Treatment methods for uveal melanoma that has metastasized only to the liver.

Abstract

Provided herein is a method for treating metastatic uveal melanoma (MUM) in patients with liver tumors but essentially no extrahepatic tumors using PKC inhibitors and c-MET inhibitors.

Description

Background Art

[0001] Cross-reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 497,590, filed Apr. 21, 2023, which is hereby incorporated by reference in its entirety for all purposes.

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

[0003] The c-MET receptor has been shown to be expressed in numerous human cancers. c-MET and its ligand, HGF, have also been shown to be co-expressed at high levels in various human cancers (particularly sarcomas). However, because receptors and ligands are typically expressed in different cell types, c-MET signaling is most commonly regulated by tumor-stromal (tumor-host) interactions. Furthermore, amplification, mutation, and rearrangement of the c-MET gene have been observed in some human cancers. Families with germline mutations that activate c-MET kinase are more prone to developing not only multiple kidney tumors but also tumors of other tissues. Numerous studies have shown a correlation between c-MET and / or HGF / SF expression and disease progression in various types of cancer (including lung, colon, breast, prostate, liver, pancreatic, brain, kidney, ovarian, stomach, skin, and bone cancers). Furthermore, overexpression of c-MET or HGF has been shown to correlate with poor prognosis and disease outcomes in numerous major human cancers, including lung cancer, liver cancer, gastric cancer, and breast cancer. c-MET is also directly associated with cancers for which there are no effective treatment regimens, such as pancreatic cancer, glioma, and hepatocellular carcinoma. PCT application PCT / IB2005 / 002837 (published as WO2006 / 021884) discloses a number of potent and selective c-MET inhibitors.

[0004] Uveal melanoma has an associated risk of metastasizing to the liver within 10 years of diagnosis of the primary tumor in approximately 40% of cases. Liver metastases occur in 95% of patients with metastatic uveal melanoma and are fatal in almost all cases. Therefore, understanding the pathology of metastatic uveal melanoma to the liver (MUM) is crucial for developing rational treatment protocols. [Overview of the Initiative]

[0005] This specification provides a method for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but essentially no extrahepatic tumors, the method comprising administering to the patient a therapeutically effective dose of a PKC inhibitor and administering to the patient a therapeutically effective dose of a cMet inhibitor.

[0006] Furthermore, this specification also provides a method for treating metastatic uveal melanoma (MUM) in patients, and this method is a) Select patients who have liver tumors but are essentially free of extrahepatic tumors, b) The patient is administered a therapeutically effective dose of a PKC inhibitor and a therapeutically effective dose of a cMet inhibitor.

[0007] Finally, this specification provides a method for treating metastatic uveal melanoma (MUM) in a patient, and said method a) Selecting patients who have liver tumors but are essentially free of extrahepatic tumors, the selection of such patients being determined by evaluating a screening test, b) The patient is administered a therapeutically effective dose of a PKC inhibitor and a therapeutically effective dose of a cMet inhibitor.

[0008] In some embodiments, the PKC inhibitor is compound 1 (darobaseltib). In some embodiments, the cMET inhibitor is compound 2 (crizotinib). [Modes for carrying out the invention]

[0009] This specification provides a method for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but essentially no extrahepatic tumors, the method comprising administering to the patient a therapeutically effective dose of a PKC inhibitor and administering to the patient a therapeutically effective dose of a cMet inhibitor.

[0010] definition The definitions of various terms used herein are listed below. When used throughout this specification and the claims, these definitions apply to the terms individually or as part of a larger group, unless otherwise limited in specific examples.

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. The terminology used herein, as well as the experimental procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are generally well-known and commonly used in the art.

[0012] As used herein, the articles “a” and “an” refer to one or more than one (i.e., at least one) grammatical object. For example, “an element” means one or more elements. Furthermore, the use of the term “including,” as well as other forms such as “include,” “includes,” and “included,” is not limited to these.

[0013] Where used herein, the term “about” will be understood by those skilled in the art and will vary to some extent in the context in which it is used. Where used herein, when referring to measurable values, such as quantity, duration, etc., the term “about” is intended to include variations of ±20% or ±10% (e.g., ±5%, ±1%, and ±0.1%) from the specified value, and in fact, such variations are appropriate for carrying out the disclosed method. For example, a dose of about 300 mg may be understood to mean that the dose may vary between 270 mg and 330 mg.

[0014] As used herein and in the claims, “comprising” may include embodiments that “consist of” and “consisting essentially of.” The terms and variations thereof “comprise(s),” “include(s),” “having,” “has,” “may,” and “contain(s)” are intended as open-ended transitional phrases, terms, or statements that require the presence of a specified component / step and permit the presence of other components / steps. However, such statements may also be interpreted as describing compositions or processes that “consist of” and “consisting essentially of” the listed compounds, thereby acknowledging the presence of only the specified compounds with any pharmaceutically acceptable carrier, and excluding other compounds.

[0015] Note that ratios, concentrations, amounts, and other numerical data may be expressed in range form as described herein. Such range forms are used for convenience and conciseness and should therefore be interpreted flexibly to include not only the numerical value explicitly stated as the limit of the range, but also all individual numerical values ​​or subranges contained within that range, as if each numerical value and subrange were explicitly stated. For example, a dose range of "approximately 200 mg to approximately 600 mg" should be interpreted to include not only the explicitly stated concentration of approximately 200 mg to approximately 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. To give a further example, a tumor size reduction of "30% to 50%" should be interpreted to include not only the explicitly stated concentration of approximately 30% to approximately 50%, but also the individual percentages (e.g., 35%, 40%, 50%) and subranges (e.g., 35% to 45%) within the specified range. The term "approximately" can include ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10% of the number being modified. In addition, the phrase "approximately x to y" includes "approximately x to approximately y".

[0016] As used herein, the terms “combination,” “therapeutic combination,” “pharmaceutical combination,” or “combination product” refer to either a fixed combination of one dosage unit form, a non-fixed combination of different dosage forms, or a kit of parts for combination administration in which two or more therapeutic agents can be administered simultaneously or separately at time intervals.

[0017] As used herein, the term “non-fixed combination” means that the active ingredients, for example, Compound 1 and Compound 2, are administered to the patient as separate entities, either in parallel, simultaneously, or sequentially, thereby providing therapeutically effective levels of the two compounds into the patient’s body.

[0018] The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described herein. Such administrations include substantially simultaneous co-administration of therapeutic agents, such as a single formulation having a certain ratio of active ingredients or separate formulations of each active ingredient (i.e., separate dosing units, e.g., separate tablets, capsules, and / or intravenous formulations). In addition, such administrations also include the use of various therapeutic agents approximately simultaneously, sequentially, or separately 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 treatment cycle. The agents may be administered at the same time as each other or consecutively. The agents may be administered in any order. The agents may be administered separately at different time points during a treatment cycle, at time intervals such that the combination therapy is effective in treating cancer. In any case, the treatment regimen will produce a beneficial effect in treating the conditions or disorders described herein.

[0019] As used herein, the term “free base equivalent” refers to the amount of an activator (e.g., compound 1 or compound 2) present in an activator or a pharmaceutically acceptable salt thereof. In other words, the term “free base equivalent” means either the amount of free base of compound 1 or compound 2, or the equivalent amount of free base of compound 1 or compound 2 provided by a salt of said compound.

[0020] As used herein, “metastasis” or “metastatic” means that cancer has spread from its primary site to other parts of the body. Cancer cells may detach from the primary tumor, enter the lymphatic system and blood vessels, circulate in the bloodstream, and grow in distal lesions in other normal tissues of the body (metastasis). Metastasis can be local or distant. Metastasis is a sequential process in which tumor cells detach from the primary tumor, travel in the bloodstream, and remain at a distant site. At the new site, the cells may grow to establish a blood supply and form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within tumor cells control this behavior, and interactions between tumor cells and host cells at the distant site are also important.

[0021] As used herein, the phrase “essentially absent” means that the presence of a tumor was not detected as determined by the common art in the relevant field of cancer therapy and diagnosis.

[0022] As used herein, a patient's “progression-free survival (PFS)” is defined as the number of days from the date of initial treatment to the earlier of the date on which the first progression of the disease (progressive disease (PD)) is recorded or the date of death.

[0023] As used herein, “progressive disease (PD)” in a patient is defined as an increase of at least 20% in the total diameter of the target lesions, relative to the minimum total measurement taken in the study, i.e., the nadia measurement. This includes the baseline total if the minimum total measured is the baseline total. New lesions or non-target lesions showing clear progression may also be observed.

[0024] As used herein, “median progression-free survival (mPFS)” is defined as the time from the start of treatment in which half of the patients in the group remain disease-free. (Determined using the Kaplan-Meier (KM) method.)

[0025] As used herein, "disease control rate (DCR)" refers to the percentage of patients in each analysis population who have complete response (CR), partial response (PR), or stable disease (SD) that persists for approximately two months or more. DCR is the sum of the percentages of CR, PR, and SD.

[0026] The term "complete response (CR)" in a patient is defined as the disappearance of all target lesions.

[0027] The term "partial response (PR)" in a patient is defined as at least a 30% decrease in the sum of the diameters of the target lesions relative to the baseline sum of the diameters of the target lesions.

[0028] As used herein, "confirmed partial response (cPR)" in a clinical setting requires confirmation at least 28 days after the initial response.

[0029] As used herein, "stable disease (SD)" in a patient is defined as a state in which neither a reduction sufficient to be judged a partial response (PR) nor an increase sufficient to be judged progressive disease (PD) is observed, based on the minimum sum of diameters during the test.

[0030] As used herein, "overall response rate (ORR)" is the percentage of patients in the analysis population who show a complete response (CR) or a partial response (PR).

[0031] As used herein, "uPR" means unconfirmed partial response.

[0032] As used herein, “to treat” or “treatment” means to inhibit a disease, for example, inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of a disease, condition, or disorder (i.e., stopping the further manifestation of the pathology and / or symptoms), or to improve a disease, for example, improving a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of a disease, condition, or disorder (i.e., improving the pathology and / or symptoms), for example, reducing the severity of the disease.

[0033] As used herein, the terms “patient,” “individual,” or “subject” refer to a human or a non-human mammal. Examples of non-human mammals include livestock and pets, such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is human.

[0034] As used herein, the term “first-line treatment MUM patient” means a patient who has not received prior systemic treatment for a metastatic condition, including not having received prior embolization, radiation therapy to metastatic sites, or resection of liver lesions.

[0035] As used herein, the term “All-Selective-Therapy MUM Patient” refers to all patients who meet the patient eligibility criteria for the clinical trials disclosed herein. All-selective-therapy MUM patients include (1) first-line-treatment MUM patients and (2) patients who have received prior treatment other than the combination disclosed herein (compound 1 and compound 2).

[0036] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” refer to a non-toxic amount of a drug sufficient to produce a desired biological outcome. This outcome may be the reduction or alleviation of signs, symptoms, or causes of a disease, or any other desired change in the biological system. The appropriate therapeutic dose in any individual case may be determined by a person skilled in the art using conventional experimental methods.

[0037] As used herein, the term “pharmaceutically acceptable” means a substance that does not interfere with the biological activity or properties of the compound and is relatively non-toxic, such as a carrier or diluent, that is, the substance can be administered to an individual without causing undesirable biological effects or harmful interactions with any of the components of a composition containing the substance.

[0038] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound has been modified by converting the present acidic or basic moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues, such as mineral or organic acid salts of amines, acidic residues, alkali or organic salts of carboxylic acids, etc. Examples of pharmaceutically acceptable salts described herein include conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts considered herein can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The term “pharmaceutically acceptable salt” is not limited to monosalts or 1:1 salts. For example, "pharmaceutically acceptable salts" include bis-salts, such as bis-hydrochloride. A list of appropriate salts can be found in Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977) (each of these is incorporated herein by reference in its entirety).

[0039] As used herein, the terms “composition” or “pharmaceutical composition” refer to a mixture of at least one compound and a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates the administration of the composition to a patient or subject. Multiple methods for administering compounds exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, intraocular, pulmonary, and topical administration.

[0040] As used herein, the term “pharmaceutically acceptable carrier” means 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 in such a way that it can perform its intended function. Typically, such a construct carries or transports a compound from one organ or part of the body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of a formulation containing the compound disclosed herein and is not harmful to the patient. Some examples of substances that can function as pharmaceutically 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 waxes; 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; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; surfactants; alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, and other non-toxic and suitable substances used in pharmaceutical formulations.

[0041] As used herein, “pharmaceutically acceptable carrier” also includes any coating agents, antimicrobial and antifungal agents, and absorption retarders that are compatible with the activity and efficacy of the compounds disclosed herein and are physiologically acceptable to the patient. Auxiliary active compounds may also be incorporated into the compositions of the present invention. “pharmaceutically acceptable carrier” may further include pharmaceutically acceptable salts of the compound(s) disclosed herein. Other additional components that may 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 are incorporated herein by reference.

[0042] 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 tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. A reduction in tumor size in a patient is defined as a reduction in tumor size measured using the RECIST 1.1 criteria.

[0043] As used herein, the term “single formulation” refers to a single carrier or vehicle formulated to deliver an effective amount of both therapeutic agents to a patient. A single vehicle is designed to deliver an effective amount of each agent together with any pharmaceutically acceptable carrier or excipient. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

[0044] The term “unit dose” is used herein to mean the administration of both drugs simultaneously in a single dosage form to the patient being treated. In some embodiments, the unit dose is a single formulation. The term “unit dose” may also, as used herein, mean the administration of both drugs separately and simultaneously in two dosage forms to the patient being treated. In certain embodiments, the unit dose comprises one or more vehicles, each vehicle containing an effective amount of at least one drug together with pharmaceutically acceptable carriers and excipients. In some embodiments, the unit dose is one or more tablets, capsules, pills, or patches administered simultaneously to the patient.

[0045] Dosages (compound 1 and compound 2) are expressed in terms of free base equivalents unless otherwise specified.

[0046] The combinations 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 content of which is incorporated herein by reference). As used herein, the term “synergistic effect” refers to the action of two agents, such as compound 1 and compound 2, in which a certain effect, such as delaying the symptomatic progression or symptoms of cancer, is greater than the simple additive effect of administering each drug alone. The synergistic effect can be calculated using preferred methods such as the sigmoid Emax equation (Holford, NHG and Scheiner, LB, Clin. Pharmacokinet. 6:429-453 (1981)), the Loewe additive equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114:313-326 (1926)), and the average effect equation (Chou, TC and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Applying each of the equations mentioned above to experimental data and creating corresponding graphs can be helpful in evaluating the combined effects of drugs. The corresponding graphs associated with the equations mentioned above are the concentration-effect curve, the isobologram curve, and the combination exponential curve, respectively.

[0047] As used herein, the term “synergistic effect” refers to the effect achieved when the active ingredients, i.e., Compound 1 and Compound 2, are used together, which is greater than the combined effect obtained when the compounds are used individually.

[0048] In this specification, in some embodiments, a combination therapy is provided comprising an effective amount of compound 1 and compound 2. The “effective amount” of the combination of drugs (i.e., compound 1 and compound 2) is an amount sufficient to provide an observable improvement to the clinically observable baseline signs and symptoms of the disorder treated by the combination.

[0049] "Oral dosage form" includes unit dosage forms that are prescribed or intended for oral administration.

[0050] As used herein, the term “normal lactate dehydrogenase (LDH) level” means LDH levels of 40 to 250 units / liter.

[0051] Treatment method In this specification, in one embodiment, a method is provided for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but essentially no extrahepatic tumors, the method comprising administering to the patient a therapeutically effective dose of a PKC inhibitor and administering to the patient a therapeutically effective dose of a cMet inhibitor.

[0052] In this specification, in another aspect, a method for treating metastatic uveal melanoma (MUM) in a patient is provided, the method is: a) Select patients who have liver tumors but are essentially free of extrahepatic tumors, b) The patient is administered a therapeutically effective dose of a PKC inhibitor and a therapeutically effective dose of a cMet inhibitor.

[0053] In one embodiment of the method described above, patients are selected by evaluating a screening test.

[0054] In further aspects of this specification, a method for treating metastatic uveal melanoma (MUM) in a patient is provided, the method is: a) Selecting patients who have liver tumors but are essentially free of extrahepatic tumors, the selection of such patients being determined by evaluating a screening test, b) The patient is administered a therapeutically effective dose of a PKC inhibitor and a therapeutically effective dose of a cMet inhibitor.

[0055] In another embodiment of the method described above, the PKC inhibitor is compound 1: [ka] or a pharmaceutically acceptable salt thereof.

[0056] In yet another embodiment, the cMet inhibitor is compound 2: [ka] or a pharmaceutically acceptable salt thereof.

[0057] In any one of the embodiments of the method described above, the patient has a liver tumor but no extrahepatic tumor.

[0058] In any one of the embodiments of the method described above, the patient is a human. In some embodiments, the patient is an adult at least 18 years of age.

[0059] In some embodiments, the treatment reduces the size of the liver tumor by at least about 10%. In some embodiments, the treatment reduces the size of the liver tumor by at least about 20%. In some embodiments, the treatment reduces the size of the liver tumor by at least about 30%. In some embodiments, the treatment reduces the size of the liver tumor by at least about 40%. In some embodiments, the treatment reduces the size of the liver tumor by at least about 50%.

[0060] In some embodiments, the treatment reduces the size of the liver tumor by at least 10%. In some embodiments, the treatment reduces the size of the liver tumor by at least 20%. In some embodiments, the treatment reduces the size of the liver tumor by at least 30%. In some embodiments, the treatment reduces the size of the liver tumor by at least 40%. In some embodiments, the treatment reduces the size of the liver tumor by at least 50%.

[0061] In some embodiments, the treatment reduces the size of the liver tumor by about 10% to about 70%. In some embodiments, the treatment reduces the size of the liver tumor by about 10% to about 60%. In some embodiments, the treatment reduces the size of the liver tumor by about 10% to about 50%. In some embodiments, the treatment reduces the size of the liver tumor by an average of at least about 30%.

[0062] In some embodiments, the treatment reduces the size of liver tumors by 10% to 70%. In some embodiments, the treatment reduces the size of liver tumors by 10% to 60%. In some embodiments, the treatment reduces the size of liver tumors by 10% to 50%. In some embodiments, the treatment reduces the size of liver tumors by an average of at least 30%.

[0063] In one embodiment, the patient's progression-free survival is 3 months or longer. In another embodiment, the patient's progression-free survival is 4, 5, 6, 7, or 8 months or longer. In yet another embodiment, the patient's progression-free survival is 5 months or longer. In yet another embodiment, the patient's progression-free survival is 6 months or longer. In yet another embodiment, the patient's progression-free survival is 7 months or longer. In yet another embodiment, the patient's progression-free survival is 8 months or longer. In one embodiment, the patient's progression-free survival is 9 months or longer. In another embodiment, the patient's progression-free survival is 10 months or longer. In yet another embodiment, the patient's progression-free survival is 11 months or longer. In yet another embodiment, the patient's progression-free survival is 3, 5, 7, 9, 10, or 11 months or longer.

[0064] In some embodiments, the treatment has a disease control rate of at least about 60%, about 70%, or about 80%. In some embodiments, the treatment has a disease control rate of at least about 85%. In some embodiments, the treatment has a disease control rate of at least about 90%. In some embodiments, the treatment has a disease control rate of at least about 92%. In some embodiments, the treatment has a disease control rate of at least about 95%. In some embodiments, the treatment has a disease control rate of at least about 98%. In some embodiments, the treatment has a disease control rate of at least about 99%. In some embodiments, the treatment has a disease control rate of at least 100%.

[0065] In another embodiment, the treatment has a disease control rate of at least 60%, 70%, or 80%. In yet another embodiment, the treatment has a disease control rate of at least 85%. In yet another embodiment, the treatment has a disease control rate of at least 90%. In one embodiment, the treatment has a disease control rate of at least 92%. In another embodiment, the treatment has a disease control rate of at least 95%. In yet another embodiment, the treatment has a disease control rate of at least 98%. In yet another embodiment, the treatment has a disease control rate of at least 99%. In some embodiments, the treatment has a disease control rate of 100%.

[0066] In one embodiment, compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered daily in doses of approximately 400 mg to approximately 600 mg.

[0067] In some embodiments, compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dose of about 400 mg to about 600 mg.

[0068] In some embodiments, compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dose of about 200 mg to about 600 mg.

[0069] In another embodiment, compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of approximately 300 mg. In some embodiments, compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of 300 mg.

[0070] In yet another embodiment, compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered twice daily (BID) at a dose of approximately 200 mg. In some embodiments, compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered twice daily (BID) at a dose of 200 mg. In some embodiments, compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered twice daily (BID) at a dose of 150 mg. In some embodiments, compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered twice daily (BID) at a dose of 100 mg.

[0071] In yet another embodiment, compound 2, or an equivalent dose of its pharmaceutically acceptable salt, is administered daily in doses of approximately 400 mg to approximately 500 mg.

[0072] In some embodiments, compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dose of about 400 mg to about 500 mg.

[0073] In some embodiments, compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of approximately 200 mg.

[0074] In some embodiments, compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily. In some embodiments, compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered every other day (e.g., administered on day 1 and not administered on day 2). In some embodiments, compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered every three days (e.g., administered on day 1 and not administered on days 2 and 3).

[0075] In some embodiments, compound 1 or an equivalent dose of its pharmaceutically acceptable salt, and compound 2 or an equivalent dose of its pharmaceutically acceptable salt, are administered daily. In some embodiments, compound 1 or an equivalent dose of its pharmaceutically acceptable salt, and compound 2 or an equivalent dose of its pharmaceutically acceptable salt, are administered independently every other day (for example, both compound 1 and compound 2 are administered on day 1 and neither compound 1 nor compound 2 are administered on day 2, or compound 1 is administered on day 1 and compound 2 is not administered, and compound 1 is not administered and compound 2 is administered on day 2). In some embodiments, compound 1 or an equivalent dose of its pharmaceutically acceptable salt, and compound 2 or an equivalent dose of its pharmaceutically acceptable salt, are administered independently every three days, in which case compound 1 and compound 2 are administered on the same day or on different days.

[0076] In some embodiments, the measure is (i) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered alone in a dose of approximately 300 mg by BID daily, and subsequent treatment cycles (ii) A dosing schedule comprising a second treatment cycle of at least one 7-day dosing cycle, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of approximately 300 mg by BID, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of approximately 200 mg by BID.

[0077] In some embodiments, the measure is (i) A first treatment cycle of a 7-day administration cycle, wherein compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered daily in a dose of approximately 300 mg by BID, and subsequent treatment cycles (ii) A dosing schedule comprising a second treatment cycle of at least three 7-day dosing cycles, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of approximately 300 mg by BID, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of approximately 200 mg by BID.

[0078] In some embodiments, the measure is (i) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered alone in a dose of 300 mg by BID daily, and subsequent treatment cycles (ii) A dosing schedule comprising a second treatment cycle of at least one 7-day dosing cycle, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 300 mg by BID and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 200 mg by BID.

[0079] In some embodiments, the measure is (i) A first treatment cycle of a 7-day administration cycle, wherein compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered alone in a dose of 300 mg by BID daily, and subsequent treatment cycles (ii) A dosing schedule comprising a second treatment cycle of at least three 7-day dosing cycles, wherein in the second treatment cycle, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily at a dose of 300 mg by BID, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily at a dose of 200 mg by BID.

[0080] In some embodiments, the second treatment cycle includes at least 7 (7) 7-day administration cycles. In some embodiments, the second treatment cycle includes at least 11 (11) 7-day administration cycles. In some embodiments, the second treatment cycle includes at least 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, or 103 7-day administration cycles.

[0081] In another embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is administered daily at a dose of approximately 600 mg based on the free base equivalent of compound 1, and compound 2, or a pharmaceutically acceptable salt thereof, is administered daily at a dose of approximately 400 mg based on the free base equivalent of compound 2.

[0082] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered in a total daily dose of about 600 mg based on the free base equivalent of compound 1, and compound 2 or a pharmaceutically acceptable salt thereof is administered in a total daily dose of about 400 mg based on the free base equivalent of compound 2.

[0083] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 600 mg based on the free base equivalent of compound 1, and compound 2 or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 400 mg based on the free base equivalent of compound 2.

[0084] In some embodiments, the second treatment cycle includes at least one 7-day administration cycle. In some embodiments of the second treatment cycle, the 7-day administration cycle includes administering compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, on a daily basis. In some embodiments of the second treatment cycle, during the 7-day administration cycle, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, are each administered daily in the respective doses described in any one of the embodiments described above.

[0085] In another embodiment, compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered at a dose of approximately 300 mg daily in a BID for at least one 7-day dosing cycle, and compound 2, or an equivalent dose of its pharmaceutically acceptable salt, is administered at a dose of approximately 200 mg daily in a BID for at least one 7-day dosing cycle.

[0086] In some embodiments, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily at a dose of 300 mg in BID over at least one 7-day administration cycle, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily at a dose of 200 mg in BID over at least one 7-day administration cycle.

[0087] In some embodiments, the treatment comprises a first treatment cycle and a second treatment cycle (each of which is described above). In some embodiments, the first treatment cycle comprises at least one 7-day administration cycle, in which compound 1 or an equivalent dose of its pharmaceutically acceptable salt is administered alone. In some embodiments, the first treatment cycle comprises at least one 7-day administration cycle, in which compound 1 or an equivalent dose of its pharmaceutically acceptable salt is administered alone in the respective doses described in any one of the embodiments described above. In some embodiments, the second treatment cycle comprises at least seven (7) 7-day administration cycles, in which compound 1 or an equivalent dose of its pharmaceutically acceptable salt and compound 2 or an equivalent dose of its pharmaceutically acceptable salt are administered, respectively. In some embodiments, the second treatment cycle comprises at least seven (7) 7-day administration cycles, in which compound 1 or an equivalent dose of its pharmaceutically acceptable salt and compound 2 or an equivalent dose of its pharmaceutically acceptable salt are administered, respectively in the respective doses described in any one of the embodiments described above. In some embodiments, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are each administered over at least seven (7) seven-day administration cycles (as described above).

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

[0089] In one embodiment, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered as a single formulation. In another embodiment, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered as a single formulation further comprising one or more pharmaceutically acceptable carriers. In yet another embodiment, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered as a single formulation further comprising one or more pharmaceutically acceptable carriers.

[0090] In yet another embodiment, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered separately.

[0091] In some embodiments, the screening test is selected from CT scans, MRI scans, PET scans, ultrasound examinations, and X-ray examinations, or a combination thereof. In some embodiments, the screening test is a CT scan (also called a CAT scan or computed tomography scan). In some embodiments, the screening test is an MRI (magnetic resonance imaging). In some embodiments, the screening test is a PET scan (positron emission tomography). In some embodiments, the screening test is an ultrasound examination. In some embodiments, the screening test is an X-ray examination.

[0092] In yet another embodiment, a method of treating MUM may further include continuing administration of compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof without interruption during an administration schedule comprising at least two consecutive 7-day administration cycles, or preferably at least four consecutive 7-day administration cycles. In some embodiments, the treatment is interrupted and then resumed according to the administration schedule disclosed herein.

[0093] In yet another embodiment, the procedure is: (i) A first treatment cycle of a 7-day administration cycle, wherein compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered daily in a dose of approximately 300 mg by BID, and subsequent treatment cycles (ii) A second treatment cycle of at least three 7-day administration cycles, in which compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily by BID at a dose of approximately 300 mg, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily by BID, according to an administration schedule that includes the second treatment cycle. In this case, the treatment shall not be interrupted during the second treatment cycle of at least three 7-day administration cycles or at least seven (7) 7-day administration cycles.

[0094] In yet another embodiment, the procedure is: (i) A first treatment cycle of a 7-day administration cycle, wherein compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered alone in a dose of 300 mg by BID daily, and subsequent treatment cycles (ii) A second treatment cycle of at least three 7-day administration cycles, in which compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily by BID at a dose of 300 mg and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered by BID, according to an administration schedule that includes the second treatment cycle. In this case, the treatment shall not be interrupted during the second treatment cycle of at least three 7-day administration cycles or at least seven (7) 7-day administration cycles.

[0095] In certain embodiments, compound 1 or an equivalent dose of its pharmaceutically acceptable salt, and compound 2 or an equivalent dose of its pharmaceutically acceptable salt are co-administered continuously without interruption during a dosing schedule comprising at least 8, 12, 24, 48, or 96 consecutive 7-day dosing cycles. In some embodiments, compound 1 or an equivalent dose of its pharmaceutically acceptable salt is co-administered continuously without interruption during a dosing schedule comprising at least 8, 12, 24, 48, or 96 consecutive 7-day dosing cycles. In other embodiments, compound 2 or an equivalent dose of its pharmaceutically acceptable salt is co-administered continuously without interruption during a dosing schedule comprising at least 8, 12, 24, 48, or 96 consecutive 7-day dosing cycles.

[0096] Exemplary periods related to the treatment process are approximately 5 years, 4 years, 3 years, 2 years, 1 year, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month.

[0097] An exemplary period related to the treatment process may be approximately five years, or any day, week, month, or year within that period. For example, a treatment cycle may include five months plus additional weeks and / or days, or one year plus additional months, weeks, and / or days.

[0098] In some embodiments, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered sequentially (i.e., sequential treatment until completion).

[0099] The GNAQ or GNA11 tumors treated may contain one or more mutations, including substitution mutations, insertion mutations, and / or deletions of GNAQ or GNA11 mutations. In some embodiments, the GNAQ or GNA11 mutations are gain-of-function mutations. In some embodiments, the GNAQ or GNA11 mutations activate the PKC signaling pathway. In various embodiments, the GNAQ or GNA11 mutations may be glutamine substitutions at codon 209 (Q209) and / or arginine substitutions at codon 183 (R183). The GNAQ or GNA11 mutations may be substitutions other than glutamine at codon 209 (Q209), substitutions other than arginine substitution at codon 183 (R183), or substitutions other than 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 may be R183Q, or the GNA11 mutation may be R183C or R183H. In further examples, GNAQ mutations or GNA11 mutations are mutations in one or more of the following: 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, a GNAQ tumor or a GNA11 tumor may contain one or more Q209P, Q209L, Q209H, Q209K, Q209Y, or R183Q mutations in GNAQ, or a GNAQ tumor or a GNA11 tumor may contain one or more Q209P, Q209L, Q209H, or Q209K mutations in GNA11. Examples of additional mutations in GNAQ or GNA11 are described in WO2020 / 146355, which is incorporated herein by reference in its entirety.

[0100] Exemplary periods related to the processes of the treatment methods disclosed herein include approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 11 weeks, approximately 12 weeks, approximately 13 weeks, approximately 14 weeks, approximately 15 weeks, approximately 16 weeks, approximately 17 weeks, approximately 18 weeks, approximately 19 weeks, approximately 20 weeks, approximately 21 weeks, approximately 22 weeks, approximately 23 weeks, approximately 24 weeks, approximately 4 months, approximately 7 months, approximately 8 months, approximately 9 months, and approximately 10 months. , including approximately 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 3 years, 4 years, and 5 years, or any day, week, month, or year in between. For example, a treatment cycle may include 5 months and additional weeks and / or days, or 1 year and additional months, weeks, and / or days.

[0101] In one embodiment, both compound 1 and compound 2 are administered orally.

[0102] In some embodiments of the method, the method includes administering a therapeutically effective amount of a combination or composition containing a compound provided herein or a pharmaceutically acceptable salt thereof to a subject (including, but not limited to, a human or an animal) in need of treatment (including a subject identified as being in need of treatment).

[0103] In another embodiment of the method, the treatment involves co-administering an amount of compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and an amount of compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof. In one embodiment, the amount of compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and the amount of compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, are a single formulation or unit dose form. In yet another embodiment, the amount of compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and the amount of compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, are separate formulations or unit dose forms.

[0104] In the methods described above, the treatment may include administering substantially simultaneously the amount of compound 1 or an equivalent dose of its pharmaceutically acceptable salt and the amount of compound 2 or an equivalent dose of its pharmaceutically acceptable salt, or administering the amount of compound 1 or an equivalent dose of its pharmaceutically acceptable salt and the amount of compound 2 or an equivalent dose of its pharmaceutically acceptable salt at different times. In some embodiments of the methods described above, the amount of compound 1 or an equivalent dose of its pharmaceutically acceptable salt and / or the amount of compound 2 or an equivalent dose of its pharmaceutically acceptable salt are administered in doses that are ineffective when administered individually or in combination with compound 2 or an equivalent dose of its pharmaceutically acceptable salt.

[0105] In one embodiment of the method described above, the subjects are those receiving first-line treatment. In another embodiment, the subjects are those receiving first-line treatment MUM.

[0106] As used herein, “extrahepatic tumor” means any tumor located outside the liver.

[0107] Dosage / Prescription The actual dose level of the active ingredient in the pharmaceutical composition may be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0108] In particular, the level of dosage selected depends on a variety of factors, including the activity of the specific compound being employed, the timing 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, overall health, and medical history of the patient being treated, as well as similar factors well known in the medical field.

[0109] A physician with ordinary skill in the art, such as an internist or veterinarian, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, an internist or veterinarian can start administering the pharmaceutical composition containing the disclosed compound at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0110] In specific embodiments, it is particularly advantageous to formulate the compound in dose unit formulations for ease of administration and uniformity of dosage. As used herein, a dose unit formulation refers to a physically separate unit suitable as a unit dose for a patient receiving treatment, each unit containing a predetermined amount of the disclosed compound calculated to produce the desired therapeutic effect, along with the necessary pharmaceutical vehicle. The dose unit formulation is defined and directly dependent on (a) the inherent characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the art of compounding / formulating such disclosed compound for the treatment of a patient's pain, depressive disorder, or drug dependence.

[0111] In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition provided herein comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0112] The optimal ratio, individual doses, and combined doses of drug compounds that produce efficacy without toxicity, as well as their concentrations, are determined using methods known to those skilled in the art, based on the kinetics of the availability of the active ingredient to the target site.

[0113] The routes of administration for any of the compositions considered herein include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical. Compounds can be formulated for administration by any preferred route, e.g., oral or parenteral, percutaneous, transmucosal (e.g., sublingual, lingual, (trans) buccal, (trans) urethral, ​​vaginal (e.g., transvaginal and perivaginal), (trans) nasal and (trans) rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

[0114] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelatin capsules, lozenges, dispersants, suspensions, liquids, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma preparations, lozenges, creams, pastes, transdermal patches, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosol preparations for inhalation, and compositions and preparations for intravesical administration. It should be understood that the preparations and compositions are not limited to the specific preparations and compositions described herein.

[0115] For oral administration, tablets, sugar-coated tablets, liquids, drops, suppositories, or capsules, caplets, and gelatin capsules are particularly preferred. 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 pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulators and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may or may not be coated, or they may be coated by known techniques for aesthetic purposes or to delay the release of the active ingredient. Oral formulations can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0116] For parenteral administration, the disclosed compound may be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration by bolus or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles may be used, and optionally contain other formulation agents such as suspending agents, stabilizers, or dispersants.

[0117] kit In one embodiment, the Disclosure provides a kit for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but essentially no extrahepatic tumors, the kit comprising a dose of compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof in an amount of about 400 mg to about 600 mg, and a dose of compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof in an amount of about 400 mg to about 500 mg. In another embodiment, the Disclosure provides a kit for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but essentially no extrahepatic tumors, the kit comprising a dose of compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof in an amount of about 300 mg, and a dose of compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof in an amount of about 200 mg. In another embodiment, the Disclosure provides a kit for treating metastatic uveal melanoma (MUM) in patients having a liver tumor but essentially no extrahepatic tumors, the kit comprising compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof in amounts of about 400 mg to about 600 mg per day, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof in amounts of about 400 mg to about 500 mg per day. In some embodiments, the kit further comprises packaging and instructions.

[0118] In additional embodiments, a pharmaceutical kit is provided. The kit includes a sealed container approved for the storage of a pharmaceutical composition, the container containing one of the pharmaceutical compositions described above. In some embodiments, the sealed container minimizes contact between air and the components, for example, an airless bottle. In other embodiments, the sealed container is a sealed tube. The kit shall include instructions for the use of the composition and information about the composition.

[0119] In certain embodiments, the combination of compounds can be administered on the same schedule, whether as a single formulation or unit dose containing all of the combination of compounds, or as separate formulations or unit doses of the combination of compounds. However, some of the compounds used in the combination may be administered more frequently than once a day, or at a different frequency than the other compounds in the combination. Therefore, in one embodiment, the kit contains in a container a formulation or unit dose containing all of the compounds in the combination of compounds, and an additional formulation or unit dose containing one of the compounds in the combination of compounds but not the additional active compound, and includes instructions for administering the dosage forms on a set schedule.

[0120] The kits provided herein include, for example, prescription information provided to the patient or healthcare provider, or as a label on the packaged pharmaceutical product. Prescription information may include, for example, information on efficacy, dosage and administration, contraindications, and side effects of the pharmaceutical product.

[0121] In all of the foregoing, the combination of compounds of the present invention may be administered alone, as a mixture, or with additional activators.

[0122] The kits provided herein may be designed to accommodate the conditions necessary to properly maintain the components contained therein (e.g., refrigeration or freezing). The kits may include a label or accompanying leaflet containing identification information for the components contained therein, and instructions for use (e.g., administration parameters, clinical pharmacology of the active ingredient(s), e.g., mechanism of action(s), pharmacokinetics and pharmacodynamics, side effects, contraindications, etc.).

[0123] Each component of the kit can be sealed in an individual container, and all of the various containers can be housed in a single package. The label or accompanying information may include manufacturer information such as lot number and expiration date. The label or accompanying information can be, for example, integrated with the physical structure containing the components, housed separately within the physical structure, or affixed to the components of the kit (e.g., ampoules, syringes, or vials).

[0124] Those skilled in the art will recognize or be able to identify many equivalents to the specific procedures, embodiments, claims, and examples described herein using conventional experiments. Such equivalents are deemed to be within the scope of this disclosure and are included in the claims appended herein. For example, it should be understood that modifying reaction conditions (including, but not limited to, reaction time, reaction size / volume, and experimental reagents, e.g., solvent, catalyst, pressure, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agent) using conventional experiments with substitutes recognized in the art is within the scope of this application.

[0125] Whenever values ​​and ranges are presented herein, it should be understood that all values ​​and ranges encompassed within those values ​​and ranges are intended to be included within the scope of this disclosure. Furthermore, all values ​​that fall within these ranges, as well as any upper or lower limits on the ranges of values, are also contemplated in this application.

[0126] The following embodiments further illustrate aspects of the present disclosure. However, they are not intended to limit the teachings of the present disclosure described herein.

[0127] Non-exclusive exemplary embodiments: Embodiment 1. A method for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but without any extrahepatic tumors, comprising administering a therapeutically effective dose of a PKC inhibitor to the patient and a therapeutically effective dose of a cMet inhibitor.

[0128] Embodiment 2. A method for treating metastatic uveal melanoma (MUM) in a patient, a) Select patients who have liver tumors but are essentially free of extrahepatic tumors, b) The method comprising administering to the patient a therapeutically effective dose of a PKC inhibitor and a therapeutically effective dose of a cMet inhibitor.

[0129] Embodiment 3. The method according to Embodiment 1 or 2, wherein the patient is selected by evaluating a screening test.

[0130] Embodiment 4. A method for treating metastatic uveal melanoma (MUM) in a patient, a) Selecting patients who have liver tumors but are essentially free of extrahepatic tumors, wherein the selection of such patients is determined by evaluating a screening test. b) The method comprising administering to the patient a therapeutically effective dose of a PKC inhibitor and a therapeutically effective dose of a cMet inhibitor.

[0131] Embodiment 5. The PKC inhibitor is compound 1: [ka] The method according to any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof.

[0132] Embodiment 6. The cMet inhibitor is compound 2: [ka] The method according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof.

[0133] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the patient does not have an extrahepatic tumor.

[0134] Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein the patient is an adult at least 18 years of age.

[0135] Embodiment 9. The method according to any one of Embodiments 1 to 8, wherein the treatment reduces the size of the liver tumor by at least 10%.

[0136] Embodiment 10. The method according to any one of Embodiments 1 to 8, wherein the treatment reduces the size of the liver tumor by at least about 10%.

[0137] Embodiment 11. The method according to any one of Embodiments 1 to 10, wherein the progression-free survival period of the patient is 3 months or longer.

[0138] Embodiment 12. The method according to any one of Embodiments 1 to 11, wherein the progression-free survival period of the patient is 4, 5, 6, 7, or 8 months or longer.

[0139] Embodiment 13. The method according to any one of Embodiments 1 to 12, wherein the progression-free survival period of the patient is 9 months or longer.

[0140] Embodiment 14. The method according to any one of Embodiments 1 to 13, wherein the progression-free survival period of the patient is 10 months or longer.

[0141] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein the progression-free survival period of the patient is 11 months or longer.

[0142] Embodiment 16. The method according to any one of Embodiments 1 to 15, wherein the treatment has a disease control rate of at least 60%, 70%, or 80%.

[0143] Embodiment 17. The method according to any one of Embodiments 1 to 16, wherein the treatment has a disease control rate of at least 85%.

[0144] Embodiment 18. The method according to any one of Embodiments 1 to 17, wherein the treatment has a disease control rate of at least 90%.

[0145] Embodiment 19. The method according to any one of Embodiments 1 to 18, wherein the treatment has a disease control rate of at least 92%.

[0146] Embodiment 20. The method according to any one of Embodiments 1 to 19, wherein the treatment has a disease control rate of at least 95%.

[0147] Embodiment 21. The method according to any one of Embodiments 1 to 20, wherein the treatment has a disease control rate of at least 98%.

[0148] Embodiment 22. The method according to any one of Embodiments 1 to 21, wherein the treatment has a disease control rate of at least 99%.

[0149] Embodiment 23. The method according to any one of Embodiments 5 to 22, wherein compound 1, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered daily in a dose of about 400 mg to about 600 mg.

[0150] Embodiment 24. The method according to any one of Embodiments 5 to 22, wherein compound 1, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered in a total daily dose of about 400 mg to about 600 mg.

[0151] Embodiment 25. The method according to any one of Embodiments 5 to 24, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily.

[0152] Embodiment 26. The method according to any one of Embodiments 5 to 25, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of approximately 300 mg.

[0153] Embodiment 27. The method according to any one of Embodiments 5 to 25, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of approximately 200 mg.

[0154] Embodiment 28. The method according to any one of Embodiments 6 to 27, wherein compound 2, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered daily in a dose of about 400 mg to about 500 mg.

[0155] Embodiment 29. The method according to any one of Embodiments 6 to 27, wherein compound 2, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered in a total daily dose of about 400 mg to about 500 mg.

[0156] Embodiment 30. The method according to any one of Embodiments 6 to 29, wherein compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily.

[0157] Embodiment 31. The method according to any one of Embodiments 6 to 30, wherein compound 2, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered twice daily (BID) at a dose of approximately 200 mg.

[0158] Embodiment 32. The method according to any one of Embodiments 6 to 30, wherein compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of approximately 250 mg.

[0159] Embodiment 33. Compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered at a dose of approximately 300 mg daily in a 7-day administration cycle at least once per day. The method according to any one of embodiments 6-26 and 28-30, wherein compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 200 mg daily in a BID at least once in a 7-day administration cycle.

[0160] Embodiment 34. The method according to any one of Embodiments 6-26 and 28-30, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg daily in a BID for at least one 7-day administration cycle, and compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg daily in a BID for at least one 7-day administration cycle.

[0161] Embodiment 35. The method according to any one of Embodiments 6-25 and 27-30, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg daily in a BID for at least one 7-day administration cycle, and compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg daily in a BID for at least one 7-day administration cycle.

[0162] Embodiment 36. The method according to any one of Embodiments 33 to 35, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are each administered over at least 7 (7) 7-day administration cycles.

[0163] Embodiment 37. The method according to any one of Embodiments 33 to 35, wherein compound 1 or an equivalent dose thereof of a pharmaceutically acceptable salt and compound 2 or an equivalent dose thereof of a pharmaceutically acceptable salt are each administered over at least 8 (8) 7-day administration cycles, at least 12 (12) 7-day administration cycles, at least 16 (16) 7-day administration cycles, at least 20 (20) 7-day administration cycles, at least 24 (24) 7-day administration cycles, or at least 28 (28) 7-day administration cycles.

[0164] Embodiment 38. The above procedure is (i) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of 300 mg by BID daily in the first treatment cycle, and subsequent treatment cycles (ii) The method according to any one of embodiments 6 to 26 and 28 to 30, wherein the administration schedule includes a second treatment cycle of at least one 7-day administration cycle, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 300 mg by BID and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 200 mg by BID.

[0165] Embodiment 39. The above procedure is (i) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of approximately 300 mg by BID daily, and the following treatment cycles (ii) The method according to any one of embodiments 6 to 26 and 28 to 30, wherein the administration schedule includes a second treatment cycle of at least three (3) seven-day administration cycles, wherein in the second treatment cycle, compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of about 300 mg by BID, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of about 200 mg by BID.

[0166] Embodiment 40. The above treatment is (iii) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of 200 mg by BID daily in the first treatment cycle, and subsequent treatment cycles (iv) The method according to any one of embodiments 6 to 25 and 27 to 30, wherein the administration schedule includes a second treatment cycle of at least one 7-day administration cycle, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 200 mg by BID, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 200 mg by BID.

[0167] Embodiment 41. The above treatment is (iii) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of approximately 200 mg by BID on a daily basis, and the following treatment cycles (iv) The method according to any one of embodiments 6 to 25 and 27 to 30, wherein the administration schedule includes a second treatment cycle of at least three (3) seven-day administration cycles, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered by BID at a dose of about 200 mg daily, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered by BID at a dose of about 200 mg daily.

[0168] Embodiment 42. The method according to any one of Embodiments 38 to 41, wherein the second treatment cycle comprises at least 7 (7) 7-day administration cycles, at least 11 (11) 7-day administration cycles, at least 15 (15) 7-day administration cycles, at least 19 (19) 7-day administration cycles, at least 23 (23) 7-day administration cycles, or at least 27 (27) 7-day administration cycles.

[0169] Embodiment 43. The method according to any one of Embodiments 5 to 42, wherein the procedure is not interrupted.

[0170] Embodiment 44. The method according to any one of Embodiments 1 to 43, wherein the metastatic uveal melanoma is a solid tumor.

[0171] Embodiment 45. The method according to Embodiment 44, wherein the solid tumor has a GNAQ mutation or a GNA11 mutation.

[0172] Embodiment 46. The method according to any one of Embodiments 6 to 45, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered as a single formulation.

[0173] Embodiment 47. The method according to any one of Embodiments 6 to 45, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered as a single formulation further comprising one or more pharmaceutically acceptable carriers.

[0174] Embodiment 48. The method according to any one of Embodiments 6 to 45, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered separately.

[0175] Embodiment 49. The method according to any one of Embodiments 3 to 48, wherein the screening test is selected from CT scan, MRI, PET scan, ultrasound examination, and X-ray examination, or a combination thereof.

[0176] Embodiment 50. The method according to Embodiment 49, wherein the screening test is a CT scan.

[0177] Embodiment 51. The method according to Embodiment 49, wherein the screening test is MRI.

[0178] Embodiment 52. The method according to Embodiment 49, wherein the screening test is an ultrasound examination.

[0179] Embodiment 53. The method according to any one of Embodiments 9 to 52, wherein the reduction in the size of the liver tumor is measured using the RECIST 1.1 criteria.

[0180] Embodiment 54. The method according to any one of Embodiments 9 to 52, wherein the size of the liver tumor is measured using a CT scan, MRI, ultrasound, or a combination thereof.

[0181] Embodiment 55. The method according to any one of Embodiments 1 to 54, wherein the patient is negative for human leukocyte antigen (HLA)-A2.

[0182] Embodiment 56. The method according to any one of Embodiments 1 to 54, wherein the patient is positive for human leukocyte antigen (HLA)-A2.

[0183] Embodiment 57. The method according to any one of Embodiments 1 to 54, wherein the patient has a BRCA1-related protein-1 (BAP1) mutation.

[0184] Embodiment 58. The method according to any one of Embodiments 1 to 54, wherein the patient does not have a BRCA1-related protein-1 (BAP1) mutation.

[0185] Embodiment 59. The method according to any one of Embodiments 1 to 54, wherein the patient has normal lactate dehydrogenase (LDH) levels.

[0186] Embodiment 60. The method according to any one of Embodiments 1 to 54, wherein the patient has a high LDH level compared to a normal lactate dehydrogenase (LDH) level.

[0187] Embodiment 61. The method according to any one of Embodiments 1 to 60, wherein it is recognized that the patient requires such treatment.

[0188] Embodiment 62. The method according to any one of Embodiments 1 to 61, wherein the PKC inhibitor or a pharmaceutically acceptable salt thereof and the cMet inhibitor or a pharmaceutically acceptable salt thereof are each administered orally.

[0189] Additional non-exclusive exemplary embodiments: Embodiment 1A. A PKC inhibitor for use in a method for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but without any extrahepatic tumors, wherein the method comprises administering a therapeutically effective dose of the PKC inhibitor to the patient and administering a therapeutically effective dose of the cMet inhibitor.

[0190] Embodiment 1B. A PKC inhibitor for use in the treatment of metastatic uveal melanoma (MUM) in a patient having a liver tumor but essentially no extrahepatic tumors, wherein a therapeutically effective dose of the PKC inhibitor is administered to the patient in combination with a therapeutically effective dose of a cMet inhibitor.

[0191] Embodiment 1C. Use of a PKC inhibitor in the manufacture of a pharmaceutical product for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but without any extrahepatic tumors, wherein a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of a cMet inhibitor.

[0192] Embodiment 1D. Use of a PKC inhibitor for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but without any extrahepatic tumors, wherein a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of a cMet inhibitor.

[0193] Embodiment 2A. A PKC inhibitor for use in a method for treating metastatic uveal melanoma (MUM) in a patient, wherein the method is a) Select patients who have liver tumors but are essentially free of extrahepatic tumors, b) The PKC inhibitor comprising administering a therapeutically effective amount of the PKC inhibitor to the patient and administering a therapeutically effective amount of the cMet inhibitor.

[0194] Embodiment 2B. A PKC inhibitor for use in the treatment of metastatic uveal melanoma (MUM) in patients, a) Patients with liver tumors but without essentially any extrahepatic tumors are selected. b) The PKC inhibitor, wherein a therapeutically effective amount of the PKC inhibitor is administered to the patient in combination with a therapeutically effective amount of a cMet inhibitor.

[0195] Embodiment 2C. Use of a PKC inhibitor in the manufacture of a pharmaceutical product for treating metastatic uveal melanoma (MUM) in a patient, a) Patients with liver tumors but without essentially any extrahepatic tumors are selected. b) The use wherein a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of the cMet inhibitor.

[0196] Embodiment 2D. Use of a PKC inhibitor for treating metastatic uveal melanoma (MUM) in a patient, a) Patients with liver tumors but without essentially any extrahepatic tumors are selected. b) The use wherein a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of the cMet inhibitor.

[0197] Embodiment 3. The use according to Embodiments 1A-1D and 2A-2D, wherein the patient is selected by evaluating the screening test.

[0198] Embodiment 4A. A PKC inhibitor for use in a method for treating metastatic uveal melanoma (MUM) in a patient, wherein the method is a) Selecting patients who have liver tumors but are essentially free of extrahepatic tumors, wherein the selection of such patients is determined by evaluating a screening test. b) The PKC inhibitor comprising administering to the patient a therapeutically effective amount of the PKC inhibitor and a therapeutically effective amount of the cMet inhibitor.

[0199] Embodiment 4B. A PKC inhibitor for use in the treatment of metastatic uveal melanoma (MUM) in a patient, a) By evaluating the screening test, patients with liver tumors but without extrahepatic tumors are selected. b) The PKC inhibitor, wherein a therapeutically effective amount of the PKC inhibitor is administered to the patient in combination with a therapeutically effective amount of a cMet inhibitor.

[0200] Embodiment 4C. Use of a PKC inhibitor in the manufacture of a pharmaceutical product for treating metastatic uveal melanoma (MUM) in a patient, a) By evaluating the screening test, patients with liver tumors but without extrahepatic tumors are selected. b) The use wherein a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of the cMet inhibitor.

[0201] Embodiment 4D. Use of a PKC inhibitor for treating metastatic uveal melanoma (MUM) in a patient, a) By evaluating the screening test, patients with liver tumors but without extrahepatic tumors are selected. b) The use wherein a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of the cMet inhibitor.

[0202] Embodiment 5. The PKC inhibitor is compound 1: [ka] The use described in any one of Embodiments 1A to 4D, or a pharmaceutically acceptable salt thereof.

[0203] Embodiment 6. The cMet inhibitor is compound 2: [ka] The use described in any one of Embodiments 1A to 5, or a pharmaceutically acceptable salt thereof.

[0204] Embodiment 7. The use according to any one of Embodiments 1A to 6, wherein the patient does not have an extrahepatic tumor.

[0205] Embodiment 8. The use according to any one of Embodiments 1A to 7, wherein the patient is an adult at least 18 years of age.

[0206] Embodiment 9. The use according to any one of Embodiments 1A to 8, wherein the treatment reduces the size of the liver tumor by at least 10%.

[0207] Embodiment 10. The use according to any one of Embodiments 1A to 8, wherein the treatment reduces the size of the liver tumor by at least about 10%.

[0208] Embodiment 11. The use according to any one of Embodiments 1A to 10, wherein the progression-free survival period of the patient is 3 months or longer.

[0209] Embodiment 12. The use according to any one of Embodiments 1A to 11, wherein the progression-free survival period of the patient is 4, 5, 6, 7, or 8 months or longer.

[0210] Embodiment 13. The use according to any one of Embodiments 1A to 12, wherein the progression-free survival period of the patient is 9 months or longer.

[0211] Embodiment 14. The use according to any one of Embodiments 1A to 13, wherein the progression-free survival period of the patient is 10 months or longer.

[0212] Embodiment 15. The use according to any one of Embodiments 1A to 14, wherein the progression-free survival period of the patient is 11 months or longer.

[0213] Embodiment 16. The use according to any one of Embodiments 1A to 15, wherein the treatment has a disease control rate of at least 60%, 70%, or 80%.

[0214] Embodiment 17. The use according to any one of Embodiments 1A to 16, wherein the treatment has a disease control rate of at least 85%.

[0215] Embodiment 18. The use according to any one of Embodiments 1A to 17, wherein the treatment has a disease control rate of at least 90%.

[0216] Embodiment 19. The use according to any one of Embodiments 1A to 18, wherein the treatment has a disease control rate of at least 92%.

[0217] Embodiment 20. The use according to any one of Embodiments 1A to 19, wherein the treatment has a disease control rate of at least 95%.

[0218] Embodiment 21. The use according to any one of Embodiments 1A to 20, wherein the treatment has a disease control rate of at least 98%.

[0219] Embodiment 22. The use according to any one of Embodiments 1A to 21, wherein the treatment has a disease control rate of at least 99%.

[0220] Embodiment 23. The use according to any one of Embodiments 5 to 22, wherein compound 1, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered daily in a dose of about 400 mg to about 600 mg.

[0221] Embodiment 24. The use according to any one of Embodiments 5 to 22, wherein compound 1, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered in a total daily dose of about 400 mg to about 600 mg.

[0222] Embodiment 25. The use according to any one of Embodiments 5 to 24, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily.

[0223] Embodiment 26. The use according to any one of Embodiments 5 to 25, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of approximately 300 mg.

[0224] Embodiment 27. The use according to any one of Embodiments 5 to 25, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of approximately 200 mg.

[0225] Embodiment 28. The use according to any one of Embodiments 6 to 27, wherein compound 2, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered daily in a dose of about 400 mg to about 500 mg.

[0226] Embodiment 29. The use according to any one of Embodiments 6 to 27, wherein compound 2, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered in a total daily dose of about 400 mg to about 500 mg.

[0227] Embodiment 30. The use according to any one of Embodiments 6 to 29, wherein compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily.

[0228] Embodiment 31. The use according to any one of Embodiments 6 to 30, wherein compound 2, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered twice daily (BID) at a dose of approximately 200 mg.

[0229] Embodiment 32. The use according to any one of Embodiments 6 to 30, wherein compound 2, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered twice daily (BID) at a dose of approximately 250 mg.

[0230] Embodiment 33. Compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered at a dose of approximately 300 mg daily in a 7-day administration cycle at least once per day. The use according to any one of embodiments 6-26 and 28-30, wherein compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 200 mg daily in a 7-day administration cycle at least once per day by BID.

[0231] Embodiment 34. Compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered at a dose of approximately 300 mg daily in a BID for at least one 7-day administration cycle. The use according to any one of embodiments 6-26 and 28-30, wherein compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 200 mg daily in a BID over at least one 7-day administration cycle.

[0232] Embodiment 35. Compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered at a dose of approximately 200 mg daily in a 7-day administration cycle at least once per day. The use according to any one of embodiments 6-25 and 27-30, wherein compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 200 mg daily in a 7-day administration cycle at least once per day by BID.

[0233] Embodiment 36. The use according to any one of Embodiments 33 to 35, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are each administered over at least 7 (7) 7-day administration cycles.

[0234] Embodiment 37. The use according to any one of Embodiments 33 to 35, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered over at least 8 (8) seven-day administration cycles, at least 12 (12) seven-day administration cycles, at least 16 (16) seven-day administration cycles, at least 20 (20) seven-day administration cycles, at least 24 (24) seven-day administration cycles, or at least 28 (28) seven-day administration cycles.

[0235] Embodiment 38. The above procedure is (v) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of 300 mg by BID daily in the first treatment cycle, and subsequent treatment cycles (vi) The use according to any one of embodiments 6-26 and 28-30, wherein the administration schedule includes a second treatment cycle of at least one 7-day administration cycle, in which compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 300 mg by BID and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg by BID.

[0236] Embodiment 39. The above procedure is (v) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of approximately 300 mg by BID on a daily basis, the first treatment cycle, and subsequent (vi) The use according to any one of embodiments 6-26 and 28-30, wherein the administration schedule includes a second treatment cycle of at least three (3) seven-day administration cycles, the second treatment cycle comprising the administration of compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof in a dose of approximately 300 mg by BID daily, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof in a dose of approximately 200 mg by BID daily.

[0237] Embodiment 40. The above treatment is (vii) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of 200 mg by BID daily in the first treatment cycle, and subsequent treatment cycles (viii) The use according to any one of embodiments 6 to 25 and 27 to 30, wherein the administration schedule includes a second treatment cycle of at least one 7-day administration cycle, in which compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered by BID at a dose of 200 mg daily, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered by BID at a dose of 200 mg daily.

[0238] Embodiment 41. The above treatment is (vii) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of approximately 200 mg by BID on a daily basis, and the following treatment cycles (viii) The use according to any one of embodiments 6-25 and 27-30, wherein the administration schedule includes a second treatment cycle of at least three (3) seven-day administration cycles, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered by BID at a dose of about 200 mg daily, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered by BID at a dose of about 200 mg daily.

[0239] Embodiment 42. The use according to any one of Embodiments 38 to 41, wherein the second treatment cycle comprises at least 7 (7) 7-day administration cycles, at least 11 (11) 7-day administration cycles, at least 15 (15) 7-day administration cycles, at least 19 (19) 7-day administration cycles, at least 23 (23) 7-day administration cycles, or at least 27 (27) 7-day administration cycles.

[0240] Embodiment 43. The use according to any one of Embodiments 5 to 42, wherein the procedure is not interrupted.

[0241] Embodiment 44. The use according to any one of Embodiments 1A to 43, wherein the metastatic uveal melanoma is a solid tumor.

[0242] Embodiment 45. The use according to Embodiment 44, wherein the solid tumor has a GNAQ mutation or a GNA11 mutation.

[0243] Embodiment 46. The use according to any one of Embodiments 6 to 45, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered as a single formulation.

[0244] Embodiment 47. The use according to any one of Embodiments 6 to 45, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered as a single formulation further comprising one or more pharmaceutically acceptable carriers.

[0245] Embodiment 48. The use according to any one of Embodiments 6 to 45, wherein Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof and Compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered separately.

[0246] Embodiment 49. The use according to any one of Embodiments 3 to 48, wherein the screening test is selected from CT scan, MRI, PET scan, ultrasound examination, and X-ray examination, or a combination thereof.

[0247] Embodiment 50. The use according to Embodiment 49, wherein the screening test is a CT scan.

[0248] Embodiment 51. The use described in Embodiment 49, wherein the screening test is MRI.

[0249] Embodiment 52. The use according to Embodiment 49, wherein the screening test is an ultrasound examination.

[0250] Embodiment 53. The use according to any one of Embodiments 9 to 52, wherein the reduction in the size of the liver tumor is measured using the RECIST 1.1 criteria.

[0251] Embodiment 54. The use according to any one of Embodiments 9 to 52, wherein the size of the liver tumor is measured using a CT scan, MRI, ultrasound, or a combination thereof.

[0252] Embodiment 55. The use according to any one of Embodiments 1A to 54, wherein the patient is negative for human leukocyte antigen (HLA)-A2.

[0253] Embodiment 56. The use according to any one of Embodiments 1A to 54, wherein the patient is positive for human leukocyte antigen (HLA)-A2.

[0254] Embodiment 57. The use according to any one of Embodiments 1A to 54, wherein the patient has a BRCA1-related protein-1 (BAP1) mutation.

[0255] Embodiment 58. The use according to any one of Embodiments 1A to 54, wherein the patient does not have a BRCA1-related protein-1 (BAP1) mutation.

[0256] Embodiment 59. The use according to any one of Embodiments 1A to 54, wherein the patient has normal lactate dehydrogenase (LDH) levels.

[0257] Embodiment 60. The use according to any one of Embodiments 1A to 54, wherein the patient has a high LDH level compared to a normal lactate dehydrogenase (LDH) level.

[0258] Embodiment 61. The use according to any one of Embodiments 1A to 60, wherein it is recognized that the patient requires such treatment.

[0259] Embodiment 62. The use according to any one of Embodiments 1 to 61, wherein the PKC inhibitor or a pharmaceutically acceptable salt thereof and the cMet inhibitor or a pharmaceutically acceptable salt thereof are each administered orally.

[0260] Where there are references to prior embodiments in relation to the embodiments described above, such references shall include embodiments having lettered reference numerals or combinations thereof. For example, references to embodiments 1A to 7 would include embodiments 1A, 1B, 1C, 1D, 2A, 2B, 2C, 3D, 3, 4A, 4B, 4C, 4D, 5, 6, and 7. [Examples]

[0261] The compounds and methods disclosed herein will be further illustrated by the following examples, but these examples should not be construed as further limiting. Unless otherwise specified, the practices of this disclosure utilize prior art of organic synthesis, cell biology, cell culture and molecular biology, which are within the scope of the art.

[0262] The processes for preparing the compounds disclosed in this specification can be found at least in WO2016 / 020864 and WO2006 / 021884, the contents of which are incorporated in their entirety.

[0263] Example 1: Clinical Data The following shows the data of a clinical trial (NCT number 03947385) for patients administered Compound 1 and Compound 2 for treating uveal melanoma (MUM) metastasized only to the liver. [Table 1]

[0264] In this trial, the mPFS for MUM patients with only liver metastases (N = 20 / 20) is about 11 months. "N" refers to the number of patients. [Table 2]

[0265] Example 1A: Update of Example 1 The following shows the data (as of April 11, 2024) of a clinical trial (NCT number 03947385) for patients administered Compound 1 and Compound 2 for treating uveal melanoma (MUM) metastasized only to the liver. [Table 3]

[0266] In this trial, the mPFS for MUM patients with only liver metastases (N = 29) is about 7.6 months [95% CI: 5, 13.6], and the median duration of response (mDOR) (n = 10) is 9.0 months [95% CI: 1.9, 15.9]. [Table 4]

[0267] As of April 11, 2024, eight patients had been administered compound 1 at 200 mg (BID) and compound 2 at 200 mg (BID). Please refer to Tables 5 and 6 below. [Table 5]

[0268] In this study, the mPFS for liver-only MUM patients (N=8) (compound 1 at 200 mg (BID) and compound 2 at 200 mg (BID) was approximately 5.1 months [95% CI: 3.7, -]. "-" indicates that the upper limit of the CI has not yet been determined. "CI" refers to the confidence interval. [Table 6]

[0269] Safety Summary: The most common adverse events (AEs) suspected to be associated with concomitant treatment of compound 1 and compound 2 in patients (n=39) across both schedules (n=39, all grades, ≥20% of points) were diarrhea (92.3%), nausea (82.1%), acneiform dermatitis (59%), peripheral edema (56.4%), vomiting (43.6%), hypoalbuminemia (35.9%), dizziness (33.3%), fatigue (30.8%), anemia (20.5%), constipation (20.5%), and hypotension (20.5%). The majority of grade I and systemic AEs were grade (gr) 1 / 2. Eight Grade 3 / 4 adverse events (AEs) suspected to be associated with the combined treatment of Compound 1 and Compound 2 were reported (20.5%). The most common were Grade 3 syncope (10.3%), Grade 3 anemia (5.1%), and ECG QT prolongation (5.1%). One case of Grade 4 neutropenia (2.6%) was also reported. All other Grade 3 AEs occurred in one patient each (2.6%). No Grade 5 AEs were observed.

[0270] Invasive liver clamp treatment with melphalan demonstrated a disease control rate (DCR) of 76.3% (Zager JS, Orloff MM, Ferrucci PF, et al.: FOCUS phase 3 trial results: Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases (PHP-OCM-301 / 301A). J Clin Oncol 40:9510, 2022). This is lower than oral treatment with compound 1 and compound 2 in combination.

[0271] The clinical trial referenced herein (NCT number 03947385) was conducted under the following patient inclusion and exclusion criteria: Inclusion criteria: • Patients must be 18 years of age or older. • You have been diagnosed with one of the following conditions: MUM: Uveal melanoma with histologically or cytologically confirmed metastatic disease. • Measurable diseases • The US East Coast Cancer Clinical Trials Group has a score of ≤1 and an estimated life expectancy of >3 months. • Sufficient organ function at the time of screening. • In the case of male patients who have not received contraception treatment and female patients who may become pregnant, adequate contraception must be in place. Additional inclusion criteria when crizotinib is used in combination: • Prior chemotherapy, other applicable therapies, or major surgery must be completed at least four weeks before initiating crizotinib. • In patients with a history of peripheral neuropathy, if the grade is 1 or less, it can be included before initiating crizotinib. Exclusion criteria: Symptomatic brain metastases have been confirmed. • History of treatment with PKC inhibitors • Patients with confirmed MSI-H / dMMR tumors who have no history of receiving immune checkpoint inhibitors. · Adverse events from previous anticancer therapy have not disappeared · An acquired immunodeficiency syndrome (AIDS)-related disease, hepatitis B virus, or hepatitis C virus has been confirmed · Active infection requiring continuous treatment · Have just received surgery or radiotherapy · Previous gastrectomy or upper intestinal resection, or any other gastrointestinal disease or defect · Pregnant or lactating women · Cardiac dysfunction · Treatment with prohibited drugs that cannot be discontinued before participating in the trial · In the case of patients administered the IDE196 powder in capsule (PIC) formulation or crizotinib, allergy to mammalian meat products and gelatin Additional exclusion criteria when combined with crizotinib: · Prior therapy that directly targeted ALK, MET, or ROS1 · Spinal cord compression · History of pneumonia or interstitial lung disease · History of syncope

[0272] This specification describes specific embodiments of the invention, including the best mode contemplated by the inventors for carrying out the invention. After reading the foregoing description, variations of the embodiments of the present disclosure may become apparent to those skilled in the art, and it is contemplated that those skilled in the art may appropriately adopt such variations. Accordingly, the invention is intended to be practiced in other ways than as specifically described herein and is intended to include modifications and equivalents of the subject matter recited in the appended claims as permitted by the applicable law. Further, all combinations of the above elements in all possible variations are included in this application unless otherwise specifically designated herein or clearly inconsistent with the context.

[0273] All patent applications, patents, and printed publications cited herein are incorporated herein by reference in their entirety, except for any definitions, denials or waivers of subject matter, and unless the incorporated material conflicts with the express disclosure herein, in which case the language of this disclosure shall prevail.

Claims

1. A method for treating metastatic uveal melanoma (MUM) in a patient having a liver tumor but essentially no extrahepatic tumors, comprising administering a therapeutically effective dose of a PKC inhibitor to the patient and a therapeutically effective dose of a cMeth inhibitor.

2. A method for treating metastatic uveal melanoma (MUM) in a patient, a) Select patients who have liver tumors but essentially no extrahepatic tumors, b) The method comprising administering to the patient a therapeutically effective dose of a PKC inhibitor and a therapeutically effective dose of a cMeth inhibitor.

3. The method according to claim 1 or 2, wherein the patient is selected by evaluating a screening test.

4. A method for treating metastatic uveal melanoma (MUM) in a patient, a) Selecting patients who have liver tumors but are essentially free of extrahepatic tumors, wherein the selection of such patients is determined by evaluating a screening test. b) The method comprising administering to the patient a therapeutically effective amount of a PKC inhibitor and a therapeutically effective amount of a cMeth inhibitor.

5. The PKC inhibitor is compound 1: 【Chemistry 1】 The method according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. The cMet inhibitor is compound 2: 【Chemistry 2】 The method according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 6, wherein the patient does not have an extrahepatic tumor.

8. The method according to any one of claims 1 to 7, wherein the treatment reduces the size of the liver tumor by at least 10%.

9. The method according to any one of claims 1 to 8, wherein the progression-free survival period of the patient is 3, 4, 5, 6, 7, 8, or 9 months or longer.

10. The method according to any one of claims 1 to 9, wherein the progression-free survival period of the patient is 10 or 11 months or longer.

11. The method according to any one of claims 1 to 10, wherein the treatment has a disease control rate of at least 60%, 70%, 80%, 85%, 90%, 92%, or 95%.

12. The method according to any one of claims 1 to 11, wherein the treatment has a disease control rate of at least 98%.

13. The method according to any one of claims 1 to 12, wherein the treatment has a disease control rate of at least 99%.

14. The method according to any one of claims 5 to 13, wherein compound 1, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered in a total daily dose of about 400 mg to about 600 mg.

15. The method according to any one of claims 5 to 14, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 300 mg.

16. The method according to any one of claims 5 to 14, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 200 mg.

17. The method according to any one of claims 5 to 16, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily.

18. The method according to any one of claims 6 to 17, wherein compound 2, or a pharmaceutically acceptable salt thereof in an equivalent dose, is administered in a total daily dose of about 400 mg to about 500 mg.

19. The method according to any one of claims 6 to 18, wherein compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of about 200 mg.

20. Compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered at a dose of approximately 300 mg daily in a 7-day dosing cycle at least once. The method according to any one of claims 6 to 15 and 17 to 19, wherein compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg daily in a BID in at least one 7-day administration cycle.

21. Compound 1, or an equivalent dose of its pharmaceutically acceptable salt, is administered at a dose of approximately 200 mg daily in a BID (Biochemical Intake) regimen for at least one 7-day dosing cycle. The method according to any one of claims 6 to 14 and 16 to 19, wherein compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg daily in a BID in at least one 7-day administration cycle.

22. The method according to claim 21, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are each administered over at least eight (8) seven-day administration cycles.

23. The above treatment (i) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of 300 mg by BID daily in the first treatment cycle, and subsequent treatments (ii) The method according to any one of claims 6 to 15 and 17 to 20, wherein the administration schedule includes a second treatment cycle of at least one 7-day administration cycle, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 300 mg by BID and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg by BID.

24. The above treatment (i) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of approximately 300 mg by BID on a daily basis, and the following treatment cycles (ii) The method according to any one of claims 6 to 15 and 17 to 20, wherein the administration schedule includes a second treatment cycle of at least three (3) seven-day administration cycles, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of about 300 mg by BID, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of about 200 mg by BID.

25. The above treatment (i) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of 200 mg by BID daily in the first treatment cycle, and subsequent treatment cycles (ii) The method according to any one of claims 6 to 14, 16 to 19, and 21, wherein the administration schedule includes a second treatment cycle of at least one 7-day administration cycle, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of 200 mg by BID, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg by BID.

26. The above treatment (i) A first treatment cycle of at least one 7-day administration cycle, wherein compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone in a dose of approximately 200 mg by BID daily, and the following treatment cycles (ii) The method according to any one of claims 6 to 14, 16 to 19, and 21, wherein the administration schedule includes a second treatment cycle of at least three (3) seven-day administration cycles, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of about 200 mg by BID, and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily in a dose of about 200 mg by BID.

27. The method according to any one of claims 23 to 26, wherein the second treatment cycle comprises at least seven (7) seven-day administration cycles, at least eleven (11) seven-day administration cycles, at least fifteen (15) seven-day administration cycles, at least nineteen (19) seven-day administration cycles, at least twenty-three (23) seven-day administration cycles, or at least twenty-seven (27) seven-day administration cycles.

28. The method according to any one of claims 1 to 27, wherein the metastatic uveal melanoma is a solid tumor.

29. The method according to claim 28, wherein the solid tumor has a GNAQ mutation or a GNA11 mutation.

30. The method according to any one of claims 6 to 29, wherein compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof and compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof are administered separately.

31. The method according to any one of claims 3 to 30, wherein the screening test is selected from CT scan, MRI, PET scan, ultrasound examination, and X-ray examination, or a combination thereof.

32. The method according to any one of embodiments 8 to 31, wherein the reduction in the size of the liver tumor is measured using the RECIST 1.1 criterion.

33. The method according to any one of claims 1 to 32, wherein it is recognized that the patient requires such treatment.

34. The method according to any one of claims 1 to 33, wherein the PKC inhibitor or a pharmaceutically acceptable salt thereof and the cMet inhibitor or a pharmaceutically acceptable salt thereof are each administered orally.

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