EP4698282A1 - Verfahren zur behandlung von nur lebermetastatischem uvealem melanom - Google Patents

Verfahren zur behandlung von nur lebermetastatischem uvealem melanom

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Publication number
EP4698282A1
EP4698282A1 EP24793593.5A EP24793593A EP4698282A1 EP 4698282 A1 EP4698282 A1 EP 4698282A1 EP 24793593 A EP24793593 A EP 24793593A EP 4698282 A1 EP4698282 A1 EP 4698282A1
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EP
European Patent Office
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
dose
administered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24793593.5A
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English (en)
French (fr)
Inventor
Matthew Anthony MAURER
Yujiro Hata
Michael Gabriel O'QUIGLEY
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Pfizer Inc
Ideaya Biosciences Inc
Original Assignee
Pfizer Inc
Ideaya Biosciences Inc
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Publication date
Application filed by Pfizer Inc, Ideaya Biosciences Inc filed Critical Pfizer Inc
Publication of EP4698282A1 publication Critical patent/EP4698282A1/de
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Uveal melanoma is the most common primary intraocular malignant tumor in adults.
  • Certain protein kinase inhibitors are described in International Publication Nos. WO 02/38561 and WO 2008/106692.
  • PKC protein kinase C
  • Sotrastaurin has been shown to have activity against certain PKC isototypes and has only recently been shown to selectively inhibit the growth of uveal melanoma cells harboring GNAQ mutations by targeting PKC/ERK1/2 and PKC/NF-xB pathways (see X. Wu, et al., Mol. Cancer Then, Vol. 11, pages 1905-1914, 2012).
  • PCT Application No. PCT/IB2015/055951 discloses a number of potent and selective PKC inhibitors.
  • c-MET receptor has been shown to be expressed in a number of human cancers.
  • c-MET and its ligand, HGF have also been shown to be co-expressed at elevated levels in a variety of human cancers (particularly sarcomas).
  • HGF histone growth factor
  • c-MET signaling is most commonly regulated by tumor-stroma (tumor-host) interactions.
  • c-MET gene amplification, mutation, and rearrangement have been observed in a subset of human cancers. Families with germline mutations that activate c-MET kinase are prone to multiple kidney tumors as well as tumors in other tissues.
  • Uveal melanoma has an associated approximate 40% risk of metastasizing to the liver within 10 years of diagnosis of the primary tumor.
  • Hepatic metastases which occur in 95% of patients with metastatic uveal melanoma, result in death in almost all cases. It is therefore important to understand the pathology of metastatic uveal melanoma (MUM) to the liver in order to develop rational treatment protocols.
  • MUM metastatic uveal melanoma
  • MUM metastatic uveal melanoma
  • Also provided herein is a method of treating metastatic uveal melanoma (MUM) in a patient, the method comprising: a) selecting a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor; and b) administering a therapeutically effective amount of a PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.
  • MUM metastatic uveal melanoma
  • a method of treating metastatic uveal melanoma comprising: a) selecting a patient having a hepatic tumor and essential absence of an extra-hepatic tumor, wherein the patient selection is determined by assessing a screening test; and b) administering a therapeutically effective amount of a PKC inhibitor and a therapeutically effective amount of a cMet inhibitor to the patient.
  • the PKC inhibitor is Compound 1 (darovasertib).
  • the cMET inhibitor is Compound 2 (crizotinib). DETAILED DESCRIPTION
  • MUM metastatic uveal melanoma
  • the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. For example, a dose of about 300 mg may be understood to mean that the dose may vary between 270 mg and 330 mg.
  • the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.”
  • the terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps.
  • such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated compounds, which allows the presence of only the named compounds, along with any pharmaceutically acceptable carriers, and excludes other compounds.
  • ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • a dose range of “about 200 mg to about 600 mg” should be interpreted to include not only the explicitly recited concentration of about 200 mg to about 600 mg, but also include individual dosage (e.g., 250 mg, 400 mg, 550 mg) and the sub-ranges (e.g., 250 mg to 450 mg) within the indicated range.
  • a tumor size reduction of “30%-50%” should be interpreted to include not only the explicitly recited concentration of about 30% to about 50%, but also include individual percentages (e.g., 35%, 40%, 50%) and the sub-ranges (e.g., 35%-45%) within the indicated range.
  • the term “about” can include ⁇ 1%, ⁇ 2%, ⁇ 3%, ⁇ 4%, ⁇ 5%, ⁇ 6%, ⁇ 7%, ⁇ 8%, ⁇ 9%, or ⁇ 10%, of the numerical value(s) being modified.
  • the phrase “about ‘x’ to ‘y’” includes “about ‘x’ to about ‘y’”.
  • combination refers to either a fixed combination in one dosage unit form, or non- fixed combination in separate dosage forms, or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently, at the same time or separately within time intervals.
  • non- fixed combination means that the active ingredients, e.g., Compound 1 and Compound 2, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • composition therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure.
  • administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of active ingredients or in separate formulations (i.e., in separate dosage units, for example, separate tablets, capsules and/or intravenous formulations) for each active ingredient.
  • administration also encompasses the use of each type of therapeutic agents in a sequential or separate manner, either at approximately the same time or at different times. Regardless of whether the active ingredients are administered as a single formulation or in separate formulations, the agents are administered to the same patient as part of the same course of therapy.
  • the agents may be administered at the same point in time or immediately following one another.
  • the agents may be administered at any order.
  • the agents may be administered separately at different times during the course of therapy in such time intervals that the combination therapy is effective in treating cancer.
  • the treatment regimen will provide beneficial effects in treating the conditions or disorders described herein.
  • free base equivalent refers to the amount of the active agent (e.g., Compound 1 or Compound 2) present in the active agent or pharmaceutically acceptable salt thereof. Stated alternatively, the term “free base equivalent” means either an amount of Compound 1 or Compound 2 free base, or the equivalent amount of Compound 1 or Compound 2 free base that is provided by a salt of said compound.
  • Metastasis or “metastatic” is meant the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.
  • essential absence indicates that there was no detectable presence of a tumor as determined by common techniques in the art of cancer therapy and diagnostics.
  • progression free survival for a patient is defined as the number of days from the first date of treatment to the date of the first documented disease progression (Progressive Disease (PD)) or date of death, whichever occurs first.
  • Progressive Disease (PD) in a patient is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum, or nadir measurement on study. This includes the baseline sum if that is the smallest sum measured. There could also be a new lesion, or a non-target lesion that has unequivocal progression.
  • mPFS Median progression free survival
  • DCR Disease control rate
  • the phrase “Partial response (PR)” in a patient is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
  • SSD Stable Disease
  • PR partial response
  • PD progressive disease
  • ORR Overall response rate
  • treating refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (z.e., arresting further development of the pathology and/or symptomology) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and/or symptomology) such as decreasing the severity of the disease.
  • the term “patient,” “individual,” or “subject” refers to a human or a non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and marine mammals.
  • the patient, subject, or individual is human.
  • First-Line MUM patients refers to patients that were not given prior systemic treatment in the metastatic setting including no prior embolization, no radiation to the metastatic sites or ablation to the liver lesions.
  • Any-Line MUM patients refers to all patients that meet the patient eligibility criteria in the clinical trial as disclosed herein. Any-line MUM patients include (1) First-line MUM patients and (2) patients who had received prior therapies other than the combination (Compound 1 and Compound 2) as disclosed herein.
  • the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein a parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts described herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts discussed herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • pharmaceutically acceptable salt is not limited to a mono, or 1 : 1, salt.
  • “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • composition refers to a mixture of at least one compound with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the composition to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound disclosed herein, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic s
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of a compound disclosed herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) disclosed herein.
  • Other additional ingredients that may be included in the pharmaceutical compositions are known in the art and described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • RECIST 1.1 refers to Response Evaluation Criteria In Solid Tumors (RECIST) guidelines version 1.1. See. Eisenhauer et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. Reduction in tumor size of a patient is defined as tumor size reduction as measured using RECIST 1.1 criteria.
  • single formulation refers to a single carrier or vehicle formulated to deliver effective amounts of both therapeutic agents to a patient.
  • the single vehicle is designed to deliver an effective amount of each of the agents, along with any pharmaceutically acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.
  • unit dose is used herein to mean simultaneous administration of both agents together, in one dosage form, to the patient being treated.
  • the unit dose is a single formulation.
  • a unit dose as used herein can also refer to the simultaneous administration of both agents separately, in two dosage forms, to the patient being treated.
  • the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the agents along with pharmaceutically acceptable carriers and excipients.
  • the unit dose is one or more tablets, capsules, pills, or patches administered to the patient at the same time.
  • the dose amounts (for Compound 1 and Compound 2) are expressed as free base equivalent amounts, unless indicated otherwise.
  • the combination of agents described herein may display a synergistic effect. See, for example, Wagle, M-C., et al., Preclinical evaluation ofPKC and MET inhibitor combination in primary and metastatic uveal melanoma, AACR Meeting 2021, the entire content of which is hereby incorporated by reference.
  • the term “synergistic effect” as used herein refers to action of two agents such as, for example, Compound 1 and Compound 2, producing an effect, for example, slowing the symptomatic progression of cancer or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)).
  • Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
  • the term “synergy” refers to the effect achieved when the active ingredients, i.e., Compound 1 and Compound 2, used together is greater than the sum of the effects that results from using the compounds alone.
  • a combination therapy comprising an effective amount of Compound 1 and Compound 2.
  • An “effective amount” of a combination of agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorders treated with the combination.
  • oral dose form includes a unit dose form prescribed or intended for oral administration.
  • normal lactate dehydrogenase (LDH) level means a range of LDH between 40-250 Units/Liter.
  • a method of treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor comprising administering a therapeutically effective amount of a PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.
  • MUM metastatic uveal melanoma
  • a method of treating metastatic uveal melanoma comprising: a) selecting a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor; and b) administering a therapeutically effective amount of a PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.
  • the patient is selected by assessing a screening test.
  • a method of treating metastatic uveal melanoma comprising: a) selecting a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor, wherein the patient selection is determined by assessing a screening test; and b) administering a therapeutically effective amount of a PKC inhibitor and a therapeutically effective amount of a cMet inhibitor to the patient.
  • the PKC inhibitor is Compound 1 :
  • the cMet inhibitor is Compound 2:
  • the patient has a hepatic tumor but does not have an extra-hepatic tumor.
  • the patient is human. In some embodiments, the patient is an adult of at least 18 years of age.
  • the treatment reduces the size of the hepatic tumor by at least about 10%. In some embodiments, the treatment reduces the size of the hepatic tumor by at least about 20%. In some embodiments, the treatment reduces the size of the hepatic tumor by at least about 30%. In some embodiments, the treatment reduces the size of the hepatic tumor by at least about 40%. In some embodiments, the treatment reduces the size of the hepatic tumor by at least about 50%.
  • the treatment reduces the size of the hepatic tumor by at least 10%. In some embodiments, the treatment reduces the size of the hepatic tumor by at least
  • the treatment reduces the size of the hepatic tumor by at least
  • the treatment reduces the size of the hepatic tumor by at least
  • the treatment reduces the size of the hepatic tumor by at least
  • the treatment reduces the hepatic tumor in a size of from about 10% to about 70%. In some embodiments, the treatment reduces the hepatic tumor in a size of from about 10% to about 60%. In some embodiments, the treatment reduces the hepatic tumor in a size of from about 10% to about 50%. In some embodiments, the treatment reduces the size of hepatic tumor in an average of at least about 30%. [0062] In some embodiments, the treatment reduces the hepatic tumor in a size of from 10% to 70%. In some embodiments, the treatment reduces the hepatic tumor in a size of from 10% to 60%. In some embodiments, the treatment reduces the hepatic tumor in a size of from 10% to 50%. In some embodiments, the treatment reduces the size of hepatic tumor in an average of at least 30%.
  • the patient has a progression free survival of greater than or equal to 3 months. In another embodiment, the patient has a progression free survival of greater than or equal to 4, 5, 6, 7, or 8 months. In yet another embodiment, the patient has a progression free survival of greater than or equal to 5 months. In yet another embodiment, the patient has a progression free survival of greater than or equal to 6 months. In still another embodiment, the patient has a progression free survival of greater than or equal to 7 months. In yet another embodiment, the patient has a progression free survival of greater than or equal to 8 months. In an embodiment, the patient has a progression free survival of greater than or equal to 9 months. In another embodiment, the patient has a progression free survival of greater than or equal to 10 months. In yet another embodiment, the patient has a progression free survival of greater than or equal to 11 months. In still another embodiment, the patient has a progression free survival of greater than or equal to 3, 5, 7, 9, 10, or 11 months.
  • 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 about 100%.
  • 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 still another embodiment, the treatment has a disease control rate of at least 90%. In an 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 still 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%.
  • Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof is administered at a dosage of about 400 mg to about 600 mg daily.
  • Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof is administered in a total daily dosage of about 400 mg to about 600 mg. In some embodiments, Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dosage of 400 mg to 600 mg.
  • Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof is administered in a total daily dosage of about 200 mg to about 600 mg. In some embodiments, Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dosage of 200 mg to 600 mg.
  • Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof is administered at a dose of about 300 mg two times per day (BID). In some embodiments, Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg two times per day (BID).
  • Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg two times per day (BID). In some embodiments, Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg two times per day (BID). In some embodiments, Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg two times per day (BID). In some embodiments, Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg two times per day (BID).
  • Compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg to about 500 mg daily.
  • Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof is administered in a total daily dosage of about 400 mg to about 500 mg. In some embodiments, Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dosage of 400 mg to 500 mg. [0073] In an embodiment, Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg two times per day (BID). In some embodiments, Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg two times per day (BID).
  • Compound 2, or an equivalent dose of pharmaceutically acceptable salt thereof is administered daily. In some embodiments, Compound 2, or an equivalent dose of 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 pharmaceutically acceptable salt thereof, is administered every 3 days (e.g., administered on day 1 and not administered on days 2-3).
  • 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.
  • 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 independently administered every other day (e.g., on day 1, Compounds 1 and 2 are both administered, and on day 2, Compounds 1 and 2 are not administered; or on day 1, Compound 1 is administered and Compound 2 is not administered, and on day 2, Compound 1 is not administered and Compound 2 is administered).
  • 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 independently administered every 3 days, wherein Compound 1 and Compound 2 are administered on the same day or on a different day.
  • the treatment is according to 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 at a dose of about 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle.
  • the treatment is according to 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 at a dose of about 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle.
  • the treatment is according to 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 at a dose of 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle.
  • the treatment is according to 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 at a dose of 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle.
  • the second treatment cycle comprises at least seven (7) 7-day dosing cycles. In some embodiments, the second treatment cycle comprises at least eleven (11) 7-day dosing cycles. In some embodiments, the second treatment cycle comprises 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 dosing cycles.
  • Compound 1 or a pharmaceutically acceptable salt thereof, is administered at a dose of about 600 mg daily based on a free base equivalent of Compound 1;
  • Compound 2 or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 mg daily based on a free base equivalent of Compound 2.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered at a total daily dosage of about 600 mg based on a free base equivalent of Compound 1; and Compound 2, or a pharmaceutically acceptable salt thereof, is administered at a total daily dosage of about 400 mg based on a free base equivalent of Compound 2.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered at a total daily dosage of 600 mg based on a free base equivalent of Compound 1; and Compound 2, or a pharmaceutically acceptable salt thereof, is administered at a total daily dosage of 400 mg based on a free base equivalent of Compound 2.
  • the second treatment cycle comprises at least one 7-day dosing cycle.
  • the 7-day dosing cycle comprises 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, daily.
  • 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 at each of the dosages as described in any one of forgoing embodiments.
  • Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg BID every day of at least one 7-day dosing cycle; and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle.
  • Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily at a dose of 300 mg BID for at least one 7-day dosing cycle; and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily at a dose of 200 mg BID for at least one 7-day dosing cycle.
  • the treatment comprises a first treatment cycle and a second treatment cycle, each of which is described above.
  • the first treatment cycle comprises at least one 7-day dosing cycle, wherein Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone.
  • the first treatment cycle comprises at least one 7-day dosing cycle, wherein Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone at each of the dosages as described in any one of forgoing embodiments.
  • the second treatment cycle comprises at least seven (7) 7-day dosing cycles, 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.
  • the second treatment cycle comprises at least seven (7) 7-day dosing cycles, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound 2, or an equivalent dose of pharmaceutically acceptable salt thereof, are each administered at each of the dosages as described in any one of forgoing 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 for at least seven (7) 7-day dosing cycles (as described above).
  • the metastatic uveal melanoma is a solid tumor.
  • the solid tumor harbors a GNAQ or GNA11 mutation.
  • 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 in a single formulation.
  • 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 in a single formulation further comprising one or more pharmaceutically acceptable carriers.
  • 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 in a single formulation further comprising one or more pharmaceutically acceptable carriers.
  • 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.
  • the screening test is selected from CT scan, MRI, PET scan, ultrasound, and X-ray, or a combination thereof.
  • the screening test is CT scan (also called CAT scan or computed tomography scan).
  • the screening test is MRI (Magnetic Resonance Imaging).
  • the screening test is PET scan (Positron Emission Tomography).
  • the screening test is ultrasound.
  • the screening test is X-ray.
  • the method of treating MUM can further comprise: continuing to administer 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, uninterrupted during a dosing schedule comprising at least two or more consecutive 7-day dosing cycles, or preferably at least four or more consecutive 7-day dosing cycles.
  • the treatment is interrupted followed by restarting the treatment according to dosing schedules disclosed herein.
  • the treatment is according to 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 at a dose of about 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle, wherein the treatment is uninterrupted during the second treatment cycle of at least three 7-day dosing cycles or at least seven (7) 7-day dosing cycles.
  • the treatment is according to a dosing schedule comprising
  • a first treatment cycle of one 7-day dosing cycle wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone at a dose of 300 mg BID every day of the first treatment cycle, followed by (ii) 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 at a dose of 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle, wherein the treatment is uninterrupted during the second treatment cycle of at least three 7- day dosing cycles or at least seven (7) 7-day dosing cycles.
  • 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 continued to be co-administered uninterrupted during a dosing schedule comprising at least eight or more, twelve or more, twenty-four or more, forty-eight or more or ninety-six or more consecutive 7-day dosing cycles.
  • Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof is continued to be co-administered uninterrupted during a dosing schedule comprising at least eight or more, twelve or more, twenty- four or more, forty-eight or more or ninety-six or more consecutive 7-day dosing cycles.
  • Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof is continued to be coadministered uninterrupted during a dosing schedule comprising at least eight or more, twelve or more, twenty-four or more, forty-eight or more or ninety-six or more consecutive 7- day dosing cycles.
  • Exemplary lengths of time associated with the course of the treatment methods is about five years, about, 4 years, about 3 years, about 2 years, about 1 year, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, or about 1 month.
  • Exemplary lengths of time associated with the course of the treatment methods is about five years and so on; or any days, weeks, months, or years in between; for example a treatment cycle can include 5 months and additional weeks and/or days, or one year and additional months, weeks, and/or days, and the like.
  • 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 continuously (i.e., a continuous treatment until termination).
  • the GNAQ or GNA11 tumor to be treated can include one or more mutations, including a substitution mutation, an insertion mutation, and/or a deletion in GNAQ or GNA11 mutation.
  • the GNAQ or GNA11 mutation is a gain of function mutation.
  • the GNAQ or GNA11 mutation activates the PKC signaling pathway.
  • the GNAQ or GNA11 mutation can be the substitution of glutamine in codon 209 (Q209) and/or a substitution of arginine in codon 183 (R183).
  • the GNAQ or GNA11 mutation can be a substitution other than glutamine in codon 209 (Q209), other than a substitution of arginine in codon 183 (R183), or other than both.
  • the GNAQ mutation is one of Q209P, Q209L, Q209H, Q209K, or Q209Y, or the GNA11 mutation is one of Q209P, Q209L, Q209K or Q209H.
  • the GNAQ mutation can be R183Q, or the GNA11 mutation can be R183C or R183H.
  • the GNAQ or GNA11 mutation is at one or more of R256, L279, R166, A168, R210, R213, R166, A231, A342, D333, G171, R147, R73, T47, E191, E221, R149, T175, T379, T85, A86, E163, D195, E319, E191, E280, E49, P293, R300, R338, R60, D155, D205, D321, 1226, R37, or V240.
  • the GNAQ or GNA11 tumor can comprise one or more of a Q209P, Q209L, Q209H, Q209K, Q209Y, or R183Q mutation in GNAQ, or the GNAQ or GNA11 tumor can comprise one or more of a Q209P, Q209L, Q209H, or Q209K mutation in GNA11. Additional examples of mutations in GNAQ or GNA11 are described in WO 2020/146355, which is incorporated by reference herewith in its entirety.
  • Exemplary lengths of time associated with the course of the treatment methods disclosed herein include: about one week; about two weeks; about three weeks; about four weeks; about five weeks; about six weeks; about seven weeks; about eight weeks; about nine weeks; about ten weeks; about eleven weeks; about twelve weeks; about thirteen weeks; about fourteen weeks; about fifteen weeks; about sixteen weeks; about seventeen weeks; about eighteen weeks; about nineteen weeks; about twenty weeks; about twenty-one weeks; about twenty-two weeks; about twenty-three weeks; about twenty four weeks; about 4 months; about seven months; about eight months; about nine months; about ten months; about eleven months; about twelve months; about thirteen months; about fourteen months; about fifteen months; about sixteen months; about seventeen months; about eighteen months; about nineteen months; about twenty months; about twenty one months; about twenty-two months; about twenty-three months; about twenty-four months; about thirty months; about three years; about four years and about five years and so on; or any days, weeks, months, or years in between; for example a treatment cycle
  • both Compound 1 and Compound 2 are administered orally.
  • the method involves the administration of a therapeutically effective amount of a combination or composition comprising compounds provided herein, or pharmaceutically acceptable salts thereof, to a subject (including, but not limited to a human or animal) in need of treatment (including a subject identified as in need).
  • the treatment includes co- administering 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.
  • 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 in a single formulation or unit dose form.
  • 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 in separate formulations or unit dose forms.
  • the treatment can include administering 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, at substantially the same time or administering 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, at different times.
  • the amount of Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, and/or the amount of Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both 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, is administered alone, but which amounts are effective in combination.
  • the subject is a First-Line subject. In another embodiment, the subject is a First-Line MUM subject.
  • extra-hepatic tumor refers to any tumor outside of liver.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of pain, a depressive disorder, or drug addiction in a patient.
  • the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • Routes of administration of any of the compositions discussed herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • the preferred route of administration is oral.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may 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, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.
  • the present disclosure provides a kit for treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extrahepatic tumor, comprising Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, in a dosage of about 400 mg to about 600 mg, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, in a dosage of about 400 mg to about 500 mg.
  • MUM metastatic uveal melanoma
  • the present disclosure provides a kit for treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor, comprising Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, in an amount of about 300 mg, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, in an amount of about 200 mg.
  • MUM metastatic uveal melanoma
  • the present disclosure provides a kit for treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extrahepatic tumor, comprising Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, in an amount from about 400 mg per day to about 600 mg per day, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, in an amount from about 400 mg per day to about 500 mg per day.
  • the kit further comprises packaging and instructions.
  • kits are provided.
  • the kit includes a sealed container approved for the storage of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions.
  • the sealed container minimizes the contact of air with the ingredients, e.g., an airless bottle.
  • the sealed container is a sealed tube.
  • An instruction for the use of the composition and the information about the composition are to be included in the kit.
  • the compounds of the combination can be dosed on the same schedule, whether by administering a single formulation or unit dose form containing all of the compounds of the combination, or by administering separate formulations or unit dose forms of the compounds of the combination.
  • the kit contains a formulation or unit dose form containing all of the compounds in the combination of compounds, and an additional formulation or unit dose form that includes one of the compounds in the combination of agents, with no additional active compound, in a container, with instructions for administering the dose forms on a fixed schedule.
  • kits provided herein comprise prescribing information, for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation.
  • Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.
  • a kit provided herein can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing).
  • a kit can contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism(s) of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.).
  • Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package.
  • Labels or inserts can include manufacturer information such as lot numbers and expiration dates.
  • the label or packaging insert can be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, syringe or vial).
  • Embodiment 1 A method of treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor, the method comprising administering a therapeutically effective amount of a PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.
  • MUM metastatic uveal melanoma
  • Embodiment 2 A method of treating metastatic uveal melanoma (MUM) in a patient, the method comprising: a) selecting a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor; and b) administering a therapeutically effective amount of a PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.
  • MUM metastatic uveal melanoma
  • Embodiment 3 The method of embodiment 1 or 2, wherein the patient is selected by assessing a screening test.
  • Embodiment 4 A method of treating metastatic uveal melanoma (MUM) in a patient, the method comprising: a) selecting a patient having a hepatic tumor and essential absence of an extra-hepatic tumor, wherein the patient selection is determined by assessing a screening test; and b) administering a therapeutically effective amount of a PKC inhibitor and a therapeutically effective amount of a cMet inhibitor to the patient.
  • MUM metastatic uveal melanoma
  • Embodiment 5 The method of any one of embodiments 1 to 4, wherein the PKC inhibitor is Compound 1 :
  • Embodiment 6 The method of any one of embodiments 1 to 5, wherein the cMet inhibitor is Compound 2: or a pharmaceutically acceptable salt thereof.
  • Embodiment 7 The method of any one of embodiments 1 to 6, wherein the patient does not have an extra-hepatic tumor.
  • Embodiment 8 The method of any one of embodiments 1 to 7, wherein the patient is an adult of at least 18 years of age.
  • Embodiment 9 The method of any one of embodiments 1 to 8, wherein the treatment reduces a size of the hepatic tumor by at least 10%.
  • Embodiment 10 The method of any one of embodiments 1 to 8, wherein the treatment reduces a size of the hepatic tumor by at least about 10%.
  • Embodiment 11 The method of any one of embodiments 1 to 10, wherein the patient has a progression free survival of greater than or equal to 3 months.
  • Embodiment 12 The method of any one of embodiments 1 to 11, wherein the patient has a progression free survival of greater than or equal to 4, 5, 6, 7, or 8 months.
  • Embodiment 13 The method of any one of embodiments 1 to 12, wherein the patient has a progression free survival of greater than or equal to 9 months.
  • Embodiment 14 The method of any one of embodiments 1 to 13, wherein the patient has a progression free survival of greater than or equal to 10 months.
  • Embodiment 15 The method of any one of embodiments 1 to 14, wherein the patient has a progression free survival of greater than or equal to 11 months.
  • Embodiment 16 The method of any one of embodiments 1 to 15, wherein the treatment has a disease control rate of at least 60%, 70%, or 80%.
  • Embodiment 17 The method of any one of embodiments 1 to 16, wherein the treatment has a disease control rate of at least 85%.
  • Embodiment 18 The method of any one of embodiments 1 to 17, wherein the treatment has a disease control rate of at least 90%.
  • Embodiment 19 The method of any one of embodiments 1 to 18, wherein the treatment has a disease control rate of at least 92%.
  • Embodiment 20 The method of any one of embodiments 1 to 19, wherein the treatment has a disease control rate of at least 95%.
  • Embodiment 21 The method of any one of embodiments 1 to 20, wherein the treatment has a disease control rate of at least 98%.
  • Embodiment 22 The method of any one of embodiments 1 to 21, wherein the treatment has a disease control rate of at least 99%.
  • Embodiment 23 The method of any one of embodiments 5 to 22, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 mg to about 600 mg daily.
  • Embodiment 24 The method of any one of embodiments 5 to 22, wherein
  • Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dosage of about 400 mg to about 600 mg.
  • Embodiment 25 The method of any one of embodiments 5 to 24, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily.
  • Embodiment 26 The method of any one of embodiments 5 to 25, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg two times per day (BID).
  • Embodiment 27 The method of any one of embodiments 5 to 25, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg two times per day (BID).
  • Embodiment 28 The method of any one of embodiments 6 to 27, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 mg to about 500 mg daily.
  • Embodiment 29 The method of any one of embodiments 6 to 27, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a total daily dosage of about 400 mg to about 500 mg.
  • Embodiment 30 The method of any one of embodiments 6 to 29, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily.
  • Embodiment 31 The method of any one of embodiments 6 to 30, wherein
  • Compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg two times per day (BID).
  • Embodiment 32 The method of any one of embodiments 6 to 30, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 250 mg two times per day (BID).
  • Embodiment 33 The method of any one of embodiments 6 to 26 and 28 to 30, wherein Compound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg BID every day of at least one 7-day dosing cycle; and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle.
  • Embodiment 34 The method of any one of embodiments 6 to 26 and 28 to 30, wherein
  • Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily at a dose of about 300 mg BID for at least one 7-day dosing cycle;
  • Compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily at a dose of about 200 mg BID for at least one 7-day dosing cycle.
  • Embodiment 35 The method of any one of embodiments 6 to 25 and 27 to 30, wherein
  • Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle; and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle.
  • Embodiment 36 The method of 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 for at least seven (7) 7-day dosing cycles.
  • Embodiment 37 The method of 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 for at least eight (8) 7-day dosing cycles, at least twelve (12) 7-day dosing cycles, at least sixteen (16) 7-day dosing cycles, at least twenty (20) 7-day dosing cycles, at least twenty four (24) 7-day dosing cycles, or at least twenty eight (28) 7-day dosing cycles.
  • Embodiment 38 The method of any one of embodiments 6 to 26 and 28 to 30, wherein the treatment is according to a dosing schedule comprising
  • a first 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 alone at a dose of 300 mg BID every day of the first treatment cycle, followed by (ii) 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 at a dose of 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle.
  • Embodiment 39 The method of any one of embodiments 6 to 26 and 28 to 30, wherein the treatment is according to a dosing schedule comprising
  • a second treatment cycle of at least three (3) 7-day dosing cycles wherein Compound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle.
  • Embodiment 40 The method of any one of embodiments 6 to 25 and 27 to 30, wherein the treatment is according to 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 at a dose of 200 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle.
  • Embodiment 41 The method of any one of embodiments 6 to 25 and 27 to 30, wherein the treatment is according to a dosing schedule comprising
  • a second treatment cycle of at least three (3) 7-day dosing cycles wherein Compound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle.
  • Embodiment 42 The method of any one of embodiments 38 to 41, wherein the second treatment cycle comprises at least seven (7) 7-day dosing cycles, at least eleven (11) 7-day dosing cycles, at least fifteen (15) 7-day dosing cycles, at least nineteen (19) 7-day dosing cycles, at least twenty-three (23) 7-day dosing cycles, or at least twenty seven (27) 7- day dosing cycles.
  • Embodiment 43 The method of any one of embodiments 5 to 42, wherein the treatment is uninterrupted.
  • Embodiment 44 The method of any one of embodiments 1 to 43, wherein the metastatic uveal melanoma is a solid tumor.
  • Embodiment 45 The method of embodiment 44, wherein the solid tumor harbors a GNAQ or GNA11 mutation.
  • Embodiment 46 The method of 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 in a single formulation.
  • Embodiment 47 The method of 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 in a single formulation further comprising one or more pharmaceutically acceptable carriers.
  • Embodiment 48 The method of 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.
  • Embodiment 49 The method of any one of embodiments 3 to 48, wherein the screening test is selected from CT scan, MRI, PET scan, ultrasound, and X-ray, or a combination thereof.
  • Embodiment 50 The method of embodiment 49, wherein the screening test is
  • Embodiment 51 The method of embodiment 49, wherein the screening test is
  • Embodiment 52 The method of embodiment 49, wherein the screening test is ultrasound.
  • Embodiment 53 The method of any one of embodiments 9 to 52, wherein reduction in the size of the hepatic tumor is measured using RECIST 1. 1 criteria.
  • Embodiment 54 The method of any one of embodiments 9 to 52, wherein the size of the hepatic tumor is measured using CT scan, MRI, ultrasound, or a combination thereof.
  • Embodiment 55 The method of any one of embodiments 1 to 54, wherein the patient is human leukocyte antigen (HLA)-A2 negative.
  • HLA human leukocyte antigen
  • Embodiment 56 The method of any one of embodiments 1 to 54, wherein the patient is human leukocyte antigen (HLA)-A2 positive.
  • HLA human leukocyte antigen
  • Embodiment 57 The method of any one of embodiments 1 to 54, wherein the patient has BRCA 1 -associated protein- 1 (BAP1) mutation.
  • BAP1 BRCA 1 -associated protein- 1
  • Embodiment 58 The method of any one of embodiments 1 to 54, wherein the patient does not have BRCA 1 -associated protein- 1 (BAP1) mutation.
  • BAP1 BRCA 1 -associated protein- 1
  • Embodiment 59 The method of any one of embodiments 1 to 54, wherein the patient has normal lactate dehydrogenase (LDH) level.
  • LDH lactate dehydrogenase
  • Embodiment 60 The method of any one of embodiments 1 to 54, wherein the patient has higher lactate dehydrogenase (LDH) level compared to normal LDH level.
  • LDH lactate dehydrogenase
  • Embodiment 61 The method of any one of embodiments 1 to 60, wherein the patient is in recognized need of such treatment.
  • Embodiment 62 The method of 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.
  • Embodiment 1 A A PKC inhibitor for use in a method of treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor, the method comprising administering a therapeutically effective amount of the PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.
  • MUM metastatic uveal melanoma
  • Embodiment IB A PKC inhibitor for use in treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor, 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.
  • MUM metastatic uveal melanoma
  • Embodiment 1C Use of a PKC inhibitor in the manufacture of a medicament for the treatment of metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor, wherein a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of a cMet inhibitor.
  • MUM metastatic uveal melanoma
  • Embodiment ID A use of a PKC inhibitor for treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extrahepatic tumor, wherein a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of a cMet inhibitor.
  • MUM metastatic uveal melanoma
  • Embodiment 2A A PKC inhibitor for use in a method of treating metastatic uveal melanoma (MUM) in a patient, the method comprising: a) selecting a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor; and b) administering a therapeutically effective amount of the PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.
  • MUM metastatic uveal melanoma
  • Embodiment 2B A PKC inhibitor for use in treating metastatic uveal melanoma (MUM) in a patient, wherein: a) a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor is selected; and b) a therapeutically effective amount of the PKC inhibitor is administered to the patient in combination with a therapeutically effective amount of a cMet inhibitor.
  • MUM metastatic uveal melanoma
  • Embodiment 2C Use of a PKC inhibitor in the manufacture of a medicament for the treatment of metastatic uveal melanoma (MUM) in a patient, wherein: a) a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor is selected; and b) a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of a cMet inhibitor.
  • MUM metastatic uveal melanoma
  • Embodiment 2D A use of a PKC inhibitor for treating metastatic uveal melanoma (MUM) in a patient, wherein: a) a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor is selected; and b) a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of a cMet inhibitor.
  • MUM metastatic uveal melanoma
  • Embodiment 3 The use of embodiments 1A to ID and 2A to 2D, wherein the patient is selected by assessing a screening test.
  • Embodiment 4A A PKC inhibitor for use in a method of treating metastatic uveal melanoma (MUM) in a patient, the method comprising: a) selecting a patient having a hepatic tumor and essential absence of an extra-hepatic tumor, wherein the patient selection is determined by assessing a screening test; and b) administering a therapeutically effective amount of the PKC inhibitor and a therapeutically effective amount of a cMet inhibitor to the patient.
  • MUM metastatic uveal melanoma
  • Embodiment 4B A PKC inhibitor for use in treating metastatic uveal melanoma (MUM) in a patient, wherein: a) a patient having a hepatic tumor and essential absence of an extra-hepatic tumor is selected by assessing a screening test; and b) a therapeutically effective amount of the PKC inhibitor is administered to the patient in combination with a therapeutically effective amount of a cMet inhibitor.
  • MUM metastatic uveal melanoma
  • a PKC inhibitor in the manufacture of a medicament for the treatment of metastatic uveal melanoma (MUM) in a patient, wherein: a) a patient having a hepatic tumor and essential absence of an extra-hepatic tumor is selected by assessing a screening test; and b) a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of a cMet inhibitor.
  • MUM metastatic uveal melanoma
  • Embodiment 4D A use of a PKC inhibitor for treating metastatic uveal melanoma (MUM) in a patient, wherein: a) a patient having a hepatic tumor and essential absence of an extra-hepatic tumor is selected by assessing a screening test; and b) a therapeutically effective amount of the PKC inhibitor is used in combination with a therapeutically effective amount of a cMet inhibitor.
  • MUM metastatic uveal melanoma
  • Embodiment 5 The use of any one of embodiments 1A to 4D, wherein the PKC inhibitor is Compound 1 :
  • Embodiment 6 The use of any one of embodiments 1A to 5, wherein the cMet inhibitor is Compound 2: or a pharmaceutically acceptable salt thereof.
  • Embodiment 7 The use of any one of embodiments 1A to 6, wherein the patient does not have an extra-hepatic tumor.
  • Embodiment 8 The use of any one of embodiments 1A to 7, wherein the patient is an adult of at least 18 years of age.
  • Embodiment 9 The use of any one of embodiments 1A to 8, wherein the treatment reduces a size of the hepatic tumor by at least 10%.
  • Embodiment 10 The use of any one of embodiments 1A to 8, wherein the treatment reduces a size of the hepatic tumor by at least about 10%.
  • Embodiment 11 The use of any one of embodiments 1A to 10, wherein the patient has a progression free survival of greater than or equal to 3 months.
  • Embodiment 12 The use of any one of embodiments 1A to 11, wherein the patient has a progression free survival of greater than or equal to 4, 5, 6, 7, or 8 months.
  • Embodiment 13 The use of any one of embodiments 1A to 12, wherein the patient has a progression free survival of greater than or equal to 9 months.
  • Embodiment 14 The use of any one of embodiments 1A to 13, wherein the patient has a progression free survival of greater than or equal to 10 months.
  • Embodiment 15 The use of any one of embodiments 1A to 14, wherein the patient has a progression free survival of greater than or equal to 11 months.
  • Embodiment 16 The use of any one of embodiments 1A to 15, wherein the treatment has a disease control rate of at least 60%, 70%, or 80%.
  • Embodiment 17 The use of any one of embodiments 1A to 16, wherein the treatment has a disease control rate of at least 85%.
  • Embodiment 18 The use of any one of embodiments 1A to 17, wherein the treatment has a disease control rate of at least 90%.
  • Embodiment 19 The use of any one of embodiments 1A to 18, wherein the treatment has a disease control rate of at least 92%.
  • Embodiment 20 The use of any one of embodiments 1A to 19, wherein the treatment has a disease control rate of at least 95%.
  • Embodiment 21 The use of any one of embodiments 1A to 20, wherein the treatment has a disease control rate of at least 98%.
  • Embodiment 22 The use of any one of embodiments 1 A to 21, wherein the treatment has a disease control rate of at least 99%.
  • Embodiment 23 The use of any one of embodiments 5 to 22, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 mg to about 600 mg daily.
  • Embodiment 24 The use of any one of embodiments 5 to 22, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dosage of about 400 mg to about 600 mg.
  • Embodiment 25 The use of any one of embodiments 5 to 24, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily.
  • Embodiment 26 The use of any one of embodiments 5 to 25, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg two times per day (BID).
  • Embodiment 27 The use of any one of embodiments 5 to 25, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg two times per day (BID).
  • Embodiment 28 The use of any one of embodiments 6 to 27, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 mg to about 500 mg daily.
  • Embodiment 29 The use of any one of embodiments 6 to 27, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a total daily dosage of about 400 mg to about 500 mg.
  • Embodiment 30 The use of any one of embodiments 6 to 29, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily.
  • Embodiment 31 The use of any one of embodiments 6 to 30, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg two times per day (BID).
  • Embodiment 32 The use of any one of embodiments 6 to 30, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 250 mg two times per day (BID).
  • Embodiment 33 The use of any one of embodiments 6 to 26 and 28 to 30, wherein
  • Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg BID every day of at least one 7-day dosing cycle;
  • Compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle.
  • Embodiment 34 The use of any one of embodiments 6 to 26 and 28 to 30, wherein
  • Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily at a dose of about 300 mg BID for at least one 7-day dosing cycle;
  • Compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily at a dose of about 200 mg BID for at least one 7-day dosing cycle.
  • Embodiment 35 The use of any one of embodiments 6 to 25 and 27 to 30, wherein
  • Compound 1 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle;
  • Compound 2 or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle.
  • Embodiment 36 The use of 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 for at least seven (7) 7-day dosing cycles.
  • Embodiment 37 The use of 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 for at least eight (8) 7-day dosing cycles, at least twelve (12) 7-day dosing cycles, at least sixteen (16) 7-day dosing cycles, at least twenty (20) 7-day dosing cycles, at least twenty four (24) 7-day dosing cycles, or at least twenty eight (28) 7-day dosing cycles.
  • Embodiment 38 The use of any one of embodiments 6 to 26 and 28 to 30, wherein the treatment is according to 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 at a dose of 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle.
  • Embodiment 39 The use of any one of embodiments 6 to 26 and 28 to 30, wherein the treatment is according to a dosing schedule comprising
  • a second treatment cycle of at least three (3) 7-day dosing cycles wherein Compound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle.
  • Embodiment 40 The use of any one of embodiments 6 to 25 and 27 to 30, wherein the treatment is according to 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 at a dose of 200 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle.
  • Embodiment 41 The use of any one of embodiments 6 to 25 and 27 to 30, wherein the treatment is according to a dosing schedule comprising
  • a second treatment cycle of at least three (3) 7-day dosing cycles wherein Compound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle.
  • Embodiment 42 The use of any one of embodiments 38 to 41, wherein the second treatment cycle comprises at least seven (7) 7-day dosing cycles, at least eleven (11) 7-day dosing cycles, at least fifteen (15) 7-day dosing cycles, at least nineteen (19) 7-day dosing cycles, at least twenty-three (23) 7-day dosing cycles, or at least twenty seven (27) 7- day dosing cycles.
  • Embodiment 43 The use of any one of embodiments 5 to 42, wherein the treatment is uninterrupted.
  • Embodiment 44 The use of any one of embodiments 1A to 43, wherein the metastatic uveal melanoma is a solid tumor.
  • Embodiment 45 The use of embodiment 44, wherein the solid tumor harbors a GNAQ or GNA11 mutation.
  • Embodiment 46 The use of 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 in a single formulation.
  • Embodiment 47 The use of 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 in a single formulation further comprising one or more pharmaceutically acceptable carriers.
  • Embodiment 48 The use of 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.
  • Embodiment 49 The use of any one of embodiments 3 to 48, wherein the screening test is selected from CT scan, MRI, PET scan, ultrasound, and X-ray, or a combination thereof.
  • Embodiment 50 The use of embodiment 49, wherein the screening test is CT scan.
  • Embodiment 51 The use of embodiment 49, wherein the screening test is MRI.
  • Embodiment 52 The use of embodiment 49, wherein the screening test is ultrasound.
  • Embodiment 53 The use of any one of embodiments 9 to 52, wherein reduction in the size of the hepatic tumor is measured using RECIST 1.1 criteria.
  • Embodiment 54 The use of any one of embodiments 9 to 52, wherein the size of the hepatic tumor is measured using CT scan, MRI, ultrasound, or a combination thereof.
  • Embodiment 55 The use of any one of embodiments 1A to 54, wherein the patient is human leukocyte antigen (HLA)-A2 negative.
  • HLA human leukocyte antigen
  • Embodiment 56 The use of any one of embodiments 1A to 54, wherein the patient is human leukocyte antigen (HLA)-A2 positive.
  • HLA human leukocyte antigen
  • Embodiment 57 The use of any one of embodiments 1A to 54, wherein the patient has BRCA 1 -associated protein- 1 (BAP1) mutation.
  • BAP1 BRCA 1 -associated protein- 1
  • Embodiment 58 The use of any one of embodiments 1A to 54, wherein the patient does not have BRCA 1 -associated protein- 1 (BAP1) mutation.
  • Embodiment 59 The use of any one of embodiments 1A to 54, wherein the patient has normal lactate dehydrogenase (LDH) level.
  • LDH lactate dehydrogenase
  • Embodiment 60 The use of any one of embodiments 1A to 54, wherein the patient has higher lactate dehydrogenase (LDH) level compared to normal LDH level.
  • LDH lactate dehydrogenase
  • Embodiment 61 The use of any one of embodiments 1A to 60, wherein the patient is in recognized need of such treatment.
  • Embodiment 62 The use of 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.
  • reference to embodiments 1A to 7 will include embodiments 1A, IB, 1C, ID, 2A, 2B, 2C, 3D, 3, 4A, 4B, 4C, 4D, 5, 6, and 7.
  • NCT# 03947385 clinical trial data for patients receiving Compound 1 and Compound 2 to treat hepatic-only metastatic uveal melanoma (MUM).
  • N refers to the number of patients.
  • Table 2 All patients were dosed with Compound 1 at 300 mg BID and Compound 2 at 200 mg BID for at least 56 days (8 weeks). “N” refers to the number of patients.
  • Example 1A Updates to Example 1
  • N refers to the number of patients.
  • Gr 3 /4 AEs suspected related to Compound 1 and Compound 2 combination treatment were reported in 8 pts (20.5%), the most common being Grade 3 syncope (10.3%) and Grade 3 anemia (5.1%) and Electrocardiogram QT prolongation (5.1%) and 1 case of Grade 4 Neutropenia (2.6%). All other gr 3 AEs occurred in 1 patient (2.6%) each. There were no Gr 5 AEs.
  • a liver clamp invasive procedure using melphalan shows the 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), which is low compared to the Compound 1 and Compound 2 combination oral treatment.
  • o MUM Uveal melanoma with histological or cytological confirmed metastatic disease.
  • AIDS acquired immunodeficiency syndrome

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