Formulations of STAT3 inhibitors and methods of use thereof

Abstract

Provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject certain doses of a composition comprising a compound of Formula (I) and a polymer excipient.

Description

Attorney Docket No. TVR-013WO FORMULATIONS OF STAT3 INHIBITORS AND METHODS OF USE THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No.63 / 580,555, filed September 5, 2023, which is incorporated by reference in its entirety herein. SUMMARY

[0002] Disclosed herein, in some embodiments, are methods of treating cancer in a subject in need thereof, comprising administering to the subject certain doses of a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a polymer excipient.

[0003] For example, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject between two and twelve tablets per day of a composition comprising: (a) at least 150 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and b) a polymer excipient.

[0004] In some embodiments, the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, gastric cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gall bladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or osteosarcoma. In some embodiments, the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] FIG.1A shows an exemplary pharmacokinetics profile at Day 29 from a Phase 2 clinical trial for the compound of Formula (I).

[0006] FIG.1B shows an exemplary pharmacokinetics profile at Day 22 from a Phase 2 clinical trial for the compound of Formula (I). 1 IPTS / 128698855.1Attorney Docket No. TVR-013WO

[0007] FIG.1C shows an exemplary concentration profile at Day 22 from a Phase 2 clinical trial for the compound of Formula (I). DETAILED DESCRIPTION

[0008] The present disclosure, in some embodiments, provides methods of treating cancer in a subject in need thereof, comprising administering to the subject certain doses of a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a polymer excipient. Definitions

[0009] As used herein the specification, “a” or “an” may mean one or more. As used herein, when used in conjunction with the word "comprising", the words “a” or “an” may mean one or more than one. As used herein “another” may mean at least a second or more. Still further, the terms “having”, “including”, “containing” and “comprising” are interchangeable and one of skill in the art is cognizant that these terms are open ended terms. Some embodiments of the invention may consist of or consist essentially of one or more elements, method steps, and / or methods of the invention. It is contemplated that any method, compound, or composition described herein can be implemented with respect to any other method, compound, or composition described herein.

[0010] "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

[0011] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically 2 IPTS / 128698855.1Attorney Docket No. TVR-013WO acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0012] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non- human animal. The terms “human,” “patient,” “subject,” and “individual” are used interchangeably herein. None of these terms require the active supervision of medical personnel.

[0013] Disease, disorder, and condition are used interchangeably herein.

[0014] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or reverses or slows the progression of the disease, disorder or condition (also “therapeutic treatment”).

[0015] A “drug holiday” as used herein, for example as related to the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a period of time after administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and before administration of the compound of Formula (I), or a pharmaceutically acceptable 3 IPTS / 128698855.1Attorney Docket No. TVR-013WO salt thereof, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is not administered to the individual.

[0016] As used herein, the compound of Formula (I), is represented by:

[0017] The compound of Formula (I) is also referred to herein as TTI-101. Methods of Use

[0018] The amount of a therapeutic agent sufficient to elicit a desired biological response varies depending on the combination of factors such as the desired biological endpoint, the pharmacokinetics of the agent, the disease being treated, the mode of administration, the type of dosage form, and the age, weight, health, and condition of the subject. A suitable dose should produce and maintain the desired biological response and therapeutic efficacy while minimizing toxicity and other side effects. In some embodiments, provided herein are methods of using a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a polymer excipient, in a subject in need thereof, such as in therapeutics or other methods described herein, which produce favorable responses (e.g., pharmacokinetic profiles) in the subject. In specific embodiments, provided herein are methods of treating cancer.

[0019] In some embodiments, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject between two and twelve tablets per day of a composition comprising: (a) at least 150 mg of the compound of Formula (I):4 IPTS / 128698855.1Attorney Docket No. TVR-013WO or a pharmaceutically acceptable salt thereof, and b) a polymer excipient.

[0020] In some embodiments, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject between two and ten tablets per day of a composition comprising: (a) at least 150 mg of the compound of Formula (I):or a pharmaceutically acceptable salt thereof, and b) a polymer excipient.

[0021] In some embodiments, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject between two and eight tablets per day of a composition comprising: (a) at least 150 mg of the compound of Formula (I):or a pharmaceutically acceptable salt thereof, and b) a polymer excipient.

[0022] In some embodiments, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject between two and four tablets per day of a composition comprising: (a) at least 150 mg of the compound of Formula (I): 5 IPTS / 128698855.1Attorney Docket No. TVR-013WOor a pharmaceutically acceptable salt thereof, and b) a polymer excipient.

[0023] In some embodiments, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject: i) two to four tablets per day of a composition comprising: (a) at least 150 mg of the compound of Formula (I):or a pharmaceutically acceptable salt thereof, and b) a polymer excipient; and ii) one or more additional agent.

[0024] In some embodiments, the additional agent is selected from the group consisting of an angiogenesis inhibitor, an anti-PD-1 antibody, and an anti-PD-L1 antibody, or a combination thereof.

[0025] In some embodiments, the additional agent is selected from the group consisting of a cyclin-dependent kinase (CDK) inhibitor (e.g., CDK4 / 6 inhibitor), an aromatase inhibitor, and hormone therapy, or a combination thereof.

[0026] In some embodiments, the methods described herein comprise a drug holiday for the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average maximum concentration (Cmax) between about 1,000 ng / mL and about 10,000 ng / mL after administration of about 400 mg to about 2,400 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof 6 IPTS / 128698855.1Attorney Docket No. TVR-013WO to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 1,000 ng / mL and about 10,000 ng / mL after administration of about 400 mg to about 1,200 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject.

[0028] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 1,000 ng / mL and about 10,000 ng / mL after administration of about 400 mg to about 600 mg dose (e.g., half of the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 1,000 ng / mL and about 6,400 ng / mL after administration of about 400 mg to about 600 mg dose (e.g., half of the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 1,000 ng / mL and about 6,200 ng / mL after administration of about 400 mg to about 600 mg dose (e.g., half of the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 1,400 ng / mL and about 6,000 ng / mL after administration of about 400 mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 1,800 ng / mL and about 6,000 ng / mL after administration of about 400 mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 2,000 ng / mL and about 6,000 ng / mL after administration of about 400 mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 2,400 ng / mL and about 6,000 ng / mL after administration of about 400 mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 2,800 ng / mL and about 6,000 ng / mL after administration of about 400 7 IPTS / 128698855.1Attorney Docket No. TVR-013WO mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 3,000 ng / mL and about 6,000 ng / mL after administration of about 400 mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 3,000 ng / mL and about 5,600 ng / mL after administration of about 400 mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 3,000 ng / mL and about 5,200 ng / mL after administration of about 400 mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 3,000 ng / mL and about 4,600 ng / mL after administration of about 400 mg to about 600 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject.

[0029] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 1,500 ng / mL and about 6,500 ng / mL after administration of about 400 mg dose (e.g., half of the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 1,800 ng / mL and about 6,200 ng / mL after administration of about 400 mg dose (e.g., half of the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 2,000 ng / mL and about 6,000 ng / mL after administration of about 400 mg dose (e.g., half of the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 3,000 ng / mL and about 6,000 ng / mL after administration of about 400 mg dose (e.g., half of the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 3,500 ng / mL and 8 IPTS / 128698855.1Attorney Docket No. TVR-013WO about 5,000 ng / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 3,000 ng / mL and about 4,000 ng / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 4,500 ng / mL and about 5,500 ng / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0030] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 3,000 ng / mL and about 6,000 ng / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 3,500 ng / mL and about 5,500 ng / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 3,500 ng / mL and about 5,000 ng / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 4,000 ng / mL and about 5,000 ng / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmaxbetween about 4,000 ng / mL and about 4,500 ng / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0031] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 1,000 ng / mL and 9 IPTS / 128698855.1Attorney Docket No. TVR-013WO about 4,600 ng / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 1,200 ng / mL and about 4,400 ng / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 1,400 ng / mL and about 4,000 ng / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average Cmax between about 2,000 ng / mL and about 3,000 ng / mL after administration of about 600 mg (e.g., half the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0032] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average area under the curve (AUC0-8hours) between about 9,000 ng*h / mL and about 31,000 ng*h / mL after administration of about 400 mg to about 2,400 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 9,000 ng*h / mL and about 31,000 ng*h / mL after administration of about 400 mg to about 1,200 mg dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0033] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 9,000 ng*h / mL and about 31,000 ng*h / mL after administration of about 400 mg to about 600 mg dose (e.g., half of the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 10,000 ng*h / mL and about 30,000 ng*h / mL after administration of about 400 mg to about 600 mg dose (e.g., half of the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein 10 IPTS / 128698855.1Attorney Docket No. TVR-013WO produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 15,000 ng*h / mL and about 30,000 ng*h / mL after administration of about 400 mg to about 600 mg dose (e.g., half of the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 11,000 ng*h / mL and about 29,000 ng*h / mL after administration of about 400 mg to about 600 mg dose (e.g., half of the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 20,000 ng*h / mL and about 25,000 ng*h / mL after administration of about 400 mg to about 600 mg dose (e.g., half of the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0034] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 9,000 ng*h / mL and about 31,000 ng*h / mL after administration of an 400 mg dose (e.g., half of the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 10,000 ng*h / mL and about 30,000 ng*h / mL after administration of an 400 mg dose (e.g., half of the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 11,000 ng*h / mL and about 29,000 ng*h / mL after administration of an 400 mg dose (e.g., half of the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 16,000 ng*h / mL and about 28,000 ng*h / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 16,000 ng*h / mL and about 24,000 ng*h / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a 11 IPTS / 128698855.1Attorney Docket No. TVR-013WO pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 23,000 ng*h / mL and about 29,000 ng*h / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0035] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 15,000 ng*h / mL and about 35,000 ng*h / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 18,000 ng*h / mL and about 30,000 ng*h / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 20,000 ng*h / mL and about 30,000 ng*h / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 20,000 ng*h / mL and about 24,000 ng*h / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0036] In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 9,000 ng*h / mL and about 28,000 ng*h / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hours between about 10,000 ng*h / mL and about 27,000 ng*h / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg)of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 11,000 ng*h / mL and about 26,000 ng*h / mL after administration of about 600 mg dose (e.g., half of the total daily dose of about 1,200 mg)of the compound of 12 IPTS / 128698855.1Attorney Docket No. TVR-013WO Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the methods described herein produce a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 13,000 ng*h / mL and about 21,000 ng*h / mL after administration of 600 mg dose (e.g., half the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0037] In some embodiments, the composition comprises about 200 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the methods described herein comprise administering to the subject two tablets per day. In some embodiments, the methods described herein comprise administering to the subject one tablet in the morning and one tablet in the evening. In some embodiments, the methods described herein comprise administering to the subject four tablets per day. In some embodiments, the methods described herein comprise administering to the subject two tablets in the morning and two tablets in the evening. In some embodiments, the methods described herein comprise administering to the subject six tablets per day. In some embodiments, the methods described herein comprise administering to the subject three tablets in the morning and three tablets in the evening. In some embodiments, the methods described herein comprise administering to the subject eight tablets per day. In some embodiments, the methods described herein comprise administering to the subject four tablets in the morning and four tablets in the evening. In some embodiments, the methods described herein comprise administering to the subject ten tablets per day. In some embodiments, the methods described herein comprise administering to the subject five tablets in the morning and five tablets in the evening. In some embodiments, the methods described herein comprise administering to the subject twelve tablets per day. In some embodiments, the methods described herein comprise administering to the subject six tablets in the morning and six tablets in the evening.

[0039] In some embodiments, the methods described herein comprise administering to the subject about 400 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 800 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 1,200 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 1,600 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some 13 IPTS / 128698855.1Attorney Docket No. TVR-013WO embodiments, the methods described herein comprise administering to the subject about 2,000 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 2,400 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 200 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 400 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 600 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 800 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 1,000 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering to the subject about 1,200 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the cancer is a liver cancer, lung cancer, head and neck cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, gastric cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gall bladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or osteosarcoma. In some embodiments, a cancer treated according to a method provided herein is a liver cancer, lung cancer, liver carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, osteosarcoma, or estrogen receptor- positive breast cancer. In some embodiments, a cancer treated according to a method provided herein is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, pancreatic cancer, or osteosarcoma. In some embodiments, the leukemia is acute myelogenous leukemia. In some embodiments, the gastric cancer is gastric adenocarcinoma.

[0041] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is comprised in a solid amorphous dispersion with the polymer 14 IPTS / 128698855.1Attorney Docket No. TVR-013WO excipient, and optionally a crystallization inhibiting polymer. Exemplary solid amorphous dispersions are set forth as in Table 1 (e.g., wherein the total wt. % in the composition does not exceed 100%). Table 1: Exemplary Solid Amorphous Dispersions (SAD)

[0042] In some embodiments, the solid amorphous dispersions are prepared using spray-dried dispersion (SDD) technique. SDD produces a single-phase, amorphous molecular dispersion (a solid solution) of the API in a polymer matrix. In general, SDDs are obtained by dissolving TTI-101 and a polymer excipient(s) in a solvent(s) and then spray drying the solution. In some embodiments, the compositions, which are used in the methods described herein, that are prepared using the SDD technique provide for a reduced pill burden compared to a composition prepared using a self-emulsifying drug dispersion (SEDD) technique. For example, three times as many pills prepared using the SEDD technique would be needed as compared to a composition prepared using the SDD technique.

[0043] In some embodiments, the solvent employed in the SDD technique to dissolve the TTI-101 is selected from: dichloromethane, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, water, or a mixture thereof. In some embodiments, the solvent employed in the SDD technique for preparing a solid amorphous dispersion comprising TTI-101 and a polymer excipient is a mixture of acetone:water.

[0044] In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 80% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 70% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 60% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 45% w / w to about 55% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 40% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some 15 IPTS / 128698855.1Attorney Docket No. TVR-013WO embodiments, the solid amorphous dispersion comprises about 45% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 50% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 55% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 60% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 65% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 70% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 75% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 80% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the polymer excipient is one or more celluloses or derivatives thereof (e.g., microcrystalline cellulose, carboxymethylcellulose, hydroxypropyl methylcellulose (HPMC) or hypromellose, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hypromellose acetate succinate (e.g., HPMCAS-L grade (LG, e.g., corresponding to acetyl content 5.0 to 9.0 percent (%), succinoyl content 14.0% to 18.0%), HPMCAS-M grade (MG, e.g., corresponding to acetyl content 7.0% to 11.0%, succinoyl content 10% to 14%), HPMCAS-H grade (HG, e.g., corresponding to acetyl content 10.0% to 14.0%, succinoyl content 4.0% to 8.0%)), HPMC phthalate (HPMCP) (e.g., HPMCP®-HP55, HPMCP®-HP55S), water-soluble cellulose ether Methocel™ (e.g., Methocel™ E3 (e.g., Methocel™ E3LV))), hydroxypropyl cellulose, hydroxyethylcellulose, ethylcellulose, and cellulose acetate phthalate), polyacrylates (e.g., polymethacrylates (e.g., copolymers comprising methacrylic acid and methyl methacrylate, copolymers comprising methacrylic acid and ethylacrylate, copolymer comprising N,N-dimethylaminoethyl methacrylate, methylmethacrylate, and butylmethacrylate (e.g., Eudragit® (e.g., Eduragit® EPO, Eudragit® L30 D-55, Eudragit® L100, Eudragit® L100-55)))), polyvinyl pyrrolidones (PVP), polyvinyl pyrrolidone vinyl acetates (PVPVA), other copolymers (e.g., copolymers comprising polyethylene glycol, polyvinylcaprolactam, and polyvinylacetate (e.g., polyvinyl acetate phthalate (PVAP); polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer)) (e.g., Soluplus®), or copolymers comprising vinyl acetate and N-vinyl-2- 16 IPTS / 128698855.1Attorney Docket No. TVR-013WO pyrrolidone (e.g., Plasdone™ (e.g., Plasdone™ S630 (e.g., Plasdone™ S630 Ultra)), or mixtures thereof.

[0046] In some embodiments, the polymer excipient is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), a copolymer comprising methacrylic acid, a copolymer comprising vinyl acetate, and N-vinyl-2-pyrrolidone, and combinations thereof.

[0047] In some embodiments, the polymer excipient is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the HPMCAS is HPMCAS L grade (HPMCAS-L).

[0048] In some embodiments, the polymer excipient is a copolymer comprising methacrylic acid and ethylacrylate, a copolymer comprising methacrylic acid and methyl methacrylate, or a copolymer comprising N,N-dimethylaminoethyl methacrylate, methylmethacrylate, and butylmethacrylate. In some embodiments, the polymer excipient is a copolymer comprising methacrylic acid and ethylacrylate. In some embodiments, the polymer excipient is a copolymer of about 1.4:1 to about 1:1.4 methacrylic acid and ethylacrylate. In some embodiments, the polymer excipient is a copolymer of about 1.2:1 to about 1:1.2 methacrylic acid and ethylacrylate. In some embodiments, the polymer excipient is a copolymer of 1:1 methacrylic acid and ethylacrylate.

[0049] In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 80% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 70% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 60% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 45% w / w to about 55% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 40% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 45% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 50% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 55% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 60% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 65% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 70% w / w of the polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 75% w / w of the polymer 17 IPTS / 128698855.1Attorney Docket No. TVR-013WO excipient. In some embodiments, the solid amorphous dispersion comprises about 80% w / w of the polymer excipient.

[0050] In some embodiments, the solid amorphous dispersion further comprises a crystallization inhibiting polymer, which helps slow or inhibit crystallization of TTI-101 when it is released from the composition in the GI tract or mediates supersaturation stabilization (e.g. , stabilization of a supersaturated solution).

[0051] In some embodiments, the crystallization inhibiting polymer is one or more celluloses or derivatives thereof (e.g., microcrystalline cellulose, carboxymethylcellulose, hydroxypropyl methylcellulose (HPMC) or hypromellose, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hypromellose acetate succinate (e.g., HPMCAS-L grade (LG, e.g., corresponding to acetyl content 5.0 to 9.0 percent (%), succinoyl content 14.0% to 18.0%), HPMCAS-M grade (MG, e.g., corresponding to acetyl content 7.0% to 11.0%, succinoyl content 10% to 14%), HPMCAS-H grade (HG, e.g., corresponding to acetyl content 10.0% to 14.0%, succinoyl content 4.0% to 8.0%)), HPMC phthalate (HPMCP) (e.g., HPMCP®-HP55, HPMCP®-HP55S), water-soluble cellulose ether Methocel™ (e.g., Methocel™ E3 (e.g., Methocel™ E3LV))), hydroxypropyl cellulose, hydroxyethylcellulose, ethylcellulose, and cellulose acetate phthalate), polyacrylates (e.g., polymethacrylates (e.g., copolymers comprising methacrylic acid and methyl methacrylate, copolymers comprising methacrylic acid and ethylacrylate, copolymer comprising N,N-dimethylaminoethyl methacrylate, methylmethacrylate, and butylmethacrylate (e.g., Eudragit® (e.g., Eduragit® EPO, Eudragit® L30 D-55, Eudragit® L100, Eudragit® L100-55)))), polyvinyl pyrrolidones (PVP), polyvinyl pyrrolidone vinyl acetates (PVPVA), other copolymers (e.g., copolymers comprising polyethylene glycol, polyvinylcaprolactam, and polyvinylacetate (e.g., polyvinyl acetate phthalate (PVAP); polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer)) (e.g., Soluplus®), or copolymers comprising vinyl acetate and N-vinyl-2- pyrrolidone (e.g., Plasdone™ (e.g., Plasdone™ S630 (e.g., Plasdone™ S630 Ultra)), or mixtures thereof.

[0052] In some embodiments, the crystallization inhibiting polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), a copolymer comprising methacrylic acid, a copolymer comprising vinyl acetate, and N-vinyl-2-pyrrolidone, and combinations thereof.

[0053] In some embodiments, the crystallization inhibiting polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the HPMCAS is HPMCAS L grade (HPMCAS-L). 18 IPTS / 128698855.1Attorney Docket No. TVR-013WO

[0054] In some embodiments, the crystallization inhibiting polymer is a copolymer comprising methacrylic acid and ethylacrylate, a copolymer comprising methacrylic acid and methyl methacrylate, or a copolymer comprising N,N-dimethylaminoethyl methacrylate, methylmethacrylate, and butylmethacrylate. In some embodiments, the polymer excipient is a copolymer comprising methacrylic acid and ethylacrylate. In some embodiments, the polymer excipient is a copolymer of about 1.4:1 to about 1:1.4 methacrylic acid and ethylacrylate. In some embodiments, the polymer excipient is a copolymer of about 1.2:1 to about 1:1.2 methacrylic acid and ethylacrylate. In some embodiments, the polymer excipient is a copolymer of 1:1 methacrylic acid and ethylacrylate.

[0055] In some embodiments, the solid amorphous dispersion comprises about 1% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 5% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 10% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 5% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 15% w / w to about 35% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 10% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 15% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 20% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 5% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 10% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 15% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 15% w / w to about 25% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 20% w / w to about 30% w / w of the crystallization inhibiting polymer.

[0056] In some embodiments, the solid amorphous dispersion comprises about 1% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 2% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 3% w / w of the crystallization 19 IPTS / 128698855.1Attorney Docket No. TVR-013WO inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 4% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 5% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 10% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 15% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 20% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 25% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 35% w / w of the crystallization inhibiting polymer. In some embodiments, the solid amorphous dispersion comprises about 40% w / w of the crystallization inhibiting polymer.

[0057] In some embodiments, when the selected crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 20% to about 60% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 20% to about 50% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 30% to about 60% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 30% to about 50% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 40% to about 60% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 40% to about 50% w / w of the crystallization inhibiting polymer / polymer excipient.

[0058] In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous 20 IPTS / 128698855.1Attorney Docket No. TVR-013WO dispersion comprises about 20% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 30% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 40% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 50% w / w of the crystallization inhibiting polymer / polymer excipient. In some embodiments, when the crystallization inhibiting polymer for the solid amorphous dispersion is the same as the polymer excipient, the solid amorphous dispersion comprises about 60% w / w of the crystallization inhibiting polymer / polymer excipient.

[0059] In some embodiments, the composition comprises 150 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 160 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 170 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 180 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 190 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 200 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 220 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 240 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 260 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 280 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 300 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the compositions described herein are comprised in a tablet. In some embodiments, the tablet comprises at least 150 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises 21 IPTS / 128698855.1Attorney Docket No. TVR-013WO at least 160 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises at least 170 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises at least 180 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises at least 190 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises at least 200 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises at least 300 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the tablet comprises about 200 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 250 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 300 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the composition employed in methods described herein further comprises at least one additional component other than the solid amorphous dispersion comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the polymer excipient. Said component can be intra-granular or extra-granular components that improve processability of the tablet manufacture (e.g., processability of roller compaction, tablet compression and film coating). The additional components can also impart good powder flow and compression characteristics to the material being compressed. Desirable characteristics of the additional components can include high-compressibility so as to allow for strong tablets to be made at low compression forces; good powder flow properties that can improve the powder flow of other excipients in the composition; and cohesiveness, for example to prevent a tablet from crumbling during processing, shipping, and handling. Other components which give physical characteristics to a finished tablet are coloring and flavoring agents (e.g., in the case of chewable tablets).

[0063] In some embodiments, the additional components include, but are not limited to, diluents, binders, fillers, disintegrants, surfactants, lubricants, flavoring agents, and colors. The additional component can serve multiple functions. For example, a diluent may also serve as a filler. As another example, a surfactant may also serve as a lubricant.

[0064] In some embodiments, diluents or fillers are added, for example, to increase the bulk weight of the blend resulting in a practical size for compression. Diluents or fillers that may be used include one or more of calcium salts such as calcium phosphate dibasic and 22 IPTS / 128698855.1Attorney Docket No. TVR-013WO sugars such as lactose, sucrose, dextrose, microcrystalline cellulose, mannitol, and maltodextrin. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. In some embodiments, the diluent or filler is microcrystalline cellulose, which can be manufactured by the controlled hydrolysis of alpha-cellulose. In some embodiments, suitable microcrystalline cellulose has an average particle size of from about 20 nm to about 200 nm. Suitable microcrystalline cellulose includes Avicel® PH 101, Avicel® PH 102, Avicel® PH 103, Avicel® PH 105, and Avicel® PH 200. In some embodiments, the diluent or filler is silicified microcrystalline cellulose, such as ProSolv® SMCC 50 or ProSolv® SMCC HD 90. In some embodiments, the diluent or filler is lactose. In some embodiments, the diluent or filler is a mixture of two or more diluents or fillers. In some embodiments, the diluent or filler is microcrystalline cellulose, silicified microcrystalline cellulose, or powdered cellulose, or a mixture thereof.

[0065] In some embodiments, the composition further comprises one or more diluents or fillers. In some embodiments, the amount of diluent or filler employed in the composition is from about 5% to about 50% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 5% to about 40% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 5% to about 30% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 5% to about 25% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 5% to about 20% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 5% to about 15% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 5% to about 10% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 10% to about 50% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 10% to about 40% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 10% to about 30% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 10% to about 20% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 15% to about 40% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 15% to about 35% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 15% to about 30% w / w. In some embodiments, the amount of 23 IPTS / 128698855.1Attorney Docket No. TVR-013WO diluent or filler employed in the composition is from about 15% to about 20% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 20% to about 50% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 20% to about 40% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 20% to about 35% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 5% to about 20% w / w. In some embodiments, the amount of diluent or filler employed in the composition is from about 20% to about 30% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 5% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 10% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 15% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 20% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 25% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 30% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 35% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 40% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 45% w / w. In some embodiments, the amount of diluent or filler employed in the composition is about 50% w / w.

[0066] In some embodiments, the composition further comprises one or more lubricants. Lubricants are typically added to prevent the tableting materials from clumping together and from stick to the tablet punches, minimize friction during tablet compression, and to allow for removal of the compressed tablet from the die. Such lubricants are included in the final tablet mix in amounts usually less than 5 by weight per weight of a composition. Examples of lubricants include, but are not limited to, colloidal silica, magnesium trisilicate, talc, magnesium carbonate, stearic acid, magnesium oxide, glycerylbehaptate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulphate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium lauryl stearate, and mixtures of magnesium stearate with sodium lauryl sulphate. In some embodiments, the lubricant is sodium lauryl sulfate or sodium stearyl fumarate, or a mixture thereof. In some embodiments, the lubricant is a mixture of two or more lubricants.

[0067] In some embodiments, the amount of lubricant employed in the composition is from about 0.01 to about 5.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.01 to about 4.0% w / w. In some embodiments, the amount 24 IPTS / 128698855.1Attorney Docket No. TVR-013WO of lubricant employed in the composition is from about 0.01 to about 3.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.1 to about 3.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.01 to about 2.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.05 to about 2.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.1 to about 2.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.01 to about 1.5% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.05 to about 1.5% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.1 to about 1.5% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.5 to about 4.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.5 to about 3.5% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.5 to about 3.0 w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.5 to about 2.5% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.5 to about 2.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.5 to 1.5% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 1.0 to about 3.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 1.0 to about 2.5% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 1.0 to about 2.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 1.5 to about 2.0% w / w. In some embodiments, the amount of lubricant employed in the composition is from about 0.5 to 1.0% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.1% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.2% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.3% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.4% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.5% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.6% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.7% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.8% w / w. In some embodiments, the amount of lubricant employed in the composition is about 0.9% w / w. In some embodiments, the amount of lubricant employed in 25 IPTS / 128698855.1Attorney Docket No. TVR-013WO the composition is about 1.0% w / w. In some embodiments, the amount of lubricant employed in the composition is about 1.5% w / w. In some embodiments, the amount of lubricant employed in the composition is about 1.8% w / w. In some embodiments, the amount of lubricant employed in the composition is about 2.0% w / w. In some embodiments, the amount of lubricant employed in the composition is about 2.5% w / w.

[0068] In some embodiments, the composition comprises two or more lubricants (e.g., two lubricants). In some embodiments, one lubricant is in an amount of about 0.3-1.2% w / w of the composition and the other lubricant is in an amount of about 0.3-1.7% w / w of the composition. In some embodiments, one lubricant is in an amount of about 0.5-1% w / w of the composition and the other lubricant is in an amount of about 0.5-1.5% w / w of the composition. In some embodiments, one lubricant is in an amount of about 0.6-0.9% w / w of the composition and the other lubricant is in an amount of about 0.7-1.3% w / w of the composition. In some embodiments, one lubricant is in an amount of about 0.8% w / w of the composition and the other lubricant is in an amount of about 1.0% w / w of the composition.

[0069] In some embodiments, glidants are added, for example, to improve tablet powder’s flowability by reducing interparticle friction and cohesion. Examples of glidants include magnesium stearate, magnesium carbonate, silica (e.g., colloidal silicon dioxide), starch and talc. Glidants may be present in the composition at an amount of from 0.01 to about 5% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.01 to about 4.0% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.01 to about 3.0% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.01 to about 2.0% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.05 to about 2.0% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.1 to about 2.0% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.01 to about 1.5% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.05 to about 1.5% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.1 to about 1.5% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.5 to 1.5% w / w. In some embodiments, the amount of glidant employed in the composition is from about 0.5 to 1.0% w / w. In some embodiments, the amount of glidant employed in the composition is about 0.1% w / w. In some embodiments, the amount of glidant employed in the composition is about 0.2% w / w. In some embodiments, the amount of glidant employed in the composition is about 0.3% w / w. In some embodiments, the 26 IPTS / 128698855.1Attorney Docket No. TVR-013WO amount of glidant employed in the composition is about 0.4% w / w. In some embodiments, the amount of glidant employed in the composition is about 0.5% w / w. In some embodiments, the amount of glidant employed in the composition is about 0.6% w / w. In some embodiments, the amount of glidant employed in the composition is about 0.7% w / w. In some embodiments, the amount of glidant employed in the composition is about 0.8% w / w. In some embodiments, the amount of glidant employed in the composition is about 0.9% w / w. In some embodiments, the amount of glidant employed in the composition is about 1.0% w / w. In some embodiments, the amount of glidant employed in the composition is about 2.0% w / w.

[0070] In some embodiments, a tablet disintegrant is present in the composition at an amount, for example, to expedite dissolution (e.g., increase the rate of tablet disintegration). Disintegrants are excipients which can oppose the physical forces of particle bonding in a tablet when the dosage form is placed in an aqueous environment. Disintegrants include starch derivatives and salts of carboxymethylcellulose. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches, e.g., sodium starch glycolate, pregelatinized starch; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross- linked polyvinyl pyrrolidone (e.g., polyvinyl polypyrrolidone (PVPP), crospovidone (polymer of N-vinyl-2-pyrrolidone), cross-linked calcium carboxymethylcellulose and cross- linked sodium carboxymethylcellulose (sodium croscarmellose); and polysaccharides. In some embodiments, the disintegrant is a mixture of two or more disintegrants.

[0071] In some embodiments, the composition further comprises one or more disintegrants. In some embodiments, the amount of disintegrant is from 0.1 to about 25% w / w of the composition. In some embodiments, the amount of disintegrant is from about 1% to about 15% w / w of the composition. In some embodiments, the amount of disintegrant is from about 1% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is from about 1% to about 8% w / w of the composition. In some embodiments, the amount of disintegrant is from about 5% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is from about 3% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is from about 3% to about 8% w / w of the composition. In some embodiments, the amount of disintegrant is from about 5% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is from about 5% to about 15% w / w of the composition. In some embodiments, the amount of disintegrant is from about 1% to about 5% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% w / w of the composition. In some embodiments, the 27 IPTS / 128698855.1Attorney Docket No. TVR-013WO amount of disintegrant is about 2% w / w of the composition. In some embodiments, the amount of disintegrant is about 3% w / w of the composition. In some embodiments, the amount of disintegrant is about 4% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% w / w. In some embodiments, the amount of disintegrant is about 6% w / w of the composition. In some embodiments, the amount of disintegrant is about 7% w / w of the composition. In some embodiments, the amount of disintegrant is about 8% w / w of the composition. In some embodiments, the amount of disintegrant is about 9% w / w of the composition. In some embodiments, the amount of disintegrant is about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 15% w / w of the composition.

[0072] In some embodiments, the composition further comprises one or more crystallization inhibiting polymers. In some embodiments, the composition comprises about 1% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 5% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 10% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 5% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w to about 35% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 10% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 20% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 5% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 10% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w to about 25% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 20% w / w to about 30% w / w of the crystallization inhibiting polymer.

[0073] In some embodiments, the composition comprises about 1% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 2% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 3% w / w of the crystallization inhibiting polymer. In some embodiments, the 28 IPTS / 128698855.1Attorney Docket No. TVR-013WO composition comprises about 4% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 5% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 10% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 20% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 25% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 35% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 40% w / w of the crystallization inhibiting polymer.

[0074] In some embodiments, the composition comprises two or more crystallization inhibiting polymers (e.g., two crystallization inhibiting polymers). In some embodiments, one crystallization inhibiting polymer is in an amount of about 5-25% w / w of the composition and the other crystallization inhibiting polymer is in an amount of about 1-10% w / w of the composition. In some embodiments, one crystallization inhibiting polymer is in an amount of about 10-20% w / w of the composition and the other crystallization inhibiting polymer is in an amount of about 3-8% w / w of the composition. In some embodiments, one crystallization inhibiting polymer is in an amount of about 12-17% w / w of the composition and the other crystallization inhibiting polymer is in an amount of about 4-7% w / w of the composition. In some embodiments, one crystallization inhibiting polymer is in an amount of about 15% w / w of the composition and the other crystallization inhibiting polymer is in an amount of about 6% w / w of the composition.

[0075] Tablets may be plain, film, sugar coated, bisected, embossed, layered, and / or sustained-release. They can be made in a variety of sizes, shapes, and colors. Tablets may be swallowed, chewed, or dissolved in the buccal cavity or beneath the tongue.

[0076] In some embodiments, the tablets are coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, protect tablet ingredients from deterioration, make large or unpleasant-tasking tablets easier to swallow, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric 29 IPTS / 128698855.1Attorney Docket No. TVR-013WO layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0077] In some embodiments, the tablet is polymer-coated. In some embodiments, the tablet is coated with Opadry® EZ white.

[0078] In some embodiments, the methods described herein employ a composition set forth as in Table 2 or Table 3 (e.g., wherein the total wt. % in the composition does not exceed 100%). Table 2: Exemplary TTI-101 CompositionsTable 3: Exemplary TTI-101 Compositions30 IPTS / 128698855.1Attorney Docket No. TVR-013WOCombinations

[0079] The phrase, "in combination with," and the terms "co-administration," "co- administering," or "co-providing", as used herein in the context of the administration of a compound described herein (e.g., a compound of Formula (I) or Formula (II)) and another agent or therapy, means that two (or more) different compounds, agents, or therapies are delivered to the subject during the course of the subject's affliction with the cancer, e.g., two (or more) different compounds, agents, or therapies are delivered to the subject after the subject has been diagnosed with the cancer and before the cancer has been cured or eliminated or treatment has ceased for other reasons.

[0080] In some embodiments, the delivery of one compound, agent, or therapy is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as "simultaneous" or "concurrent delivery." In other embodiments, the delivery of one compound, agent, or therapy ends before the delivery of the other compound, agent, or therapy begins. In some embodiments of either case, the treatment (e.g., administration of compound, composition, or therapy) is more effective because of combined administration. For example, the second compound, agent, or therapy is more effective, e.g., an equivalent effect is seen with less of the second compound, agent, or therapy, or the second compound, agent, or therapy reduces symptoms to a greater extent, than would be seen if the second compound, agent, or therapy were administered in the absence of the first compound, agent, or therapy, or the analogous situation is seen with the first compound, agent, or therapy. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one compound, agent, or therapy delivered in the absence of the other. The effect of the two compounds or therapies can be partially additive, wholly additive, or greater than additive (e.g., synergistic). The delivery can be such that the first compound, agent, or therapy delivered is still detectable when the second is delivered. 31 IPTS / 128698855.1Attorney Docket No. TVR-013WO

[0081] In some embodiments, the first compound, agent, or therapy and second compound, agent, or therapy can be administered simultaneously (e.g., at the same time), in the same or in separate compositions, or sequentially. Sequential administration refers to administration of one compound, agent, or therapy before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes; 1 , 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours; 4, 5, 6, 7, 8, 9 or more days; 1 , 2, 3, 4, 5, 6, 7, 8 or more weeks before) administration of an additional, e.g., secondary, compound, agent, or therapy. The order of administration of the first and secondary compound, agent, or therapy can also be reversed.

[0082] In some embodiments, the methods described herein further comprise administering to the subject one or more additional agent.

[0083] In some embodiments, the additional agent is selected from the group consisting of an angiogenesis inhibitor, an anti-PD-1 antibody, and an anti-PD-L1 antibody, or a combination thereof. In some embodiments, the additional agent is an anti-PD-1 antibody. In other embodiments, the additional agent is a combination of an anti-PD-L1 antibody and an angiogenesis inhibitor.

[0084] Exemplary anti-PD-1 antibodies include, but are not limited to, cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, and XmAb20717. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0085] Exemplary anti-PD-L1 antibodies include, but are not limited to, atezolizumab, avelumab, durvalumab, envafolimab, FS118, BCD-135, BGB-A333, BGBA- 317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, and CX-072. In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, avelumab, durvalumab, and envafolimab. In some embodiments, the anti-PD-L1 antibody is atezolizumab.

[0086] Exemplary angiogenesis inhibitors include, but are not limited to, bevacizumab, sorafenib, sunitinib, nilotinib, pazopanib, dasatinib, regorafenib, cabozantinib, lenvatinib, ponatinib, ziv-aflibercept, axitinib, tivozanib, everolimus, lenalidomide, thalidomide, vandetanib, orvandetanib, and ramucirumab. In some embodiments, the angiogenesis inhibitor is bevacizumab. 32 IPTS / 128698855.1Attorney Docket No. TVR-013WO

[0087] In some embodiments, the additional agent is selected from the group consisting of a cyclin-dependent kinase (CDK) inhibitor (e.g., CDK4 / 6 inhibitor), an aromatase inhibitor, and hormone therapy, or a combination thereof.

[0088] Exemplary cyclin-dependent kinase inhibitors include, but are not limited to, palbociclib, ribociclib, abemaciclib, roniciclib, trilaciclib, lerociclib, milciclib, TQB3303, GLR2007, SHR-6390, PF-06873600, XZP-3287, ON-123300, ETH-155008, HEC-80797, JS- 104, PF-07220060, RMC-4550, and SRX-3177, and pharmaceutically acceptable salts thereof. In some embodiments, the cyclin-dependent kinase inhibitor is palbociclib or ribociclib.

[0089] Exemplary aromatase inhibitors include, but are not limited to, letrozole, anastrozole, exemestane, and testalactone, and pharmaceutically acceptable salts thereof.

[0090] Exemplary hormone therapy includes, but are limited to, elacestrant, fulvestrant, goserelin, leuprolide, megestrol, tamoxifen, and toremifene, and pharmaceutically acceptable salts thereof. EXAMPLES Example 1. Tablet composition for the compound of Formula (I)

[0091] An exemplary tablet composition was prepared with a SDD of TTI-101 and methacrylic acid and ethyl acrylate copolymer as the polymer excipient (Table 4). The composition was mixed, roller compacted (RC), milled, blended, compressed and coated with a film to form an exemplary tablet. Intra and extra-granular components were added to improve processability of roller compaction, tablet compression, and film coating.33 IPTS / 128698855.1Attorney Docket No. TVR-013WOExample 2. TTI-101 in Patients With Cancers and in Healthy Volunteers

[0092] In one Phase I trial, TTI-101 was assessed in patients with advanced cancers. In another trial, TTI-101 was assessed in healthy volunteers.

[0093] The first trial was performed similar to the trial outlined below in Table 5 (for patients with advanced cancers) and was made up of a first cohort of subjects receiving Composition 1, a second cohort of subjects receiving Composition 2, and a third cohort of subjects receiving Composition 3. Composition 1 corresponds to a composition of the compound of Formula (I) dissolved in 60:40 Labrasol® / PEG400 and encapsulated in a hard gelatin capsule (unit dose: 36 mg). Composition 2 corresponds to a self-emulsifying drug dispersion (SEDD) capsule composition of the compound of Formula (I) comprising Kolliphor® RH 40 (PEG-40 hydrogenated castor oil), PEG600, Polysorbate 20, Labrasol®, and citric acid (unit dose: 80 mg). Composition 3 corresponds to the tablet composition of the compound of Formula (I) as described in Example 1, Table 4.

[0094] The second trial was similar to the trial outlined below in Table 6 (for healthy volunteers) and was made up of a cohort of subjects receiving Composition 3. Table 5. Trial Information for TTI-101 in Patients with Advanced Cancers34 IPTS / 128698855.1Attorney Docket No. TVR-013WO35 IPTS / 128698855.1Attorney Docket No. TVR-013WOTable 6. Trial Information for TTI-101 in Healthy Volunteers36 IPTS / 128698855.1Attorney Docket No. TVR-013WO

[0095] In another trial (Phase 2), TTI-101 was assessed as monotherapy (Cohort A) and in combination with pembrolizumab therapy (Cohort B) or in combination with atezolizumab and bevacizumab therapy (Cohort C) in patients with locally advanced or metastatic, and unresectable hepatocellular carcinoma (HCC). In Cohort A, Composition 3 was administered to the patients. In Cohort B, Composition 3 was administered to the patients in combination with pembrolizumab as an intravenous (IV) infusion. In Cohort C, 37 IPTS / 128698855.1Attorney Docket No. TVR-013WO Composition 3 was administered to the patients in combination with atezolizumab and bevacizumab, both as IV infusions. A cycle is 21 days.

[0096] In another trial (Phase 2), TTI-101 was assessed in patients with breast cancer (metastatic hormone receptor-positive and human epidermal receptor 2 (HER2)-negative breast cancer). Composition 3 was administered to the patients in combination with palbociclib (as an oral capsule) or ribociclib (as an oral tablet) and an aromatase inhibitor (AI) (as an oral tablet) or in combination with fulvestrant (as an oral tablet). A cycle is 28 days.

[0097] Composition 3 was administered as outlined below in Table 7. The pharmacokinetics of oral dosing of TTI-101 according to the above trials were assessed (Tables 8-14). In Tables 8-16, “n” corresponds to number of assessed participants. Table 7. Dosing Regimen for TTI-101 Tablet Composition (Composition 3)Table 8. Phase 2 Hepatocellular CarcinomaTable 9. Phase 2 Breast Cancer38 IPTS / 128698855.1Attorney Docket No. TVR-013WO n / a: not collected; Mean ± SD Table 10. Phase 1 Normal Healthy Volunteers: Arm A (Part 1)Mean ± SD Table 11. Phase 1 Normal Healthy Volunteers: Arm B (Part 2)Mean ± SD Table 12. Phase 1 Advanced Cancers(1) Target dose was 6.25 mg / kg, actual dose in mg based on patient body weight. Mean ± SD. All subjects were fed prior to dosing. 39 IPTS / 128698855.1Attorney Docket No. TVR-013WO (2) Target dose was 6.25 mg / kg, actual dose in mg based on patient body weight. Mean ± SD. All subjects were fed prior to dosing (3) Target dose was 6.25 mg / kg, actual dose in mg based on patient body weight. All subjects fasted prior to dosing. Table 13. Phase 1 Advanced Cancers – Initial PK*n / a: not collected *Note: All subjects fasted. Initial PK prior to evaluation of Fed vs Fasted (subjects in Table 12). Target doses were 6.25 and 12.5 mg / kg, actual dose in mg based on patient body weight. Mean ± SD. Table 14. Phase 1 Advanced Cancersn / a: not collected Target doses were 1.75, 3.25, and 6.5 mg / kg, actual dose in mg based on patient body weight. Mean ± SD. 40 IPTS / 128698855.1Attorney Docket No. TVR-013WO

[0098] Exposures with 800 mg per day dose (400 mg twice a day) of Composition 3 was higher than exposures observed in healthy volunteers dosed with 1200 mg per day (600 twice a day) of Composition 3.

[0099] FIG.1A shows an exemplary pharmacokinetics profile at Day 29 (Cycle 2, Day 1) from the Phase 2 breast cancer trial for the compound of Formula (I). FIG.1B shows an exemplary pharmacokinetics profile at Day 22 (Cycle 2, Day 1) from the Phase 2 HCC trial for the compound of Formula (I). Furthermore, the exposures are consistently above the IC90 (estimated at 1320 ng / ml (1320 / 471.5=2.8 µM)). Table 15. Phase 2 Hepatocellular Carcinoma[000100] An overlap in TTI-101 mean exposure was observed in the monotherapy arm for Phase 2 HCC trial at steady state (Day 22) between doses of 400 mg and 600 mg. FIG. 1C shows an exemplary concentration profile at Day 22 (Cycle 2, Day 1) from the Phase 2 HCC trial for the compound of Formula (I). 41 IPTS / 128698855.1

Claims

Attorney Docket No. TVR-013WO CLAIMS 1. A composition for use in treating cancer in a subject in need thereof, wherein the composition comprises: (a) at least 150 mg of the compound of Formula (I):or a pharmaceutically acceptable salt thereof, and b) a polymer excipient. wherein the use comprises administering to the subject between two and eight tablets comprising the composition per day.

2. The composition for use of claim 1, wherein the use exhibits a pharmacokinetic profile characterized by an average maximum concentration (Cmax) between about 3,000 ng / mL and about 6,000 ng / mL after administration of about 400 mg to about 600 mg dose (e.g., half the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject.

3. The composition for use of claim 1, wherein the use exhibits a pharmacokinetic profile characterized by an average Cmax between about 3,000 ng / mL and about 4,000 ng / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

4. The composition for use of claim 1, wherein the use exhibits a pharmacokinetic profile characterized by an average Cmaxbetween about 4,500 ng / mL and about 5,500 ng / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

5. The composition for use of claim 1, wherein the use exhibits a pharmacokinetic profile characterized by an average Cmaxbetween about 3,500 ng / mL and about 5,000 ng / mL after administration of about 600 mg dose (e.g., half the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

6. The composition for use of claim 1, wherein the use exhibits a pharmacokinetic profile characterized by an average area under the curve (AUC0-8hours) between about 15,000 42 IPTS / 128698855.1Attorney Docket No. TVR-013WO ng*h / mL and about 30,000 ng*h / mL after administration of about 400 mg to about 600 mg dose (e.g., half the total daily dose of about 800 mg to about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

7. The composition for use of claim 1, wherein the use exhibits a pharmacokinetic profile characterized by an average AUC0-8hours between about 16,000 ng*h / mL and about 24,000 ng*h / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

8. The composition for use of claim 1, wherein the use exhibits a pharmacokinetic profile characterized by an average AUC0-8hoursbetween about 23,000 ng*h / mL and about 29,000 ng*h / mL after administration of about 400 mg dose (e.g., half the total daily dose of about 800 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

9. The composition for use of claim 1, wherein the use exhibits a pharmacokinetic profile characterized by an average AUC0-8hours between about 20,000 ng*h / mL and about 24,000 ng*h / mL after administration of 600 mg dose (e.g., half the total daily dose of about 1,200 mg) of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

10. The composition for use of any one of claims 1-9, wherein the composition comprises about 200 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

11. The composition for use of any one of claims 1-10, comprising administering to the subject two tablets per day.

12. The composition for use of claim 11, comprising administering to the subject one tablet in the morning and one tablet in the evening.

13. The composition for use of any one of claims 1-10, comprising administering to the subject four tablets per day.

14. The composition for use of claim 13, comprising administering to the subject two tablets in the morning and two tablets in the evening.

15. The composition for use of any one of claims 1-10, comprising administering to the subject six tablets per day.

16. The composition for use of claim 15, comprising administering to the subject three tablets in the morning and three tablets in the evening.

17. The composition for use of any one of claims 1-10, comprising administering to the subject eight tablets per day. 43 IPTS / 128698855.1Attorney Docket No. TVR-013WO 18. The composition of claim 17, comprising administering to the subject four tablets in the morning and four tablets in the evening.

19. The composition for use of any one of claims 1-10, comprising administering to the subject about 400 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, optionally comprising administering to the subject about 200 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

20. The composition for use of any one of claims 1-10, comprising administering to the subject about 800 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, optionally comprising administering to the subject about 400 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

21. The composition for use of any one of claims 1-10, comprising administering to the subject about 1,200 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, optionally comprising administering to the subject about 600 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

22. The composition for use of any one of claims 1-10, comprising administering to the subject about 1,600 mg per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, optionally comprising administering to the subject about 800 mg twice per day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

23. The composition for use of any one of claims 1-22, wherein the polymer excipient is in an amount of about 10-30% w / w of the composition or about 15-25% w / w of the composition.

24. The composition for use of any one of claims 1-23, wherein the polymer excipient is a copolymer comprising methacrylic acid and ethylacrylate, a copolymer comprising methacrylic acid and methyl methacrylate, or a copolymer comprising N,N- dimethylaminoethyl methacrylate, methylmethacrylate, and butylmethacrylate.

25. The composition for use of any one of claims 1-24, wherein the composition further comprises a diluent or filler.

26. The composition for use of claim 25, wherein the diluent or filler is in an amount of about 15-40% w / w of the composition or about 20-35% w / w of the composition, optionally wherein the diluent or filler is a mixture of two or more diluents or fillers, optionally wherein the diluent or filler is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, and powdered cellulose, or a combination thereof.

27. The composition for use of any one of claims 1-25, wherein the composition further comprises a disintegrant. 44 IPTS / 128698855.1Attorney Docket No. TVR-013WO 28. The composition for use of claim 27, wherein the disintegrant is in an amount of about 1-10% w / w of the composition or about 3-8% w / w of the composition, optionally wherein the disintegrant is a mixture of two or more diluents, optionally wherein the disintegrant is croscarmellose sodium.

29. The composition for use of any one of claims 1-28, further comprising a lubricant.

30. The composition for use of claim 29, wherein the lubricant is in an amount of about 0.5-4% w / w of the composition or about 1-3% w / w of the composition, optionally wherein the lubricant is a mixture of two or more lubricants, optionally wherein the lubricant is selected from the group consisting of sodium lauryl sulphate, magnesium sulfate, and sodium stearyl fumarate, or a combination thereof.

31. The composition for use of any one of claims 1-30, wherein the composition further comprises a crystallization inhibiting polymer.

32. The composition for use of claim 31, wherein the crystallization inhibiting polymer is in an amount of about 10-30% w / w of the composition or about 15-25% w / w of the composition, optionally wherein the crystallization inhibiting polymer is a mixture of two or more the crystallization inhibiting polymers, optionally wherein the crystallization inhibiting polymer is Hypromellose acetate succinate.

33. The composition for use of any one of claims 1-22, wherein the composition comprises: a) at least 150 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; b) a polymer excipient in an amount of about 20-35% w / w of the composition; wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the polymer excipient is comprised in a solid amorphous dispersion; c) a crystallization inhibiting polymer in an amount of about 15-35% w / w of the composition; d) a diluent or filler in an amount of about 5-25% of the composition; e) a disintegrant in an amount of about 1-8% w / w of the composition; and f) a lubricant in an amount of about 0.1-3% w / w of the composition.

34. The composition for use of any one of claims 1-22, wherein the composition comprising: a) at least 150 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; 45 IPTS / 128698855.1Attorney Docket No. TVR-013WO b) a polymer excipient in an amount of about 15-25% w / w of the composition; wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the polymer excipient is comprised in a solid amorphous dispersion; c) a crystallization inhibiting polymer in an amount of about 15-25% w / w of the composition; d) a diluent or filler in an amount of about 20-35% of the composition; e) a disintegrant in an amount of about 3-8% w / w of the composition; and f) a lubricant in an amount of about 1-3% w / w of the composition.

35. The composition for use of claim 33 or 34, wherein the composition comprises about 200 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

36. The composition for use of any one of claims 1-22, wherein the composition comprising: a) about 200 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; b) a polymer excipient in an amount of about 15-25% w / w of the composition; wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the polymer excipient is comprised in a solid amorphous dispersion; c) a first crystallization inhibiting polymer in an amount of about 10-20% w / w of the composition; d) a second crystallization inhibiting polymer in an amount of about 3-8% w / w of the composition; e) a diluent or filler in an amount of about 20-35% of the composition; f) a disintegrant in an amount of about 3-8% w / w of the composition; and g) a first lubricant in an amount of about 0.5-1% w / w of the composition; and h) a second lubricant in an amount of about 0.5-1.5% w / w of the composition.

37. The composition for use of any one of claims 1-36, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, gastric cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gall bladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, or lymphoma. 46 IPTS / 128698855.1Attorney Docket No. TVR-013WO 38. The composition for use of any one of claims 1-37, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, prostate cancer, cervical cancer, brain cancer, pancreatic cancer, myelodysplastic syndrome, leukemia, lymphoma, neuroblastoma, kidney cancer, skin cancer, or metastatic melanoma, optionally wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia or pancreatic cancer.

39. The composition for use of any one of claims 1-38, wherein the cancer is: i) breast cancer; or ii) liver cancer, optionally wherein the liver cancer is hepatocellular carcinoma.

40. The composition for use of any one of claims 1-39, further comprising administering to the subject one or more additional agent, optionally wherein the additional agent is: i) selected from the group consisting of an angiogenesis inhibitor, an anti-PD-1 antibody, and an anti-PD-L1 antibody, or a combination thereof; or ii) selected from the group consisting of a cyclin-dependent kinase (CDK) inhibitor (e.g., CDK4 / 6 inhibitor), an aromatase inhibitor, and hormone therapy, or a combination thereof 47 IPTS / 128698855.1

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