg. In yet another embodiment, compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 250mg. In yet another embodiment, compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is orally administered as a tablet. In another embodiment, compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is administered twice a day (BID).

[0076] In another embodiment, Compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 200 mg once per day (QD).In yet another embodiment, Compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 250 mg once per day (QD).

[0077] In one embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 200 mg BID, and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 200 mg BID. In another embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 300 mg BID, and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 200 mg BID. In yet another embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 200 mg BID, and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 250 mg BID. In yet another embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 300 mg BID, and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the combination at a dose of 250 mg BID.

[0078] In one embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 200 mg, and compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 200 mg. In another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 300 mg, and compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 200 mg. In yet another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 200 mg, and compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 250 mg. In yet another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 300 mg, and compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the combination at a dose of 250 mg.

[0079] In one embodiment, any of the above combinations is a non-fixed combination.

[0080] Administration of the pharmaceutical combinations provided herein may result in beneficial effects, e.g., synergistic therapeutic effects, e.g., in terms of alleviating symptoms, slowing progression, or inhibition, and may also result in further surprising beneficial effects, e.g., reduced side effects, improved quality of life, or reduced morbidity, compared to monotherapy with only one of the pharmacologic active ingredients used in the combination of the present invention.

[0081] In one embodiment of the foregoing embodiment, the subject is a first line treatment subject. In another embodiment of the foregoing embodiment, the subject is a first line treatment MUM subject.

[0082] Treatment method In one aspect, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject compound 1: [ka] or a pharma- ceutically acceptable salt thereof; Compound 2: [ka] or a pharma- ceutically acceptable salt thereof, Where: Compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily (BID) at a dose of about 300 mg, equivalent to the free base of Compound 1; Compound 2, or a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 200 mg, equivalent to the free base amount of Compound 2.

[0083] In another aspect, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject an amount of Compound 1: [ka] or a pharma- ceutically acceptable salt thereof; Compound 2: [ka] or a pharma- ceutically acceptable salt thereof, Where: Compound 1 or a pharma- ceutically acceptable salt thereof is administered daily at a dose of about 400 mg to about 600 mg, calculated as the amount of the free base of Compound 1; In this method, compound 2 or a pharma- ceutically acceptable salt thereof is administered daily at a dose of about 400 mg to about 500 mg, calculated as the amount equivalent to the free base of compound 2.

[0084] In another aspect, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutical acceptable salt thereof, and and administering to the patient compound 2 or a pharma- ceutically acceptable salt thereof, Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 200 mg; Compound 2, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 200 mg.

[0085] In yet another aspect, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutical acceptable salt thereof, and and administering to the patient compound 2 or a pharma- ceutically acceptable salt thereof, wherein Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 300 mg; Compound 2, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered BID in a dose of about 250 mg.

[0086] In another aspect, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutical acceptable salt thereof, and and administering to the patient compound 2 or a pharma- ceutically acceptable salt thereof, wherein Compound 1 or a pharma- ceutically acceptable salt thereof is administered daily at a dose of about 600 mg, equivalent to the free base of Compound 1; Compound 2 or a pharma- ceutically acceptable salt thereof is administered daily at a dose of about 400 mg, equivalent to the free base of Compound 2.

[0087] In yet another aspect, provided herein is a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutical acceptable salt thereof, and and administering Compound 2 or a pharma- ceutically acceptable salt thereof, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 300 mg, calculated as the free base equivalent of compound 1, and compound 2 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 250 mg, calculated as the free base equivalent of compound 2.

[0088] In one embodiment, the uveal melanoma is metastatic uveal melanoma. In another embodiment, the uveal melanoma is a solid tumor with a GNAQ mutation or a GNA11 mutation. In another embodiment, the uveal melanoma is a metastatic uveal melanoma with a GNAQ mutation or a GNA11 mutation.

[0089] In yet another embodiment, the solid tumor harboring a GNAQ mutation or a GNA11 mutation is a cutaneous melanoma.

[0090] In yet another embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 200 mg, as the free base equivalent of Compound 1. In one embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 300 mg, as the free base equivalent of Compound 1. In another embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered once daily (QD) at a dose of about 200 mg, as the free base equivalent of Compound 1. In yet another embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered once daily (QD) at a dose of about 300 mg, as the free base equivalent of Compound 1.

[0091] In another embodiment, Compound 2 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 200 mg, as the free base equivalent of Compound 2. In one embodiment, Compound 2 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 250 mg, as the free base equivalent of Compound 2. In another embodiment, Compound 2 or a pharma- ceutically acceptable salt thereof is administered once daily (QD) at a dose of about 200 mg, as the free base equivalent of Compound 2. In yet another embodiment, Compound 2 or a pharma- ceutically acceptable salt thereof is administered once daily (QD) at a dose of about 250 mg, as the free base equivalent of Compound 2.

[0092] In another embodiment, administration of Compound 1, or a pharma- ceutically acceptable salt thereof, is uninterrupted during a dosing schedule comprising at least one seven-day dosing cycle.

[0093] In yet another embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, are administered in a single formulation. In yet another embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, are administered in a single formulation further comprising one or more pharma- ceutically acceptable carriers.

[0094] In one embodiment, compound 1, or a pharma- ceutically acceptable salt thereof, and compound 2, or a pharma- ceutically acceptable salt thereof, are administered separately.

[0095] In another embodiment, the treatment comprises administering Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, substantially simultaneously. In yet another embodiment, the treatment comprises administering Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, at different times.

[0096] In yet another embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered to a subject, followed by administration of Compound 2, or a pharma- ceutically acceptable salt thereof. In one embodiment, Compound 2, or a pharma- ceutically acceptable salt thereof, is administered to a subject, followed by administration of Compound 1, or a pharma- ceutically acceptable salt thereof.

[0097] In one embodiment, administration of compound 1, or a pharma- ceutically acceptable salt thereof, and compound 2, or a pharma- ceutically acceptable salt thereof, reduces the size of one or more lesions of uveal melanoma or solid tumors harboring a GNAQ mutation or a GNA11 mutation in the subject.

[0098] In another embodiment, administration of Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, reduces the growth rate of one of multiple lesions of uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in the subject.

[0099] In yet another embodiment, the method comprises administering to a subject in need thereof Compound 1: [ka] The method includes administering

[0100] In yet another embodiment, the method comprises administering to a subject in need thereof Compound 2: [ka] The method includes administering

[0101] In one embodiment, compound 1, or a pharma- ceutically acceptable salt thereof, and compound 2, or a pharma- ceutically acceptable salt thereof, are administered orally.

[0102] In one embodiment, an uninterrupted treatment cycle refers to a subject or patient not missing a dose of Compound 1 and / or Compound 2. For example, when Compound 1 is administered at 300 mg BID in one 7-day administration cycle without interruption, 300 mg of Compound 1 is administered twice per day for 7 consecutive days.

[0103] In another embodiment, a method of treating uveal melanoma or a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a subject in need thereof may further comprise: (i) first administering Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, to a patient in need thereof for a treatment period comprising at least four consecutive seven-day dosing cycles according to the dosing regimen of any of the preceding embodiments, and then (ii) increasing the dose of Compound 1, or a pharma- ceutically acceptable salt thereof, to 300 mg BID or 600 mg total daily, as applicable, and / or (iii) reducing the dose of Compound 2, or a pharma- ceutically acceptable salt thereof, to 200 mg BID or 250 mg total daily, as applicable.

[0104] In yet another embodiment, the method of treating uveal melanoma or solid tumors with GNAQ or GNA11 mutations in a subject in need thereof may further comprise continuing to administer compound 1 or a pharma- ceutically acceptable salt thereof and compound 2 or a pharma- ceutically acceptable salt thereof without interruption during a dosing schedule comprising at least two or more consecutive 7-day dosing cycles, or preferably at least four or more consecutive 7-day dosing cycles. In a particular embodiment, compound 1 or a pharma- ceutically acceptable salt thereof and compound 2 or a pharma- ceutically acceptable salt thereof are continued to be co-administered without interruption during a dosing schedule comprising at least 8 or more, 12 or more, 24 or more, 48 or more, or 96 or more consecutive 7-day dosing cycles. In one embodiment, compound 1 or a pharma- ceutically acceptable salt thereof is continued to be co-administered without interruption during a dosing schedule comprising at least 8 or more, 12 or more, 24 or more, 48 or more, or 96 or more consecutive 7-day dosing cycles. In another embodiment, Compound 2, or a pharma- ceutically acceptable salt thereof, continues to be co-administered without interruption during a dosing schedule comprising at least 8 or more, 12 or more, 24 or more, 48 or more, or 96 or more consecutive 7-day dosing cycles.

[0105] Exemplary lengths of time associated with a course of treatment are about 5 years, about 4 years, about 3 years, about 2 years, about 1 year, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, or about 1 month.

[0106] Exemplary lengths of time associated with a course of treatment can be about 5 years, or any number of days, weeks, months, or years, e.g., a treatment cycle can include 5 months plus additional weeks and / or days, or a year plus additional months, weeks, and / or days, etc.

[0107] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, are administered sequentially (ie, continuous treatment until completion).

[0108] The GNAQ or GNA11 tumor to be treated may contain one or more of a number of mutations, including substitution mutations, insertion mutations, and / or deletions in the GNAQ or GNA11 mutation. In some embodiments, the GNAQ or GNA11 mutation is a gain-of-function mutation. In some embodiments, the GNAQ or GNA11 mutation activates the PKC signaling pathway. In various embodiments, the GNAQ or GNA11 mutation may be a substitution of glutamine (Q209) at codon 209 and / or a substitution of arginine (R183) at codon 183. The GNAQ or GNA11 mutation may be a substitution other than glutamine (Q209) at codon 209, a substitution other than arginine (R183) at codon 183, or both. In some embodiments, the GNAQ mutation is one of Q209P, Q209L, Q209H, Q209K, or Q209Y, or the GNA11 mutation is one of Q209P, Q209L, Q209K, or Q209H. In further embodiments, the GNAQ mutation can be R183Q, or the GNA11 mutation can be R183C or R183H. In still further examples, the GNAQ or GNA11 mutation is at one or more of R256, L279, R166, A168, R210, R213, R166, A231, A342, D333, G171, R147, R73, T47, E191, E221, R149, T175, T379, T85, A86, E163, D195, E319, E191, E280, E49, P293, R300, R338, R60, D155, D205, D321, I226, R37, or V240. In further examples, the GNAQ tumor or GNA11 tumor may include one or more of the following mutations in GNAQ: Q209P, Q209L, Q209H, Q209K, Q209Y, or R183Q; alternatively, the GNAQ tumor or GNA11 tumor may include one or more of the following mutations in GNA11: Q209P, Q209L, Q209H, or Q209K. Additional examples of mutations in GNAQ or GNA11 are described in WO2020 / 146355, which is incorporated by reference in its entirety.

[0109] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject Compound 1: [ka] or a pharma- ceutically acceptable salt thereof; Compound 2: [ka] and a pharma- ceutically acceptable salt thereof, Where: Compound 1 or a pharma- ceutically acceptable salt thereof is administered daily at a dose of about 400 mg to about 600 mg, calculated as the amount of the free base of Compound 1; In this method, compound 2 or a pharma- ceutically acceptable salt thereof is administered daily at a dose of about 400 mg to about 500 mg, calculated as the amount equivalent to the free base of compound 2.

[0110] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof; Where: Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 200 mg; Compound 2, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered BID at a dose of about 200 mg.

[0111] In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma-ceutically acceptable salt thereof; Where: Compound 1, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 300 mg; Compound 2, or an equivalent amount of a pharma- ceutically acceptable salt thereof, is administered BID in a dose of about 250 mg.

[0112] In one embodiment, compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 200 mg as the free base equivalent of compound 1, and compound 2 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 200 mg as the free base equivalent of compound 2. In one embodiment, compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 300 mg as the free base equivalent of compound 1, and compound 2 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 200 mg as the free base equivalent of compound 2. In one embodiment, compound 1 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 300 mg as the free base equivalent of compound 1, and compound 2 or a pharma- ceutically acceptable salt thereof is administered BID at a dose of about 250 mg as the free base equivalent of compound 2.

[0113] In another embodiment, the cancer to be treated is selected from the group consisting of lung cancer, colon and rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, glioma, glioblastoma, neuroblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, retinoblastoma, cervical cancer, melanoma and / or skin cancer, bladder cancer, uterine cancer, testicular cancer, esophageal cancer, and solid tumors. In some embodiments, the cancer is lung cancer, colon cancer, breast cancer, neuroblastoma, leukemia, and lymphoma. In other embodiments, the cancer is lung cancer, colon cancer, breast cancer, neuroblastoma, leukemia, or lymphoma. In further embodiments, the cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer. In further embodiments, the cancer is hepatocellular carcinoma (HCC). In a further embodiment, the cancer is gastric cancer. In a further embodiment, the cancer is colon cancer. In another embodiment, the cancer is parotid gland carcinoma.

[0114] In another embodiment, the cancer to be treated is a solid tumor with a GNA11 mutation or a GNAQ mutation. In yet another embodiment, the cancer is uveal melanoma. In yet another embodiment, the cancer is uveal melanoma with a GNA11 mutation or a GNAQ mutation. In yet another embodiment, the cancer is metastatic uveal melanoma. In yet another embodiment, the cancer is metastatic uveal melanoma with a GNA11 mutation or a GNAQ mutation. In one embodiment, the cancer is cutaneous melanoma. In one embodiment, the cancer is cutaneous melanoma with a GNA11 mutation or a GNAQ mutation. In one embodiment, the cancer is parotid carcinoma with a GNA11 mutation or a GNAQ mutation.

[0115] In another embodiment, the cancer to be treated is a tumor with c-MET amplification or high expression of c-MET. In another embodiment, the cancer to be treated is a tumor with high expression of c-MET. c-MET amplification can be determined using various techniques, for example, next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). High expression of c-MET can be determined using techniques such as immunohistochemistry (IHC). In one embodiment, the c-MET amplified cancer is NSCLC or HCC. In another embodiment, the cancer with high expression of c-MET is NSCLC, HCC, colon cancer, or gastric cancer.

[0116] In one embodiment, the cancer is a hematological cancer, such as leukemia or lymphoma. In certain embodiments, the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In certain embodiments, the leukemia is myeloid, lymphocytic, myelocytic, lymphoblastic, or megakaryocytic leukemia.

[0117] In one embodiment, provided herein are Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0118] In one embodiment, provided herein is Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, for use in treating uveal melanoma in a patient in need thereof.

[0119] In one embodiment, provided herein is Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, for use in treating metastatic uveal melanoma in a patient in need thereof.

[0120] In one embodiment, provided herein is Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, for use in treating a solid tumor harboring a GNAQ mutation or a GNA11 mutation in a patient in need thereof.

[0121] In another embodiment, provided herein are Compound 1 and Compound 2 for use in treating cutaneous melanoma in a patient in need thereof.

[0122] In one embodiment, provided herein are compound 1 or a pharma- ceutically acceptable salt thereof and compound 2 or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for treating or otherwise alleviating a symptom of a PKC-related disease and / or a c-MET-related disease described herein, such as uveal melanoma or a tumor with a mutation in GNAQ or GNA11. In one embodiment, the uveal melanoma is metastatic uveal melanoma. In another embodiment, the uveal melanoma is a solid tumor with a GNAQ mutation or GNA11 mutation. In another embodiment, the uveal melanoma is a metastatic uveal melanoma with a GNAQ mutation or GNA11 mutation. In one embodiment, the disease is a tumor with a mutation in GNAQ or GNA11.

[0123] Exemplary lengths of time associated with a course of treatment methods disclosed herein include about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 4 months, about 7 months, about 8 months, about 9 months, about 10 months, about 12 months, about 14 months, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, about 60 weeks, about 61 weeks, about 62 weeks, about 63 weeks, about 64 weeks, about 65 weeks, about 66 weeks, about 67 weeks, about 6 about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 30 months, about 3 years, about 4 years, and about 5 years, etc.; or any number of days, weeks, months, or years, for example, a treatment cycle can include 5 months plus additional weeks and / or days, or 1 year plus additional months, weeks, and / or days, etc.

[0124] Exemplary lengths of time associated with a course of treatment can be about 5 years, about 4 years, about 3 years, about 2 years, about 1 year, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, or about 1 month.

[0125] In one embodiment of the method, the method involves administering a therapeutically effective amount of a combination or composition comprising a compound provided herein, or a pharma- ceutically acceptable salt thereof, to a subject (including, but not limited to, a human or animal) in need of treatment (including a subject identified as in need).

[0126] In another embodiment of the method, the treatment comprises co-administering an amount of Compound 1 or a pharma- ceutically acceptable salt thereof with an amount of Compound 2 or a pharma- ceutically acceptable salt thereof. In one embodiment, the amount of Compound 1 or a pharma- ceutically acceptable salt thereof and the amount of Compound 2 or a pharma- ceutically acceptable salt thereof are in a single formulation or unit dosage form. In yet another embodiment, the amount of Compound 1 or a pharma- ceutically acceptable salt thereof and the amount of Compound 2 or a pharma- ceutically acceptable salt thereof are in separate formulations or unit dosage forms.

[0127] In the aforementioned methods, the treatment may include administering the amount of Compound 1 or a pharma- ceutically acceptable salt thereof and the amount of Compound 2 or a pharma- ceutically acceptable salt thereof at about the same time, or administering the amount of Compound 1 or a pharma- ceutically acceptable salt thereof and the amount of Compound 2 or a pharma- ceutically acceptable salt thereof at different times. In some embodiments of the aforementioned methods, the amount of Compound 1 or a pharma- ceutically acceptable salt thereof and / or the amount of Compound 2 or a pharma- ceutically acceptable salt thereof are administered in dosages that are not effective when one or both of Compound 1 or a pharma- ceutically acceptable salt thereof and Compound 2 or a pharma- ceutically acceptable salt thereof are administered alone, but are effective when combined.

[0128] In one embodiment of the aforementioned method, the treatment reduces the size of one of multiple lesions of uveal melanoma or solid tumor harboring a GNAQ mutation or a GNA11 mutation in the subject.

[0129] In one embodiment of the foregoing method, the treatment reduces the size of one of multiple lesions of metastatic uveal melanoma in the subject.

[0130] In one embodiment of the aforementioned method, the treatment reduces the size of one of multiple lesions of a solid tumor harboring a GNAQ mutation or a GNA11 mutation in the subject.

[0131] In one embodiment of the aforementioned method, the treatment reduces the growth rate of one of multiple lesions of uveal melanoma or solid tumors harboring a GNAQ mutation or a GNA11 mutation in the subject.

[0132] In one embodiment of the aforementioned method, the treatment reduces the growth rate of one of multiple lesions of metastatic uveal melanoma in the subject.

[0133] In one embodiment of the aforementioned method, the treatment reduces the growth rate of one of multiple lesions of a solid tumor harboring a GNAQ mutation or a GNA11 mutation in the subject.

[0134] In one embodiment of the aforementioned method, the subject is a first line treatment subject. In another embodiment, the subject is a first line treatment MUM subject.

[0135] Pharmaceutical Compositions In one aspect, provided herein is a pharmaceutical composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof, Compound 2 or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier. In one embodiment, the pharmaceutical composition is for use in treating uveal melanoma in a patient. In yet another embodiment, the uveal melanoma is a solid tumor having a GNAQ mutation or a GNA11 mutation. In yet another embodiment, the uveal melanoma is a metastatic uveal melanoma. In yet another embodiment, the metastatic uveal melanoma is a solid tumor having a GNAQ mutation or a GNA11 mutation. In one embodiment, the pharmaceutical composition is for use in treating a solid tumor having a GNAQ mutation or a GNA11 mutation in a patient. In one embodiment, the pharmaceutical composition is for use in treating a solid tumor having a GNAQ mutation or a GNA11 mutation in a patient, wherein the solid tumor is a cutaneous melanoma.

[0136] In one embodiment, the pharmaceutical composition reduces the size of one or more lesions of uveal melanoma or solid tumors carrying GNAQ or GNA11 mutations in the subject. In another embodiment, the pharmaceutical composition reduces the growth rate of one of multiple lesions of uveal melanoma or solid tumors carrying GNAQ or GNA11 mutations in the subject. In yet another embodiment, the uveal melanoma is metastatic uveal melanoma.

[0137] In one embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the pharmaceutical composition in a dose selected from the group consisting of about 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and 600 mg. In another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the pharmaceutical composition in a dose of about 200 mg. In yet another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the pharmaceutical composition in a dose of about 300 mg. In yet another embodiment, compound 1 or a corresponding amount of its pharma- ceutically acceptable salt is present in the pharmaceutical composition in a dose of 300 mg. In yet another embodiment, compound 1 or a corresponding amount of its pharma- ceutical acceptable salt is orally administered as a tablet. In another embodiment, compound 1 or a corresponding amount of its pharma- ceutical acceptable salt is administered twice a day (BID).

[0138] In one embodiment, compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the pharmaceutical composition in a dose selected from the group consisting of about 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and 600 mg. In another embodiment, compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the pharmaceutical composition in a dose of about 200 mg. In another embodiment, compound 2 or a corresponding amount of its pharma- ceutically acceptable salt is present in the pharmaceutical composition in a dose of 200 mg. In yet another embodiment, compound 2 or a corresponding amount of its pharma- ceutical acceptable salt is present in the pharmaceutical composition in a dose of about 250 mg. In yet another embodiment, compound 2 or a corresponding amount of its pharma- ceutical acceptable salt is orally administered as a tablet. In another embodiment, compound 2 or a corresponding amount of its pharma- ceutical acceptable salt is administered twice a day (BID).

[0139] In one embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition at a dose of about 200 mg BID, and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is administered at a dose of about 200 mg BID. In yet another embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition at a dose of about 200 mg BID, and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is administered at a dose of about 250 mg BID. In another embodiment, compound 1 or a corresponding amount of a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition at a dose of about 300 mg BID, and compound 2 or a corresponding amount of a pharma- ceutically acceptable salt thereof is administered at a dose of about 200 mg BID. In yet another embodiment, compound 1 or a corresponding amount of a pharma- ceutical acceptable salt thereof is present in the pharmaceutical composition at a dose of about 300 mg BID, and compound 2 or a corresponding amount of a pharma- ceutical acceptable salt thereof is administered at a dose of about 250 mg BID.

[0140] In one embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, is present in the pharmaceutical composition at a dose of 300 mg BID, as the free base equivalent of Compound 1, and Compound 2, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 200 mg BID, as the free base equivalent of Compound 2.

[0141] In one embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, is present in the pharmaceutical composition at a dose of 200 mg BID, as the free base equivalent of Compound 1, and Compound 2, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 200 mg BID, as the free base equivalent of Compound 2.

[0142] In one embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, is present in the pharmaceutical composition at a dose of 300 mg BID, as the free base equivalent of Compound 1, and Compound 2, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 250 mg BID, as the free base equivalent of Compound 2.

[0143] In one embodiment, compound 1 or a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition at a dose of about 200 mg as the free base equivalent of compound 1, and compound 2 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 200 mg as the free base equivalent of compound 2. In yet another embodiment, compound 1 or a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition at a dose of about 200 mg as the free base equivalent of compound 1, and compound 2 or a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition at a dose of about 250 mg as the free base equivalent of compound 2. In another embodiment, compound 1 or a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition at a dose of about 300 mg as the free base equivalent of compound 2, and compound 2 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 200 mg as the free base equivalent of compound 2. In yet another embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, is present in the pharmaceutical composition in a dose of about 300 mg, as the free base equivalent of Compound 1, and Compound 2, or a pharma- ceutically acceptable salt thereof, is present in the pharmaceutical composition in a dose of about 250 mg, as the free base equivalent of Compound 2.

[0144] In another aspect, provided herein is a pharmaceutical composition or combination comprising a compound disclosed herein in association with a pharma- ceutically acceptable carrier.

[0145] In another aspect, provided herein is a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition of Compound 1, or a pharma- ceutically acceptable salt thereof, and Compound 2, or a pharma- ceutically acceptable salt thereof, further comprises one or more pharma- ceutically acceptable carriers.

[0146] In one embodiment of the pharmaceutical composition, Compound 1 or a pharma- ceutically acceptable salt thereof and Compound 2 or a pharma- ceutically acceptable salt thereof are in the same formulation. In another embodiment of the combination, Compound 1 and Compound 2 are in separate formulations. In a further embodiment of this embodiment, the formulations are for simultaneous or sequential administration.

[0147] Administration of the pharmaceutical composition includes administering the combination in a single formulation or unit dosage form, administering the individual agents of the combination simultaneously but separately, or administering the individual agents of the combination sequentially by any suitable route. The dosage of the individual agents of the combination may require one of the agents to be administered more frequently compared to the other agent(s) of the combination. Thus, to allow for proper administration, the packaged pharmaceutical product may include one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the combination of agents but not the other agent(s) of the combination.

[0148] In one embodiment of the foregoing embodiment, the subject is a first line treatment subject. In another embodiment of the foregoing embodiment, the subject is a first line treatment MUM subject.

[0149] Administration / Dosage / Formulation Actual dosage levels of the active ingredient in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration without causing toxicity to the patient.

[0150] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and past medical history of the patient being treated, and similar factors well known in the medical arts.

[0151] A medical practitioner, e.g., a physician or veterinarian, having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can begin administering a pharmaceutical composition dosed with a disclosed compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0152] In a specific embodiment, it is particularly advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage.As used herein, dosage unit form refers to a physically discrete unit suitable as a unitary dosage for a patient to be treated, each unit containing a predetermined amount of the disclosed compound calculated to produce a desired therapeutic effect together with a necessary pharmaceutical vehicle.The dosage unit form is determined by and directly depends on (a) the unique characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the technical field of compounding / formulating such disclosed compound for the treatment of pain, depressive disorder, or drug dependency in a patient.

[0153] In one embodiment, the compounds provided herein are formulated using one or more pharma- ceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a disclosed compound and a pharma- ceutically acceptable carrier.

[0154] The optimal ratios, individual and combined dosages, and concentrations of drug compounds that provide efficacy without toxicity are based on the kinetics of the availability of the active ingredients to the target site and are determined using methods known to those skilled in the art.

[0155] The route of administration of any of the compositions discussed herein includes oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical. The compounds may be formulated for administration by any suitable route, for example, oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., vaginal and perivaginal), (trans)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

[0156] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelatin capsules, troches, dispersions, suspensions, liquids, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, patches, lotions, disks, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions are not limited to the specific formulations and compositions described herein.

[0157] For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gelatin capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binding agents such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques for aesthetics or delayed release of the active ingredient. Oral preparations may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0158] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, e.g., intravenous, intramuscular or subcutaneous injection or infusion, or for administration as a bolus or continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles may be used, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents.

[0159] kit In one aspect, the disclosure provides a kit for treating uveal melanoma or solid tumors having a GNAQ mutation or a GNA11 mutation, comprising a unit dose of about 400 mg to about 600 mg of Compound 1 or an equivalent dose of a pharma- ceutically acceptable salt thereof, and a unit dose of about 400 mg to about 500 mg of Compound 2 or an equivalent dose of a pharma- ceutically acceptable salt thereof. In another embodiment, the disclosure provides a kit for treating uveal melanoma or solid tumors having a GNAQ mutation or a GNA11 mutation, comprising a unit dose of about 300 mg of Compound 1 or an equivalent dose of a pharma- ceutically acceptable salt thereof, and a unit dose of about 200 mg of Compound 2 or an equivalent dose of a pharma- ceutically acceptable salt thereof. In another embodiment, the present disclosure provides a kit for treating uveal melanoma or solid tumors with GNAQ mutation or GNA11 mutation, comprising compound 1 in an amount of about 400 mg per day to about 600 mg per day or a corresponding amount of a pharma- ceutically acceptable salt thereof, and compound 2 in an amount of about 400 mg per day to about 500 mg per day or a corresponding amount of a pharma- ceutically acceptable salt thereof. In some embodiments, the kit further comprises packaging and instructions. In yet another embodiment, the uveal melanoma is metastatic uveal melanoma. In yet another embodiment, the metastatic uveal melanoma is a solid tumor with GNAQ mutation or GNA11 mutation. In one embodiment, the kit is for use in treating a solid tumor with GNAQ mutation or GNA11 mutation in a patient. In one embodiment, the kit is for use in treating a solid tumor with GNAQ mutation or GNA11 mutation in a patient, wherein the solid tumor is a cutaneous melanoma.

[0160] In certain embodiments, the kit comprises a pharmaceutical product comprising a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent, and a pharmaceutical composition comprising Compound 2, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

[0161] In some embodiments, the kit comprises a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof; Compound 2, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier or diluent.

[0162] In additional embodiments, pharmaceutical kits are provided. The kits include a sealed container approved for storage of pharmaceutical compositions, which contains one of the pharmaceutical compositions described above. In some embodiments, the sealed container minimizes contact between air and the components, such as an airless bottle. In other embodiments, the sealed container is a sealed tube. The kits shall include instructions for use of the composition and information about the composition.

[0163] In a specific embodiment, the compounds of the combination can be administered on the same schedule, whether they are administered in a single formulation or unit dosage form that contains all the compounds of the combination, or in separate formulations or unit dosage forms of the compounds of the combination.However, some of the compounds used in the combination may be administered more frequently than once a day, or may be administered at a different frequency than other compounds of the combination.Therefore, in one embodiment, the kit contains a formulation or unit dosage form that contains all the compounds of the combination of compounds, and an additional formulation or unit dosage form that contains one of the compounds of the combination of compounds but does not contain an additional active compound, in a container, and contains instructions for administering the dosage form on a certain schedule.

[0164] Kits provided herein include prescribing information, e.g., to a patient or health care provider, or as a label on a packaged pharmaceutical formulation. Prescribing information can include, e.g., efficacy, dosage and administration, contraindications, and side effect information for the pharmaceutical formulation.

[0165] In all of the foregoing, the combination compounds of the present invention may be administered alone, as mixtures, or together with additional active agents.

[0166] The kits provided herein can be designed for conditions necessary to properly maintain the components contained therein (e.g., refrigeration or freezing). The kits can contain labels or inserts containing the identity of the components contained therein and instructions for use (e.g., administration parameters, clinical pharmacology of the active ingredient(s), e.g., mechanism(s) of action, pharmacokinetics and pharmacodynamics, side effects, contraindications, etc.).

[0167] Each component of the kit can be enclosed within an individual container, and all of the various containers can be contained within a single package. The label or package insert can include manufacturer information such as lot number and expiration date. The label or package insert can, for example, be integral to the physical structure that contains the component, be contained separately within the physical structure, or be affixed to the component of the kit (e.g., an ampoule, syringe, or vial).

[0168] Those skilled in the art will recognize or be able to ascertain, without more than routine experimentation, many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and the appended claims. For example, it should be understood that it is within the scope of this application to vary reaction conditions, including but not limited to reaction times, reaction sizes / volumes, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, such as nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized substitutes, without more than routine experimentation.

[0169] When values ​​and ranges are provided herein, it is to be understood that all values ​​and ranges encompassed by those values ​​and ranges are encompassed within the scope of the disclosure. Moreover, all values ​​that fall within those ranges, as well as the upper or lower limits of a range of values, are also contemplated by the application.

[0170] The following examples further illustrate aspects of the present disclosure, but are not intended to limit the teachings of the disclosure in any way. EXAMPLES

[0171] The compounds and methods disclosed herein are further illustrated by the following examples which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology which are within the skill of the art.

[0172] Processes for preparing the compounds disclosed herein can be found at least in WO2016 / 020864 and WO2006 / 021884, the contents of which are incorporated by reference in their entireties.

[0173] Example 1: Clinical Data In a human clinical trial evaluating compound 1 (darovasertib) and compound 2 (crizotinib) in metastatic uveal melanoma (MUM), patients with metastatic uveal melanoma (MUM) were treated. The results are shown in Tables 1-4. [Table 1]

[0174] Clinical Data Observations (Table 1) 1. All patients demonstrated tumor shrinkage of target lesions (n=16 evaluable patients with at least one scan). 2. The patient population was heavily pretreated (e.g., prior treatment including 2 or more lines of therapy) metastatic uveal melanoma (MUM) patients with 2 or more scans (n=13) * . Four patients had a confirmed partial response (PR). Three of these four patients had previously received immunotherapy. b. Five patients showed greater than 30% tumor shrinkage. [Table 2] [Table 3] [Table 4]

[0175] Clinical Data Observations (Table 4) Tumor shrinkage was observed in 89% of all evaluable patients with MUM treated with one line of therapy (n=31 / 35). The overall response rate (ORR) observed in all evaluable patients with MUM treated with one line of therapy was 31% (n=11 / 35, confirmed partial response (cPR)). Tumor shrinkage of more than 30% was observed in 43% of all evaluable patients with MUM treated with one line of therapy (n=15 / 35). Disease control rates (including DCR, cPR as best overall response, uPR (unconfirmed partial response), or SD (stable disease)) were observed in 83% of all evaluable patients with MUM treated with one line of therapy (n=29 / 35). The confirmed partial response (cPR) observed in all evaluable patients with MUM treated with one line of therapy was 31% (n=11 / 35). The overall response rate (ORR) observed in all evaluable patients with first-line MUM was 50% (n=4 / 8 cPR). Tumor shrinkage was observed in 75% of evaluable first-line MUM patients (n=6 / 8). Tumor shrinkage of greater than 30% was observed in 63% of evaluable first-line MUM patients (n=5 / 8). Disease control rates (including DCR, cPR, uPR, or SD as best overall response) were observed in 75% of evaluable first-line MUM patients (n=6 / 8). Confirmed partial responses (cPR) were observed in 50% of evaluable first-line MUM patients (n=6 / 8).

[0176] Although median progression-free survival (mPFS) has not yet been reached, mPFS is greater than 5 months for first-line MUM patients and approximately 5 months for all-line MUM patients.

[0177] Median duration of response (DOR) has not yet been reached in first-line MUM patients or all-line MUM patients. In all-line MUM patients, 7 of 11 patients with cPR have maintained a response. In first-line MUM patients, 4 of 4 patients with cPR have maintained a response. Data in Table 4 are current as of June 26, 2022.

[0178] Example 2 Patient Eligibility Criteria Inclusion Criteria: Patients must be aged 18 or over Have been diagnosed with any of the following: MUM: uveal melanoma with histologically or cytologically confirmed metastatic disease; or Non-MUM: Advanced cutaneous melanoma, colorectal cancer, or other solid tumors that have progressed after previous standard treatments or have no satisfactory alternative treatments and have evidence of GNAQ / 11 hotspot mutations Measurable disease - Eastern Cooperative Oncology Group score ≦1 and life expectancy >3 months Adequate organ function at the time of screening For men not using contraceptive therapy and for women of childbearing potential, adequate contraception is in place. Prior chemotherapy, other applicable treatments, or major surgery must have been completed at least 4 weeks prior to starting crizotinib Patients with a history of peripheral neuropathy may be included if it was grade ≤1 prior to initiation of crizotinib Exclusion criteria: - Confirmed symptomatic brain metastases -Previous treatment with PKC inhibitors - Patients with confirmed MSI-H / dMMR tumors and no history of immune checkpoint inhibitor treatment Adverse events from previous anti-cancer therapy have not disappeared Have been diagnosed with AIDS-related illness, Hepatitis B virus, or Hepatitis C virus Active infection requiring ongoing treatment - Have recently undergone surgery or radiation therapy - History of gastrectomy or upper intestinal resection or any other gastrointestinal disorder or defect Pregnant or breastfeeding women Cardiac dysfunction Treatment with prohibited substances that cannot be discontinued prior to study entry Allergies to mammalian meat products and gelatin in patients receiving the IDE196 powder-in-capsule (PIC) formulation or crizotinib Prior therapy directly targeting ALK, MET, or ROS1 Spinal cord compression History of pneumonia or interstitial lung disease History of syncope [Table 5]

[0179] Table 5 shows a crossover study comparison with other treatments relevant to MUM patients. Compound 1 is administered at 300 mg BID and Compound 2 is administered at 200 mg BID.

[0180] This specification describes certain embodiments of the invention, including the best mode known to the inventors for carrying out the invention. It is anticipated that, upon reading the foregoing description, variations of the disclosed embodiments may become apparent to those skilled in the art, who may adopt such variations as appropriate. It is therefore intended that the invention be practiced otherwise than as specifically described herein, and that the invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by this application unless otherwise indicated herein or clearly contradicted by context.

[0181] All patent applications, patents, and printed publications cited herein are incorporated by reference in their entirety, except for any definitions, disclaimers or disclaimers of subject matter, and except to the extent that the incorporated material contradicts the explicit disclosure of this specification, in which case the language of the present disclosure will control.

Claims

1. A compound 1: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof; Compound 2: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, Compound 1, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered daily at a dose of about 400 mg to about 600 mg; A combination wherein Compound 2, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered daily at a dose of about 400 mg to about 500 mg.

2. The method, (i) at least one first treatment cycle of 7-day administration cycles, wherein Compound 1, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered alone at a dose of about 300 mg BID daily for said first treatment cycle, followed by (ii) at least one second treatment cycle of 7-day dosing cycles, wherein Compound 2, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID, and Compound 1, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg BID, every day during said second treatment cycle.

3. The method according to a dosing schedule comprising at least one seven-day dosing cycle, Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, is administered BID at a dose of about 300 mg daily for said at least one 7-day dosing cycle; 2. The combination of claim 1, wherein Compound 2 or an equivalent amount of a pharmaceutically acceptable salt thereof is administered BID at a dose of about 200 mg daily for said at least one 7-day administration cycle.

4. 3. The combination of claim 2, wherein the second treatment cycle is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 24, 48, or 96 consecutive 7-day administration cycles.

5. 3. The combination of claim 2, wherein Compound 1 or a pharmaceutically acceptable salt thereof and Compound 2 or a pharmaceutically acceptable salt thereof are co-administered without interruption for at least one 7-day administration cycle.

6. The combination of claim 1, wherein the metastatic uveal melanoma is a solid tumor having at least one GNAQ or GNA11 mutation.

7. 2. The combination of claim 1, wherein Compound 1 or an equivalent amount of a pharmaceutically acceptable salt thereof is administered twice daily (BID) at a dose of 300 mg.

8. 2. The combination of claim 1, wherein the treatment comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, and Compound 2, or a pharmaceutically acceptable salt thereof, substantially simultaneously.

9. 2. The combination of claim 1, wherein administering compound 1, or a pharmaceutically acceptable salt thereof, and compound 2, or a pharmaceutically acceptable salt thereof, reduces the size of one or more lesions of the metastatic uveal melanoma in the subject.

10. 2. The combination of claim 1, wherein administering compound 1, or a pharmaceutically acceptable salt thereof, and compound 2, or a pharmaceutically acceptable salt thereof, reduces the growth rate of one of multiple lesions of the metastatic uveal melanoma in the subject.

11. The method comprises administering to a subject in need thereof: 【Transformation 3】 and 【Chemistry 4】 The combination of claim 1, comprising administering

12. The combination of claim 1, wherein Compound 1 or a pharmaceutically acceptable salt thereof and Compound 2 or a pharmaceutically acceptable salt thereof are administered orally.

13. Compound 1, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 200 mg; The combination according to any one of claims 1, 6 and 8 to 12, wherein compound 2 or an equivalent amount of a pharmaceutically acceptable salt thereof is administered BID at a dose of about 200 mg.

14. Compound 1, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 300 mg; The combination according to any one of claims 1, 6 and 8 to 12, wherein compound 2 or an equivalent amount of a pharmaceutically acceptable salt thereof is administered BID at a dose of about 250 mg.

15. Compound 1, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 300 mg; The combination according to any one of claims 1 to 12, wherein compound 2 or an equivalent amount of a pharmaceutically acceptable salt thereof is administered BID at a dose of about 200 mg.

16. A compound of formula I: 【Chemistry 1】 and, Compound 2: 【Chemistry 2】 A combination of Compound 1 is administered orally at a dose of approximately 300 mg twice daily (BID); Compound 2 is administered orally at a dose of approximately 200 mg BID, combination.

17. The combination described in claim 1 or 16, wherein the subject is a human.

18. The combination of claim 1 or 16, wherein compound 1 and compound 2 are present in separate formulations or unit dosage forms.

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