Methods of treating cancer using combinations of GCN2 modulators and belzutifan

Abstract

A method of treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof and selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; administering to the human cancer patient an effective amount of a HIF-2α antagonist and an effective amount of the compound of formula (I): when the tumor sample expresses both HIF-1α and HIF-2α, or a pharmaceutically acceptable salt thereof and belzutifan.

Description

METHODS OF TREATING CANCER USING COMBINATIONS OF GCN2 MODULATORS AND BELZUTIFAN BACKGROUND Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020 (World Health Organization). Targeted therapy and immunotherapy have expanded the horizons for treatment of solid tumors by improving prognosis drastically. However, tumor recurrence, drug resistance, and drug intolerance continue to be major challenges in the management of advanced cancer (Wang et al., “Drug resistance and combating drug resistance in cancer,” Cancer Drug Resistance, 2019, 2(2): 141-160; Chakraborty et al., “The difficulties in cancer treatment” Ecancermedicalscience, 2012, 6:ed16). Cancer cells often experience a variety of stressors in their microenvironment such as hypoxia, low pH, and deficiencies in nutrients. In order to survive harsh tumor microenvironments, cancer cells actively utilize adaptive stress pathways such as the integrated stress response (ISR) (Ye et al., “The GCN2-ATF4 pathway is critical for tumor cell survival and proliferation in response to nutrient deprivation,” EMBO J., 2010, 29(12): 2082-2096; Pakos-Zebrucka et al., “The integrated stress response,” EMBO Rep., 2016, 17(10): 1374-1395). The ISR consists of 4 kinases: protein kinase ribonucleic acid [RNA]- like endoplasmic reticulum kinase, protein kinase double-stranded RNA-dependent, general control nonderepressible 2 (GCN2), and heme-regulated inhibitor (Donnelly et al., “The eIF2α kinases: their structures and functions,” Cell Mol Life Sci., 2013, 70(19): 3493- 3511). These four kinases sense unique stressors and phosphorylate α-subunit of eukaryotic initiation factor 2 (eIF2α) (Albert et al., “Adaptive Protein Translation by the Integrated Stress Response Maintains the Proliferative and Migratory Capacity of Lung Adenocarcinoma Cells,” Mol Cancer Res., 2019, 17(12): 2343-2355). The high molecular weight kinase GCN2 senses amino acid deficiency as part of the ISR. Under amino acid starvation, uncharged transfer RNA accumulates and activates GCN2 (Anda et al., “Activation of Gcn2 in response to different stresses,” PLOS ONE, 2017, 12(8): E0182143). Phosphorylation of eIF2α by ISR kinases, such as GCN2, inhibits general protein synthesis during cellular stress but also promotes the translation of select mRNAs including activating transcription factor 4 (ATF4) which is a key effector of the ISR (Pakos-Zebrucka et al.). Once translated, ATF4 translocates to the nucleus and drives the expression of genes involved in adaptation to stress such as autophagy, antioxidantresponse, amino acid biosynthesis, and metabolism (Pakos-Zebrucka et al.; Harding et al., “An integrated stress response regulates amino acid metabolism and resistance to oxidative stress,” Mol Cell, 2003, 11(3): 619-633). Other factors which activate GCN2 include ultraviolet light, viral infection, and oxidative stress (Costa-Mattioli et al., “The integrated stress response: From mechanism to disease,” Science, 2020, 368(6489): eaat5314). ATF4 is important for tumor cells to maintain homeostasis of amino acid metabolism. Activation of the ISR pathway promotes tumor cell survival under nutrient deprivation (Ye et al.). GCN2 / ATF4 expression is elevated in primary human liver, breast, lung, and head and neck tumors and GCN2 activation compared to normal tissue has been observed in colon, breast, and lung tumor samples. ISR activation plays a dual role in cell fate decisions. During acute stress conditions, ISR can promote adaptation and during chronic stress conditions this pathway can turn apoptotic which results in increased phosphorylation of eIF2α for an extended time (Wortel et al., “Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells,” Trends Endocrinol Metabol., 2017, 28(11): 794-806). By reducing protein synthesis or activating apoptotic pathways, prolonged activation of ISR can be harmful to cell growth (Wortel et al.; Harding et al., “Ppplr14 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) dephosphorylation in mammalian development,” Proc Natl Acad Sci USA, 2009, 106(6); 1832-1837; Münch, “The different axes of the mammalian mitochondrial unfolded protein response,” BMC Biology, 2018; 16(1): 81). Persistent ISR activation as a consequence of mutation of eIF2α phosphatases has been shown to have a deleterious effect on embryogenesis due to inhibition of protein synthesis (Harding et al., “Ppplr14 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) dephosphorylation in mammalian development,” Proc Natl Acad Sci USA, 2009, 106(6); 1832-1837). GCN2 activation also can have antiproliferative effects through suppression of general protein synthesis and induction of cell cycle arrest preventing cells from growing during times of nutrient scarcity (Lehman et al., “Translation Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress,” PLOS Genetics, 2015, 11(6): e1005212). Therefore, continuous activation of the GCN2 pathway could suppress protein synthesis and cell growth, thereby inhibiting tumorproliferation. Hypoxia-inducible factors (HIFs) are heterodimeric oxygen-sensitive basic helix-loop-helix transcription factors that play central roles in cellular adaptation to low oxygen environments. The von-Hippel Lindau tumor suppressor (pVHL) functions as a master regulator of HIF activity by targeting the hydroxylated HIF-alpha subunit for ubiquitylation and proteasomal degradation. Mutations in pVHL can be found in familial and sporadic hemangioblastomas, clear cell carcinomas of the kidney, pheochromocytomas and inherited forms of erythrocytosis, illustrating the importance of disrupted molecular oxygen sensing in the pathogenesis of these diseases. Curr Pharm Des.2009; 15(33): 3895–3903. Approval of the HIF-2α antagonist belzutifan (WELIREG) for patients with von Hippel-Lindau (VHL) driven-disease has enabled clinical opportunities to target the HIF-2 axis in cancer. This is particularly important for patients with clear cell renal cell carcinoma (ccRCC), in which 90% of tumors are VHL deficient. However, only one in four primary tumors express HIF-2α exclusively, whereas approximately two thirds of tumors express a combination of HIF-1α and HIF- 2α. See FIG.1. Cancer Cell 2008, 14 (6), 435-446. Clinical studies to date suggest an overall response rate (ORR) of 20-25% for belzutifan monotherapy, highlighting the need for a rational combination strategy to address patient populations with HIF-1α and HIF-2α-driven tumors. Thus, there remains an unmet need to develop new therapeutic strategies that target patient populations having cancer driven by both HIF-1α and HIF-2α and that utilize modulation, either activation or inhibition of the GCN2 pathway for the treatment of a variety of cancers. SUMMARY Provided herein are methods of selecting patients that would benefit from treatment with a compound of formula (I). The methods generally comprise analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α, selecting the human cancer patient based on the expression level of HIF-1α and the expression level of HIF-2α, and then administering, when HIF- 1α is expressed in the tumor sample, to the subject an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and an effective amount of belzutifan. Methods are also provided for treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof. The methods describedherein generally comprise administering to the subject an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and an effective amount of belzutifan. In one aspect, provided herein is a method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; selecting the human cancer patient to be treated based on the expression level of HIF-1α and the expression level of HIF-2α; and administering to the human cancer patient an effective amount of a compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α, ,In another aspect, provided herein is a method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; administering to the human cancer patient an effective amount of a HIF-2α antagonist and an effective amount of the compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α, O ,or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; administering to the human cancer patient an effective amount of belzutifan and an effective amount of a compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α, O HN , or aIn another aspect, provided herein is a method of treating cancer in a human subject in need thereof, the method comprising: obtaining a tumor sample from the human subject; determining an expression level of HIF-1α and an expression level of HIF-2α in the tumor sample; selecting the human subject for treatment when the tumor samples expresses both HIF-1α and HIF-2α; and administering, to the human subject, an effective amount of a compound of formula (I), O , or aIn another aspect, provided herein is a method of treating cancer in a human subject in need thereof, the method comprising: obtaining a tumor sample from thehuman subject; determining an expression level of HIF-1α and an expression level of HIF-2α in the tumor sample; selecting the human subject for treatment when the tumor sample expresses both HIF-1α and HIF-2α; and administering, to the human subject, an effective amount of a HIF-2α antagonist and an effective amount of a compound of formula (I), O HN , or aIn another aspect, provided herein is a method of treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof, the method comprising administering to the subject an effective amount of belzutifan and an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the locally advanced or metastatic renal cell carcinoma has predominantly clear cell histology. In certain embodiments, the locally advanced or metastatic renal cell carcinoma is a histologically or cytologically confirmed locally advanced or metastatic renal cell carcinoma. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 120 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan daily. In certain embodiments, administering theeffective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan twice or three times daily. In certain embodiments, the effective amount of belzutifan is administered to the subject in a fasted state. In certain embodiments, the renal cell carcinoma is locally advanced renal cell carcinoma. In certain embodiments, the renal cell carcinoma is metastatic renal cell carcinoma. In certain embodiments, the renal cell carcinoma has predominantly clear cell histology. In certain embodiments, the renal cell carcinoma is a histologically or cytologically confirmed locally advanced or metastatic renal cell carcinoma. In certain embodiments, the about 120 mg belzutifan is administered orally to the subject. In certain embodiments, the about 120 mg belzutifan is administered orally to the subject daily. In certain embodiments, the about 120 mg belzutifan is administered orally to the subject once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan twice or three times daily. In certain embodiments, the about 120 mg belzutifan is administered to the subject in a fasted state. In certain embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In certain embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In certain embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, daily. In certain embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, oncedaily. In certain embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily for 28 consecutive days. In certain embodiments, the effective amount of the compound of formula (I) is administered to the subject in a fasted state. In certain embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, at least about 1 hour before a meal or at least about 2 hours after a meal once daily for 28 consecutive days. In certain embodiments, the subject has previously been administered at least two and no more than 5 prior lines of therapy. In certain embodiments, the subject exhibits progressive disease after being administered the at least two and no more than 5 prior lines of therapy. In certain embodiments, the method comprises administering an effective amount of a pharmaceutically acceptable salt of the compound of formula (I). In certain embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a potassium salt of the compound of formula (I). In certain embodiments, the potassium salt of the compound of formula (I) is a hydrate. In certain embodiments, the potassium salt of the compound of formula (I) is a monohydrate. BRIEF DESCRIPTION OF THE FIGURES FIG.1 is a pie chart reflecting HIF biology and subtypes in ccRCC. FIG.2 is a graph showing the correlation between the ratio of HIF2α-to-HIF1α and belzutifan efficacy in RXF-616 xenograft, MFE-280 cell line, RXF-2873 xenograft and 786-O cell line; FIG.3 is a graph showing HIF2α vs HIF1α protein expression across available RCC PDX models; FIGS.4A-4C illustrate graphs showing the results of CDX model 786-O treated with 0.1 mg / kg or 1 mg / kg belzutifan in combination with various doses of HC-7366. Spider plot shows individual tumor growth curves. Animals with <14 mm3 tumorvolume for three consecutive measurements were considered as complete responders (CR) and tumors with >50% regressions were partial responders (PR). FIG.5A illustrates a graph showing the results of CDX model A-498 treated with the indicated doses of HC-7366 and / or belzutifan. Tumor size was measured for 28 days; FIG.5B illustrates a western blot used to determine expression levels of ATF4 target ASNS; FIG.5C illustrates a western blot used to determine expression levels of ATF4 target PSAT1; FIG.5D illustrates a western blot used to determine expression levels of HIF biology protein HIF-2α; FIG.5E illustrates a western blot used to determine expression levels of HIF biology protein GLUT1; FIG.5F illustrates a western blot used to determine expression levels of cell cycle protein phospho-Rb (S807 / S811) (pRb). Western blots for additional cell cycle proteins are also provided: CDK1 (see FIG.5G), CDK2 (see FIG.5H), and CYCLIN D1 (see FIG.5I); FIG.6A illustrates a graph of HC-7366 showing combination benefit in a belzutifan-resistant PDX. The ccRCC PDX model, RXF-616, was treated with belzutifan and / or HC-7366 at the indicated doses for 18 days; FIG.6B illustrates a western blot used to determine expression of HIF-1α; FIG.6C illustrates a western blot used to determine expression of HIF-2α; FIG.6D illustrates a western blot used to determine expression of cell cycle protein pRb. Western blots for additional cell cycle proteins are also provided: CDK1 (see FIG.6E), CDK2 (see FIG.6F), CDK4 (see FIG.6G) and CYCLIN B1 (see FIG. 6H); FIG.6I illustrates a western blot used to determine expression of pathway engagement marker ASNS; FIG.6J illustrates a western blot used to determine expression of pathway engagement marker PSAT1; FIG.6K illustrates a western blot used to determine expression of apoptotic marker PUMA;FIG.7A illustrates a graph showing that HC-7366 combines significantly with belzutifan in MFE-280. MFE-280 was treated with the indicated doses for 21 days; FIG.7B illustrates a western blot used to determine expression of HIF-2α at Day 4; FIG.7C illustrates a western blot used to determine expression of CYCLIN D1, a HIF-2α target gene, at Day 4; FIG.7D illustrates a western blot used to determine expression of HIF-1α at Day 21; FIG.7E illustrates a western blot used to determine expression of HIF-2α at Day 21; and FIG.7F illustrates a western blot used to determine expression of cell cycle marker pRb. Western blots for additional cell cycle proteins are also provided: CDK1 (see FIG.7G), CDK2 (see FIG.7H), and CDK4 (see FIG.7I). DETAILED DESCRIPTION As generally described herein, the present disclosure provides methods of selecting human cancer patients for treatment with the compound of formula (I) based on expression levels of HIF-1α and HIF-2α. The methods described herein generally comprise administering to the subject effective amounts of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and belzutifan. The present disclosure also provides methods of treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof. The methods described herein generally comprise administering to the subject effective amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and belzutifan. Definitions To facilitate an understanding of the present invention, a number of terms and phrases are defined below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components. Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein. The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element. The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood fromthe context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context. The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10%, ±5%, ±3%, ±2%, or ±1% variation from the nominal value unless otherwise indicated or inferred from the context. At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention. As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls. As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.“Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., the compound of formula (I)), which salt is compatible with pharmaceutical administration. As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-4 alkyl, and the like. Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, K+, Ca2+, NH4+, and NW4+(where W can be a C1-4alkyl group), and the like. For therapeutic use, salts of the compounds of the present invention (e.g., the compound of formula (I)) are contemplated as being pharmaceutically acceptable.However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil / water or water / oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates, fatty acid esters, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. For examples of excipients, see Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975). 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 certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a non-human animal. As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables. As used herein, “administering” means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasaladministration or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic, or immunotherapy). The compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). As used herein, “fasting state” or “fasted state” means at least 1 hour before food or at least 2 hours after food is consumed by a subject. The terms “disease,” “disorder,” and “condition” are used interchangeably herein. 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 retards or slows the progression of the disease, disorder or condition (e.g., “therapeutic treatment”). In general, an “effective amount” of a compound (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) refers to an amount sufficient to elicit the desired biological response, e.g., to treat locally advanced or metastatic renal cell carcinoma. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.Compounds Compound of Formula (I) The compound of formula (I), shown below, is a selective modulator of general control nonderepressible 2 (GCN2), e.g., activation or inhibition of GCN2, and also known as 6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-N- methylimidazo[1,5-a]pyrazine-1-carboxamide: (I). the(I) is described in Example 1. PCT International Application No. PCT / US2022 / 013383, published as WO 2022 / 159746, which is incorporated herein by reference, describes the synthesis of the compound of formula (I) and also discloses the GCN2 inhibitory activity of the compound of formula (I). In certain embodiments, any of the compounds disclosed in WO2022 / 159746 can be used according to the methods described herein. In one aspect, provided herein is a method of administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In another aspect, provided herein is a method of administering an effective amount of a pharmaceutically acceptable salt of the compound of formula (I) for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In certain embodiments, the methods described herein further comprise administering an effective amount of belzutifan to the subject.In certain embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a potassium salt. In certain embodiments, the potassium salt of the compound of formula (I) is a hydrate. In certain embodiments, the potassium salt of the compound of formula (I) is a monohydrate. A method of preparing a potassium salt of the compound of formula (I) is described in Example 1. Belzutifan Belzutifan is a hypoxia-inducible factor-2 alpha (HIF-2α) antagonist and is represented by the following structural formula: Belzutifan ismedication used for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma, central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) in adult patients not requiring immediate surgery. Belzutifan and its methods of use and administration are disclosed in, for example, U.S. Patent Nos.9,908,845 and 9,969,689, which are incorporated herein by reference. Belzutifan may also be referred to as MK-6482, PT2977, or under the trade name Welireg®. In certain embodiments, provided herein is a method of administering an effective amount of belzutifan for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In certain embodiments, the methods described herein further comprise administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject. Pharmaceutical Compositions Provided herein are pharmaceutical compositions generally comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In one aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients.In another aspect, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula (I) and one or more pharmaceutically acceptable excipients. In another aspect, provided herein is a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In another aspect, provided herein is a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of a compound of formula (I) and one or more pharmaceutically acceptable excipients. In one aspect, provided herein is a method of administering a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients for the treatment of locally advanced or metastatic renal cell carcinoma. In another aspect, provided herein is a method of administering a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula (I) and one or more pharmaceutically acceptable excipients for the treatment of locally advanced or metastatic renal cell carcinoma. In one aspect, provided herein is a method of administering an effective amount of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients for the treatment of locally advanced or metastatic renal cell carcinoma. In another aspect, provided herein is a method of administering a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of a compound of formula (I) and one or more pharmaceutically acceptable excipients for the treatment of locally advanced or metastatic renal cell carcinoma. In one aspect, provided herein is a method of administering a pharmaceutical composition described herein for the treatment of locally advanced or metastatic renal cell carcinoma. In another aspect, provided herein is a method of administering an effective amount of a pharmaceutical composition described herein for the treatment of locally advanced or metastatic renal cell carcinoma.In certain embodiments, the methods described herein further comprise administering an effective amount of belzutifan to the subject. In certain embodiments, the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 40 mg to about 150 mg, about 75 mg to about 150 mg, about 125 mg to about 150 mg, about 10 mg to about 125 mg, about 10 mg to about 75 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 125 mg, about 20 mg to about 75 mg, about 20 mg to about 40 mg, about 40 mg to about 125 mg, about 40 mg to about 75 mg, or about 75 mg to about 125 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 10 mg to about 150 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, or about 150 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 10 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 20 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 40 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 75 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 125 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the compound of formula (I), or apharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 150 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of a compound of formula (I) in a pharmaceutical composition described herein is about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 40 mg to about 150 mg, about 75 mg to about 150 mg, about 125 mg to about 150 mg, about 10 mg to about 125 mg, about 10 mg to about 75 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 125 mg, about 20 mg to about 75 mg, about 20 mg to about 40 mg, about 40 mg to about 125 mg, about 40 mg to about 75 mg, or about 75 mg to about 125 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of a compound of formula (I) in a pharmaceutical composition described herein is about 10 mg to about 150 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of a compound of formula (I) in a pharmaceutical composition described herein is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, or about 150 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of a compound of formula (I) in a pharmaceutical composition described herein is about 10 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of a compound of formula (I) in a pharmaceutical composition described herein is about 20 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of a compound of formula (I) in a pharmaceutical composition described herein is about 40 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of a compound of formula (I) in a pharmaceutical composition described herein is about 75 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of a compound of formula (I) in a pharmaceutical composition described herein is about 125 mg, on a free acid equivalent weight basis. In certain embodiments, the amount of the pharmaceutically acceptable salt of acompound of formula (I) in a pharmaceutical composition described herein is about 150 mg, on a free acid equivalent weight basis. In another aspect, provided herein are pharmaceutical compositions comprising: (i) about 10 mg to about 150 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis; and (ii) one or more pharmaceutically acceptable excipients. In another aspect, provided herein are pharmaceutical compositions comprising: (i) about 10 mg to about 150 mg of a pharmaceutically acceptable salt of the compound of formula (I), on a free acid equivalent weight basis; and (ii) one or more pharmaceutically acceptable excipients. In another aspect, provided herein are pharmaceutical compositions comprising about 10 mg to about 150 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, and one or more pharmaceutically acceptable excipients, for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In another aspect, provided herein are pharmaceutical compositions comprising about 10 mg to about 150 mg of a pharmaceutically acceptable salt of the compound of formula (I), on a free acid equivalent weight basis, and one or more pharmaceutically acceptable excipients, for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In another aspect, provided herein are pharmaceutical compositions comprising about 10 mg to about 75 mg of the compound of formula (I), or an equivalent amount of a pharmaceutically acceptable salt thereof on a free acid equivalent weight basis, and one or more pharmaceutically acceptable excipients, for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In another aspect, provided herein are pharmaceutical compositions comprising about 20 mg of the compound of formula (I), or an equivalent amount of a pharmaceutically acceptable salt thereof on a free acid equivalent weight basis, and one or more pharmaceutically acceptable excipients, for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In another aspect, provided herein are pharmaceutical compositions comprising about 75 mg of the compound of formula (I), or an equivalent amount of a pharmaceutically acceptable salt thereof on a free acid equivalent weight basis, and oneor more pharmaceutically acceptable excipients, for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In certain embodiments, the pharmaceutical compositions described herein are administered in combination with belzutifan for the treatment of locally advanced or metastatic renal cell carcinoma in a subject in need thereof. In certain embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a potassium salt. In certain embodiments, the potassium salt of the compound of formula (I) is a hydrate. In certain embodiments, the potassium salt of the compound of formula (I) is a monohydrate. The pharmaceutical compositions described herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In certain embodiments, the pharmaceutical compositions described herein are administered orally. The pharmaceutical compositions described herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time. The pharmaceutical compositions described herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.In certain embodiments, the pharmaceutical compositions provided herein are administered to the patient as a solid dosage form. In certain embodiments, the solid dosage form is a capsule. In certain embodiments, the pharmaceutical composition is an immediate release capsule formulation comprising the potassium salt monohydrate of the compound of formula (I). In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the capsule comprises one or more of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the capsule comprises each of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the capsule comprises 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 75 mg or 100 mg of the potassium salt monohydrate of the compound of formula (I), on a free acid equivalent weight basis. Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21sted., Lippincott Williams & Wilkins, 2005. Methods of Patient Selection Provided herein are methods treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof by administering to the subject an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof and an effective amount of belzutifan. The disclosure also provides methods of selecting patients that would benefit from treatment with a compound of formula (I). The methods generally comprise analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α, selecting the human cancer patient based on the expression level of HIF-1α and the expressionlevel of HIF-2α, and then administering, when HIF-1α is expressed in the tumor sample, to the subject an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and an effective amount of belzutifan. In one aspect, provided herein is a method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; selecting the human cancer patient to be treated based on the expression level of HIF-1α and the expression level of HIF-2α; and administering to the human cancer patient an effective amount of a compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α, ,In another aspect, provided herein is a method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; administering to the human cancer patient an effective amount of a HIF-2α antagonist and an effective amount of the compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α, O ,or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; administering to the human cancer patient an effective amount of belzutifan and an effective amount of a compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α, ,In another aspect, provided herein is a method of treating cancer in a human subject in need thereof, the method comprising: obtaining a tumor sample from the human subject; determining an expression level of HIF-1α and an expression level of HIF-2α in the tumor sample; selecting the human subject for treatment when the tumor samples expresses both HIF-1α and HIF-2α; and administering, to the human subject, an effective amount of a compound of formula (I), O , or aIn another aspect, provided herein is a method of treating cancer in a human subject in need thereof, the method comprising: obtaining a tumor sample from thehuman subject; determining an expression level of HIF-1α and an expression level of HIF-2α in the tumor sample; selecting the human subject for treatment when the tumor sample expresses both HIF-1α and HIF-2α; and administering, to the human subject, an effective amount of a HIF-2α antagonist and an effective amount of a compound of formula (I), , or aIn certain embodiments, the expression level of HIF-1α is at least about one tenth, at least about one quarter, at least about half, at least about three quarters, or at least about nine tenths of the expression level of HIF-2α. In certain embodiments, the expression level of HIF-1α is about equal to the expression level of HIF-2α. In certain embodiments, the expression level of HIF-1α is greater than the expression level of HIF-2α. In certain embodiments, the expression level of HIF-1α is at least about five times, at least about ten times, at least about twenty-five times, at least about fifty times, or at least about one hundred times greater than the expression level of HIF-2α. In certain embodiments, the expression level of HIF-1α and the expression level of HIF-2α is determined by immunohistochemistry. In certain embodiments, the expression level of HIF-1α and the expression level of HIF-2α is determined by western blot. In certain embodiments, the HIF-2α antagonist is belzutifan. In certain embodiments, the cancer is selected from renal cell carcinoma, locally advanced renal cell carcinoma, metastatic renal cell carcinoma, and endometrial cancer. In certain embodiments, the locally advanced or metastatic renal cell carcinoma has predominantly clear cell histology. In certain embodiments, the locally advancedrenal cell carcinoma has predominantly clear cell histology. In certain embodiments, the metastatic renal cell carcinoma has predominantly clear cell histology. In certain embodiments, the locally advanced or metastatic renal cell carcinoma is a histologically or cytologically confirmed locally advanced or metastatic renal cell carcinoma. In certain embodiments, the locally advanced renal cell carcinoma is a histologically or cytologically confirmed locally advanced renal cell carcinoma. In certain embodiments, the locally advanced renal cell carcinoma is a histologically confirmed locally advanced renal cell carcinoma. In certain embodiments, the locally advanced renal cell carcinoma is a cytologically confirmed locally advanced renal cell carcinoma. In certain embodiments, the metastatic renal cell carcinoma is a histologically or cytologically confirmed metastatic renal cell carcinoma. In certain embodiments, the metastatic renal cell carcinoma is a histologically confirmed metastatic renal cell carcinoma. In certain embodiments, the metastatic renal cell carcinoma is a cytologically confirmed metastatic renal cell carcinoma. In certain embodiments, the locally advanced renal cell carcinoma is inoperable. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 60 mg to about 180 mg, about 75 mg to about 180 mg, about 100 mg to about 180 mg, about 120 mg to about 180 mg, about 150 mg to about 180 mg, about 60 mg to about 150 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 120 mg, about 75 mg to 150 mg, about 100 mg to about 120 mg, about 100 mg to about 150 mg, about 100 to about 180 mg, or about 120 mg to about 150 mg belzutifan. In certain embodiments, the effective amount of belzutifan is administered to the subject orally. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 60 mg to about 180 mg, about 75 mg to about 180 mg, about 100 mg to about 180 mg, about 120 mg to about 180 mg, about 150 mg to about 180 mg, about 60 mg to about 150 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 120 mg, about 75 mg to 150 mg, about 100 mg to about 120 mg, about 100 mg to about 150 mg, about 100 to about 180 mg, or about 120 mg to about 150 mg belzutifan.In certain embodiments, the effective amount of belzutifan is administered to the subject daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 60 mg to about 180 mg, about 75 mg to about 180 mg, about 100 mg to about 180 mg, about 120 mg to about 180 mg, about 150 mg to about 180 mg, about 60 mg to about 150 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 120 mg, about 75 mg to 150 mg, about 100 mg to about 120 mg, about 100 mg to about 150 mg, about 100 to about 180 mg, or about 120 mg to about 150 mg belzutifan daily. In certain embodiments, the effective amount of belzutifan is administered to the subject once, twice, three, four, five, or more times daily. In certain embodiments, the effective amount of belzutifan is administered to the subject once daily. In certain embodiments, the effective amount of belzutifan is administered to the subject twice daily. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 60 mg to about 180 mg, about 75 mg to about 180 mg, about 100 mg to about 180 mg, about 120 mg to about 180 mg, about 150 mg to about 180 mg, about 60 mg to about 150 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 120 mg, about 75 mg to 150 mg, about 100 mg to about 120 mg, about 100 mg to about 150 mg, about 100 to about 180 mg, or about 120 mg to about 150 mg belzutifan once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 60 mg, about 75 mg, about 100 mg, about 120 mg, about 150 mg, or about 180 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 60 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 75 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 100 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 120 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject about 150 mg belzutifan. In certainembodiments, administering the effective amount of belzutifan comprises administering to the subject about 180 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 60 mg, about 75 mg, about 100 mg, about 120 mg, about 150 mg, or about 180 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 60 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 75 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 100 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 150 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 180 mg belzutifan. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 60 mg, about 75 mg, about 100 mg, about 120 mg, about 150 mg, or about 180 mg belzutifan daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 60 mg belzutifan daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 75 mg belzutifan daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 100 mg belzutifan daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 150 mg belzutifan daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 180 mg belzutifan daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 60 mg, about 75 mg, about 100 mg,about 120 mg, about 150 mg, or about 180 mg belzutifan once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 60 mg belzutifan once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 75 mg belzutifan once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 100 mg belzutifan once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 150 mg belzutifan once daily. In certain embodiments, administering the effective amount of belzutifan comprises administering orally to the subject about 180 mg belzutifan once daily. In certain embodiments, the effective amount of belzutifan is administered to the subject in a fasted state. In certain embodiments, the effective amount of belzutifan is administered to the subject in a fed state. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject the effective amount of belzutifan at least 1 hour before a meal or at least 2 hours after a meal. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject the effective amount of belzutifan at least 1 hour before a meal. In certain embodiments, administering the effective amount of belzutifan comprises administering to the subject the effective amount of belzutifan at least 2 hours after a meal. In some embodiments, the about 120 mg belzutifan is administered orally to the subject. In some embodiments, the about 120 mg belzutifan is administered orally to the subject daily. In some embodiments, the about 120 mg belzutifan is administered orally to the subject once daily. In some embodiments, the about 120 mg belzutifan is administered to the subject in a fasted state. In some embodiments, the about 120 mg belzutifan is administered to the subject in a fed state. In some embodiments, the about 120 mg belzutifan is administered to the subject at least about 1 hour before a meal or at least 2hours after a meal. In some embodiments, the about 120 mg belzutifan is administered to the subject at least 1 hour before a meal. In some embodiments, the about 120 mg belzutifan is administered to the subject at least 2 hours after a meal. In another aspect, provided herein is a method of treating renal cell carcinoma in a subject in need thereof, the method consisting of administering to the subject an effective amount of a compound of formula (I), O HN , or aIn another aspect, provided herein is a method of treating renal cell carcinoma in a subject in need thereof, the method consisting of administering to the subject about 120 mg belzutifan and an effective amount of a compound of formula (I), O , or aIn some embodiments, the renal cell carcinoma is locally advanced renal cell carcinoma. In some embodiments, the renal cell carcinoma is metastatic renal cell carcinoma. In some embodiments, the renal cell carcinoma has predominantly clear cell histology.In some embodiments, the renal cell carcinoma is a histologically or cytologically confirmed locally advanced or metastatic renal cell carcinoma. In some embodiments, the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and about 120 mg belzutifan are administered orally to the subject. In some embodiments, the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg to about 150 mg, about 15 mg to about 150 mg, about 20 mg to about 150 mg, about 25 mg to about 150 mg, about 30 mg to about 150 mg, about 35 mg to about 150 mg, about 40 mg to about 150 mg, about 45 mg to about 150 mg, about 50 mg to about 150 mg, about 55 mg to about 150 mg, about 60 mg to about 150 mg, about 65 mg to about 150 mg, about 70 mg to about 150 mg, about 75 mg to about 150 mg, about 80 mg to about 150 mg, about 85 mg to about 150 mg, about 90 mg to about 150 mg, about 95 mg to about 150 mg, about 100 mg to about 150 mg, about 105 mg to about 150 mg, about 110 mg to about 150 mg, about 115 mg to about 150 mg, about 120 mg to about 150 mg, about 125 mg to about 150 mg, about 130 mg to about 150 mg, about 135 mg to about 150 mg, about 140 mg to about 150 mg, or about 145 mg to about 150 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg to about 150 mg, about 15 mg to about 145 mg, about 20 mg to about 140 mg, about 25 mg to about 135 mg, about 30 mg to about 135 mg, about 35 mg to about 130 mg, about 40 mg to about 125 mg, about 45 mg to about 120 mg, about 50 mg to about 115 mg, about 55 mg to about 110 mg, about 60 mg to about 105 mg, about 65 mg to about 100 mg, about 70 mg to about 95 mg, about 75 mg to about 90 mg, or about 80 to about 85 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg to about 75 mg, about 15 mg to about 75 mg, about 20 mg toabout 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, about 40 mg to about 75 mg, about 45 mg to about 75 mg, about 50 mg to about 75, about 55 mg to about 75 mg, about 60 mg to about 75 mg, about 65 mg to about 75 mg, or about 70 mg to about 75 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 20 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 40 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 75 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 125 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 150 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 105 mg, at least about 110 mg, at least about 115 mg, at least about 120 mg, at least about 125 mg, at least about 130 mg, at least about 135 mg, at least about 140 mg, or at least about 145 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering about 10 mg to about 75 mg a compound of formula (I), or an equivalent amount of a pharmaceutically acceptable salt thereof on a free acid equivalent weight basis, to the subject. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering about 20 mg a compound of formula (I), or an equivalent amount of a pharmaceutically acceptable salt thereof on a free acid equivalent weight basis, to the subject. In some embodiments, administering the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering about 75 mg a compound of formula (I), or an equivalent amount of a pharmaceutically acceptable salt thereof on a free acid equivalent weight basis, to the subject. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg to about 150 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administeringorally to the subject about 10 mg to about 150 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 150 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, daily. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 150 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 150 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily for 28 consecutive days. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis. In some embodiments, the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject daily. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, daily. In some embodiments, the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject once daily. In some embodiments, administering the effective amount of the compound of formula(I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily. In some embodiments, the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject once daily for 28 consecutive days. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily for 28 consecutive days. In some embodiments, the subject is in a fasted state. In some embodiments, the subject is in a fed state. In some embodiments, the effective amount of the compound of formula (I) is administered to the subject in a fasted state. In some embodiments, administering to the subject the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject the effective amount at least 1 hour before a meal or at least 2 hours after a meal. In some embodiments, administering to the subject the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject the effective amount at least 1 hour before a meal. In some embodiments, administering to the subject the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject the effective amount at least 2 hours after a meal. In some embodiments, administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, at least about 1 hour before a meal or at least about 2 hours after a meal once daily for 28 consecutive days. In some embodiments, the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.In some embodiments, the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally to the subject once daily for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 consecutive days. In some embodiments, the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally to the subject once daily for 28 consecutive days. In some embodiments, the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally to the subject once daily for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 consecutive days. In some embodiments, the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally to the subject once daily for at least 28 consecutive days. In some embodiments, the subject has previously been administered at least two and no more than 5 prior lines of therapy. In some embodiments, the subject has previously been administered more than one line of therapy. In some embodiments, the subject has previously been administered at least two prior lines of therapy. In some embodiments, the subject has previously been administered at least three lines of therapy. In some embodiments, the subject has previously been administered at least 4 lines of therapy. In some embodiments, the subject has previously been administered at least 5 lines of therapy. In some embodiments, the subject has previously been administered fewer than 6 lines of therapy. In some embodiments, the subject has previously been administered two, three, 4, or 5 prior lines of therapy. In some embodiments, the subject has previously been administered more than 5 lines of therapy. In some embodiments, the subject has previously been administered one prior line of therapy. In some embodiments, the subject has not been administered a prior line of therapy. In some embodiments, the subject exhibits progressive disease after being administered the at least two and no more than 5 prior lines of therapy. In some embodiments, the subject exhibits progressive disease after being administered the more than one line of therapy. In some embodiments, the subject exhibits progressive disease after being administered the at least two prior lines of therapy. In some embodiments, the subject exhibits progressive disease after being administered the at least three lines of therapy. In some embodiments, the subjectexhibits progressive disease after being administered the at least 4 lines of therapy. In some embodiments, the subject exhibits progressive disease after being administered the at least 5 lines of therapy. In some embodiments, the subject exhibits progressive disease after being administered the fewer than 6 lines of therapy. In some embodiments, the subject exhibits progressive disease after being administered the two, three, 4, or 5 prior lines of therapy. In some embodiments, the subject exhibits progressive disease after being administers the more than 5 lines of therapy. In some embodiments, the subject exhibits progressive disease after being administered one prior line of therapy. In some embodiments, the subject exhibits progressive disease after not being administered a prior line of therapy. In certain embodiments, at least one of the prior lines of therapy and the therapy is belzutifan. In certain embodiments, the patient is refractory to treatment with belzutifan. Prior lines of therapy include, but are not limited to, surgery, radiation therapy (e.g., external beam radiation therapy or internal radiation therapy), chemotherapy (e.g., alkylating agents, nitrosoureas, anti-metabolites, plant alkaloids and natural products, anti-tumor antibiotics, hormonal agents, and biological response modifiers), antibody- drug conjugates, gene therapy, DNA therapy, viral therapy (e.g., oncolytic virus therapy), RNA therapy, adjuvant therapy, and immunotherapy (e.g., immune checkpoint inhibition, adoptive cell therapies, (e.g., tumor-infiltrating lymphocyte therapy, engineered T-cell receptor therapy, CAR T-cell therapy, natural killer cell therapy), or monoclonal antibodies). In some embodiments, the method comprises administering an effective amount of a pharmaceutically acceptable salt of the compound of formula (I). In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a potassium salt of the compound of formula (I). In some embodiments, the potassium salt of the compound of formula (I) is a hydrate. In some embodiments, the potassium salt of the compound of formula (I) is a monohydrate. In another aspect, provided herein are methods of treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein.In another aspect, provided herein are methods of treating locally advanced renal cell carcinoma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein. In another aspect, provided herein are methods of treated metastatic renal cell carcinoma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein. In certain embodiments, the method further comprises administering an effective amount of belzutifan. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human. EXAMPLES In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.Example 1: Synthesis of 6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6- difluorophenyl)-N-methylimidazo[1,5-a]pyrazine-1-carboxamide (Compound of Formula (I)) and HC-7366-Kacetate 2,5-Dibromopyrazine (10 g, 42 mmol, 1 equiv.), ethyl 2- [(diphenylmethylidene)amino]acetate (11.8 g, 44 mmol, 1.05 equiv.), tetrabutylammonium bromide (TBAB) (13.6 g, 42 mmol, 1 equiv.) and K2CO3(17.4 g, 126 mmol, 3 equiv.) in (N-methyl-2-pyrrolidone) NMP (200 mL) were stirred overnight at 100 °C in an oil bath. The reaction mixture was cooled and filtered. The filtrate was diluted with 200 mL of water. The resulting solution was extracted with 2 x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2 x 200 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column, eluting with ethyl acetate / petroleum ether (PE) (1 / 10). The collected fractions were combined and concentrated to give ethyl 2-(5-bromopyrazin-2-yl) -2- [(diphenylmethylidene)amino]acetate (8 g, 45% yield) as a yellow solid. LCMS (ES, m / z): [M+H]+: 424 Synthesis of 1-b: ethyl 2-amino-2-(5-bromopyrazin-2-yl) acetate Into a 250 mL round-bottom flask, was placed ethyl 2-(5-bromopyrazin-2-yl)-2- [(diphenylmethylidene)amino] acetate (8 g, 18.8 mmol, 1 equiv.), tetrahydrofuran (THF) (10 mL) and HCl (aqueous, 1 M) (20 mL). The resulting solution was stirred for 30 min at 25 °C. The solution formed was diluted with 50 mL of water and extracted with 2 x 50 mL of dichloromethane. The aqueous layers were adjusted to pH 8 with NH3.H2O and further extracted with 3 x 50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Ethyl 2- amino-2-(5-bromopyrazin-2-yl)acetate (4.7 g, 96% yield) was isolated as a yellow solid which was used in next step directly without further purification. LCMS (ES, m / z): [M+H]+: 260 Synthesis of 1-c: ethyl 6-bromoimidazo [1,5-a]pyrazine-1-carboxylate Into a 50 mL round-bottom flask, was placed ethyl 2-amino-2-(5-bromopyrazin- 2-yl) acetate (4.2 g, 0.02 mol, 1 equiv.) and triethyl orthoformate (20 mL). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The reaction mixture was cooled, and the solids collected by filtration. Air drying gave ethyl 6-bromoimidazo [1,5-a]pyrazine-1-carboxylate (2.2 g, 50% yield) as a brown solid. LCMS (ES, m / z): [M+H]+: 270 Synthesis of 1-d: 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 3-Bromo-2,4-difluoroaniline (10 g, 48 mmol, 1 equiv.), [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (3.5 g, 4.8 mmol, 0.1 equiv.), bis(pinacolato)diboron (18.3 g, 72 mmol, 1.5 equiv.) and potassium acetate (KOAc) (14.2 g, 144.2 mmol, 3 equiv.) were dissolved in dioxane (240 mL). The resulting solution was stirred overnight at 100 °C in an oil bath. The reaction mixture was cooled, and the solids removed by filtration. The filtrate was concentrated and diluted with dichloromethane (DCM) (100 mL), then washed with 2 x 100 mL ofwater and 100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate / petroleum ether (1 / 10).2,4-Difluoro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8 g, 65% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H]+: 256 Synthesis of 1-e: ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1- carboxylate Ethyl 6-bromoimidazo[1,5-a]pyrazine-1-carboxylate (500 mg, 1.9 mmol, 1 equiv.), 2,4-difluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (708 mg, 2.8 mmol, 1.5 equiv.), Pd(dppf)Cl2(135 mg, 0.2 mmol, 0.1 equiv.), K2CO3(767 mg, 5.6 mmol, 3 equiv) in dioxane (10 mL) and H2O (2 mL) were stirred for 1 h at 60 °C in an oil bath. The reaction mixture was cooled, diluted with water (20 mL) and extracted with 3 x 20 mL of dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / PE (1 / 2). Ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5- a]pyrazine-1-carboxylate (200 mg 34% yield) was isolated as a brown solid. LCMS (ES, m / z): [M+H]+: 319 Synthesis of 1-f: ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6- difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylate Ethyl 6-(3-amino-2, 6-difluorophenyl)imidazo[1,5-a]pyrazine-1- carboxylate (150 mg, 0.5 mmol, 1 equiv.) in DCM (5 mL) was treated with pyridine (186 mg, 2.3 mmol, 5 equiv.), then 5-chloro-2-methoxypyridine-3-sulfonyl chloride (137 mg, 0.6 mmol, 1.2 equiv.). The resulting solution was stirred overnight. The resulting mixture was concentrated and purified by Flash-Prep-HPLC with the following conditions: Column, WelFlashTM C18-I, Spherical C1820-40 μm; mobile phase: 0.1% Formic Acid / 5-70% MeCN over 15 min; Detector, 254 & 220 nm. Ethyl 6-[3-(5-chloro-2- methoxypyridine-3-sulfonamido)-2,6- difluorophenyl]imidazo[1,5-a]pyrazine-1- carboxylate (320 mg 97% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H]+: 524 Synthesis of 1-g: 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6- difluorophenyl]imidazo[1,5-a] pyrazine-1-carboxylic acid Ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6- difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylate (200 mg, 0.4 mmol, 1 equiv),methanol (MeOH) (2 mL), THF (2 mL) , H2O (2 mL) and LiOH (27 mg, 1.1 mmol, 3 equiv) were stirred for 1 h at 60 °C in an oil bath. After concentration, the crude product was purified by Flash-Prep-high performance liquid chromatography (HPLC) with the following conditions: Column, WelFlashTM C18-I, Spherical C1820-40 μm; mobile phase: 5-60% acetonitrile (MeCN) / 0.1% ammonia over 15 min; Detector, 254 nm.6-[3-(5-Chloro-2-methoxypyridine-3-sulfonamido)-2,6- difluorophenyl]imidazo[1,5-a] pyrazine-1-carboxylic acid (170 mg, 90% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H]+: 496 Synthesis of 6-[3-(5-chloro-2-methoxypyridine- 3-sulfonamido)-2,6-difluorophenyl]- N-methylimidazo[1,5-a]pyrazine-1-carboxamide 6-[3-(5-Chloro-2-methoxypyridine-3-sulfonamido)-2,6- difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylic acid (170 mg, 0.3 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (4 mL) was treated with diisopropylethylamine (DIEA) (133 mg, 1 mmol, 3 equiv), methylamine hydrochloride (16 mg, 0.5 mmol, 1.5 equiv) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU) (195 mg, 0.5 mmol, 1.5 equiv). The resulting solution was stirred for 1 hr, then concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions: Column, WelFlashTM C18-I, Spherical C1820-40 μm, 120 g; mobile phase: 5-60% MeCN / 0.1% formic acid over 20 min.6-[3-(5-Chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N- methylimidazo[1,5-a]pyrazine-1-carboxamide (43 mg, 25% yield) was isolated as an off-white solid. Liquid chromatography / mass spectrometry (LCMS) (ES, m / z): [M+H]+: 5091H nuclear magnetic resonance spectroscopy (NMR) (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 5.0 Hz, 2H), 8.51 (d, J = 2.6 Hz, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.42 (td, J = 8.8, 5.8 Hz, 1H), 7.25 (td, J = 9.3, 1.4 Hz, 1H), 3.92 (s, 3H), 2.84 (d, J = 4.7 Hz, 3H).Preparation of the Compound of Formula (I) Potassium Salt – HC-7366-K -3-sulfonamido)-2,6-- (as prepared in Example 1) in aqueous isopropyl alcohol (IPA) was slowly added 1.1 equivalents of an aqueous KOH solution and the solution heated. The resulting mixture was cooled, the solid collected, washed with IPA / water, and then dried under heat and vacuum to afford potassium ((5-chloro-2-methoxypyridin-3-yl)sulfonyl)(2,4-difluoro-3-(1- (methylcarbamoyl)imidazo[1,5-a]pyrazin-6-yl)phenyl)amide.19F NMR (400 MHz, DMSO-d6): -129.62 and -127.72 ppm. Example 2: FIG.2 is a graph showing the correlation between the ratio of HIF2α-to-HIF1α and belzutifan efficacy in RXF-616 xenograft, MFE-280 cell line, RXF-2873 xenograft and 786-O cell line. TGI was determined for RXF-616, MFE-280 and 786-O using methods similar to those further described herein. Experimental procedures for the RXF-2873 were similar to those for the RXF-616, as further described herein. FIG.2 shows that the amount of TGI is proportional to the HIF2 / HIF1 ratio for treatment with belzutifan alone. FIG.3 is a graph showing HIF2α vs HIF1α protein expression (via simple western blot) across various RCC PDX models. FIG.3 shows HIF2α vs HIF1α protein expression in the following: 786-O, RXF-2873, RXF-1220, MRI-H 166, RXF-2540, RXF-1781, RXF-2178, RXF-631, MFE-280, RXF-2282, RXF-2502, RXF-2304, RXF- 616, RXF-2304, RXF-488, RXF-2773, RXF-2667, and RXF-393. All cell lines with the prefix “RXF” were obtained from Charles River. The data presented in FIG.3 illustrates the type of analysis that can be performed to determine which patients would benefit from combination treatment of HC-7366 and belzutifan. That is, patients exhibiting both HIF-2α and HIF-1α protein expression would benefit from combination treatment of HC-7366 and belzutifan. Patients exhibiting protein expression of onlyHIF-2α, and / or HIF-2α and low HIF-1α, would likely benefit from belzutifan monotherapy benefit. Example 3: FIGS.4A-4C illustrate graphs showing the results of CDX model 786-O treated with 0.1 mg / kg or 1 mg / kg belzutifan in combination with various doses of HC-7366. CDX model 786-O is considered a HIF-2 driven model. Spider plot shows individual tumor growth curves. Animals with <14 mm3 tumor volume for three consecutive measurements were considered as complete responders (CR) and tumors with >50% regressions were partial responders (PR). FIG.4A illustrates a graph showing that, when compared with vehicle, HC- 7366 monotherapy, and belzutifan monotherapy, combination treatment with HC-7366 and belzutifan enhances the reduction of tumor volume. The doses illustrated in FIG.4A for HC-7366 are 3 mg / kg. The doses for belzutifan are 0.1 mg / kg, which is considered subtherapeutic. FIG.4B illustrates a graph showing that, when compared with vehicle, HC- 7366 monotherapy, and belzutifan monotherapy, combination treatment with HC-7366 and belzutifan enhances the reduction of tumor volume. The doses illustrated in FIG.4B for HC-7366 are 0.5 mg / kg. The doses for belzutifan are 1 mg / kg, which is considered a therapeutic dose. Comparing the results from FIG.4A and FIG.4B, the combination of HC-7366 and belzutifan enables treatment with a subtherapeutic dose of belzutifan to achieve a comparable reduction in tumor volume. FIG.4C illustrates a graph of tumor volume vs. days of treatment for treatment with belzutifan alone or in combination with HC-7366. The graph shows that combination benefit for treatment with belzutifan and HC-7366 was comparable to belzutifan alone, however, the inset bar graph shows that the number of complete responders to combination treatment increased significantly as compared with belzutifan alone. Cell Line The 786-O kidney cell line (ATCC) was maintained in vitro with RPMI1640 medium supplemented with 10% fetal bovine serum at 37ºC in an atmosphere of 5% CO2 in the air. The cells in exponential growth phase were harvested and quantitated by cell counter before tumor inoculation. Cells were free of human and animal pathogens as tested by h-IMPACT-I and IMPACT-III (IDEXX Bioresearch, Columbia,MO). Additionally, the cell authenticity was verified by STR based DNA fingerprinting assay. Cells were maintained in EMEM with 10% FBS and cultured up to 4 passages prior to implantation. Cells were harvested at ~80% confluence, washed twice with PBS and suspended in PBS at 50×106cells / mL for implantation. Animal in vivo efficacy studies All animal research methods and studies for the 786-O model were approved by the University of Minnesota Institutional Animal Care and Use Committee (IACUC protocol# 2009-38458A) and performed in accordance with current regulations and standards of the U.S. Department of Agriculture and the NIH. Female Athymic Nude- Foxn1nu mice (7-8 weeks of age animals, 20-25 grams, from Envigo) were allowed to acclimate for 7 days after arrival at the facility. Mice were housed in a 12-hour light / dark cycle facility under pathogen-free conditions in microisolator cages with standard laboratory chow and water ad libitum. Test Article and Formulation HC-7366-K (Potassium Monohydrate, lot # 66162-122A1) was synthesized according to the methods described herein. A correction factor of 1.13 was used to account for salt content and purity for this particular batch to deliver appropriate doses of HC-7366-K. HC-7366-K was in 0.5% methylcellulose formulation and kept at 2-8 °C. HC-7366 dosing formulation was prepared every 7 days. Belzutifan (Batch No.: 119030) was synthesized according to the methods described herein and prepared fresh daily in 20% ethanol, 40% PEG400, and 40% water formulation.Table 1: Treatment Groups for 786-O Cell Line 5 10 15 Tumor InoculationFemale athymic nude mice (7-8 weeks of age) were implanted into the flank subcutaneously under Isoflurane anesthesia with 5×106789-O cells / mouse in a total volume of 0.1mL PBS on Day 0. A total of 72 tumor-bearing mice were enrolled in each study; n=8 / group with n=9 treatment groups (see Table 1 above). Randomization was performed based on “Matched distribution” method (StudyDirector software, version 3.1.399.19). The treatment was initiated on the same day of randomization (day 0) per study design. The date of randomization was denoted as day 0. Body weight and tumor volume were measured twice weekly. The body weights and tumor volumes were measured by using StudyDirector software (version 3.1.399.19). Tumors were measured using a caliper. Tumor volume was calculated using the formula [tumor volume (mm3) = π / 6 × length × width2) and plotted as means ± SEM. The %TGI (tumor growth inhibition) was calculated by the formula 100 × (1- ΔT / ΔC), if ΔT > 0 of the mean values. ΔT, mean tumor volume of the drug-treated group on the observation day of the study − mean tumor volume of the drug-treated group on the initial day of dosing; ΔC, mean tumor volume of the control group on the observation day of the study − mean tumor volume of the control group on the initialday of dosing. Regression was calculated using the formula = 100 × ΔT / Tinitial, if ΔT < 0. Animals with <14 mm3tumor volume for three consecutive measurements were considered as complete responders (CR) and tumors with >50% regressions were partial responders (PR). The % change in body weight was calculated by the formula (body weight on observation day − body weight on initial day) / body weight on initial day × 100%. Animal well-being and behavior, including grooming and ambulation, were monitored at least twice per week. Animals were euthanized based on the following: 1) dosing error, 2) morbidity criteria, 3) 20% or greater body weight loss compared to initial weight, or 4) tumor volume greater than or equal to 2200 mm3or ulceration. Animals were euthanized at the end of the study using CO2 asphyxiation. Statistical Analyses For the evaluation of the statistical significance of antitumor efficacy for 786-O, Conover’s non-parametric all-pairs comparison test for multiple comparisons was performed. Statistical analysis was only carried out if at least 50% of the initially randomized animals remained in the relevant group. All p-values < 0.05 were considered statistically significant. Statistical calculations were performed using GraphPad Prism bioanalytic software.Table 2: TGI Chart for 786-O Cell Line Example 4: FIG.5A illustrates a graph showing the results of CDX model A-498 treated with the indicated doses of HC-7366 and / or belzutifan. Tumor size was measured for 28 days. FIG.5A is graph showing that, when compared with vehicle, HC-7366 monotherapy results in 35% tumor growth inhibition (TGI), and belzutifan monotherapy results in 68% TGI, combination treatment with HC-7366 and belzutifan enhances the reduction of tumor volume, resulting in 85% TGI. The doses illustrated in FIG.5A for HC-7366 are 0.5 mg / kg. The doses for belzutifan are 1 mg / kg. FIG.5B illustrates a western blot used to determine expression levels of ATF4 target ASNS. FIG.5B shows that HC-7366 treatment leads to ISR activation as evidenced by clinically translatable PD marker ASNS. FIG.5C illustrates a western blot used to determine expression levels of ATF4 target PSAT1. FIG.5B shows that HC-7366 treatment leads to ISR activation as evidenced by clinically translatable PD marker PSAT1.FIG.5D illustrates a western blot used to determine expression levels of HIF biology protein HIF-2α. FIG.5D shows that combination treatment with HC-7366 and belzutifan results in an enhanced reduction of HIF-2α expression than with HC-7366 alone and comparable to belzutifan alone. FIG.5E illustrates a western blot used to determine expression levels of HIF biology protein GLUT1. FIG.5E shows that combination treatment with HC-7366 and belzutifan results in an enhanced reduction of GLUT1 expression than with HC-7366 alone, further evidence of a reduction of an overall reduction in HIF-2α biology. FIG.5F illustrates a western blot used to determine expression levels of cell cycle protein phospho-Rb (S807 / S811) (pRb). Western blots for additional cell cycle proteins are also provided: CDK1 (see FIG.5G), CDK2 (see FIG.5H), and CYCLIN D1 (see FIG.5I). FIGS.5F-5I shows an overall reduction in cell cycle expression resulting from combination treatment with HC-7366 and belzutifan. Cell Line The A-498 cell line (ATCC) was maintained in MEM supplemented with 10% fetal bovine serum and 0.01 mM non-essential amino acids. The cells in exponential growth phase were harvested and quantitated by cell counter before tumor inoculation. Cells were free of human and animal pathogens as tested by h-IMPACT-I and IMPACT-III (IDEXX Bioresearch, Columbia, MO). Additionally, the cell authenticity was verified by STR based DNA fingerprinting assay. Cells were maintained in EMEM with 10% FBS and cultured up to 4 passages prior to implantation. Cells were harvested at ~80% confluence, washed twice with PBS and suspended in PBS at 50×106cells / mL for implantation. Animal in vivo efficacy studies All animal research methods and studies for the A-498 model were approved by the University of Minnesota Institutional Animal Care and Use Committee (IACUC protocol# 2009-38458A) and performed in accordance with current regulations and standards of the U.S. Department of Agriculture and the NIH. Female Athymic Nude- Foxn1nu mice (7-8 weeks of age animals, 20-25 grams, from Envigo) were allowed to acclimate for 7 days after arrival at the facility. Mice were housed in a 12-hour light / dark cycle facility under pathogen-free conditions in microisolator cages with standard laboratory chow and water ad libitum. Test Article and FormulationHC-7366-K (Potassium Monohydrate, lot # 66162-122A1) was synthesized according to the methods described herein. A correction factor of 1.13 was used to account for salt content and purity for this particular batch to deliver appropriate doses of HC-7366-K. HC-7366-K was in 0.5% methylcellulose formulation and kept at 2-8 °C. HC-7366 dosing formulation was prepared every 7 days. Belzutifan (Batch No.: 119030) was synthesized according to the methods described herein and prepared fresh daily in 20% ethanol, 40% PEG400, and 40% water formulation. Table 3: Treatment Groups for A-498 Cell LineTumor Inoculation Female athymic nude mice (7-8 weeks of age) were implanted into the flank subcutaneously under Isoflurane anesthesia with 5×106A-498 cells per mouse in a total volume of 0.1mL PBS with 1:1 matrigel on Day 0. A total of 72 tumor-bearing mice were enrolled in each study; n=8 / group with n=9 treatment groups (see Table 3 above). Randomization was performed based on “Matched distribution” method (StudyDirector software, version 3.1.399.19). The treatment was initiated on the same day of randomization (day 0) per study design. The date of randomization was denoted as day 0. Body weight and tumor volume were measured twice weekly. The body weights and tumor volumes were measured by using StudyDirector software (version 3.1.399.19). Tumors were measured using a caliper. Tumor volume was calculated using the formula [tumor volume (mm3) = π / 6 × length × width2) and plotted as means ± SEM. The percent TGI (tumor growth inhibition) was calculated by the formula 100 × (1-ΔT / ΔC), if ΔT > 0 of the mean values. ΔT, mean tumor volume of the drug-treated group on the observation day of the study – mean tumor volume of the drug-treated group on the initial day of dosing; ΔC, mean tumor volume of the control group on the observation day of the study – mean tumor volume of the control group on the initial day of dosing. Regression was calculated using the formula = 100 × ΔT / Tinitial, if ΔT < 0. Animals with <14 mm3tumor volume for three consecutive measurements were considered as complete responders (CR) and tumors with >50% regressions were partial responders (PR). The % change in body weight was calculated by the formula (body weight on observation day – body weight on initial day) / body weight on initial day × 100%. Animal well-being and behavior, including grooming and ambulation, were monitored at least twice per week. Animals were euthanized based on the following: 1) dosing error, 2) morbidity criteria, 3) 20% or greater body weight loss compared to initial weight, or 4) tumor volume greater than or equal to 2200 mm3or ulceration. Animals were euthanized at the end of the study using CO2 asphyxiation. Statistical Analyses For the evaluation of the statistical significance of antitumor efficacy for A-498, Conover’s non-parametric all-pairs comparison test for multiple comparisons was performed. Statistical analysis was only carried out if at least 50% of the initiallyrandomized animals remained in the relevant group. All p-values < 0.05 were considered statistically significant. Statistical calculations were performed using GraphPad Prism bioanalytic software. Table 4: TGI Chart for A-498 Cell LineProtein extraction: Total protein was extracted from tumor tissues (PDXs and CDXs from these studies described above and 16 RXF-616 tumors purchased from Charles Rivers) and homogenized by polytron in lysis buffer consisting of 2x Laemmli SDS sample buffer (Novex), supplemented with 10% BME (Gibco), 1X benzonase (EMD Millipore Sigma), phosphatase inhibitors (Sigma) and Mini protease inhibitor tablet (Roche). The homogenate was incubated at room temperature for 10 min, then boiled for 10 min, followed by centrifugation for 10 min at max speed on a benchtop centrifuge. Protein was quantitated using Pierce 660 nm Protein Assay Kit (ThermoFisher). Protein detection was performed on the Jess SimpleWestern high-throughput protein analysis platform (ProteinSimple) according to manufacturer’s protocol using either a 12-230 kDa Separation Module (ProteinSimple, SM-W004) or a 66-440 kDa Separation Module (ProteinSimple, SM-W005) and Total Protein Detection Module(ProteinSimple, DM-TP01). Antibodies: ASNS (ProteinTech, 1:400, Cat# 14681-1-88), PSAT1 (Abclonal, 1:200, Cat# A14214), HIF-1α (abcam, 1:50, Cat# Ab308433), HIF- 2α (CST, Cat# 59973S), phospho-Rb (S807 / 811; CST, 1:100, Cat# 9308), pRb (S780; Abclonal, 1:100, Cat# AP0117), CDK1 (Abclonal, 1:100, Cat# A0220), CDK2 (CST, 1:100, Cat# 2546), CDK4 (CST, 1:100, Cat# 12790), Cyclin B1 (CST, 1:100, Cat# 12231), Cyclin D1 (CST, Cat# 2922), PUMA (CST, Cat# 98672S), and GLUT1 (AbClonal, Cat# A11208). Calculation of Ratios: The chemiluminescence value normalized to total protein (TPA) for HIF-2α was divided by the chemiluminescence value normalized to TPA for HIF-1α. This was graphed on the X-axis while the TGI% for 1 mg / g belzutifan at end of study (EoS) was plotted on the y-axis using Prism (GraphPad). Additionally, HIF-1α expression value in chemiluminescence was plotted on the x-axis versus the HIF-2α expression value in chemiluminescence. Example 5: FIG.6A illustrates a graph of HC-7366 showing combination benefit in a belzutifan-resistant PDX. The ccRCC PDX model, RXF-616, was treated with belzutifan and / or HC-7366 at the indicated doses for 18 days. FIG.6A is graph showing that, when compared with vehicle, belzutifan monotherapy results in modest TGI, whereas HC-7366 monotherapy results in significant TGI. Further, combination treatment with HC-7366 and belzutifan enhances the reduction of tumor volume than belzutifan alone. The doses illustrated in FIG.6A for HC-7366 monotherapy are 0.5 mg / kg (A) and 1 mg / kg (B). The doses for belzutifan monotherapy are 1 mg / kg. The doses for HC-7366 and belzutifan combination therapy are: HC-73660.5 mg / kg and belzutifan 1 mg / kg (D); and HC-73661 mg / kg and belzutifan 1 mg / kg (E). Vehicle The control vehicle and vehicle for HC-7366 is 5% (v / v) DMSO and 95% (v / v) Captisol (20% w / v) in PBS (final pH 7.4) The control vehicle and vehicle for PT2977 (belzutifan) is 20% ethanol, 40% PEG400, 40% water. Tumor Stock Tumor xenografts were derived from surgical specimens from cancer patients after excision at surgery. Tumor fragments were subcutaneously implanted into immunodeficient mice and are therefore referred to as patient-derived tumor xenografts(PDX). Following their primary implantation into immunodeficient mice (passage 1), the tumor xenografts were passaged until establishment of a stable growth pattern. At that point, master stocks of early passage PDXs were frozen in liquid nitrogen. A stock batch is usually only used for a limited number of further passages. Animal Husbandry Female NMRI nu / nu mice (Crl:NMRI-Foxn1nu, Charles River Laboratories) aged 4-6 weeks were housed in individually ventilated cages (TECNIPLAST Sealsafe- IVC-System, TECNIPLAST, Hohenpeissenberg, Germany). They were kept under a 14L:10D artificial light cycle. The temperature inside the cages was maintained at 22 – 26 °C with a relative humidity of 45–65% and 60–65 air changes / hour in the cage. Feed and water were provided ad libitum. All materials were autoclaved prior to use. Mice had an acclimatization period of at least one week on arrival prior to use. Where necessary, a nutrient fortified water gel (DietGel Recovery from ClearH₂O, Maine, USA) was provided to animal cages and changed at least every other day. Tumor Implantation Tumor fragments were obtained from xenografts (RXF-616) in serial passage in immunodeficient mice. After removal from donor mice, tumors were cut into fragments (3–4 mm edge length) and placed in PBS containing 10% penicillin / streptomycin. Recipient animals were anesthetized by inhalation of isoflurane and received unilateral tumor implants subcutaneously in the flank. Enrollment / Initiation of Experiments Animals were monitored until the tumor implants reached the study volume criteria of 50-250 mm³, preferably 80-200 mm³ in a sufficient number of animals. Mice were assigned to groups aiming at comparable group median and mean tumor volumes. The process of the assignment to groups (enrollment, stratified randomization) is referred to as randomization in this report. The day of randomization was designated as Day 0 of the experiment. Animals were routinely monitored at least twice daily on working days and at least once daily on weekends and public holidays. Table 5: Treatment Groups for RXF-616 XenograftTumor Growth Inhibition Calculations The absolute tumor volumes (ATVs) were determined by two-dimensional measurement with a digital caliper (S_Cal EVO Bluetooth, Switzerland) on the day of randomization and then twice weekly. Tumor volumes were calculated according to the formula: Tumor volume = (l × w²) × 0.5, where l = largest diameter and w = width (perpendicular diameter) of the tumor (in mm). The tumor growth inhibition value (TGI in %) was calculated using the group mean absolute tumor volumes according to the following formula: TGI^ [%] =(1 – (T^ − T₀) / (C^ − C₀))× 100, where T₀ and C₀ are the group mean absolute tumor volumes in the test and the vehicle control group prior to the start of the dosing (i.e. day of randomization) and T^ and C^ are the corresponding median or mean absolute tumor volumes on the last day of an experiment or the last day on which at least 50% animals per group remained. TGI values have the meaning described in Table 6 (assuming that C^ > C₀):Table 6: Definition of TGI Values Antitumor efficacy of all groups was assessed using the vehicle control group as a reference. Tumor growth inhibition (TGI) was determined by the comparison of ATVs of the test groups with the control group on Day 28 (final treatment day) and is expressed as TGI value in percent [%]. Animals (n=4) from all groups were subjected to sample collection on Day 4, 2 hrs after administration of treatment for PK / PD analysis. These animals were excluded from the statistical analysis. Statistical Analysis For the evaluation of the statistical significance of antitumor efficacy, the non- parametric Kruskal-Wallis test followed by Dunn’s method for multiple comparisons was performed. Statistical analysis was only carried out if at least 50% of the initially randomized animals remained in the relevant group. All p-values < 0.05 were considered statistically significant. Statistical calculations were performed using GraphPad Prism bioanalytic software. Table 7: TGI Chart for RXF-616 XenograftFIG.6B illustrates a western blot used to determine expression of HIF-1α. FIG. 6B shows that combination treatment of the RXF-616 with HC-7366 and belzutifan results in enhanced reduction in expression of HIF-1α than with belzutifan alone as well as showing that HIF-1α was reduced by HC-7366 alone. FIG.6C illustrates a western blot used to determine expression of HIF-2α. FIG. 6C shows that combination treatment of the RXF-616, a cell line considered to be belzutifan resistant, with HC-7366 and belzutifan results in an insignificant change in expression of HIF-2α than with belzutifan alone. FIG.6D illustrates a western blot used to determine expression of cell cycle protein pRb. Western blots for additional cell cycle proteins are also provided: CDK1 (see FIG.6E), CDK2 (see FIG.6F), CDK4 (see FIG.6G) and CYCLIN B1 (see FIG. 6H). FIGS.6D-6H show an overall reduction in cell cycle expression resulting from combination treatment with HC-7366 and belzutifan. FIG.6I illustrates a western blot used to determine expression of pathway engagement marker ASNS. FIG.6I shows that HC-7366 treatment leads to ISR activation as evidenced by clinically translatable PD marker ASNS. FIG.6J illustrates a western blot used to determine expression of pathway engagement marker PSAT1. FIG.5B shows that HC-7366 treatment leads to ISR activation as evidenced by clinically translatable PD marker PSAT1. FIG.6K illustrates a western blot used to determine expression of apoptotic marker PUMA. FIG.6K shows that HC-7366, whether alone or in combination with belzutifan, increases expression of PUMA, however belzutifan alone shows no response. Western Protein Analysis was performed according to the methods previously described herein. Example 6: FIG.7A illustrates a graph showing that HC-7366 combines significantly with belzutifan in MFE-280. MFE-280 was treated with the indicated doses for 21 days. FIG.7A is graph showing that, when compared with vehicle, HC-7366 monotherapy results in significant TGI, and belzutifan monotherapy results in significant TGI, but comparable to HC-7366 alone, whereas combination treatment with HC-7366 and belzutifan enhances the reduction of tumor volume beyond both HC-7366 monotherapyand belzutifan monotherapy. The doses illustrated in FIG.7A for HC-7366 are 0.5 mg / kg. The doses for belzutifan are 1 mg / kg. Cell Lines MFE-280 (Cat # 98050131) human endometrium adenocarcinoma cell line was purchased from the European Collection of Authenticated Cell Cultures (Sigma- ECACC). The cells in exponential growth phase were harvested and quantitated by cell counter before tumor inoculation. Cells were free of human and animal pathogens as tested by h-IMPACT-I and IMPACT-III (IDEXX Bioresearch, Columbia, MO). Additionally, the cell authenticity was verified by STR based DNA fingerprinting assay. Cells were maintained in EMEM with 10% FBS and cultured up to 4 passages prior to implantation. Cells were harvested at ~80% confluence, washed twice with PBS and suspended in PBS at 50×106cells / mL for implantation. Animal in vivo efficacy studies All animal research methods and studies for the MFE-280 model were approved by the University of Minnesota Institutional Animal Care and Use Committee (IACUC protocol# 2009-38458A) and performed in accordance with current regulations and standards of the U.S. Department of Agriculture and the NIH. Female Athymic Nude- Foxn1nu mice (7-8 weeks of age animals, 20-25 grams, from Envigo) were allowed to acclimate for 7 days after arrival at the UMN facility. Mice were housed in a 12-hour light / dark cycle facility under pathogen-free conditions in microisolator cages with standard laboratory chow and water ad libitum. Test Article and Formulation HC-7366-K (Potassium Monohydrate, lot # 66162-122A1) was synthesized and according to the methods described herein. A correction factor of 1.13 was used to account for salt content and purity for this particular batch to deliver appropriate doses of HC-7366. HC-7366-K was in 0.5% methylcellulose formulation and kept at 2-8 °C. HC-7366-K dosing formulation was prepared every 7 days. Belzutifan (Batch No.: 119030) was obtained according to the methods described herein and prepared fresh daily in 20% ethanol, 40% PEG400, and 40% water formulation. Table 8: Treatment Groups for MFE-280Tumor Inoculation Female athymic nude mice (7-8 weeks of age) were implanted into the flank subcutaneously under Isoflurane anesthesia with 10×106MFE-280 cells / mouse in a total volume of 0.2 mL PBS. A total of 72 tumor-bearing mice were enrolled in each study; n=8 / group with n=9 treatment groups (see above) Mice for MFE-280 were randomized into treatment groups once the average tumor reached 200 mm3. The treatment was initiated on the same day of randomization (day 0) per study design. The date of randomization was denoted as day 0. Body weight and tumor volume were measured twice weekly. The body weights and tumor volumes were measured by using StudyDirector software (version 3.1.399.19). Tumors were measured using a caliper. Tumor volume was calculated using the formula [tumor volume (mm3) = π / 6 × length × width2) and plotted as means ± SEM. The %TGI (tumor growth inhibition) was calculated by the TGI^ [%] =(1 – (T^ − T₀) / (C^ − C₀))× 100, if ΔT > 0 of the mean values. ΔT, mean tumor volume of the drug-treated group on the observation day of the study − mean tumor volume of the drug-treated group on the initial day of dosing; ΔC, mean tumor volume of the control group on the observation day of the study − mean tumor volume of the control group on the initial day of dosing. Regression was calculated using the formula REG [%] = (T^ − T₀) / T₀ × 100, if ΔT < 0. Animals with <14 mm3tumor volume for three consecutive measurements were considered as complete responders (CR) and tumors with >50% regressions were partial responders (PR). The % change in body weight was calculated by the formula (body weight on observation day − body weight on initial day) / body weight on initial day × 100%. Animal well-being and behavior, including grooming and ambulation, were monitored at least twice per week. Animals were euthanized based on the following: 1) dosing error, 2) euthanized based on morbidity criteria, 3) 20% or greater body weight loss compared to initial weight, or 4) tumor volume greater than or equal to 2200 mm3or ulceration. Animals were euthanized at the end of the study using CO2 asphyxiation. Statistical Analyses Tumor volume data were analyzed for statistics using 2-way ANOVA followed by Dunnett multiple comparisons test (GraphPad Prism) for the MFE-280 model. For the evaluation of the statistical significance of antitumor efficacy for 786-O, Conover’s non-parametric all-pairs comparison test for multiple comparisons was performed.Statistical analysis was only carried out if at least 50% of the initially randomized animals remained in the relevant group. All p-values < 0.05 were considered statistically significant. Statistical calculations were performed using GraphPad Prism bioanalytic software. Table 9: TGI Chart for MFE-280 Cell Line FIG.7B illustrates a western blot used to determine expression of HIF-2α at Day 4. FIG.7B shows that combination treatment with HC-7366 and belzutifan results in reduced expression of HIF-2α. FIG.7C illustrates a western blot used to determine expression of CYCLIN D1, a HIF-2α target gene, at Day 4. FIG.7C shows that combination treatment with HC- 7366 and belzutifan results in reduced expression of CYCLIN D1. FIG.7D illustrates a western blot used to determine expression of HIF-1α at Day 21. FIG.7D shows that HC-7366 is the primary driver of reducing expression of HIF-1α when compared with both belzutifan alone and the combination of HC-7366 and belzutifan. FIG.7E illustrates a western blot used to determine expression of HIF-2α at Day 21. FIG.7E shows that expression of HIF-2α remains reduced after 21 days with both treatment of belzutifan alone and the combination of HC-7366 and belzutifan. FIG.7F illustrates a western blot used to determine expression of cell cycle marker pRb. Western blots for additional cell cycle proteins are also provided: CDK1(see FIG.7G), CDK2 (see FIG.7H), and CDK4 (see FIG.7I). FIGS.7F-7I show an overall reduction in cell cycle expression resulting from combination treatment with HC-7366 and belzutifan. Western Protein Analysis was performed according to the methods previously described herein. Example 7: Immunohistochemistry Experimental methods for analyzing expression levels of HIF-1α and HIF-2α are performed according to the methods described in Gordan et al. Cancer Cell 2008, 14 (6), 435-446, as well as methods known to those of ordinary skill in the art. As described and shown herein, the GCN2 modulator HC-7366 has potent monotherapy efficacy in both CDX and PDX ccRCC models. HC-7366 treatment leads to ISR activation as evidenced by clinically translatable PD markers (e.g., ASNS, PSAT1). HC-7366 treatment causes HIF-1a reduction in multiple tumor models, with the corresponding reduction in HIF-1α target genes. HIF-2α reduction is cell line specific. Since the majority of ccRCC tumors express both HIF-1α and HIF-2α, the above experiments were performed to test belzutifan, a HIF-2α antagonist, in combination with HC-7366. The combination of HC-7366 and belzutifan shows significant efficacy benefit in both CDX and PDX ccRCC models, as well as in a CDX endometrial cancer model expressing both HIF-1α and HIF-2α. Target engagement was apparent in HC-7366-treated tumors with increases in ATF4 targets, along with reductions in HIF-1α and cell cycle proteins, with corresponding decreases in HIF-2α in the belzutifan-treated tumors. Combination of HC-7366 and belzutifan further decreased cell cycle markers, in line with efficacy, providing evidence that reduction of cell cycle proteins is a mechanism of action. HIF-1α is reduced in HC-7366-treated tumors and macrophages in various indications, suggesting a common efficacy mechanism for HC-7366. These data support the use of protein expression levels of HIF-1α and HIF-2α as biomarkers for selecting human cancer patients for treatment with a combination of HC-7366 and belzutifan.

[0101] In particular, the data presented herein demonstrates that tumors that are resistant to belzutifan treatment are driven by both HIF-1α and HIF-2α, with such tumors representing the majority of cases. Thus, selecting patient populations for treatment with the combination of HC-7366 and belzutifan according to whether thetumor expresses both HIF-1α and HIF-2α provides an improved therapeutic strategy that leads to better outcomes for human cancer patients. INCORPORATION BY REFERENCE This application refers to various issued patents, published patent applications, journal articles, and / or other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. EQUIVALENTS The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

CLAIMS WHAT IS CLAIMED:

1. A method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; selecting the human cancer patient to be treated based on the expression level of HIF-1α and the expression level of HIF-2α; and administering to the human cancer patient an effective amount of a compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α, O HN , or a2. A method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; administering to the human cancer patient an effective amount of a HIF-2α antagonist and an effective amount of the compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α,O HN , or a3. A method of selecting patients to be treated for cancer, the method comprising: analyzing a tumor sample from a human cancer patient for an expression level of HIF-1α and an expression level of HIF-2α; administering to the human cancer patient an effective amount of belzutifan and an effective amount of a compound of formula (I) when the tumor sample expresses both HIF-1α and HIF-2α, ,4. A method of treating cancer in a human subject in need thereof, the method comprising: obtaining a tumor sample from the human subject; determining an expression level of HIF-1α and an expression level of HIF-2α in the tumor sample;selecting the human subject for treatment when the tumor samples expresses both HIF-1α and HIF-2α; and administering, to the human subject, an effective amount of a compound of formula (I), ,5. A method of treating cancer in a human subject in need thereof, the method comprising: obtaining a tumor sample from the human subject; determining an expression level of HIF-1α and an expression level of HIF-2α in the tumor sample; selecting the human subject for treatment when the tumor sample expresses both HIF-1α and HIF-2α; and administering, to the human subject, an effective amount of a HIF-2α antagonist and an effective amount of a compound of formula (I), O , or a6. The method of any one of the preceding claims, wherein the expression level of HIF- 1α is at least about one tenth, at least about one quarter, at least about half, at least about three quarters, or at least about nine tenths of the expression level of HIF-2α.

7. The method of any one of the preceding claims, wherein the expression level of HIF- 1α is substantially equal to the expression level of HIF-2α.

8. The method of any one of the preceding claims, wherein the expression level of HIF- 1α is greater than the expression level of HIF-2α.

9. The method of any one of the preceding claims, wherein the expression level of HIF- 1α is at least about five times, at least about ten times, at least about twenty-five times, at least about fifty times, or at least about one hundred times greater than the expression level of HIF-2α.

10. The method of any one of the preceding claims, wherein the expression level of HIF-1α and the expression level of HIF-2α is determined by immunohistochemistry.

11. The method of any one of the preceding claims, wherein the HIF-2α antagonist is belzutifan.

12. The method of any one of the preceding claims, wherein the cancer is selected from renal cell carcinoma, locally advanced renal cell carcinoma, metastatic renal cell carcinoma, and endometrial cancer.

13. The method of any one of the preceding claims, wherein the locally advanced or metastatic renal cell carcinoma has predominantly clear cell histology.

14. The method of any one of the preceding claims, wherein the locally advanced or metastatic renal cell carcinoma is a histologically or cytologically confirmed locally advanced or metastatic renal cell carcinoma.

15. The method of any one of the preceding claims, wherein administering the effective amount of belzutifan comprises administering to the subject about 120 mg belzutifan.

16. The method of any one of the preceding claims, wherein administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan.

17. The method of any one of the preceding claims, wherein administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan daily.

18. The method of any one of the preceding claims, wherein administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan once daily.

19. The method of any one of the preceding claims, wherein the effective amount of belzutifan is administered to the subject in a fasted state.

20. The method of any one of the preceding claims, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis.

21. The method of any one of the preceding claims, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis.

22. The method of any one of the preceding claims, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, daily.

23. The method of any one of the preceding claims, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily.

24. The method of any one of the preceding claims, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily for 28 consecutive days.

25. The method of any one of the preceding claims, wherein the effective amount of the compound of formula (I) is administered to the subject in a fasted state.

26. The method of any one of the preceding claims, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 10 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, at least about 1 hour before a meal or at least about 2 hours after a meal once daily for 28 consecutive days.

27. The method of any one of the preceding claims, wherein the subject has previously been administered at least two and no more than 5 prior lines of therapy.

28. The method of any one of the preceding claims, wherein the subject exhibits progressive disease after being administered the at least two and no more than 5 prior lines of therapy.

29. The method of any one of the preceding claims, wherein at least one of the prior lines of therapy and the therapy is belzutifan.

30. The method of any one of the preceding claims, wherein the patient is refractory to treatment with belzutifan.

31. The method of any one of the preceding claims, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a potassium salt of the compound of formula (I).

32. The method of any one of the preceding claims, wherein the potassium salt of the compound of formula (I) is a hydrate.

33. The method of any one of the preceding claims, wherein the potassium salt of the compound of formula (I) is a monohydrate.

34. A method of treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), O HN Cl or at 35. A method of treating locally advanced or metastatic renal cell carcinoma in a subject in need thereof, the method comprising administering to the subject an effective amount of belzutifan and an effective amount of a compound of formula (I), O Cl(I), or a pharmaceutically acceptable l salt thereof. t36. The method of claim 34 or 35, wherein the locally advanced or metastatic renal cell carcinoma has predominantly clear cell histology.

37. The method of any one of claims 34-36, wherein the locally advanced or metastatic renal cell carcinoma is a histologically or cytologically confirmed locally advanced or metastatic renal cell carcinoma.

38. The method of any one of claims 35-37, wherein administering the effective amount of belzutifan comprises administering to the subject about 120 mg belzutifan.

39. The method of any one of claims 35-38, wherein administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan.

40. The method of any one of claims 35-39, wherein administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan daily.

41. The method of any one of claims 35-40, wherein administering the effective amount of belzutifan comprises administering orally to the subject about 120 mg belzutifan once daily.

42. The method of any one of claims 35-41, wherein the effective amount of belzutifan is administered to the subject in a fasted state.

43. A method of treating renal cell carcinoma in a subject in need thereof, the method consisting of administering to the subject an effective amount of a compound of formula (I),O HN Cl(I), or a pharmaceutically acceptable l salt thereof. t 44. A method of treating renal cell carcinoma in a subject in need thereof, the method consisting of administering to the subject about 120 mg belzutifan and an effective amount of a compound of formula (I), O Cl(I), or a pharmaceutically acceptable l salt thereof. t 45. The method of claim 43 or 44, wherein the renal cell carcinoma is locally advanced renal cell carcinoma.

46. The method of claim 43 or 44, wherein the renal cell carcinoma is metastatic renal cell carcinoma.

47. The method of any one of claims 43-46, wherein the renal cell carcinoma has predominantly clear cell histology.

48. The method of any one of claims 43-47, wherein the renal cell carcinoma is a histologically or cytologically confirmed locally advanced or metastatic renal cell carcinoma.

49. The method of any one of claims 44-48, wherein the about 120 mg belzutifan is administered orally to the subject.

50. The method of any one of claims 44-49, wherein the about 120 mg belzutifan is administered orally to the subject daily.

51. The method of any one of claims 44-50, wherein the about 120 mg belzutifan is administered orally to the subject once daily.

52. The method of any one of claims 44-51, wherein the about 120 mg belzutifan is administered to the subject in a fasted state.

53. The method of any one of claims 34-52, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 20 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis.

54. The method of any one of claims 34-53, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 20 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on afree acid equivalent weight basis.

55. The method of any one of claims 34-54, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 20 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, daily.

56. The method of any one of claims 34-55, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 20 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily.

57. The method of any one of claims 34-56, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 20 mg to about 75 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, once daily for 28 consecutive days.

58. The method of any one of claims 34-57, wherein the effective amount of the compound of formula (I) is administered to the subject in a fasted state.

59. The method of any one of claims 34-58, wherein administering the effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises administering orally to the subject about 20 mg to about 75 mg of the compound of formula(I), or a pharmaceutically acceptable salt thereof, on a free acid equivalent weight basis, at least about 1 hour before a meal or at least about 2 hours after a meal once daily for 28 consecutive days.

60. The method of any one of claims 34-59, wherein the subject has previously been administered at least two and no more than 5 prior lines of therapy.

61. The method of claim 59, wherein the subject exhibits progressive disease after being administered the at least two and no more than 5 prior lines of therapy.

62. The method of any one of claims 34-60, wherein the method comprises administering an effective amount of a pharmaceutically acceptable salt of the compound of formula (I).

63. The method of claim 62, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a potassium salt of the compound of formula (I).

64. The method of claim 63, wherein the potassium salt of the compound of formula (I) is a hydrate.

65. The method of claim 63 or 64, wherein the potassium salt of the compound of formula (I) is a monohydrate.

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