3-fluoro-5-(((LS,2ar)-l, 3,3,4, 4-pentafluoro-2a-hydroxy-2,2a, 3,4-tetrahydro-lh-cyclopenta[CD]inden-7-yl)oxy)- benzonitrile dosing regimen for use in the treatment of cancer

Abstract

Disclosed herein are methods of treating cancer with a hypoxia inducible factor-2α (HIF-2α) inhibitor, 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile ((Compound (I)) having the structure: (I)

Description

This application claims the benefit of priority of U.S. Provisional Application No. 63 / 642,703, filed on May 4, 2024, and U.S. Provisional Application No. 63 / 692,084, filed on September 7, 2024, the contents of each are incorporated herein by reference in their entirety. Field of the disclosure Disclosed herein are methods of treating cancer with a hypoxia inducible factor-2a (HIF-2a) inhibitor, 3-fluoro-5-(((lS,2aR)-l,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (Compound (I)) having the structure: (Il- Compound (I) is also referred to as NKT2152. Background Compound (I) is being developed for treating diseases mediated by aberrant activity of HIF-2a including cancer, such as renal cancer, glioblastoma, neuroblastoma, pheochromocytomas and paragangliomas, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors (GIST), pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, and retinal tumors and non-cancer diseases such as pulmonary artery hypertension (PAH), reflux esophagitis, hepatic steatosis, nonalcoholic steatohepatitis (NASH), inflammatory disease such as inflammatory bowel disease, autoimmune disease such as Graft-versus-Host-Disease, and iron overload. Compound (I) and a crystalline form of Compound (I), referred to as Compound (I) Form A, having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2° 20 as measured by X-ray powder diffraction using (Cu Ka) an X-ray wavelength of 1.5418 A are disclosed in PCT Application Publication No. WO 2020 / 214853, filed on April 16, 2020, the entire content of which is incorporated herein by reference. Compound (I) Form A is currently in a Phase 1 / 2 open label dose-escalation and expansion trial (Study) in patients with clear cell renal cell carcinoma (ccRCC) as a monotherapy. Multiple oral doses of Compound (I) Form A, formulated as immediate-release capsules, are being used in the Study to evaluate the safety, tolerability, PK, PD, and anti-tumor activity. The Study consists of two parts or phases: Phase 1, to identify the maximum tolerated dose (MTD) and / or the recommended doses for expansion (RDEs) of Compound (I) Form A in patients with relapsed or refractory ccRCC, and Phase 2, to evaluate the antitumor activity of Compound (I) Form A by objective response rate (ORR) at the RDEs in patients with ccRCC and determine the recommended Phase 2 dose (RP2D). For any therapeutic agent, there is a need to identify a dosing regimen that maximizes its clinical benefits by optimizing its pharmacokinetic (PK) exposure and pharmacodynamic (PD) response while minimizing the adverse events. The methods disclosed herein fullfill this and related needs. Summary During the Study, it was discovered that Compound (I) exhibited slow elimination and high accumulation after 50 mg, 100 mg, 200 mg, or 300 mg once-a-day (QD) dosing of Compound (I) Form A. A PK steady state for Compound (I) was not observed on continuous QD dosing up to 83 days. See Fig. 1 A. Significant suppression of erythropoietin (EPO), a PD marker of HIF-2a inhibition, with quick onset was observed at all of the above dosage levels. See Fig. 2A. Based on the above PK data, it was unexpectedly discovered that Compound (I) Form A could be administered at different sequential loading and maintenance dosing schedules to rapidly achieve and then maintain a potential therapeutic plasma level of Compound (I) in patients. The following loading and maintenance dosing schedules of Compound (I) Form A: (i) 100 mg QD x 7 days then 100 mg QW, (ii) 200 mg QD x 7 days then 200 mg QW, (iii) 200 mg QD x 14 days then 50 mg QD, and (iv) 200 mg QD x 28 days then 50 mg QD were evaluated in the above Study. A 2-compartmental population PK model with first-order oral absorption and first-order elimination was developed based on evaluable data available up to October 23, 2023 (n=79) from the above Study. The model described the PK data of Compound (I) after administration of both a single dose and multiple doses of Compound (I) Form A, as well as after dose reductions and dose holds. The PK parameter values for absorption rate constant (Ka), apparent total clearance (CL / F), apparent intercompartment clearance (Q / F), apparent volume of distribution of the central compartment (Vc / F), and apparent volume of distribution of the peripheral compartment (Vp / F) of distribution of Compound (I) were, generally, 0.684 h1, 0.512 L / h, 24.4 L / h, 153 L, and 624 L, respectively. Higher body weight appeared to correlate with higher Vc / F and Vp / F values but not CL / F. The model-estimated median terminal ti / 2 of Compound (I) was 38 days. Between-patient variability was moderate on CL / F (49%), Vc / F (37%), Vp / F (34%), and Ka (81%). The PK modeling analysis suggested no time- or concentration-dependent PK nonlinearity. The high accumulation of Compound (I) following continuous once-daily dosing of Compound (I) Form A and the model-estimated long ti / 2 were due to slow elimination and large distribution volume of Compound (I). Next, an indirect population PK-EPO response model was also developed based on the PK and EPO data of Compound (I) (n=79) from the Study. The EPO data was limited to < Week 5 to avoid confounding effects that resulted in EPO rebound. The EPO model had first-order EPO elimination and zero-order EPO production which was inhibited by Compound (I) after administration of Compound (I) Form A. The model described the EPO inhibition at different dosages, and the model-estimated IC50 and Imax of Compound (I) were 63.2 ng / mL and 75.0 %, respectively. See Fig. IB. Suppression of EPO with quick onset was observed at all above dosage levels. See Fig. 2B. After administration of Compound (I) Form A, preliminary Compound (I) exposureresponse analysis in efficacy and safety populations with evaluable PK data (n = 79) did not reveal clinically meaningful correlations for selected efficacy endpoints (such as ORR, target lesion size change, time to response). Within the observed exposure range, higher average concentrations of Compound (I) correlated with earlier and higher incidences of Grade >2 and Grade >3 anemia. The exposure-response analysis suggested that lower baseline hemoglobin and 02 saturation were associated with higher risks of anemia and hypoxia, respectively. Based on overall safety, tolerability, PK, PD, and preliminary efficacy data of Compound (I) above, and comparison of the PK exposures with clinically observed and simulated PK of 200 mg QD x 14 days then 50 mg QD and 100 mg QD x 7 days then 100 mg QW (see Fig. 3), 200 mg QD x 14 days then 50 mg QD (also referred to herein as recommended dosage for dose expansion phase of the Study with daily maintenance doses or RDE-d) and 100 mg QD x 7 days then 100 mg QW (also referred to herein as recommended dosage for dose expansion phase of the Study with weekly maintenance doses or RDE-w) dosages of Compound (I) Form (A) were selected for evaluation in a randomized phase 2 expansion of the Study in ccRCC patients. In Fig. 3, the model estimated typical PK profiles of Compound (I) at RDE-w and RDE-d are overlaid with the concentration thresholds as labeled. Collectively, the available data and analysis continue to support the Dose Expansion study of Compound (I) Form A at RDE-w and RDE-d (a 3.5-fold difference in weekly maintenance dose). Since all the above tested dosage levels of Compound (I) Form A had significant and similar EPO suppression, dosage levels lower than RDE-w may be efficacious and allow better safety and tolerability, and / or reduce drug-drug interaction risks with Compound (I) as Compound (I) is a CYP3A4 inducer, especially in the gut. In parallel, the slow CL / F and long ti / 2 of Compound (I) suggest that less frequent maintenance dosing schedules of Compound (I) Form A (e.g., Q2W, Q3W, or Q4W. In one embodiment Q2W or Q4W) may offer similar efficacy as maintenance QW or maintenance QD dosing, better safety and tolerability, and / or a reduction in drug-drug interaction risks with Compound (I) as a CYP3A4 inducer, especially in the gut. Accordingly, amongst the various aspects of the present disclosure, provided herein are dosing regimens for Compound (I) or Compound (I) Form A. In a first aspect, provided is a method of treating cancer comprising administering to a patient in need thereof: (a) one or more loading doses during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of Compound (I) or Compound (I) Form A having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2° 20 as measured by X-ray powder diffraction using (Cu Ka) an X-ray wavelength of 1.5418 A; and (b) one or more maintenance doses during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in each of the one or more loading doses in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in each of the one or more maintenance doses is the same as in each of the one or more loading doses in (a), the one or more maintenance doses are administered to the patient less frequently than the one or more loading doses are administered during the loading period. In a second aspect, provided is Compound (I) or Compound (I) Form A having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2° 20 as measured by X-ray powder diffraction using (Cu Ka) an X-ray wavelength of 1.5418 A, for use in the manufacture of a medicament for the treatment of cancer in a patient which medicament is administered as: (a) one or more loading doses during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of the Compound (I) or Compound (I) Form A; and -4- (b) one or more maintenance doses during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in each of the one or more loading doses in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in each of the one or more maintenance doses is the same as in each of the one or more loading dose in (a), the one or more maintenance doses are administered to the patient less frequently than the one or more loading doses are administered during the loading period. In a third aspect, provided is Compound (I) or Compound (I) Form A having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2° 20 as measured by X-ray powder diffraction using (Cu Ka) an X-ray wavelength of 1.5418 A, for use in the treatment of cancer comprising administering to a patient in need thereof: (a) one or more loading doses during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of the Compound (I) or Compound (I) Form A; and (b) one or more maintenance doses during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in each of the one or more loading doses in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in each of the one or more maintenance doses is the same as in each of the one or more loading doses in (a), the one or more maintenance doses are administered to the patient less frequently than the one or more loading dose is administered during the loading period. In a fourth aspect, provided is a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a Compound (I) or Compound (I) Form A having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2° 20 as measured by X-ray powder diffraction using (Cu Ka) an X-ray wavelength of 1.5418 A in a dosing regimen comprising: (a) administering one or more loading doses during a loading period, wherein each loading dose comprises the Compound (I) or Compound (I) Form A; and (b) administering one or more maintenance doses during a maintenance period, wherein each maintenance dose comprises less than or the same amount of Compound (I) or Compound (I) Form A present in each of the one or more loading doses in (a), provided that, when the amount of Compound (I) or the Compound (I) Form A in each of the one or more maintenance doses is the same as in each of the one or more loading doses in (a), the one or more maintenance doses are administered to the patient less frequently than the one or more loading doses are administered during the loading period. In a first subembodiment of the fourth aspect, the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a median trough plasma concentration of Compound (I) (Ctrough) in the patient of about 936 ng / mL (with 90% prediction interval of 265 to 2220 ng / mL) and about 3460 ng / mL (with 90% prediction interval of 1170 to about 8120 ng / mL) at RDE-w and RDE-d, respectively, after the first maintenance dose is administered to the patient (for sake of clarity after the loading dosage and first maintaince dose are administered to the patient). In a second subembodiment of the fourth aspect, the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a weekly area under the plasma concentration-time curve (AUCo-i68h) value of Compound (I) in the patient of about 177000 and about 624000 ng»hr / ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment (for sake of clarity after the loading dosage and RDE-w or RDE-d are administered to the patient). In a third subembodiment of the fourth aspect, the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a maximum plasma concentration (Cmax) of Compound (I) in the patient of about 1420 and about 3870 ng / ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment. In a fourth subembodiment of the fourth aspect, the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a minimum plasma concentration (Cmin) of Compound (I) in the patient of about 973 and about 3650 ng / ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment. Brief Description of the Drawings Figs. 1A and IB depict plots of mean (+SE) plasma Compound (I) concentration-time profiles by dosage on linear scale as of the 5 October 2023 analysis in Example 3. Fig. 1A depicts cohorts with 50 mg, 100 mg, 200 mg, or 300 mg QD dosing schedules of Compound (I) Form A and Fig. IB depicts cohorts with sequential loading and maintenance treatments of Compound (I) Form A. Figs. 2A and 2B depicts plot of mean (+SE) percent serum erythropoietin concentration change from baseline-time profiles by cohort as of the 5 October 2023 analysis in Example 3. Fig. 2A depicts cohorts with 50 mg, 100 mg, 200 mg, or 300 ng QD dosing schedules of Compound (I) - 6- Form A and Fig. 2B depicts cohorts with sequential loading and maintenance treatments of Compound (I) Form A. Fig. 3 depicts model-simulated typical PK profiles of Compound (I) at the proposed RDE-w and RDE-d dosages of Compound (I) Form A. Fig. 4 depicts a representative XRPD diffractogram of Form A polymorph of 3-tluoro-5-(((lS,2aR)-l,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile, Compound (I), crystallized from pentanol and hexane according to the method described in Example 25 in WO 2020 / 214853. Fig. 5 depicts model-simulated typical PK profiles of Compound (I) at the depicted RDE-w and RDE-d dosages of Compound (I) Form A. Fig. 6 depicts a Phase 2 Mono-expansion study design involving a first cohort administered a Compound (I) Form A dosage, a second cohort administered a RDE-w dosage of Compound (I) Form A, and a third cohort pre-treated with belzutifan. Fig. 7 depicts a study design, wherein patients are administered a regimen comprising 200 mg QD x 7 days of Compound (I) Form A (W1D1 to W1D7) followed by 200 mg QW of Compound (I) Form A starting at W2D1. Fig. 8 depicts a study design, wherein patients are administered a regimen comprising 200 mg QD x 14 days of Compound (I) Form A (W1 and W2) followed by 50 mg QD of Compound (I) Form A starting at W3. Fig. 9 depicts a population PK model comprising simulated PK profiles of Compound (I) for dosages with sequential loading and maintenance dosing regimens of Compound (I) Form A. Fig. 10 depicts simulated Compound (I) PK profiles for Q4W maintenance treatments of 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig. 11 depicts simulated Compound (I) PK profiles for Q3W maintenance treatments of 50 mg, 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig. 12 depicts simulated Compound (I) PK profiles for Q2W maintenance treatments of 50 mg, 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig. 13 depicts simulated PK profiles for tested Compound (I) Form A dosages. Fig. 14 depicts simulated Compound (I) PK profiles for 2 days-on / 26 days-off maintenance treatments of Compound (I) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig. 15 depicts simulated Compound (I) PK profiles for 4 days-on / 24 days-off maintenance treatments of Compound (I) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig. 16 depicts simulated Compound (I) PK profiles for 7 days-on / 21 days-off maintenance treatments of Compound (1) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig. 17 depicts the study design for the Compound (I) Form A Phase 1 / 2 open label doseescalation and expansion trial. Fig. 18 depicts the patient demographics for the Compound (I) Form A Phase 1 / 2 open label dose-escalation and expansion trial, as of the 16 June 2024 analysis in Example 4. Fig. 19 depicts PK profiles of Compound (I) following treatment with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig. 20 depicts EPO levels in patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig. 21 depicts the response rate and confidence interval in various categories of patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig. 22 depicts the number of target lesions in patients treated with Compound (I) Form A categorized by prognosis in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig. 23 depicts the number of target lesions in patients treated with Compound (I) Form A categorized by objective response in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig. 24 depicts time to disease progression or death of any cause in months in patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig. 25 depicts the median progression-free survival (PFS) in months and confidence interval in various categories of patients treated with Compound (I) Form A in the dose escalation portion of the Study. Median and 95% confidence interval were estimated based on Loglog transformation and methods by Breslow, Brookmeyer, and Crowley, as of the 16 June 2024 analysis in Example 4. Fig. 26 depicts adverse events reported by > 10% of patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Detailed Description Definitions: Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meaning: As used herein, “a” and “an” mean one or more, unless the context clearly dictates otherwise. As used herein, “about” means + 10%, in one embodiment + 5% of listed value. For example, a reaction carried out at about 10 °C includes 9 °C and 11 °C, and all temperatures contained in between 9 °C and 11 °C. As used herein, “AUC” means area under the concentration-time curve and is the definite integral of the concentration of an administered compound (e.g, Compound (I)) found in blood plasma, after a dose is given, as a function of time, as measured using liquid chromatographymass spectrometry. As used herein, “AUCiast” means area under the concentration-time curve up to the last measurable concentration after a dose is given. As used herein, “Cmax” means the maximum (peak) concentration of an adminstered compound (e.g, Compound (I)) found in blood plasma, after a dose is given and reflects the rate and extent of absorption, as measured using liquid chromatography-mass spectrometry. As used herein, “Cmin” means the minimum concentration of an adminstered compound (e.g, Compound (I)) found in blood plasma, before a dose is given, as measured using liquid chromatography-mass spectrometry. As used herein, a “loading” dose is an initial dose of a drug (e.g,, Compound (I) or Compound (I) Form A) that is given to a patient at the beginning of a course of treatment during the loading period before initiation of a maintenance dose of the drug. The loading dose can be administered QD, twice a day (BID), or three times a day (TID). As used herein, “loading period” means a number of days on which a loading dose is administered to a patient. As used herein a “maintenance” dose is a dose of a drug (e.g., Compound (I) or Compound (1) Form A) administered to maintain therapeutic drug concentrations after administration of a loading dosage. As used herein, “maintenance period” means a number of days on which a maintenance dose is administered to a patient. As used herein, “QD” means once a day e.g., 20 mg QD means 20 mg administered once a day, 30 mg QD means 30 mg administered once a day, etc. -9- As used herein, “QW” means once a week e.g., 10 mg QW means 10 mg administered once a week, 20 mg QW means 20 mg administered once a week, 30 mg QW means 30 mg administered once a week, etc. As used herein, “Q2W” means once in two weeks e.g., 10 mg Q2W means 10 mg administered once in 2 weeks, 20 mg Q2W means 20 mg administered once in 2 weeks, 30 mg Q2W means 30 mg administered once in 2 weeks, etc. As used herein, “Q3W” means once in three weeks e.g., 10 mg Q3W means 10 mg administered once in 3 weeks, 20 mg Q3W means 20 mg administered once in 3 weeks, 30 mg Q3W means 30 mg administered once in 3 weeks, etc. As used herein, “Q4W” means once in four weeks e.g., 10 mg Q4W means 10 mg administered once in 4 weeks, 20 mg Q4W means 20 mg administered once in 4 weeks, 30 mg Q4W means 30 mg administered once in 4 weeks, etc. Compound (I) and Compound (I) Form A can be prepared by the method disclosed in PCT Applications Publication Nos. WO / 2022 / 086822 or WO / 2023 / 064305. Micronized Compound (I) Form A can be prepared by methods well known in the art. Particle size can be determined by methods known in the art, such as laser light diffaction, dynamic light scattering, or sieve analysis. In one embodiment the micronized Compound (I) Form A has a D90 value of < 25 pm. In one embodiment, the micronized Compound (I) Form A has a D90 value of < 20 pm. In one embodiment, the micronized Compound (I) Form A has a D90 value of < 15 pm. In one embodiment, the micronized Compound (I) Form A has a D90 value of about 14 pm. In one embodiment, the micronized Compound (I) Form A has a D90 value of 14 ± 4 pm. In one embodiment, the micronized Compound (I) Form A has a D90 value of 14 ± 2 pm. In another embodiment, the micronized Compound (I) Form A has a D90 value of about 13.6 pm. In one embodiment, the micronized Compound (I) Form A has a D50 value of < 10 pm. In one embodiment, the micronized Compound (I) Form A has a D50 value of < 6 pm. In one embodiment, the micronized Compound (I) Form A has a D50 value of about 6 pm. In one embodiment, the micronized Compound (I) Form A has a D50 value of 6 ± 3 pm. In one embodiment, the micronized Compound (I) Form A has a D50 value of 6 ± 2 pm. In one embodiment, the micronized Compound (I) Form A has a D50 value of 6 ± 1 pm. In another embodiment, the micronized Compound (I) Form A has a D50 value of about 5.9 pm. In one embodiment, the micronized Compound (I) Form A has a D10 value of < 3 pm. In one embodiment, the micronized Compound (I) Form A has a D10 value of about 3 pm. In one embodiment, the micronized Compound (I) Form A has a D10 value of 3 ± 2 pm. In one embodiment, the micronized Compound (I) Form A has a D10 value of 3 ± 1 pm. In one embodiment, the micronized Compound (I) Form A has a D10 value of 3 ± 0.5 pm. In another - 10- embodiment, the micronized Compound (I) Form A has a DIO value of 2.6 pm. In another embodiment, the micronized Compound (I) Form A has a D10 value of about 3 pm, a D50 value of about 6 pm, and a D90 value of about 14 pm. In another embodiment, the micronized Compound (I) Form A has a D10 value of 3 + 2 pm, a D50 value of 6 ± 3 pm, and a D90 value of 14 + 4 pm. In another embodiment, the micronized Compound (1) Form A has a D10 value of 3 + 1 pm, a D50 value of 6 + 2 pm, and a D90 value of 14 + 3 pm. In another embodiment, the micronized Compound (I) Form A has a DIO value of 3 + 0.5 pm, a D50 value of 6 + 1 pm, and a D90 value of 14 + 2 pm. In another embodiment, the micronized Compound (I) Form A has a D10 value of 2.6 pm, a D50 value of 5.9 pm, and a D90 value of 13.6 pm. The terms D10, D50, and D90 are well known in the art, i.e, D50 indicates size under which 50% by weight of the particles in the sample exist. For example, the D10 value of 2.6 pm means that 10% by weight of the particles in the sample have a size below 2.6 pm. It is understood that the particle sizes given herein are subject to variations depending on the apparatuses and methods used. “XRPD” means X-ray powder diffraction, an analytical technique which measures the diffraction of X-rays in the present of a solid component. Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern. A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable carrier / excipient” as used in the specification and claims includes both one and more than one such excipient. The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life. The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human. “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease (i.e., stabilizing) or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. A “therapeutically effective amount” means the amount of Compound (I) or Compound (I) Form A that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated. For avoidance of doubt, all PK data presented herein relates to the observed Compound (I) concentration following administration of Compound (I) Form A. Embodiments: Al. Embodiment Al provides a method of treating cancer as described in the first or fourth aspects of the Summary or a compound for use as described in the second or third aspects of the Summary. A2. Embodiment A2 comprises the method or use of embodiment Al, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2° 26. A3. Embodiment A3 comprises the method or use of embodiment Al, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2° 20. A4. Embodiment A4 comprises the method or use of embodiment Al, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 11.4, 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2° 0. A5. Embodiment A5 comprises the method or use of embodiment Al, wherein the Compound (I) Form A exhibits an X-ray powder diffraction pattern comprising at least one peak (in some embodiments at least two peaks, at least three peaks, at least four peaks, at least five - 12 - peaks, at least six peaks, or at at least seven peaks) at angular positions shown in Table 1 below, in addition to peaks at angular positions 15.8, 18.6, wherein the angular positions may vary by + 0.2° Table 1:     Compound (I) Form A X-ray powder diffraction pattern Angle (2-Theta °) d value (A) Intensity % 9.2 9.59 6.9 10.1 8.79 19.5 11.4 7.75 21.6 12.9 6.87 21.6 13.7 6.48 15.2 14.0 6.33 3.5 15.4 5.75 3.8 15.8 5.59 100 16.6 5.35 9.8 17.4 5.09 6.7 18.0 4.93 10.2 18.6 4.77 25.3 19.6 4.53 15.3 20.1 4.41 24.3 20.7 4.29 4 21.0 4.23 3.9 21.4 4.15 13.2 21.7 4.09 18.5 22.1 4.03 10.6 22.6 3.94 5.3 23.8 3.74 3 24.1 3.69 4.5 25.0 3.55 14.7 26.0 3.43 13.9 26.7 3.33 3.4 27.2 3.28 6.4 27.6 3.23 4.4 27.8 3.20 3.8 28.2 3.16 7.3 Angle (2-Theta °) d value (A) Intensity % 29.0 3.07 6.2 29.6 3.02 9.3 30.1 2.97 4.4 30.6 2.92 3 31.0 2.88 2.9 31.7 2.82 3.5 31.9 2.80 4 32.4 2.76 5.1 33.6 2.66 5.4 34.2 2.62 3.3 34.6 2.59 4.3 35.4 2.53 3.2 35.8 2.50 3.3 A6. Embodiment A6 comprises the method or use of embodiment A5, wherein the at least two, at least three, at least four, at least five, at least six, or at least seven peaks are selected from 10.1, 11.4, 12.9, 13.7, 19.6, 20.1, 21.4, 21.7, 25.0, and 26.0, wherein the angular positions may vary by + 0.2° 20. A7. Embodiment A7 comprises the method or use of embodiment Al, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions substantially as shown in Fig. 4. A8. Embodiment A8 comprises the method or use of any one of embodiments Al to A7, wherein the angular positions of the X-ray diffraction peaks denoted therein may vary by + 0.1°20. Loading Dose A9. Embodiment A9 comprises the method or use of any one of embodiments Al to A8, wherein each of the one or more loading doses comprise about 20 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered once daily (QD). A10. Embodiment A10 comprises the method or use of any one of embodiments Al to A9, wherein each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. All. Embodiment All comprises the method or use of any one of embodiments Al to A10, wherein each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 3, 4, or 5 consecutive days (for sake of clarity, when 50 mg QD of Compound (I) Form A is administered for 3 consecutive days or for 4 consecutive days, the loading period is 3 days and 4 days, respectively). A12. Embodiment A12 comprises the method or use of any one of embodiments Al to A10, wherein each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7+1 consecutive days. In an embodiment of A12, each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 7 consecutive days. A13. Embodiment Al3 comprises the method or use of any one of embodiments Al to A10, wherein each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 14 ± 2 consecutive days. In an embodiment of A13, each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 + 1 consecutive days. In another embodiment of A13, each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 consecutive days. A14. Embodiment A14 comprises the method or use of any one of embodiments Al to A10, wherein each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 ± 2 consecutive days. In an embodiment of A14, each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 + 1 consecutive days. In another embodiment of A14, each of the one or more loading doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 consecutive days. A15. Embodiment A15 comprises the method or use of any one of embodiments Al to A9, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. A16. Embodiment A16 comprises the method or use of any one of embodiments Al to A9 and A15, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 3, 4, or 5 consecutive days. A17. Embodiment A17 comprises the method or use of any one of embodiments Al to A9 and A15, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 + 1 consecutive days. In an embodiment of A17, each of the one or more loading doses comprise about 100 mg Compound (1) or the Compound (1) Form A and the one or more loading dose is administered QD for 7 consecutive days. Al8. Embodiment Al8 comprises the method or use of any one of embodiments Al to A9 and A15, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 14 + 2 consecutive days. In an embodiment of Al8, each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14+1 consecutive days. In another embodiment of A18, each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 consecutive days. A19. Embodiment A19 comprises the method or use of any one of embodiments Al to A9 and A15, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 + 2 consecutive days. In an embodiment of A19, each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28+1 consecutive days. In another embodiment of A19, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 consecutive days. A20. Embodiment A20 comprises the method or use of any one of embodiments Al to A9, wherein each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. A21. Embodiment A21 comprises the method or use of any one of embodiments Al to A9 and A20, wherein each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 3, 4, or 5 consecutive days. A22. Embodiment A22 comprises the method or use of any one of embodiments Al to A9 and A20, wherein each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 + 1 consecutive days. In an embodiment of A22, each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 7 consecutive days. A23. Embodiment A23 comprises the method or use of any one of embodiments Al to A9 and A20, wherein each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 14 + 2 consecutive days. In an embodiment of A23, each of the one or more loading doses comprise about 150 mg Compound (1) or the Compound (1) Form A and the one or more loading dose is administered QD for 14+1 consecutive days. In another embodiment of A23, each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 consecutive days. A24. Embodiment A24 comprises the method or use of any one of embodiments Al to A9 and A20, wherein each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 + 2 consecutive days. In an embodiment of A24, each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 + 1 consecutive days. In another embodiment of A24, each of the one or more loading doses comprise about 150 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 consecutive days. A25. Embodiment A25 comprises the method or use of any one of embodiments Al to A9, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. A26. Embodiment A26 comprises the method or use of any one of embodiments Al to A9 and A25, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 3, 4, or 5 consecutive days. A27. Embodiment A27 comprises the method or use of any one of embodiments Al to A9 and A25, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 + 1 consecutive days. In an embodiment of A27, each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 7 consecutive days. A28. Embodiment A28 comprises the method or use of any one of embodiments Al to A9 and A25, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 14 + 2 consecutive days. In an embodiment of A28, each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 + 1 consecutive days. In an embodiment of A28, each of the one - 17 - or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 consecutive days. A29. Embodiment A29 comprises the method or use of any one of embodiments Al to A9 and A25, wherein each of the one or more loading doses comprise about 200 mg Compound (1) or the Compound (1) Form A and wherein the one or more loading dose is administered QD for 28 + 2 consecutive days. In an embodiment of A29, each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 + 1 consecutive days. In another embodiment of A29, each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 consecutive days. A30. Embodiment A30 comprises the method or use of any one of embodiments Al to A9, wherein each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. A31. Embodiment A31 comprises the method or use of any one of embodiments Al to A9 and A30, wherein each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 3, 4, or 5 consecutive days. A32. Embodiment A32 comprises the method or use of any one of embodiments Al to A9 and A30, wherein each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 + 1 consecutive days. In an embodiment of A32, each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 7 consecutive days. A33. Embodiment A33 comprises the method or use of any one of embodiments Al to A9 and A30, wherein each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 14 + 2 consecutive days. In an embodiment of A33, each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14+1 consecutive days. In an embodiment of A33, each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 consecutive days. A34. Embodiment A34 comprises the method or use of any one of embodiments Al to A9 and A30. wherein each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 + 2 consecutive days. In an embodiment of A34, each of the one or more loading doses - 18 - comprise about 250 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD 28 + 1 consecutive days. In an embodiment of A34, each of the one or more loading doses comprise about 250 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered for 28 consecutive days. A35. Embodiment A35 comprises the method or use of any one of embodiments Al to A9, wherein each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. A36. Embodiment A36 comprises the method or use of any one of embodiments Al to A9 and, wherein each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 3, 4, or 5 consecutive days. A37. Embodiment A37 comprises the method or use of any one of embodiments Al to A9 and A35 wherein each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 + 1 consecutive days. In an embodiment of A37, each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 7 consecutive days. A38. Embodiment A38 comprises the method or use of any one of embodiments Al to A9 and A35, wherein each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 14 + 2 consecutive days. In an embodiment of A38, each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 + 1 consecutive days. In an embodiment of A38, each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 consecutive days. A39. Embodiment A39 comprises the method or use of any one of embodiments Al to A9 and A35, wherein each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 + 2 consecutive days. In an embodiment of A39, each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 + 1 consecutive days. In an embodiment of A39, each of the one or more loading doses comprise about 300 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 consecutive days. A40. Embodiment A40 comprises the method or use of any one of embodiments Al to A9, wherein each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. A41. Embodiment A41 comprises the method or use of any one of embodiments Al to A9 and A40, wherein each of the one or more loading doses comprise about 20 mg Compound (1) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 3, 4, or 5 consecutive days. A42. Embodiment A42 comprises the method or use of any one of embodiments Al to A9 and A40, wherein each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 + 1 consecutive days. In an embodiment of A42, each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 7 consecutive days. A43. Embodiment A43 comprises the method or use of any one of embodiments Al to A9 and A40, wherein each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 14 ± 2 consecutive days. In an embodiment of A43, each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14+1 consecutive days. In an embodiment of A43, each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 14 consecutive days. A44. Embodiment A44 comprises the method or use of any one of embodiments Al to A9 and A40, wherein each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 + 2 consecutive days. In an embodiment of A44, each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28+1 consecutive days. In another embodiment of A44, each of the one or more loading doses comprise about 20 mg Compound (I) or the Compound (I) Form A and the one or more loading dose is administered QD for 28 consecutive days. Maintenance Dose Embodiments B B. Embodiment B comprises the method or use of any one of embodiments Al to A44, wherein each maintenance dose comprises the same amount of Compound (I) or the Compound (I) Form A present in each of the one or more loading doses, and the one or more -20- maintenance doses are administered to the patient less frequently than the one or more loading dose are administered during the loading period. Bl. Embodiment Bl comprises the method or use of any one of embodiments Al to A14 and B, wherein each of the one or more maintenance doses comprise about 50 mg Compound (1) or the Compound (1) Form A and wherein the one or more maintenance dose is administered once weekly (QW). B2. Embodiment B2 comprises the method or use of any one of embodiments Al to A8, A15 to A19, and B, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. B3. Embodiment B3 comprises the method or use of any one of embodiments Al to A8, A20 to A24, and B, wherein each of the one or more maintenance doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. B4. Embodiment B4 comprises the method or use of any one of embodiments Al to A8, A25 to A29, and B, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. B5. Embodiment B5 comprises the method or use of any one of embodiments Al to A8, A30 to A34, and B, wherein each of the one or more maintenance doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. B6. Embodiment B6 comprises the method or use of any one of embodiments Al to A8, A35 to A39, and B, wherein each of the one or more maintenance doses comprise about 300 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. B7. Embodiment B7 comprises the method or use of any one of embodiments Al to A8, A40 to A44, and B, wherein each of the one or more maintenance doses comprise about 20 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. B8. Embodiment B8 comprises the method or use of any one of embodiments Al to A14, B, and Bl, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered once every two weeks (Q2W). B9. Embodiment B9 comprises the method or use of any one of embodiments Al to A14, B, and Bl, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered once every four weeks (Q4W). B10. Embodiment B10 comprises the method or use of any one of embodiments A1 to A8, A15 to Al 9, B, and B2, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q2W. B11. Embodiment B11 comprises the method or use of any one of embodiments A1 to A8, A15 to Al 9, B, and B2, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q4W. B12. Embodiment B12 comprises the method or use of any one of embodiments Al to A8, A20 to A24, B, and B3, wherein each of the one or more maintenance doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q2W. B13. Embodiment B13 comprises the method or use of any one of embodiments Al to A8, A20 to A24, B, and B3, wherein each of the one or more maintenance doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q4W. B14. Embodiment B14 comprises the method or use of any one of embodiments Al to A8, A25 to A29, B, and B4, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q2W. B15. Embodiment B15 comprises the method or use of any one of embodiments Al to A8, A25 to A29, B, and B4, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q4W. B16. Embodiment B16 comprises the method or use of any one of embodiments Al to A8, A30 to A34, B, and B5, wherein each of the one or more maintenance doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q2W. B17. Embodiment B17 comprises the method or use of any one of embodiments Al to A8, A30 to A34, B, and B5, wherein each of the one or more maintenance doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q4W. Bl8. Embodiment B18 comprises the method or use of any one of embodiments Al to A8, A35 to A39, B, and B6, wherein each of the one or more maintenance doses comprise about 300 mg Compound (1) or the Compound (1) Form A and wherein the one or more maintenance dose is administered Q2W. B19. Embodiment B19 comprises the method or use of any one of embodiments Al to A8, A35 to A39, B, and B6, wherein each of the one or more maintenance doses comprise about 300 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q4W. B32. Embodiment B32 comprises the method or use of any one of embodiments Al to A8, A40 to A44, B, and B7, wherein each of the one or more maintenance doses comprise about 20 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q2W. B33. Embodiment B33 comprises the method or use of any one of embodiments Al to A8, A40 to A44, B, and B7, wherein each of the one or more maintenance doses comprise about 20 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered Q4W. Embodiments C C. Embodiment C comprises the method or use of any one of embodiments Al to A8 and A15 to A39, wherein each maintenance dose comprises less Compound (I) or Compound (I) Form A than each of the one or more loading doses, and wherein the one or more maintenance dose is administered once a day. Cl. Embodiment Cl comprises the method or use of any one of embodiments Al to A8 and A15 to A19, wherein each of the one or more maintenance doses comprise 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C2. Embodiment C2 comprises the method or use of any one of embodiments A20 to A24, wherein each of the one or more maintenance doses comprise 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C3. Embodiment C3 comprises the method or use of any one of embodiments A20 to A24, wherein each of the one or more maintenance doses comprise 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C4. Embodiment C4 comprises the method or use of any one of embodiments A25 to A29, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C5. Embodiment C5 comprises the method or use of any one of embodiments A25 to A29, wherein each of the one or more maintenance doses comprise about 100 mg Compound (1) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C6. Embodiment C6 comprises the method or use of any one of embodiments A25 to A29, wherein each of the one or more maintenance doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C7. Embodiment C7 comprises the method or use of any one of embodiments A30 to A34, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C8. Embodiment C8 comprises the method or use of any one of embodiments A30 to A34, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C9. Embodiment C9 comprises the method or use of any one of embodiments A30 to A34, wherein each of the one or more maintenance doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. CIO. Embodiment CIO comprises the method or use of any one of embodiments A30 to A34, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. Cl 1. Embodiment Cl 1 comprises the method or use of any one of embodiments A35 to A39, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C12. Embodiment C12 comprises the method or use of any one of embodiments A35 to A39, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C13. Embodiment C13 comprises the method or use of any one of embodiments A3 5 to A39, wherein each of the one or more maintenance doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C14. Embodiment C14 comprises the method or use of any one of embodiments A35 to A39, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C15. Embodiment C15 comprises the method or use of any one of embodiments A3 5 to A39, wherein each of the one or more maintenance doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. C16. Embodiment C16 comprises the method or use of any one of embodiments A10 to A39, wherein each of the one or more maintenance doses comprise about 50 mg Compound (1) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. Embodiments D D. Embodiment D comprises the method or use of any one of embodiments Al to A8 and A15 to A39, wherein each maintenance dose comprises less Compound (I) or Compound (I) Form A than each of the one or more loading doses, and the one or more maintenance doses are administered to the patient less frequently than the one or more loading doses are administered during the loading period. DI. Embodiment DI comprises the method or use of any one of embodiments Al to A8 and A15 to A19, wherein each of the one or more maintenance doses comprise 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D2. Embodiment D2 comprises the method or use of any one of embodiments A20 to A24, wherein each of the one or more maintenance doses comprise 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D3. Embodiment D3 comprises the method or use of any one of embodiments A20 to A24, wherein each of the one or more maintenance doses comprise 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D4. Embodiment D4 comprises the method or use of any one of embodiments A25 to A29, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D5. Embodiment D5 comprises the method or use of any one of embodiments A25 to A29, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D6. Embodiment D6 comprises the method or use of any one of embodiments A25 to A29, wherein each of the one or more maintenance doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D7. Embodiment D7 comprises the method or use of any one of embodiments A30 to A34, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. -25 - D8. Embodiment D8 comprises the method or use of any one of embodiments A30 to A34, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D9. Embodiment D9 comprises the method or use of any one of embodiments A30 to A34, wherein each of the one or more maintenance doses comprise about 150 mg Compound (1) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D10. Embodiment D10 comprises the method or use of any one of embodiments A30 to A34, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. Dll. Embodiment Dll comprises the method or use of any one of embodiments A3 5 to A39, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D12. Embodiment D12 comprises the method or use of any one of embodiments A35 to A39, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D13. Embodiment D13 comprises the method or use of any one of embodiments A35 to A39, wherein each of the one or more maintenance doses comprise about 150 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. DI4. Embodiment D14 comprises the method or use of any one of embodiments A35 to A39, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. DI5. Embodiment DI5 comprises the method or use of any one of embodiments A35 to A39, wherein each of the one or more maintenance doses comprise about 250 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. D16. Embodiment D16 comprises the method or use of any one of embodiments A10 to A39, wherein each of the one or more maintenance doses comprise about 20 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. Embodiments E El. Embodiment El comprises the method or use of any one of embodiments Al to A8, wherein each of the one or more loading doses comprise about 100 mg or about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. E2. Embodiment E2 comprises the method or use of embodiments Al to A8 and El, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. E3.   Embodiment E3 comprises the method or use of any one of embodiments Al to A8 and El to E2, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 consecutive days. E4.   Embodiment E4 comprises the method or use of any one of embodiments Al to A8 and El, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD. E5.   Embodiment E5 comprises the method or use of any one of embodiments Al to A8, El, and E4, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 consecutive days. E6. Embodiment E6 comprises the method or use of embodiment Al to A8, El, and E4, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 14 consecutive days. E7. Embodiment E7 comprises the method or use of embodiment Al to A8, El, and E4, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 consecutive days. E8.   Embodiment E8 comprises the method or use of any one of embodiments Al to A8, E2, and E3, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. E9.   Embodiment E9 comprises the method or use of any one of embodiments Al to A8, E4, or E5, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW. E10. Embodiment E10 comprises the method or use of any one of embodiments Al to A8, E4, E5, E6, and E7, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD. Embodiments F Fl. Embodiment Fl comprises the method or use of any one of embodiments Al to E10, wherein the one or more loading doses and the one or more maintenance doses are administered orally. F2. Embodiment F2 comprises the method or use of any one of embodiments Al to E10 and Fl, wherein each consecutive loading dose is administered at the same time of day or + 0.5, 1, 2, 3, or 4 hours before or after the prior loading dose is administered. F3. Embodiment F3 comprises the method or use of any one of embodiments Al to A39, C to C15, E8, E9, and Fl to F2, wherein each follow-up maintenance dose, when administered QW, is administered at the same time of day ± 0.5, 1, 2, 3, or 4 hours after the first of the one or more maintenance dose. F4. Embodiment F4 comprises the method or use of any one of embodiments Bl to B6, DI to D15, E10, and Fl to F2, wherein the first of the one or more maintenance doses, when administered QW, is administered the following day, after the last of the one or more loading doses. F5. Embodiment F5 comprises the method or use of any one of embodiments Bl to B6, DI to D15, E10, and Fl to F2, wherein the first of the one or more maintenance doses, when administered QW, is administered the second day after the last of the one or more loading doses. F6. Embodiment F6 comprises the method or use of any one of embodiments Bl to B6, DI to D15, E10, and Fl to F2, wherein the first of the one or more maintenance doses, when administered QW, is administered the third day after the last of the one or more loading doses. F7. Embodiment F7 comprises the method or use of any one of embodiments B1 to B6, DI to D15, E10, and Fl to F2, wherein the first of the one or more maintenance doses, when administered QW, is administered the fourth day after the last of the one or more loading doses. F8. Embodiment F8 comprises the method or use of any one of embodiments Bl to B6, DI to D15, E10, and Fl to F2 is wherein the first of the one or more maintenance doses, when administered QW, is administered the fifth day after the last of the one or more loading doses. F9. Embodiment F9 comprises the method or use of any one of embodiments Bl to B6, DI to D15, E10, and Fl to F2, wherein the first of the one or more maintenance doses, when administered QW, is administered the sixth day after the last of the one or more loading doses. F10. Embodiment F10 comprises the method or use of any one of embodiments B1 to B6, DI to D15, E10, and Fl to F2, wherein the first of the one or more maintenance doses, when administered QW, is administered the seventh day after the last of the one or more loading doses. Fil. Embodiment Fl comprises the method or use of any one of embodiments F4 to F10, wherein, following the first of the one or more maintenance doses, each subsequent maintenance dose is administered seven days after the prior maintenance dose. Fl2. Embodiment Fl2 comprises the method or use of any one of embodiments Al to E10 and Fl to Fl 1, wherein a single bolus of the one or more loading dose is administered. Fl3. Embodiment Fl3 comprises the method or use of any one of embodiments Al to E10 and Fl to Fl 1, wherein two or more doses of Compound (I) or Compound (I) Form A are administered to obtain the one or more loading dose. In a subembodiment of embodiment F13, the two or more doses of Compound (I) or Compound (I) Form A are each 10 mg, 25 mg, 50 mg, 100 mg, and / or 150 mg. Fl4. Embodiment Fl4 comprises the method or use of any one of embodiments Al to E10 and Fl to F13, wherein a single bolus of the one or more maintenance dose is administered. Fl5. Embodiment Fl5 comprises the method or use of any one of embodiments Al to E10 and Fl to F13, wherein two or more doses of Compound (I) or Compound (I) Form A are administered to obtain the one or more maintenance dose. In a subembodiment of embodiment F15, the two or more doses of Compound (I) or Compound (I) Form A are each 10 mg, 25 mg, 50 mg, and / or 100 mg. Fl6. Embodiment Fl6 comprises the method or use of any one of embodiments Al to F15, wherein the dosage regimen is adjusted to provide the optimum desired response (e.g., a steady state of Compound (I) Form A in plasma that is therapeutic), and the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. F17. Embodiment F17 comprises the method or use of any one of embodiments Al to Fl5, wherein the dosage regimen is adjusted by lowering the one or more maintenance dose because the patient experiences a toxicity. F18. Embodiment F18 comprises the method or use of embodiment E10, wherein the dosage regimen is adjusted by lowering the one or more maintenance dose to 30 mg / day QD because the patient experiences a toxicity. F19. Embodiment F19 comprises the method or use of embodiment E10 or F18, wherein the dosage regimen is adjusted by lowering the one or more maintenance dose to 20 mg / day QD because the patient experiences a toxicity. F20. Embodiment F20 comprises the method or use of embodiment E8, wherein the dosage regimen is adjusted by lowering the one or more maintenance dose to 50 mg QW because the patient experiences a toxicity. F21. Embodiment F21 comprises the method or use of embodiment E8 or F20, wherein the dosage regimen is adjusted by lowering the one or more maintenance dose to 30 mg QW because the patient experiences a toxicity. In the embodiments above, reference to an embodiment, includes combination with subembodiments contained therein. Patient Criteria Embodiments G Gl. Embodiment G1 comprises the method or use of any one of embodiments Al to F21, wherein the patient satisfies at least one of the following conditions: (a) the patient has locally advanced or metastatic ccRCC, and has progressed during treatment, are relapsed, refractory and not amenable to curative therapy or standard therapy and has progressed during treatment with at least 1 prior therapeutic regimen; (b) the patient has measurable disease per RECIST 1.1 criteria; (c) the patient is > 18 years of age; (d) the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; (e) the patient has a life expectancy of > 3 months; (f) the patient has adequate organ function defined as follows: (i) a bone marrow ANC > l.Ox 109 / L; hemoglobin level > 10 g / dL without transfusion or erythropoietin support within two weeks prior to a first dose of Compound (I) or Compound (I) Form A; platelet count > 75,000 / pL; (ii) hepatic transaminase levels (aspartate aminotransferase / alanine aminotransferase [AST / ALT]) < 2.5 x ULN (< 5 x ULN if liver metastases is present); total bilirubin (TBILI) < 1.5 x ULN in the absence of Gilbert’s disease; and (iii) a renal serum creatinine level < 2.0 X ULN or calculated creatinine clearance (CrCL) > 40 mL / min (as determined by a Cockcroft-Gault formula); (g) if a female patient of childbearing potential, the female patient meets all of the following criteria prior to first administration of Compound (I) or Compound (I) Form A (in some embodiments, a female patient is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone levels within the institutional laboratory postmenopausal range and a negative -30- serum or urine beta human chorionic gonadotropin); or is menopausal (amenorrhea for >12 months)): (i)   the female patient is not pregnant (negative serum pregnancy test); (ii)    the female patient is not breastfeeding; and (iii) the female patient is willing to use a protocol-recommended method or use of contraception or to abstain from heterosexual intercourse from the start of treatment or until at least 6 months after the last dose of treatment; (h) if a male patient who can father a child, the male patient must meet all of the following criteria (in some embodiments of the method or uses disclosed herein, a male patient is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy): (i) the male patient is willing to use a protocol-recommended method or use of contraception or abstain from heterosexual intercourse with females of childbearing potential from the start of treatment until at least 6 months after the last dose of treatment; and (ii) the male patient must be willing to refrain from sperm donation from the start of treatment until at least 6 months after the last dose of treatment; (i) the patient must be able to swallow oral medications; and (j) any ambulatory patient must complete a six-minute walk test (in some embodiments, the walking distance needs to be at least 400 meters, and the change of oxygen saturation needs to be within a 5% range). G2. Embodiment G2 comprises the method or use of Gl, wherein the patient satisfies at least two of the conditions (a) through (j) above. G3. Embodiment G3 comprises the method or use of Gl, wherein the patient satisfies at least three of the conditions (a) through (j) above. G4. Embodiment G4 comprises the method or use of Gl, wherein the patient satisfies at least four of the conditions (a) through (j) above. G5. Embodiment G5 comprises the method or use of Gl, wherein the patient satisfies at least five of the conditions (a) through (j) above. G6. Embodiment G6 comprises the method or use of Gl, wherein the patient satisfies at least six of the conditions (a) through (j) above. G7. Embodiment G7 comprises the method or use of Gl, wherein the patient satisfies at least seven of the conditions (a) through (j) above. G8. Embodiment G8 comprises the method or use of Gl, wherein the patient satisfies at least eight of the conditions (a) through (j) above. -31 - G9. Embodiment G12 comprises the method or use of Gl, wherein the patient satisfies each of the conditions (a) through (j) above. G10. Embodiment G10 comprises the method or use of any one of embodiments Gl to G9, wherein the patient is excluded from treatment if at least one of the following conditions are satisfied: (aa) the patient has known symptomatic brain metastases requiring >10 mg / day of prednisone (or its equivalent). (bb) the patient with previously diagnosed brain metastases unless they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to the start of Compound (I) or Compound (I) Form A treatment, fulfill any steroid requirement for these metastases, and are neurologically stable based on central nervous system imaging > four weeks after CNS-directed treatment; (cc) the patient has a pulse oximetry reading less than 95% at screening prior to first administration of Compound (I) or Compound (I) Form A; (dd) the patient has any current requirement for intermittent or chronic supplemental oxygen prior to first administration of Compound (I) or Compound (I) Form A; (ee) the patient has any chronic lung condition which has required supplemental oxygen in the past prior to first administration of Compound (I) or Compound (I) Form A; (ff) the patient has evidence of impending airway compromise (such as endobronchial tumor, lymphangitic spread, significant extrinsic compression of major airway) prior to first administration of Compound (I) or Compound (I) Form A; (gg) the patient has ascites requiring drainage within 28 days prior to first administration of Compound (I) or Compound (I) Form A; (hh) the patient has a history of of another malignancy prior to first administration of Compound (I) or Compound (I) Form A except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage 1 or Stage 2 cancers currently in complete remission, or any other cancer that has been in complete remission for > 2 years; (ii) the patient has failed to recover from the effects of prior anticancer therapy to baseline level or Grade 1 severity (except for alopecia) per NCI CTCAE prior to first administration of Compound (I) or Compound (I) Form A; (jj) the patient has significant cardiovascular disease, including myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism, within six months prior to start of Compound (I) or Compound (I) Form A treatment; symptomatic -32- dysrhythmias or unstable dysrhythmias requiring medical therapy; angina requiring therapy, symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; > Grade 3 hypertension (diastolic blood pressure >100 mmHg or systolic blood pressure >160 mmHg) despite adequate use of antihypertensives; or history of congenital prolonged QT syndrome or repeated demonstration of a QTc interval > 480 ms; ejection fraction < 40%; clinically significant pericardial or pleural effusion in the opinion of an investigator; (kk) the patient has received prior investigational therapy or standard therapy within five half-lives of the agent or four weeks before a first administration of Compound (I) or Compound (I) Form A, whichever is shorter; (11) the patient has a bleeding diathesis or coagulopathy; (mm) the patient has a deep vein thrombosis (DVT) / pulmonary embolism unless the patient is not symptomatic and has received two weeks or more of adequate anticoagulation; (nn) the patient has manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease; (oo) the patient has any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with treatment with Compound (I) or Compound (I) Form A; (pp) the patient has had major surgery within four weeks before Compound (I) or Compound (I) Form A administration (in some embodiments, the following procedures are not considered to be major surgeries: thoracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic or ultrasonographic procedures, mediastinoscopy, skin biopsy, incisional biopsy, image-guided biopsy for diagnostic purposes, and routine dental procedures); (qq) the patient has known HIV; (rr) the patient has an active infection requiring systemic treatment; (ss) the patient is actively participating in a therapeutic clinical trial; (tt) the patient has received prior treatment with an HIF-2a inhibitor, unless prior belzutifan treatment. GI 1. Embodiment GI 1 comprises the method or use of G10, wherein the patient is excluded from treatment if at least two of the conditions (aa) through (tt) above are satisfied. G12. Embodiment G12 comprises the method or use of G10, wherein the patient is excluded from treatment if at least three of the conditions (aa) through (tt) above are satisfied. G13. Embodiment G13 comprises the method or use of G10, wherein the patient is excluded from treatment if at least four of the conditions (aa) through (tt) above are satisfied. -33 - G14. Embodiment G14 comprises the method or use of GIO, wherein the patient is excluded from treatment if at least five of the conditions (aa) through (tt) above are satisfied. G15. Embodiment G15 comprises the method or use of G10, wherein the patient is excluded from treatment if at least six of the conditions (aa) through (tt) above are satisfied. G16. Embodiment G16 comprises the method or use of G10, wherein the patient is excluded from treatment if at least seven of the conditions (aa) through (tt) above are satisfied. G17. Embodiment G17 comprises the method or use of GIO, wherein the patient is excluded from treatment if at least eight of the conditions (aa) through (tt) above are satisfied. G18. Embodiment G18 comprises the method or use of G10, wherein the patient is excluded from treatment if at least nine of the conditions (aa) through (tt) above are satisfied. G19. Embodiment G19 comprises the method or use of G10, wherein the patient is excluded from treatment if at least ten of the conditions (aa) through (tt) above are satisfied. G20. Embodiment G20 comprises the method or use of G10, wherein the patient is excluded from treatment if at least eleven of the conditions (aa) through (tt) above are satisfied. G21. Embodiment G21 comprises the method or use of G10, wherein the patient is excluded from treatment if at least twelve of the conditions (aa) through (tt) above are satisfied. G22. Embodiment G22 comprises the method or use of G10, wherein the patient is excluded from treatment if each of the conditions (aa) through (tt) above are satisfied. G23. Embodiment G23 comprises the method or use of any one of embodiments G1 to G22, wherein the patient is willing to and able to take a high-fat meal within thirty minutes prior to Compound (I) or Compound (I) Form A dosing on Week 1 Day 1. G24. Embodiment G24 comprises the method or use of any one of embodiments G1 to G22, wherein the patient has adequate hepatic and renal function defined below: (i) Hepatic: normal hepatic function (total bilirubin < upper limit of normal (ULN) and aspartate aminotransferase (AST) < ULN) or mild hepatic impairment (total bilirubin < ULN and AST > ULN, or total bilirubin > 1.0 x to 1.5 x ULN) (ii) Renal: measured or calculated creatinine clearance (CrCL) > 60 mL / min (Cockcroft-Gault formula); G25. Embodiment G25 comprises the method or use of any one of embodiments G1 to G24, wherein the patient is excluded from treatment if the patient has any gastrointestinal (GI) malfunction, surgeries, or conditions that could affect absorption of oral Compound (I) Form A and / or midazolam as assessed by an investigator. G26. Embodiment G26 comprises the method or use of any one of embodiments Gl to G25, wherein the patient is excluded from treatment if the patient uses any drugs, investigational agents, fruits, or herbs that are strong or moderate CYP3A inhibitors or inducers within fourteen days prior to Day -3 (or 5 times the half-life of the drug, whichever is longer). G27. Embodiment G27 comprises the method or use of any one of embodiments G1 to G26, wherein the patient has relapse or progressive disease following prior treatment with belzutifan (in some embodiments, the patient received at least 28 days of treatment with belzutifan). G28. Embodiment G28 comprises the method or use of any one of embodiments G1 to G27, wherein the patient has a willingness to undergo a pretreatment and post-treatment biopsy of the tumor. G29. Embodiment G29 comprises the method or use of any one of embodiments G1 to G28, wherein the patient is excluded from treatment if the patient has a history of toxicity or intolerance to treatment with belzutifan or other HIF-2a inhibitor; G30. Embodiment G30 comprises the method or use of any one of embodiments G1 to G29, wherein the patient is excluded from treatment if the patient has a known presence of HIF2-a mutation G323E or HIF-1B mutation F446L. Embodiments H Hl. Embodiment Hl comprises the method or use of any one of embodiments Al to G30, wherein the cancer to be treated is selected from a cancer in the Utility section below. H2. Embodiment H2 comprises the method or use of any one of embodiments Al to G30, wherein the cancer to be treated is selected from renal cancer, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, bladder cancer, liver cancer, leiomyomas, leiomyosarcomas, polycythaemia, and retinal cancers. H3. Embodiment H3 comprises the method or use of any one of embodiments Al to F21, wherein the Compound (I) or Compound (I) Form A is administered in combination with at least one other anticancer agent, preferably as provided in the Combinations and Combination Therapy section below. H4. Embodiment H4 comprises the method or use of embodiment H3, wherein the at least one other anticancer agent is selected from palbociclib, ribociclib, abemaciclib, sasanlimab, cemiplimab-rwlc, nivolumab, pembrolizumab, dostarlimab, atezolizumab, durvalumab, avelumab, and rituximab. H5. Embodiment H5 comprises the method or use of embodiment H3, wherein the at least one other anticancer agent is cabozantinib. H6. Embodiment H6 comprises the method or use of any one of embodiments Al to H5, wherein the patient is a human. H7. Embodiment H7 comprises the method or use of any one of embodiments Al to H6, wherein the treatment of cancer includes arresting or reducing the development of the cancer or its clinical symptoms. H8. Embodiment H8 comprises the method or use of any one of embodiments Al to H6, wherein the treatment of cancer includes causing regression of the cancer or its clinical symptoms. H9. Embodiment H9 comprises the method or use of any one of embodiments Al to H6, wherein the treatment of cancer includes causing the clinical symptoms of the cancer not to develop where the patient is exposed to or predisposed to the cancer but does not yet experience or display symptoms of the cancer. Embodiments I II. Embodiment II comprises the method or use of any one of embodiments Al to H9, wherein Compound (I) Form A is administered. 12. Embodiment 12 comprises the method or use of embodiment II, wherein Compound (I) Form A is micronized. 13. Embodiment 13 comprises the method or use of embodiment II or 12, wherein Compound (I) Form A is micronized having a D90 value of 14 ± 4 pm. 14. Embodiment 14 comprises the method or use of any one of embodiments II to 13, wherein Compound (I) Form A is micronized having a D90 value of 14 ± 2 pm. 15. Embodiment 15 comprises the method or use of any one of embodiments II to 14, wherein Compound (I) Form A is micronized having a D50 value of 6 ± 3 pm. 16. Embodiment 16 comprises the method or use of any one of embodiments II to 15, wherein Compound (I) Form A is micronized having a D50 value of 6 ± 1 pm. 17. Embodiment 17 comprises the method or use of any one of embodiments II to 16, wherein Compound (I) Form A is micronized having a DIO value of 3 + 2 pm. 18. Embodiment 18 comprises the method or use of any one of embodiments II to 17, wherein Compound (I) Form A is micronized having a DIO value of 3 ± 0.5 pm. As will be apparent to those skilled in the art, dosages outside of these disclosed dosages and ranges may be administered in some cases. Further, it is noted that the ordinary skilled clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in consideration of individual response. Utility Compound (I) and Compound (I) Form A are useful for the treatment of HIF-2a-mediated diseases, which include, but are not limited to, various types of cancers, such as acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancers, AIDS-related lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stem glioma, brain tumor, breast cancer, brenner tumor, bronchial tumor, bronchioloalveolar carcinoma, brown tumor, Burkitt's lymphoma, carcinoid tumor, carcinoma, carcinosarcoma, Castleman’s disease, central nervous system embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell renal cell carcinoma, clear-cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, endometrial cancer, endometrial uterine cancer, endometrioid tumor, enteropathy -associated T-cell lymphoma, ependymoblastoma, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, germinoma, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, hemangioblastoma, hemangiopericytoma, hemangiosarcoma, hematological malignancy, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, juvenile myelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, klatskin tumor, krukenberg tumor, laryngeal cancer, lentigo maligna melanoma, leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant triton tumor, malt lymphoma, mantle cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid cancer, medulloblastoma, medulloepithelioma, melanoma, meningioma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, urothelial carcinoma, mixed mullerian tumor, monocytic leukemia, mouth cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease, myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal cancer, neoplasm, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, nonmelanoma skin cancer, non-small cell lung cancer, ocular oncology, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancoast tumor, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor of intermediate differentiation, pineoblastoma, pituicytoma, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pie uropul monary blastoma, polyembryoma, precursor T-lymphoblastic lymphoma, primitive neuroectodermal tumor, prostate cancer, pseudomyxoma peritonei, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, sacrococcygeal teratoma, salivary gland cancer, sarcoma, Schwann omatosis, sebaceous gland carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, sezary syndrome, signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphatic cancer, testicular cancer, thecoma, throat cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell cancer of renal pelvis and ureter, transitional cell carcinoma, urachal cancer, urethral cancer, urogenital neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, verner morrison syndrome, verrucous carcinoma, visual pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor or any combination thereof. In some embodiments, the methods comprising administering a HlF-2a inhibitor disclosed herein and an immunotherapeutic agent described herein are applied to the treatment of cancers of the adrenal glands, blood, bone marrow, brain, breast, cervix, colon, head and neck, kidney, liver (e,.g, hepatocellular carcinoma), lung, ovary', pancreas, plasma cells, rectum, retina, skin, spine, throat, or any combination thereof. In some embodiments, the method of treating cancer (such as hepatocellularcarcinoma) disclosed in any one of embodiments Al to F21, further comprise administering atezolizumab (Tecentriq®) and bevacizumab (Avastin®). Pharmaceutical Compositions In general, Compound (I) or Compound (I) Form A will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. In general, Compound (I) or Compound (I) Form A will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. The compositions are comprised of, in general, Compound (I) or Compound (I) Form A in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of Compound (I) or Compound (I) Form A. The excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient, that is generally available to one of skill in the art. -39- Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Compound (I) or Compound (I) Form A may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds, which may contain antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In addition to the formulations described previously, Compound (I) or Compound (I) Form A may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored basis, such as sucrose, acacia, or tragacanth. Compound (I) or Compound (I) Form A may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases, such as cocoa butter, polyethylene glycol, or other glycerides. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed„ 2000). The amount of compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of Compound (I) or Compound (I) Form Abased on the total formulation, with the balance being one or more suitable pharmaceutical excipients, such as those described above. For example, Compound (I) or Compound (I) Form A may be present at about 180 wt. %. Combinations and Combination Therapies Compound (I) or Compound (I) Form A may be used in combination with one or more other drugs in the treatment of diseases or conditions for which Compound (I) or Compound (I) Form A or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously, or sequentially, with Compound (I) or Compound (I) Form A. When Compound (I) or Compound (I) Form A is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and Compound (I) or Compound (I) Form A is preferred. However, the combination therapy may also include therapies in which Compound (I) or Compound (I) Form A and one or more other drugs are administered on different overlapping schedules. It is also contemplated that, when used in combination with one or more other active ingredients, Compound (I) or Compound (I) Form A and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to Compound (I) or Compound (I) Form A. The above combinations include combinations of Compound (I) or Compound (I) Form A with one other drug, two other drugs, three other drugs, or more. Likewise, Compound (I) or Compound (I) Form A may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for -41 - which a compound of this disclosure is useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously, or sequentially, with Compound (I) or Compound (I) Form A. When Compound (I) or Compound (I) Form A is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to Compound (I) or Compound (1) Form A can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to Compound (I) or Compound (I) Form A. The weight ratio of Compound (I) or Compound (I) Form A to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Where the subject in need is suffering from or at risk of suffering from cancer, the subject may be treated with Compound (I) or Compound (I) Form A in any combination with one or more anti-cancer agents. In some embodiments, one or more of the anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2’-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec™), geldanamycin, 17-N-Allylamino- 17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, TaxolIM, also referred to as “paclitaxel”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of Taxol™, such as Taxotere™. Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases by stabilizing microtubules and may be useful for treating cancer in combination with the compounds described herein. Suitable anti-cancer agents may also include inhibitors of kinase associated cell proliferative disorders. Kinases prone to inhibition include, but are not limited to, Aurora-A, BTK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lek, Fer, Fes, Syk, Itk, Bmx, GSK3, INK, MEK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, RAF, Rsk, and SGK. In particular, inhibitors of CDK4 / 6, including abemaciclib (Verzenio), palbociclib (Ibrance), dalpiciclib, and ribociclib (Kisqali), have the potential to be synergistic with HIF-2a inhibitors and reverse the resistance to HIF-2a inhibition; Other anti-cancer agents may include mitogen-activated protein kinase signaling inhibitors, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., rituxan); MET inhibitors, such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitors, such as sunitinib, -42 - sorafenib, regorafinib, lenvatinib, vandetanib, cabozantinib, axitinib, pazopanib, or tivozanib; EGFR inhibitors, such as afatinib, brivanib, cabozantinib, erlotinib, gefitinib, neratinib, or lapatinib; PI3K inhibitors, such as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946. BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, or TG100-115; MTOR inhibitors, such as rapamycin (sirolimus), temsirolimus, everolimus, ridaforolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, or GDC0349; MEK inhibitors, such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, or AZD833O; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155, etc); TGF beta receptor kinase inhibitors, such as LY2157299; or BTK inhibitors, such as ibrutinib. Other anti-cancer agents include proteasome inhibitors, such as carfilzomib, MLN9708, delanzomib, or bortezomib; BET inhibitors, such as INCB054329, OTX015, CPI-0610; LSD1 inhibitors, such as GSK2979552, INCB059872; HDAC inhibitors, such as panobinostat, vorinostat; DNA methyl transferase inhibitors, such as azacytidine, decitabine, and other epigenetic modulators; SHP-2 inhibitors, such as TNO155; the Bcl2 inhibitor ABT-199, and other Bcl-2 family protein inhibitors; Beta catenin pathway inhibitors, notch pathway inhibitors and hedgehog pathway inhibitors; and antibodies or other therapeutic proteins that target VEGF, including bevacizumab and aflibercept. Other anti-cancer agents / drugs that may be used in combination with the compounds of the invention disclosed herein include, but are not limited to, liver X receptor (LXR) modulators, including LXR agonists and LXR beta-selective agonists; and aryl hydrocarbon receptor (AhR) inhibitors. Other anti-cancer agents that may be employed in combination with a compound of this disclosure include Adriamycin; Dactinomycin; Bleomycin; Vinblastine; Cisplatin; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or Ril2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-la; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride; or combinations thereof. Other anti-cancer agents that may be employed in combination with Compound (I) or Compound (I) Form A include 20-epi-l; 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; Bfgf inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; R.sub.ll retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; SDI 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Other anticancer agents that may be employed in combination with a compound of this disclosure include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen -46- mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), and triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful in combination with a compound of this disclosure include, but are not limited to, vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), and biological response modifiers (e.g., interferon alpha). Examples of alkylating agents that may be employed in combination a compound of this disclosure) include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), and triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of hormones and antagonists useful in combination with a compound of this disclosure include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), gonadotropin releasing hormone analogs (e.g., leuprolide). Other agents that may be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methyl hydrazine derivatives (e.g., procarbazine), and adrenocortical suppressant (e.g., mitotane, aminoglutethimide). Other anti-cancer agents that may be employed in combination with Compound (I) or Form A include anti-cancer agents which act by arresting cells in the G2-M phases due by stabilizing microtubules, include Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPL2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTL286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi). One or more additional immune checkpoint inhibitors may be used in combination with Compound (I) or Compound (I) Form A for treatment of HIF-2a-associated diseases, disorders, or conditions. Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologies) against immune checkpoint molecules, such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, G1TR, CSF1R, JAK, P13K delta, P13K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, SHP-2, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PDl antibody is pembrolizumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A (atezolizumab) or MED14736 (durvalumab). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383. In some embodiments, -49- the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g. an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is sasanlimab, cemiplimab-rwlc, nivolumab, pembrolizumab, dostarlimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab (BGB-A287), toripalimab, INCMGA00012 (MGA012), AMP-224, AMP-514 (MED10680), or acrixolimab (YBL-006). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g. an anti- PD-L1 antibody. In some embodiments, the anti-PD-Ll antibody is atezolizumab, durvalumab, avelumab, KN035, Cosibelimab, AUNP12, CA-170, or BMS-986189. Compound (I) or Compound (I) Form A may also be used to increase or enhance an immune response, including increasing the immune response to an antigen or to improve immunization; increasing vaccine efficacy; and increasing inflammation. In some embodiments, Compound (I) or Compound (I) Form A may be used to enhance the immune response to vaccines including, but not limited to, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GV AX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. Other immune-modulatory agents also include those that block immune cell migration, such as antagonists to chemokine receptors, including CCR2 and CCR4, Sting agonists, and Toll receptor agonists. Other anti-cancer agents also include those that augment the immune system, such as adjuvants and adoptive T cell transfers. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation. Examples The following examples are merely illustrative of the disclosure and should not be considered limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent to those skilled in the art in light of the present disclosure and the accompanying claims. Example 1 Formulation of Compound (I) Form A Compound (I) Form A was formulated as immediate release capsules supplied at 10, 25, 50 and 200 mg dose strengths. Information about the composition of Compound (I) Form A capsules is disclosed in Tables 2a and 2b below. -50- Table 2a: Composition of Compound (I) Form A Capsules (lOmg, 50 mg, and 200 mg Dose Strengths and Blends) Component Function Quality Standard 10 mg Strength (Blend) 10 mg Strength 50 mg and 200 mg Strength (Common Blend) 50 mg Strength 200 mg Strength Composition of Capsule Fill (%) Amount (mg) / capsule Composition of Capsule Fill (%) Amount (mg) / capsule Amount (mg) / capsule Micronized Compound (I) Form A PSD (pm): D10:D50:D90 = 1:6:14 Drug Substance 10.75 10.00 48.54 50.0 200.0 Mannitol Diluent USP 76.34 71.00 30.10 31.0 124.0 Sodium lauryl sulfate Surfactant NF 2.69 2.50 12.14 12.5 50.0 Crospovidone Disintegrant NF 4.84 4.50 4.37 4.5 18.0 Copovidone Binder NF 5.38 5.00 4.86 5.0 20.0 Purified Water3 Granulation Solvent USP N / A N / A N / A N / A N / A Total Final Blend N / A 100.0 93.0 100.0 103.0 412.0 “Purified water is used as a manufacturing aid and is not present in significant quantities in the finished product. WO 2025 / 235290                                   PCT / US2025 / 027249 Table 2b: Composition of Compound (I) Form A Capsules (lOmg, 25 mg, 50 mg, and 200 mg Dose Strengths and Blends) Components / F unction 10 mg strength % 25 mg strength % 50 mg strength % 200 mg strength % Intragranular Ingredients Micronized Form A PSD: 1:6:14 Drug Substance 10 10.75% 25 25.84% 50 48.54% 200 48.54% Mannitol Diluent 71 76.34% 56 57.88% 31 30.10% 124 30.10% Sodium lauryl sulfate Non-sprayed surfactant 0.24 0.26% 3.9 4.03% 10 9.71% 40 9.71% Crospovidone Disintegrant 4.5 4.84% 4.5 4.65% 4.5 4.37% 18 4.37% Copovidone Non-sprayed binder 4.43 4.76% 4.41 4.56% 4.375 4.25% 17.5 4.25% Granulation media Copovidone Sprayed binder 0.57 0.61% 0.59 0.61% 0.625 0.61% 2.5 0.61% Sodium lauryl sulfate Sprayed surfactant 2.26 2.43% 2.35 2.43% 2.5 2.43% 10 2.43% Purified Water Granulation Solvent - - - - Total 93 100% 96.75 100% 103 100% 412 100% WO 2025 / 235290                                   PCT / US2025 / 027249 Preparation of 50 mg and 200 mg granule only capsule formulation: Sieved (30 mesh) micronized Compound (I) Form A, Pearlitol (Mannitol), sodium lauryl sulfate, crospovidone, and copovidone were transferred to a granulator and mixed to prepare a dry blend. Granulation media was prepared by mixing sodium lauryl sulfate and copovidone in water until dissolved. Wet granules were prepared by spraying the granulation media onto the dry blend and granulating at 300RPM. The resulting wet granules were dried and milled. The milled dry blend was transferred, sieved (0.6 mm / #30 mesh), and encapsulated to generate 50 mg and 200 mg dose strength capsules. Preparation of 10 mg and 25 mg granule only capsule formulations: The above formulations were prepared using the same manufacturing process and equipment as the 50 / 200 mg common granule but varying the amounts of micronized form A and diluent while maintaining a sodium lauryl sulfate to micronized form A weight / weight ratio of 0.25. Example 2 Compound (1) Form A Phase 1 / 2 Open Label Dose-Escalation and Expansion Trial in Patients with ccRCC (Protocol Number NKT2152-101, version 10.0) Compound (I) Form A is currently in Phase 1 / 2 study in patients with ccRCC. Compound (I) Form A is being examined in an ongoing open-label, multi-center, non-randomized, multipledose study to evaluate the safety, tolerability, PK, PD, and anti-tumor activity of increasing immediate-release, oral doses (in capsules) of Compound (I) Form A as a single agent in sequential dose levels. Summary of Clinical Data As of 16 June 2023, 61 patients have been treated with Compound (I) Form A; 15 of whom were treated with a continuous daily dosing schedule with dosages of 50 mg, 100 mg, 200 mg, or 300 mg once daily (QD) of Compound (I) Form A; and 46 of whom were treated with a loading dose followed by a maintenance dose of Compound (I) Form A at the following dosages: 200 mg QD x 7 days then 200 mg QW, 200 mg QD x 14 days then 50 mg QD, 100 mg QD x 7 days then 100 mg QW, or 200 mg QD x 28 days then 50 mg QD. Overall, Compound (I) has been well tolerated. A total of 59 / 61 patients (96.7%) experienced treatment-emergent adverse events (TEAEs). The most common TEAEs were anemia (41 / 61 patients, 67.2%) and fatigue (25 / 61 patients, 41.0%). A single Grade 5 TEAE was reported (disease progression unrelated to Compound (I) Form A treatment). Four / 61 patients (6.6%) had a maximum TEAE severity of Grade 4: hypoxia, pain in extremity, acute kidney injury, sepsis, and bronchial obstruction in 1 patient each. The MTD was not reached. Four / 61 patients (6.6%) experienced a dose reduction of Compound (I) Form A due to TEAEs. No TEAE resulting in a dose reduction occurred in more than 1 patient. Treatment interruptions due to TEAEs occurred in 28 / 61 patients (45.9%). Hypoxia, fatigue, and nausea were the most commonly reported TEAEs leading to treatment interruption occurring in 8 / 61 patients (13.1%), 6 / 61 patients (9.8%), and 4 / 61 patients (6.6%) overall, respectively. A total of 6 / 61 patients (9.8%) discontinued treatment due to a TEAE. Hypoxia and fatigue were the only TEAEs that resulted in treatment discontinuation in more than 1 patient (hypoxia occurred in 3 / 61 patients [4.9%] and fatigue occurred in 2 / 61 patients [3.3%] overall). Serious TEAEs were reported in 19 / 61 patients (33.1%). Serious TEAEs were treatment related in 5 / 61 patients (8.2%). Serious TEAEs that occurred in more than 1 patient overall included hypoxia (4 / 61 patients, 6.6%), pneumonia (2 / 61 patients, 3.3%), pericardial effusion (2 / 61 patients, 3.3%), and pain in extremity (2 / 61 patients, 3.3%). With a sample cutoff date of 15 February 2023, plasma Compound (I) PK data was obtained from 50 patients at 8 dosage levels, including 50 mg, 100 mg, 200 mg, and 300 mg QD of Compound (I) Form A, 100 mg QD x 7 days then 100 mg QW of Compound (I) Form A, 200 mg QD x 7 days then 200 mg QW of Compound (I) Form A, 200 mg QD x 14 days then 50 mg QD of Compound (I) Form A, and 200 mg QD x 28 days then 50 mg QD of Compound (I) Form A. Based on serial PK data at Week 1 (Day 1), dose-limited absorption rate with higher PK variability was observed at 300 mg of Compound (I) Form A. AUC values were approximately dose proportional following QD dosing on Day 1 and Day 22. For patients receiving continuous QD dosing of Compound (I) Form A, significant accumulation of Compound (I) was observed with cohort mean accumulation of AUC ratio ranging from 8.29 to 10.9 on Day 22, and an apparent steady state of Compound (I)was not achieved based on trough concentration data before dose modifications. Patients receiving loading and maintenance doses of Compound (I) Form A showed relatively flat trough PK profiles of Compound (I) after switching to maintenance doses. EPO data was collected from 61 patients treated with a continuous daily dosing schedule or a loading / maintenance dose schedule of Compound (I) Form A. Rapid and significant EPO suppression was observed at all tested dosages. As of f 6 June 2023, 3f out of 61 patients remained on treatment. A 2-compartmental population PK model with first-order oral absorption and first-order elimination adequately described the PK data of Compound (I) after a single dose, multiple doses, as well as PK after dose reductions and dose holds of Compound (I) Form A. The typical PK parameter values (CV%) for absorption rate constant (Ka), apparent total clearance (CL / F), -54- apparent intercompartment clearance (Q / F), apparent volume of distribution of the central compartment (Vc / F), and apparent volume of distribution of the peripheral compartment (Vp / F) of Compound (I) were 0.741 (72%), 0.472 L / h (80%), 27.1 L / h (54%), 133 L (76%), and 543 L (84%), respectively; the model-estimated median terminal ti / 2 of Compound (I) was 39 days following administration of Compound (1) Form A. The modeling analysis suggested no time- or concentration-dependent nonlinearity and that the high accumulation of Compound (I) following continuous daily dosing of Compound (I) Form A is due to slow elimination. Subsequently, an indirect population PK-EPO response model was developed based on the PK and EPO data from this study. The EPO model had first-order EPO elimination and zero-order production which was inhibited by Compound (I). The model-estimated half-maximal inhibitory concentration (IC50) and maximum fractional inhibition (Imax) of Compound (I) were 57.3 ng / mL and 0.758, respectively, following administration of Compound (I) Form A. The model adequately described the EPO inhibition at different dosage levels. Rationale for Phase 2 Expansion Dosage Selection RDE Selection Based on Clinical Safety and Efficacy Data Based on review of the overall safety, tolerability, PK, PD, and preliminary efficacy, two RDEs of Compound (I) Form A: 200 mg QD x 14 then 50 mg QD (RDE-d) and 100 mg QD x 7 then 100 mg QW (RDE-w) were endorsed by the Safety Review Committee (SRC) and selected for further evaluation in the phase 2 portion of the study in order to determine a final RP2D. Overall, dosage levels of Compound (I) Form A at or below the RDE-d level were well tolerated with promising preliminary efficacy observed in heavily pre-treated ccRCC patients. As of 18 April 2023, at the 200 mg QD x 14 then 50 mg QD dose level (RDE-d), 9 patients were enrolled and dosed with Compound (I) Form A. Duration of treatment ranged from 57 to 251 days. Overall, safety and tolerability were favorable in this cohort. Two DLTs were observed in 1 patient (Grade 3 fatigue, Grade 3 hypoxia). The most common TEAEs were anemia (100% n=9), nausea (44%, n=4), and fatigue (33%, n=3). Hypoxia occurred in 1 patient (Grade 3). Serious TEAEs occurred in 3 patients, however, only 1 was considered related to Compound (I). Drug interruptions due to treatment-related TEAEs (TRAEs) occurred in 22% (n=2), dose reductions due to TRAEs in 11% (n=l), and drug discontinuations due to TRAEs in 11% (n=l) of patients. Promising anti-tumor activity was also observed. Best overall response was PR (confirmed) in 2 patients, SD in 6 patients, and PD in 1 patient. As of 18 April 2023, 5 patients were continuing Compound (I) Form A treatment with a maximum duration of treatment up to 35+ weeks. Four patients discontinued treatment (2 patients due to disease progression and 2 patients due to TEAE). At the 100 mg QD x 7 then 100 mg QW dose level (RDE-w), 9 patients were enrolled and dosed with Compound (I) Form A. Safety and tolerability were favorable in this cohort. No DLTs were observed at this dose level. The most common TEAEs were anemia (89%, n=8) and fatigue (44%, n=4). Two patients reported grade 3 hypoxia. Of note, both patients also had an underlying medical history of chronic obstructive lung disease. Serious TEAEs were reported in 1 patient but were not considered related to Compound (I) Form A. Drug interruptions due to TRAEs occurred in 33% (n=3 patients), dose reductions due to TRAEs in 11% (n=l), and no patients discontinued treatment due to a TRAE. Promising anti-tumor activity was also observed. Best overall response was PR (unconfirmed) in 2 patients, SD in 4 patients, and PD in 2 patients. One patient is not yet evaluable. As of 18 April 2023, 7 patients were continuing Compound (I) Form A treatment with a maximum duration of treatment up to 29+ weeks. Two patients discontinued treatment due to disease progression. Ten patients at an intermediate dosage between RDE-d and RDE-w were enrolled and dosed with Compound (I) Form A. At this intermediate dosage of 200 mg QD x 7 then 200 mg QW dose of Compound (I) Form A, no DLTs were observed. The most common TEAEs were anemia (60%, n=6), hypoxia (30%, n=3), fatigue (50%, n=5), and dizziness (30%, n=3). Of the 3 patients with hypoxia, one had maximum grade 2, and two had maximum grade 3. Serious TEAEs were reported in 3 patients and considered related to Compound (I) in one patient (Grade 3 hypoxia). At this dosage level, best overall response was PR (unconfirmed) in two patients, SD in 4 patients, and PD in 4 patients, and treatment was ongoing in 4 patients as of the data snapshot. 6 patients discontinued treatment (4 due to disease progression, 1 due to AE, and 1 due to physician decision). This dosage was well tolerated with promising preliminary efficacy observed. 9 patients at dosage above RDE-d were enrolled and dosed with 200 mg QD x 28 then 50 mg QD of Compound (I) Form A. In this dosage, anemia was observed in 67% (n=6; maximum Grade 1 n=l, maximum Grade 2 n=5) patients. Hypoxia was observed in 44% (n=4; maximum Grade 2 n=l, maximum Grade 3 n=2, maximum Grade 4n=l) patients. Grade 3 or higher treatment related TEAEs were reported in 44% (n=4) patients (hypoxia n=2, pleural effusion n=2, fatigue n=2, pericardial effusion n=l). Serious TEAEs were reported in 44% (n=4) patients with 2 patients having serious TEAEs considered related to Compound (I): hypoxia (maximum Grade 2 n=l, maximum Grade 4 n=l), fatigue (Grade 3 n=l), pericardial effusion (Grade 3 n=l), pleural effusion (Grade 3 n=l). Best overall response at the 200 mg QD x 28, then 50 mg QD level was PR (unconfirmed) in 2 patients, SD in 1 patient, and PD in 3 patients. As of the 18 April 2023 data snapshot, 3 patients were ongoing. Three patients discontinued treatment due to PD and 3 patients discontinued treatment before the initial post-baseline tumor assessment (2 patients due to TEAEs and 1 patient withdrew consent). Though no DLTs were observed at this cohort, given the overall safety / efficacy profile observed, the SRC did not recommend further evaluation of this dose level. RDE Selection Supported by Clinical Pharmacology Analysis Loading and maintenance dosing regimens PK data from the early cohorts that were treated with QD dosing of Compound (I) Form A showed continuous PK accumulation of Compound (I) and steady state of Compound (I) was not observed. PK simulation profiles at RDE-w and RDE-d suggested that it takes approximately 28 weeks to reach steady-state PK of Compound (I) after QD dosing of Compound (I) Form A according to the population PK model. The unique PK with very slow elimination necessitated sequential loading and maintenance dosing schedules to achieve and maintain target exposure levels. See Fig. 5. The total maintenance doses of Compound (I) Form A per week are 100 mg and 50 mg for RDE-w and RDE-d, respectively. After the first maintenance dose of Compound (I) Form A, RDE-w and RDE-d allow a reasonably large range of exposure of Compound (I) with estimated mean CtrOugh around 1080 ng / mL and 3600 ng / mL, respectively (a 3.34-fold range). Reference concentrations considered for RDE selection Pharmacologically active concentration thresholds were estimated for Compound (I) Form A using different approaches. Compound (I) Form A inhibited VEGFA secretion in 786-0 cells with IC90 of 201 ng / mL in human plasma (after protein binding adjustment). In an A498 xenograft mouse model, tumor growth inhibition was estimated using a PK-tumor growth inhibition model, and the human equivalent IC90 of Compound (I) was estimated to be 2070 ng / mL (after crossspecies protein binding normalization). According to the preliminary clinical PK-EPO model, Compound (I) Form A inhibited EPO production with an IC90 of 516 ng / mL. See Fig. 5. At RDE-w, the population PK model-estimated mean Chough (90% prediction interval) of Compound (I) was 1080 ng / mL (380 - 2300 ng / mL), suggesting that RDE-w is efficacious, consistent with the observed efficacy in patients at this dosage level in the Phase 1 Dose Escalation. Serum EPO level is a sensitive PD marker for HIF2a inhibition. In the pivotal Phase 2 study of belzutifan, patients with VHL disease associated RCC showed a mean EPO decrease by 60.2% following 120 mg belzutifan daily; and, in a Phase 1 dose escalation in patients with advanced RCC, a mean EPO decrease by 63% was observed across tested belzutifan dose levels (see Center for Drug Evaluation and Research (2022). "Assessing the Effects of Food on Drugs in INDs and ND As—Clinical Pharmacology Considerations." Food and Drug Administration). In the Phase 1 Dose Escalation of Compound (I) Form A, significant EPO suppression was observed at all tested dosage levels, and the magnitude of suppression was similar to that of belzutifan at the -57 - approved dose of 120 mg QD. Significant serum EPO suppression may not reflect adequate HIF2a inhibition within the tumor. No correlation between clinical EPO suppression and efficacy has been reported. Higher dosages of belzutifan are being tested in advanced RCC patients at up to 200 mg TID (NCT04846920) which is 5 times the approved belzutifan dose for the initially approved indications (see WEL1REG™ (belzutifan) Prescribing Information. Merck & Co., Inc.). In the in vitro VEGFA secretion inhibition study in 786-0 cells, the unbound IC50 (ICso.u) values were 22.6 and 2.59 nM for belzutifan and Compound (I) Form A, respectively. After corrections for the potency and unbound fraction in plasma (fu, 0.55 for belzutifan and 0.0487 for Compound (I)), the model-estimated average plasma concentration of Compound (I) at RDE-w and RDE-d in the first week of maintenance treatment were 1.07 and 3.78 times the average steady-state belzutifan concentration at 120 mg QD, respectively, further supporting the RDE selection. Exposure-response analysis Exposure-safety and exposure-efficacy correlations were explored with selected clinical endpoints based on population PK model-estimated individual PK exposures corrected by actual doses. Due to different dosing intervals and dose modifications, average concentration (Cavg), defined as Cavg = AUCo-t / t of each patient was used in the analyses, where t is time of the last dose or the time of the event of interest. In the preliminary exposure-safety analysis, the maximal hemoglobin decrease from baseline correlated with baseline value (p<0.001) but not with Cavg of Compound (I) (p>0.373). No statistically significant and clinically meaningful correlation was observed for Grade >2 or Grade >3 anemia, Grade >2 or Grade >3 hypoxia. A trend of higher probability of Grade >3 TEAEs at higher Cavg was observed (p=0.20), but no trend was observed for Grade >3 TRAEs (p=0.62). No clinical meaningful correlation was observed between time to the first dose modification due to AEs and average concentration. At the RDE-d, 7 of 9 patients had no dose modification for >14 weeks, suggesting good tolerability and safety. In a preliminary exposure-efficacy analysis, no clinically meaningful correlations with PK exposures of Compound (I) were observed for objective response, time to objective response, or best SLD change. However, patients with higher Cavg tended to have a deeper SLD decrease at the first post-treatment scan (week 9) after excluding 4 patients who showed >50% disease progression (p=0.25). It is possible that the diseases of these 4 patients didn’t dependent on HIF2a signaling. In summary, RDE-w (100 mg QD x 7 days then 100 mg QW) and RDE-d (200 mg QD x 14 days then 50 mg QD) dosages of Compound (I) Form A were selected based on integrated data analysis. Pharmacologically active concentrations of Compound (I) were achieved at the above -58 - RDEs. Both RDE-w and RDE-d were efficacious with manageable safety in the Dose Escalation. PK-PD modeling and Exposure-Response analyses suggested better tumor response at higher exposures of Compound (I). RDE-w allows for Compound (I) exposure comparable to belzutifan (120 mg QD), while RDE-d allows for 3.5 fold higher maintenance dose intensity and potentially better efficacy. Trial Objectives and Purpose Primary Objectives Phase 1 • To identify the maximum tolerated dose (MTD) and / or the recommended doses for expansion (RDEs) of Compound (I) Form A in patients with relapsed or refractory ccRCC Phase 2 • To evaluate the antitumor activity of Compound (I) Form A by ORR at the RDEs in patients with ccRCC • To determine the recommended Phase 2 dose (RP2D) Primary Endpoints Phase 1 • Incidence of DLT events during the DET monitoring period (first 21-days of dosing) Phase 2 • Achieving investigator assessed ORR defined as either a CR or PR by RECIST 1.1 based on computed tomography (CT) or magnetic resonance imaging (MRI) scans Secondary Objectives • To evaluate the overall safety and tolerability of Compound (I) Form A monotherapy • To determine the PK profile of Compound (I) Form A monotherapy • To assess the PD effects of treatment with Compound (I) Form A • To evaluate the ORR of Compound (I) Form A (Phase 1 only) • To evaluate PFS, OS, duration of response and disease control rate of Compound (I) Form A Secondary Endpoints Phase 1 and Phase 2 • Incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 • Changes in clinical laboratory parameters, vital signs and electrocardiogram (ECG) parameters and physical examination findings • Compound (I) Form A single-dose and multiple-dose PK parameters such as maximum concentration observed (Cmax), time at which maximal concentration was observed (tmax), area under the concentration-time curve during a dosing interval (AUCo-t), area under the concentration time curve from time zero to infinity (AUCo-oo), if data allow • ORR (Phase 1 only) • Duration of response and disease control rate (defined as CR + PR + stable disease for > 8 weeks) • Time to response • Progression free survival • Overall survival • 6- and 12-month landmark OS Exploratory Objectives Phase 1 and Phase 2 • To explore biomarkers potentially predictive of response to Compound (I) Form A • To determine the effect of Compound (I) Form A on plasma levels of 4p-hydroxycholesterol as a biomarker of CYP3A4 activity • To determine the genotypes and infer the phenotypes of metabolic enzymes that are possibly involved in Compound (I) Form A metabolism • To evaluate the effect of Compound (I) Form A on the patient reported outcome for quality of life based on European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) (Phase 2 only) Exploratory Endpoints • Compound (I) Form A effects on Serum erythropoietin (EPO) and Whole Blood Circulating tumor DNA (ctDNA) • Change from baseline in the patient reported outcomes for quality of life based on EORTC-QLQ-C30. Sub-Study Objectives • Objectives for the drug-drug interaction (DDI) and food effect (FE) sub-study are included in sub-study 1. • Objectives for the preliminary urinary excretion and metabolite profiling sub-study are included in sub-study 2. • Objectives for the belzutifan pre-treated patient sub-study are included in sub-study 3. Investigational Plan Overall Study Design This study will be conducted in two parts, Phase 1 and Phase 2. Phase 1 will be conducted as a dose escalation trial in patients with ccRCC tumors to determine the MTD / RDEs of Compound (1) Form A. Phase 2 will be conducted as an expansion trial to further explore the safety, pharmacokinetics, and preliminary efficacy of the MTD or RDE to determine the RP2D in patients with advanced ccRCC. Study procedures are described below and the schedule of assessments is tabulated in Table 3 and Table 4. Patients will undergo clinic visits weekly for the first 4 weeks, then will have a visit two weeks apart at the Week 6 visits, a visit three weeks apart at the Week 9 visit and then every 4 weeks for up to 1 year from the initiation of treatment, or until withdrawal criteria are met as describedbelow. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will occur at 12-week intervals. Patients who are discontinued from treatment or who choose to withdraw will be asked to return to the clinic for a follow-up safety visit 28 days after taking their last dose of study drug. In addition, a sub-study is added to this study to assess the effect of a high-fat meal on the PK of Compound (I) Form A and the effect of Compound (I) Form A treatment on the PK of a single oral dose of midazolam. The design is provided below. The design of another sub-study for preliminary determination of urinary excretion and metabolite profiling is provided below. The sub-study of belzutifan pre-treated patients is provided below. o N) Table 3:     Phase 1 Schedule of Assessments Assessment PreTreatment Period Treatment Period Post-Treatment Period Screening (Day -281 to Day -1) Week I1 (Day 1) Weeks 2, 3,4,5, 61 (± 1 d) Weeks 9, 13, 17, and every 4 weeks1 (± 2 d)through Week 49 Extended treatment2 every 12 weeks (± 1 week) Safety Follow-up 28 days after last dose of study drug (±7d) Long Term Follow-up (every 6 months) Informed Consent X Medical History X Physical Examination3 X X X X X X Vital Signs4 X X X X X X Six-minute walk22 X Weight X X X X X X Height X ECOG X X X X X X Dispense / Collect Study Drug X X X X Hematology5 X X X X X X Serum Chemistry6 X X X X X X PT / aPTT / INR X WO 2025 / 235290                                   PCT / US2025 / 027249 0> GJ Iron Panel7 X X X X Urinalysis X X8 X8 X8 X X Pregnancy Test X X9 X9 X9 X X9 ECG X X10 X10 X10 Tumor Assessment X X11 X11 DNA Sequencing 12 X Circulating Tumor DNA13 X X PK Sample X14 x14-15 X15 PD Sample X17 X17 X17 Archival Tissue Samples18 X Image Transfer19 X X X Echocardiogram / MU GA2 0 X X Study Drug Administration 6 Adverse Events X X X X X Concomitant Medications X X X X X Patient Status21 X 1. Assessments to be done on Day 1 of each visit week. For the Week 2-6 Visits, all patients will return to clinic on Weeks 2, 3, 4, and 6. Procedure windows should be adhered to when completing assessments: Pre-dose and post-dose at 0.5 hours (± 10 minutes), 1 hour (± 10 minutes), 1.5 hours (± 15 minutes), 2 hours (± 15 minutes), 4 hours (± 15 minutes), 6 hours (± 15 minutes), 8 hours (± 30 minutes), 12 hours (±1 hour), and 24 hours ( ± 2 hours). Patients assigned to the WO 2025 / 235290                                   PCT / US2025 / 027249 QW dosing schedule will have an additional clinic visit on Week 5 to obtain a single pre-dose PK sample. These assessments can be performed ± 1 day (24 hours). For the Week 9, 13, 17 and visits every 4 weeks thereafter, assessments can be performed ± 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1 DI need not be repeated. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Physical examination to be performed before study drug administration at the Week 1,4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through Week 49. 4. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature, and oxygen saturation and obtained only prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 5. Hematology assessments include complete blood count (CBC), differential, platelet count, and reticulocyte count. 6. Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, COz), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel. BNP and NT-proBNP is required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs. 7. Iron panel assessments including iron (Fe), ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 8. Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 9. Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation. For female patients of child-bearing potential who discontinue treatment, home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A. 10. An ECG will be obtained before and at 1.5 hours (± 15 minutes) after study drug administration at the Week 1 and Week 4 Visits. ECGs will be obtained prior to study drug administration only at Weeks 2, 3, 6, 9, and every 4 weeks, thereafter, through Week 49 (e.g., Week 13, Week, 17, Week 21, etc.). WO 2025 / 235290                                   PCT / US2025 / 027249 11. Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening / baseline (within 35 days) and every 8 weeks (± 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (± 1 week). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. 12. At the Week 1 visit, 17 mL of whole blood as 2 x 8.5 mL Pax Gene Tubes should be collected for genetic sequencing. 13. At the Week 1 and Week 9 visits, 20 mL of whole blood as 2 x 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA. 14. At the Week 1 and Week 4 Visits, patients will take their dose of Compound (I) Form A in the clinic and will have 4 mL of blood drawn for PK assessments at 0.5 hour (±10 minutes ) before and at 0.5 hour (±10 minutes), 1 hour (±10 minutes), 1.5 hour (±15 minutes), 2 hours (± 15 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), and 24 hours (±2 hour) after study drug administration. 15. Patients assigned to the QD dosing schedule will take their dose of Compound (I) Form A in the clinic at weeks 2, 3, 6, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49 Visits. A 4 mL blood sample for PK assessments will be obtained before study drug administration on these days. 16. Patients assigned to the OW dosing schedule will take their dose of Compound (I) Form A in the clinic at weeks 2, 3, 5, 6, 9, 13, 17, 21, 25, 29, 33, 37,41, 45, and 49 Visits. A 4 mL blood sample for PK assessments will be obtained before study drug administration on these days. 17. At the Week 1 and Week 4 visits, patients will have blood drawn for PD assessments at 1 hour before (+10 minutes / -40 minutes) study drug administration. S              Other samples for PD assessments will be obtained before study drug administration at the Week 2, 3, 6, 9, 13,17, 21, 25, 29, 33, 37,41, 45, and 49 Visits. Patients will take their dose of Compound (I) Form A in the clinic on these days. 18. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin-fixed, paraffin-embedded blocks. 19. Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual. 20. An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). 21. For consenting patients and after completion of the 28-day post-treatment follow-up visit, long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc. Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 22. Patients enrolled under PA vlO will have a 6MWT during Screening visit. Table 4:     Phase 2 Schedule of Assessments WO 2025 / 235290                                   PCT / US2025 / 027249 Assessment Pre Treatment Period Treatment Period Post-Treatment Period Screening (Day -281 to Day -1) Week I1 (Day 1) Weeks 2, 3,4,61 (± 1 d) Weeks 9, 13, 17, and every 4 weeks1 (± 2 d) through Week 49 Extended treatment every 12 weeks (± 1 week) Safety Follow-up 28 days after last dose of study drug (±7d) Long Term Follow-up (every 6 months) Informed Consent X Medical History X Physical Examination X X3 X3 X3 X X Vital Signs4 X X X X X X Six-minute walk19 X Weight X X X X X X Height X ECOG X X X X X X EORTC-QLQ-C305 X X X X X Dispense / Collect Study Drug X X X X Hematology6 X X X X X X Serum Chemistry7 X X X X X X WO 2025 / 235290                                   PCT / US2025 / 027249 PT / aPTT / INR X Iron Panel8 X X X X Urinalysis X X9 X9 X9 X X Pregnancy Test X X10 X10 X10 X10 X10 ECG Refer to Table 5 Tumor Assessment11 X X X DNA Sequencing12 X Circulating Tumor DNA13 X X PK Sample Refer to Table 5 PD Sample Refer to Table 5 Tissue Samples14 X X Image Transfer15 X X X Echocardiogram / MUGA1 6 X X Study Drug Administration17 ______________________________V_____________________________ Adverse Events X X X X X Concomitant Medications X X X X X Patient Status18 X 1. Assessments to be done on Day 1 of each visit week. For the Week 2-6 Visits, all patients will return to clinic on Weeks 2, 3, 4, and 6. Procedure windows should be adhered to when completing assessments: Pre-dose and post-dose at 0.5 hours (± 10 minutes), 1 hour (± 10 minutes), 1.5 hours (± 15 minutes), 2 hours (± 15 minutes), 4 hours (± 15 minutes), 6 hours (± 15 minutes), 8 hours (± 30 minutes), 12 hours (± 1 hour), and 24 hours (± 2 hours). For Week 9, 13, 17 and WO 2025 / 235290                                   PCT / US2025 / 027249 0> co visits every 4 weeks thereafter, assessments can be performed ± 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. PK / PD sample collection windows are included in Table 5. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Physical examination to be performed before study drug administration at the Week 1,4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through Week 49. 4. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature, and oxygen saturation and obtained only prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 5. EORTC-QLQ-C30 should be done on Day 1 of Weeks 1, 4, 9, 13, and then every 4 weeks for the first year of treatment and every 12 weeks during extended treatment. 6. Hematology assessments include complete blood count (CBC), differential, platelet count, and reticulocyte count. 7. Routine scrum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO2), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel. BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs. 8. Iron panel assessments including iron (Fe), ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 9. Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 10. Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation. For female patients of child-bearing potential who discontinue treatment, home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A. WO 2025 / 235290                                   PCT / US2025 / 027249 11. Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening / baseline (within 35 days) and every 8 weeks (± 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (± 1 week). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. At Screening (within 35 days prior to enrollment), a CT / MRI of the brain should be obtained to rule out newly diagnosed, untreated brain metastases or to document stability of previously treated brain metastases. CT / MRI brain scans should be performed at every on-study tumor assessment for chest / abdomen / pelvis for patients with brain metastases or primary brain tumors. 12. At the Week 1 visit, 17 mL of whole blood as 2 x 8.5 mL Pax Gene Tubes should be collected for genetic sequencing. 13. At the Week 1 and Week 9 visits, 20 mL of whole blood as 2 x 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA. 14. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin-fixed, paraffin-embedded blocks. In Phase 2 only, for the belzutifan pre-treated cohort, biopsy tissue samples are required during screening and at Week 9 from the same lesion as the pre-treatment biopsy (preferred) or at least from the same organ. For other Phase 2 Expansion cohorts, biopsy tissue samples during screening and at Week 9 are optional. 15. Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual. 16. An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement S              should be used throughout the study). 17. On study visit days, Compound (I) Form A should be administered after all study assessments have been completed with the exception of post-dose PKs and / or ECGs. 18. For consenting patients and after completion of the 28-day post-treatment follow-up visit, long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc. Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 19. Patients enrolled under PA vlO will have a 6MWT during Screening visit. WO 2025 / 235290                                   PCT / US2025 / 027249 Table 5:     PK and PD Sampling Schedule in Phase 2 Expansion Day Timepoint Compound (I) Form A PK1 PD markers1 ECG2 Week 1 (Day 1) Pre-dose X X Triplicate 2 hours post dose ±10 mins X Triplicate 4 hours post dose ±10 mins X 6 hours post dose ± 10 mins X Week 1 (Day 2) Pre-dose (24 hours post the Day 1 dose ± 2 hrs) X X Triplicate Week 2 (Day 8) Pre-dose X X Triplicate 2 hours post dose ± 10 mins X3 Triplicate3 4 hours post dose ± 10 mins X3 6 hours post dose ±10 mins X3 Week 2 (Day 9) Pre-dose (24 hours post the Day 8 dose ± 2 hrs) X3 Week 3 (Day 15) Pre-dose X X Triplicate 2 hours post dose ±10 mins X4 Triplicate4 4 hours post dose ±10 mins X4 Day Timepoint Compound (I) Form A PK1 PD markers1 ECG2 6 hours post dose ±10 mins X4 Week 3 (Day 16) Pre-dose (24 hours post the Day 15 dose ± 2 hrs) X4 Week 4 (Day 22) Pre-dose X X X Week 6 (Day 36) Pre-dose X X X Week 9 (Day 57) Pre-dose X X Triplicate 2 hours post dose ±10 mins X Triplicate Week 13 (Day 85) Pre-dose X X X Week 17 (Day 113) Pre-dose X X X Week 21 (Day 141) Pre-dose X X X Week 25 (Day 169) Pre-dose X X X Week 29 (Day 197) Pre-dose X X X Week 33 (Day 225) Pre-dose X X X Week 37 (Day 253) Pre-dose X X X Week 41 (Day 281) Pre-dose X X X Week 45 (Day 309) Pre-dose X X X Week 49 (Day 337) Pre-dose X X X 1. The 24-hour post-dose sample will be collected prior to the dose on the next visit date, if applicable. 2. Single ECG collected via central ECG machine is required during Screening. For triplicate readings. ECGs are to be collected 10 seconds in duration. 2 minutes (±1 minute) apart, with patient resting in supine position for 5 minutes prior to recording using central ECG machine. These triplicate ECGs should be time 5            matched with the PK sample to allow concentration-QT analysis. In addition, safety ECG (X) should be collected at the indicated timepoints. When ECG timepoints coincide with PK, vital signs, or other PD assessments, ECG collections should always be performed prior to other assessments. 3. RDE-w only 4. RDE-d only Phase 1 In the dose-escalation portion of the study, patients with ccRCC will be assigned to sequential dose cohorts. Using a 3 + 3 design, 3 to 6 patients will be enrolled in each dose cohort to receive Compound (I) Form A at a single dose level. The initial dose level will be 200 mg orally once daily. The dose levels will be increased by 100% until the second clinically significant Grade 2 or greater toxicities or dose-limiting toxicity (DLT) that is at least possibly related to the study drug is reported. Thereafter, the dose levels will be increased by 50% or less. The SRC, composed of sponsor representatives and principal investigators from participating sites, will meet to make all dose escalation decisions. Decisions to dose escalate will be made based on observed DLTs as well as additional supportive data such as overall safety profile, PK, pharmacodynamics, and efficacy. Alternative dosing schedules (for example, once weekly, or combination of different dose levels or dosing frequency instead of once daily dosing) may also be considered if the PK / PD profile supports a change in the dosing frequency. In addition, the SRC may review the severity of a DLT to determine if additional patients should be evaluated at a particular dose level even if the overall DLT rate would permit continued dose escalation. Escalation will proceed until a dose is deemed intolerable or until the Sponsor and SRC determine that a suitable dose has been achieved based on available data (PK, PD, safety, and clinical activity). All patients at each dose level must complete a minimum of 3 weeks of treatment before enrollment of patients at the next dose level. If 0 / 3 patients in a dose cohort experience a DLT during the observation period, escalation to the next higher dose level may occur. If 1 / 3 patients in a cohort experiences a DLT, then up to an additional 3 patients will be enrolled to reach a total of up to 6 patients at that dose level. If no more than 1 / 6 patients develop a DLT, escalation to the next higher dose level may occur. The dose level at which 2 or more of the 3 to 6 patients experience a DLT will be deemed intolerable, and the dose level below will be declared the MTD. At least 6 patients will be treated at the MTD. Intermediate dose levels in dose escalation may be used to further characterize safety and additional dosing levels and schedules may be explored using the same 3 + 3 design. Approximately 61 patients may be enrolled in this part of the study. Patients have been dosed according to the dose-escalation regimens in Table 6 below. Table 6:     Doses Evaluated 200 mg QD 300 mg QD 100 mg QD 50 mg QD 200 mg QD x 7 days then 200 mg QW 200 mg QD x 14 days then 50 mg QD 100 mg QD x 7 days then 100 mg QW 200 mg QD x 28 days then 50 mg QD Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening / baseline and every 8 weeks (± 1 week) from Week 1 Day 1 5 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (± 1 week) as outlined in the Schedule of Assessments in Table 3 and Table 4. When the last scan in the 8-week interval ends at Week 49, the next week starts the 12-week interval. The same technique will be used for imaging at baseline and each follow-up assessment. In the event that DLTs arc not observed and the MTD cannot be identified, efforts will be made, 10 using PK, PD, and anti-tumor activity data, to identify the optimal biologic dose (OBD), i.e., the dose that will most effectively produce the desired effect while remaining in the range of acceptable toxicity. The RDE will be determined based on the MTD, the overall safety profile with continued treatment, and PK data. Patient safety will be monitored with frequent physical examinations, vital sign 15 measurements, electrocardiograms (ECGs), and hematology and chemistry laboratory studies, and by recording all AEs, as in Table 3 and Table 4. In dose escalation cohorts, serial blood samples will be obtained for analysis of the Compound (I) Form A PK and PD (e.g., assessment of EPO and / or other markers of the HIF2a pathway) at the Week 1 (Day 1) and Week 4 Visits, and before study drug administration at 20 additional visits. A formalin-fixed, paraffin-embedded tumor tissue block or 20 unstained slides of tumor sample (archival or recent) for biomarker evaluation will be requested for all patients at study entry. In the FE / DDI sub-study 1, the urinary excretion and metabolite profiling sub-study 2, and the bclzutifan prc-trcatmcnt sub-study 3, additional PK assessments will be conducted, as described below. Phase 2 After determination of the RDEs, approximately 50 patients with ccRCC will be enrolled and treated with Compound (I) Form A at the selected RDEs in an effort to further assess antitumor activity and safety. Additional PK and PD data will also be collected. Two RDEs were selected based on data from Phase 1 Dose Escalation. See Fig. 6. The lower RDE starts with 100 mg QD for 7 days followed by weekly maintenance dose of 100 mg (RDE-w). The higher RDE starts with 200 mg QD for 14 days followed by daily maintenance dose of 50 mg (RDE-d). Forty patients with no prior treatment with a HIF2a inhibitor will be randomized in a 1:1 fashion to RDE-w and RDE-d, 20 in each arm, to determine the RP2D for Compound (I) Form A. In addition, approximately 10 evaluable patients who have had prior treatment with the HIF2a inhibitor belzutifan will be enrolled at the RDE-d as described below. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin-fixed, paraffin-embedded blocks. In addition, for the belzutifan pre-treated cohort, biopsy tissue samples are required during screening and at Week 9 from the same lesion as the pre-treatment biopsy (preferred) or at least from the same organ. For the other Phase 2 Expansion cohorts, biopsy tissue samples during screening and at Week 9 are optional. Number of Patients Phase 1: Approximately 61 patients diagnosed with advanced ccRCC may be enrolled in the dose-escalation portion of the study to identify the MTD and / or the RDEs (including 12 patients in the FE / DDI substudy 1 and 5 patients in the urine excretion / metabolite substudy 2). Phase 2: Approximately 50 patients diagnosed with advanced ccRCC may be enrolled in the expansion cohort, including 20 patients at RDE-w and RDE-d, each without prior treatment with HIF2a inhibitor belzutifan and 10 patients who have had prior treatment with the HIF2a inhibitor belzutifan, as described below for sub-study 3. Treatment Assignment Following confirmation of eligibility, patients will be sequentially assigned to the next open dose cohort. The initial dose cohort will begin treatment at a dosage of 200 mg orally, once daily. Additional dosing levels and schedules may be explored based on available patient data. For expansion phase, two RDEs were selected based on data from Phase 1 Dose Escalation. Upon randomization, RDE-w starts with 100 mg QD for 7 days followed by weekly maintenance dose of 100 mg, and RDE-d starts with 200 mg QD for 14 days followed by daily maintenance dose of 50 mg. See sub-study 3 below for the sub-study in patients with prior belzutifan treatment for their treatment assignment. Dose Escalation Using a 3 + 3 design, 3 patients will be enrolled in each dose cohort. Dose escalation will be in 100% increments until the second Grade 2 or greater toxicity that is at least possibly related to the study drug is reported. Thereafter, sequential dose levels will increase by increments of up to 50% as determined by an SRC taking into consideration the available capsule strengths. Should 0 / 3 patients in a dose cohort develop a DLT, enrollment of patients in the next higher dose cohort will proceed. If 1 / 3 patients in a cohort develop a DLT, up to an additional 3 patients will be enrolled to reach a total of up to 6 patients in that dose cohort. If no more than 1 / 6 patients develop a DLT, escalation to the next higher dose level may occur. Should 2 or more patients in any dose cohort experience DLT, that dose level will be declared intolerable, and the next lower dose level will be declared the MTD. At least 6 patients must be treated at the MTD. Intermediate dose levels may be used to allow for a further exploration of safety. At any dose levels already confirmed to be safe and well tolerated, additional patients can be backfilled at the discretion of the SRC to collect additional PK, pharmacodynamic, and antitumor activity data. The SRC will continue to monitor the cumulative safety data from the cohorts previously declared safe and the current dose cohort under evaluation. Enrollment of patients to the current dose cohort under evaluation will take precedent. The process for dose escalation is described below. Intra-patient dose escalation will be permitted during the dose-escalation portion of this study as described below. Definition of Dose-limiting Toxicity Dose-limiting toxicities will be defined as the occurrence of any of the following events in the first 21 days of treatment for which there is no clear alternative explanation (e.g., disease related). Hematologic • Any Grade 5 toxicity • Febrile neutropenia (absolute neutrophil count [ANC] < I .OOO / pL with a single temperature > 38.3°C (101°F) or a sustained temperature of > 38°C (100.4°F) for more than one hour.) • Grade 4 neutropenia lasting for > 5 days (in the absence of growth factor support) • Grade 3 thrombocytopenia with > Grade 1 bleeding • Grade 4 thrombocytopenia • Grade 4 anemia unexplained by underlying disease, or bleed N on-hematologic • Any Grade 5 toxicity Gastrointestinal • Grade 3 nausea, vomiting, or diarrhea that persists for > 72 hours in the absence of optimal medical intervention; or persisting > 48 hours with optimal medical intervention. Any Grade 4 should be a DLT Hepatic • Grade 4 elevation of serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) • Grade 3 elevation of serum ALT or AST for > 7 days regardless of serum bilirubin level • Grade > 3 elevation of serum ALT or AST in conjunction with a Grade > 2 elevation in serum bilirubin • Laboratory criteria meeting Hy’s Law (ALT / AST > 3 x upper limit of normal (ULN) in conjunction with total bilirubin > 2 x ULN (without evidence of cholestasis) Pulmonary • Any Grade > 3 hypoxia Other • Grade 3 or 4 non-hematologic AEs except: o Electrolyte abnormalities that last < 72 hours, are not clinically complicated, and resolve spontaneously or respond to conventional medical interventions. • Exclusion of other transient non-clinically significant Grade 3 non-hematological toxicities may be determined after discussion with the investigator and the Medical Monitor • Any Compound (I) Form A-related toxicity, for which no other cause can be determined, resulting in patients not being able to receive 80% of the intended study drug during the first 21 days of treatment • In addition, clinically significant or persistent toxicities that are not included in the above criteria may be considered a DLT following a review by NiKang and investigators Patients who do not receive at least 80% of the intended cumulative Compound (I) Form A doses during the first 21 days of treatment for reasons other than toxicity will not be evaluable for DLTs. Patients enrolled in either the food effect / DDI or urine excretion / metabolic profiling substudies will not be evaluated for DLTs. The assigned dose levels / regimens have been cleared by the SRC, and safety assessments will continue. Dose Modification To permit full assessment of the dose being evaluated, no dose modifications will be allowed during the 21-day DLT observation period (except after resolution of a DLT as described below). Patients who experience a DLT may be allowed to continue in the study with a dose modification after consultation with the sponsor’s medical monitor and after resolution of the toxicity to less than Grade 2 or to the baseline level. After the initial 21 days (or in the event of a resolved DLT in the 21-day period), if the patient experiences toxicity that requires dose modification, the guidelines in the Table 7 below will be used to determine the dose modification required. If the investigator believes that the guidelines should not apply, he / she will contact the sponsor’s medical monitor to discuss the circumstances and the appropriate dose modification. Dose reduction of Compound (I) Form A by one and, if needed, 2 dose levels (if available) and / or by changing to a lower dosing frequency will be allowed depending on the type and severity of toxicity encountered. Dose level modifications for patients randomized to receive RDE-d and RDE-w are listed in Table 8. The site should contact the sponsor’s medical monitor to discuss the circumstances and the appropriate dose modification. Individual patients who initiated treatment at a dose level below the highest tolerable dose evaluated, and who have not experienced a greater than Grade 2 toxicity during the previous treatment cycle at the Week 17 visit, may have the Compound (I) Form A dose escalated if both the Principal Investigator and the Medical Monitor agree that a dose escalation 5 is medically warranted after considering the potential safety profile of the investigational drug, including cumulative drug toxicity (e.g., for a patient with SD who is tolerating the current dose level of therapy). The maximal intra-patients dose escalation level should be one level below or at the current actively enrolling level. In such patients, successive adjustments to progressively higher dose levels can be made at intervals of > 3 weeks with the condition that the above 10 referenced criteria are satisfied. Table 7: Dose Modifications Toxicity Occurrence Action No mandatory dose reductions of Compound (I) Form A if successfully managed. Hematologic - Anemia Gr 3 or 4 (An erythropoiesis-stimulating agent (ESA) may be Requiring active intervention Any considered for hemoglobin (HgB) <10 g / dL.) Hematologic - Non-Anemia 1st Hold study drug. Once toxicity has resolved to Gr < 2 or Grade (Gr) 3 or 4 ANC + fever, or baseline, restart Compound (I) Form A at the next lower dose ANC < 500 / pL for > 7 days, or level. Platelets < 25,000 / pL or 2nd Hold study drug. Once toxicity has resolved to Gr < 2 or Platelets < 50,000 / pL with active bleeding baseline, restart Compound (I) Form A 1 dose level below the most recent dose level. ^rd Discontinue Compound (I) Form A. Gastrointestinal / Hepatic 1st Hold study drug. Once toxicity has resolved to Gr < 2 or Gr 3 or 4 nausea, vomiting, or diarrhea if persistent baseline, restart Compound (I) Form A at the next lower dose for > 72 hours despite optimal antiemetic or level. antidiarrheal therapy 2nd Hold study drug. Once toxicity has resolved to Gr < 2 or Gr 3 or greater increase in ALT / AST if persists for baseline, restart Compound (I) Form A at 1 dose level below >72 hours the most recent dose level. 3rd Discontinue Compound (I) Form A. Pulmonary Gr 4 hypoxia Any Run a test of BNP and NT-proBNP. WO 2025 / 235290                                   PCT / US2025 / 027249 A grade 4 event results in discontinuation of treatment. Pulmonary Gr 3 hypoxia 1st Hold study drug and initiate oxygen supply per individual hospital protocol. Once toxicity has resolved to Gr <2 or baseline, Compound (I) Form A may be restarted. Dose reduction by one dose level may be considered after discussion with Sponsor medical monitor. Require TTE and consider pulmonary imaging and full pulmonary function tests including evaluation of V / Q mismatch if feasible; Run a test of BNP and NT-proBNP; optional PK assessment. 2nd Hold study drug and initiate oxygen supply per individual hospital protocol. Once toxicity has resolved to Gr <2 or baseline, Compound (I) Form A may be re-started at 1 dose level below the most recent dose level after discussing with the sponsor medical monitor. Require TTE and consider pulmonary imaging and full pulmonary function tests including evaluation of V / Q mismatch if feasible; Run a test of BNP and NT-proBNP; optional PK assessment. ^rd Run a test of BNP and NT-proBNP; WO 2025 / 235290                                   PCT / US2025 / 027249 Discontinue Compound (I) Form A. Pulmonary Any Dose hold if warranted, in discussion with Sponsor Medical Gr 2 hypoxia Monitor Hepatic 1st Discontinue Compound (I) Form A Grade 3 or 4 increase in transaminase levels if accompanied by a Grade 2 increase in bilirubin level and an alkaline phosphatase level < 2x ULN Other 1st Hold study drug. Once toxicity has resolved to Gr < 2 or Any > Gr 2 neurological toxicity discussed with the baseline, restart Compound (I) Form A at the next lower dose medical monitor level. Any other Gr 3 or 4 toxicity 2nd Hold study drug. Once toxicity has resolved to Gr < 2 or Any Gr 3 or 4 laboratory toxicity considered baseline, restart Compound (I) Form A at 2 dose levels below clinically significant by the investigator the initial dose level. 3rd Discontinue Compound (I) Form A. Abbreviations: Gr = grade; ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal WO 2025 / 235290                                   PCT / US2025 / 027249 Table 8:     Phase 2 Dose Level Modifications RDE-d: 200 mg QD for 14 days then 50 mg QD If a patient experiences a toxicity as defined in Table 7, the first dose reduction will be to 30 mg / day QD If a patient continues to experience a toxicity as defined in Table 7, the second dose reduction will be to 20 mg / day QD RDE-w: 100 mg QD for 7 days then 100 mg QW If a patient experiences a toxicity as defined in Table 7, the first dose reduction will be to 50 mg QW If a patient continues to experience a toxicity as defined in Table 7, the second dose reduction will be to 30 mg QW In the event that a toxicity that results in holding treatment for a period of more than 14 days has not resolved to a level which would allow continuation of therapy, there should be a 5 discussion with the Medical Monitor about whether to continue observation until recovery or whether therapy should be discontinued. Replacement of Patients Patients who discontinue study drug administration before the completion of 21 days of treatment or who do not receive at least 80% of the intended doses for the first 21 days for 10 reasons other than toxicity may be replaced in dose escalation. Dose escalation will not take place until the appropriate number of patients has completed treatment for 21 days at the designated dose level. Selection and Withdrawal of Patients Note: Selection criteria for the main study are also applicable to the sub-study. Additional 15 inclusion and exclusion criteria for the sub-studies are detailed below. Inclusion Criteria Patients must meet all of the following criteria to be enrolled in this study. 1. Has the ability to understand and willingness to sign a written informed consent form before the performance of any study procedures 2. Has locally advanced or metastatic ccRCC and has progressed during treatment, are relapsed, refractory and not amenable to curative therapy or standard therapy and has progressed during treatment with at least 1 prior therapeutic regimen 3. Must have measurable disease per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) 4. Is of age > 18 years 5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 6. Has a life expectancy of > 3 months 7. Has adequate organ function defined as follows: a. Bone marrow: ANC > LOx 109 / L; Hgb level > 10 g / dL without transfusion or erythropoietin support within 2 weeks prior to first dose; platelet count > 75,000 / pL b. Hepatic: transaminase levels (AST / ALT) < 2.5 x ULN (< 5 x ULN if liver metastases is present); total bilirubin (TBILI) < 1.5 x ULN in the absence of Gilbert’s disease c. Renal: serum creatinine level < 2.0 x ULN or calculated creatinine clearance (CrCL) > 40 mL / min (Cockcroft-Gault formula) 8. If a female patient of child-bearing potential, has a negative serum pregnancy test result within 7 days before first study drug administration 9. If a female patient, must be surgically sterile, must be post-menopausal, or must agree to use physician-approved method of birth control during screening, during the study, and for a minimum of 6 months after the last study drug administration; or if a male patient with a female partner, must agree to use physician-approved method of birth control during screening, during the study, and for a minimum of 6 months after the last study drug administration 10. Female patients of childbearing potential must meet all of the following criteria: a. Not pregnant (negative serum pregnancy test during Screening) b. Not breastfeeding c. Willing to use a protocol-recommended method of contraception or to abstain from heterosexual intercourse from the start of treatment or until at least 6 months after the last dose of treatment. Note: A female patient is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and folliclestimulating hormone levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin); or is menopausal (amenorrhea for > 12 months). 11. Male patients who can father a child must meet all of the following criteria: a. Willing to use a protocol-recommended method of contraception or to abstain from heterosexual intercourse with females of childbearing potential from the start of treatment until at least 6 months after the last dose of treatment, and b. Willing to refrain from sperm donation from the start of treatment until at least 6 months after the last dose of treatment. Note: A male patient is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. 12. Able to swallow oral medications. 13. Ambulatory subjects need to take a 6-minute walk test (6MWT). Walking distance needs to be at least 400 meters and the change of oxygen saturation needs to be within a 5% range. Exclusion Criteria Patients will be excluded from this study if they meet any of the following criteria. 1. Known symptomatic brain metastases requiring > 10 mg / day of prednisone (or its equivalent). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to the start of Compound (I) Form A treatment, fulfill the above steroid requirement for these metastases, and are neurologically stable based on central nervous system imaging >4 weeks after central nervous system (CNS)-directed treatment 2. Having one or more of the following conditions: a. A pulse oximetry reading less than 95% at screening; b. Any current requirement for intermittent or chronic supplemental oxygen; c. Any chronic lung condition which has required supplemental oxygen in the past d. Evidence of impending airway compromise (such as endobronchial tumor, lymphangitic spread, significant extrinsic compression of major airway) per investigator; e. Ascites requiring drainage within 28 days prior to W1D1 3. History of another malignancy except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage 1 or stage 2 cancers currently in complete remission, or any other cancer that has been in complete remission for > 2 years 4. Has failed to recover from the effects of prior anticancer therapy to baseline level or Grade 1 severity (except for alopecia) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE); patients with treatable adverse effects such as hypothyroidism or hypertension may be enrolled if the adverse effect is controlled with treatment 5. Significant cardiovascular disease, including myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism, within 6 months prior to start of Compound (I) Form A treatment; symptomatic dysrhythmias or unstable dysrhythmias requiring medical therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association (NYHA) Class 3 or 4 congestive heart failure (Table 9); > Grade 3 hypertension (diastolic blood pressure >100 mmHg or systolic blood pressure >160 mmHg) despite adequate use of antihypertensives; or history of congenital prolonged QT syndrome or repeated demonstration of a QTc interval > 480 ms; ejection fraction < 40%; clinically significant pericardial or pleural effusion in the opinion of the investigator. 6. Has received prior investigational therapy or standard therapy within 5 half-lives of the agent or 4 weeks before the first administration of study drug, whichever is shorter 7. Has a bleeding diathesis or coagulopathy 8. Deep vein thrombosis (DVT) / pulmonary embolism are allowed as long as patient is not symptomatic and received 2 weeks or more of adequate anticoagulation 9. Has manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease 10. Has any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with participation in the trial or interfere with the interpretation of trial results 11. Has had major surgery or radiation therapy within 4 weeks before first study drug administration; the following procedures are not considered to be major surgeries: thoracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic or ultrasonographic procedures, mediastinoscopy, skin biopsy, incisional biopsy, image-guided biopsy for diagnostic purposes, and routine dental procedures 12. Has known human immunodeficiency virus (HIV) 13. Has an active infection requiring systemic treatment 14. Is actively participating in another therapeutic clinical trial 15. Has received prior treatment with a HIF2a inhibitor (unless participating in the substudy 3 that requires previous belzutifan treatment) Withdrawal Criteria Patients have the right to withdraw from the study and study treatment at any time for any reason. The investigator may discontinue a patient from the study and / or study treatment for any of the following reasons. • Disease progression • Occurrence of an adverse event (AE), development of an intercurrent illness / condition, or change in patient’s condition that leads the investigator to be concerned about the patient’s welfare • Dose-limiting or intolerable toxicity • Non-compliance with study procedures • Failure to comply with study drug administration instructions, to return for follow-up, or to meet other requirements of the study • Pregnancy in a female patient during the study • Death • Withdrawal of consent The primary reason for permanent treatment discontinuation will be recorded in the case report form (CRF). Patients who discontinue from study treatment must complete the safety follow-up visit 28 ± 7 days after the last dose of Compound (I) Form A is taken unless subsequent therapy is initiated earlier, in which case, this visit should occur before the start of subsequent therapy, and long-term follow-up assessments according to the Schedule of Assessments in Table 3 and Table 4. During the safety follow-up visit, the patient should be evaluated for continuation or resolution of any adverse or serious adverse events (AEs / SAEs). The only exception to this is when a patient specifically withdraws consent for any further contact with him or her or persons previously authorized by the patient to provide this information. Patients should notify the Investigator in writing of the decision to withdraw consent from future follow up, whenever possible. The withdrawal of consent should be explained in detail in the medical records by the Investigator, as to whether the withdrawal is only from further receipt of the investigational product or also from study procedures and / or post-treatment study follow-up and entered on the appropriate CRF page. If vital status (whether the patient is alive or dead) is being measured, publicly available information should be used to determine vital status only as appropriately directed in accordance with local law. Consenting patients who discontinue study treatment for any reason will undergo long term follow-up assessments every 6 months for up to 3 years following enrollment of the last patient into the study. Table 9:     New York Heart Association Functional Classification Class Functional Capacity: How a patient with cardiac disease feels during physical activity I Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. II Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain. III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain. IV Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort increases. Sub-study 1: Pharmacokinetic Drug-Drug Interaction and Food Effect Sub-study Sub-Study Objectives Primary sub-study objectives: • To have a preliminary assessment of the effect of Compound (I) Form A treatment on the PK of a single oral dose of midazolam • To have a preliminary assessment of the effect of a high-fat meal on the PK of oral Compound (I) Form A Secondary sub-study objective: • To assess incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Exploratory sub-study objectives: • To explore biomarkers potentially predictive of response to Compound (I) Form A DPI and FE Sub-Study Design In this pilot drug-drug interaction (DDI) and food effect (FE) sub-study, up to 12 eligible patients with advanced clear cell renal cell carcinoma will be enrolled to enable 10 evaluable patients. To assess the effect of Compound (I) Form A treatment on the PK of a single oral dose of midazolam, each patient will receive a single oral dose of 5 mg midazolam on Day -3. Patients will then receive 200 mg Compound (I) Form A QD from Week 1 Day 1 to Day 7, followed by 200 mg Compound (I) Form A QW starting on Day 8 (Week 2). A second oral dose of 5 mg midazolam will be administered on Day 15 (Week 3) with the Compound (I) Form A dose on the same day. Plasma midazolam and 1’-hydroxymidazolam PK will be determined up to 72 hours after both midazolam doses, and the DDI will be assessed within each patient. The effect of a high-fat meal on Compound (I) Form A PK will be evaluated in the same patients as for the DDI assessment. On Week 1 Day 1, patients will receive a single dose of 200 mg Compound (I) Form A under fasted conditions or with a high-fat meal. Patients will be enrolled into Group 1 (fasted) or Group 2 (high-fat meal) in an alternating manner. The FE on Compound (I) Form A PK will be compared between the two groups based on the 24-hour PK profile of Compound (I) Form A. After the first dose of Compound (I) Form A, all subsequent Compound (I) Form A doses will be administered on an empty stomach as defined in the main protocol, i.e., Compound (I) Form A should be taken at least 2 hours after the last meal and at least 1 hour before the next meal. See Fig. 7. A Schedule of Assessments for the DDI and FE Sub-Study is shown in Table 10. Inclusion Criteria In addition to the inclusion criteria above, the following inclusion criteria are applicable to this sub-study 1. Willing to and able to take a high-fat meal within 30 min prior to the Compound (I) Form A dosing on Week 1 Day 1. 2. Adequate hepatic and renal function a. Hepatic: normal hepatic function (total bilirubin < upper limit of normal (ULN) and aspartate aminotransferase (AST) < ULN) or mild hepatic impairment (total bilirubin < ULN and AST > ULN, or total bilirubin > 1.0 x to 1.5 x ULN) b. Renal: measured or calculated creatinine clearance (CrCL) > 60 mL / min (Cockcroft-Gault formula) Exclusion Criteria In addition to the exclusion criteria above, the following exclusion criteria are required in this sub-study: 1. Any gastrointestinal (GI) malfunction, surgeries, or conditions that could affect absorption of oral Compound (I) Form A and / or midazolam as assessed by the investigator 2. Use of any drugs, investigational agents, fruits, or herbs that are strong or moderate CYP3A inhibitors or inducers within 14 days prior to Day -3 (or 5 times the half-life of the drug, whichever is longer). Example strong and moderate clinical CYP3A inhibitors can be found at https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3 and also at https: / / www.fda.gov / drugs / drug-interactions-labeling / healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems. Study Design Rationale Compound (I) Form A dosage selection The Compound (I) Form A dosage for this sub-study is loading doses of 200 mg QD x 7 days followed by maintenance doses of 200 mg QW. The weekly maintenance doses are expected to maintain relatively steady exposure levels (steady state) following the loading doses. This dosage was evaluated by the Safety Review Committee (SRC) and was deemed safe and well tolerated with no dose limiting toxicity. In addition, this dose allowed for significant and sustained EPO suppression indicative of HIF2a inhibition. This dosage is to be further evaluated in future trials if supported by cumulative data. Drug-Drug Interaction Design In the DDI portion of this sub-study, the second dose of oral midazolam will be on Day 15. This will be after 7-day Compound (I) Form A loading doses and 1 maintenance dose on Day 8 and will be co-administered with a second Compound (I) Form A maintenance dose on Day 15. Given the CYP3A4 degradation ti / 2 of approximately 1 day in the gut and approximately 3 days in the liver, and an estimated overall ti / 2 of 36 hours, the design of the midazolam dosing is considered adequate to reveal clinically meaningful CYP3A4 induction and effect on the oral midazolam PK (see Yang, et al. Curr Drug Metab 9: 384-394, 2008; Rowland Yeo, et al. Eur J PharmSci43: 160-173,2011). Food reduces absorption of midazolam due to the delayed absorption and increased first-pass effect (see Bomemann, et al. 26: 55-59, 1986). As a result, midazolam dosing should be after overnight fasting and at least 1 hour before a meal. Food Effect Design Given the slow elimination of Compound (I) and ethical considerations, within-patient FE assessment with a crossover design is not feasible. Thus, the FE will be assessed with two parallel groups (up to 6 patients per group). In addition, it is infeasible to collect complete PK profiles as that would require a long washout period with dosing interruption. This preliminary FE assessment will be based on a partial PK profile on Day 1 up to 24 hours, and estimated Cmax, Tmax, and AUCo-24. This is considered adequate as the absorption phase is < 24 hours in duration based on available PK data with cohort median Tmax< 4.55 hours. Dosage and Administration of Study Drugs Compound (I) Form A On Week 1 Day 1, Compound (I) Form A will be given to patients at 200 mg QD x 7 days. On Week 2 (Day 8), patients will start 200 mg Compound (I) Form A QW. The dose on Week 1 Day 1 will be given either under fasted conditions (Group 1) or with a high-fat meal (Group 2). Patients will be enrolled to either of the 2 groups in an alternating manner. The fasted conditions and the high-fat meal are defined as below (see Center for Drug Evaluation and Research (2022). "Assessing the Effects of Food on Drugs in INDs and NDAs— Clinical Pharmacology Considerations." Food and Drug Administration). Fasted Condition Following an overnight fast of at least 8 hours, patients will receive oral dosing of study drug(s) with 8 oz (240 mL) of room temperature water. No food will be allowed for at least 4 hours post-dose and no water will be allowed for at least 2 hours post-dose. Fed Condition with a high-fat meal Following an overnight fast of at least 8 hours, patients will consume a high-fat (approximately 50% of total caloric content), high-calorie (approximately 800-1000 calories total) breakfast meal containing approximately 500 to 600 calories from fat, approximately 250 calories from carbohydrates, and approximately 150 calories from protein, in the clinic. Patients must begin eating the meal 30 (±5) min prior to the planned administration of Compound (I) Form A on Week 1 Day 1. Patients should eat this meal in 30 min or less; however, oral Compound (I) Form A should be administered 30 min after the start of the meal, regardless of whether the meal was completed or not. Patients will ingest oral Compound (I) Form A with 8 oz (240 mL) of room temperature water. No food will be allowed for at least 4 hours post-dose. No water will be allowed for at least 2 hours post-dose. The breakfast meal will be provided by the clinical site. A list of appropriate breakfast meals will be provided to clinical sites and patients by the sponsor. An example test meal would be two eggs fried in butter, two strips of bacon (or ham or cheese of similar caloric content), two slices of toast with butter, 4 oz of hash brown potatoes, and 8 oz (240 mL) of whole-fat milk. A different breakfast meal to suit specific dietary requirements may be substituted by the clinical site, provided that it has a similar amount of calories and protein, and carbohydrate and fat content. The nutrient content of the proposed meal must be calculated and submitted to the sponsor (or designee) for review and approval at least 3 days in advance of the patient’s scheduled fed day. On Day 15 (Week 3), Compound (I) Form A will be administered, followed immediately by the second dose of midazolam, to patients in the morning after an overnight fast of at least 8 hours and should be taken with at least 240 mL of room temperature water. The fasting will continue for at least 2 hours before a patient can ingest a standard meal. The water will be restricted for 1 hour before and after the study drug intake. The rest of the doses of Compound (I) Form A will be administered on an empty stomach. Administration of midazolam Midazolam (5 mg) for oral administration will be procured by each participating site and dispensed using the manufacturer specified dispensing instructions. Qualified personnel will prepare and dispense the midazolam dose in accordance with the current package insert. Two midazolam doses will be administered: the first on Study Day-3 alone, and the other on Day 15 (Week 3) with a co-administration of Compound (I) Form A. Midazolam will be administered to patients in the morning after an overnight fast of at least 8 hours and should be taken with at least 240 mL of room temperature water. The fasting will continue for at least 2 hours before a patient can ingest a standard meal. The water will be restricted for 1 hour before and after the study drug intake. The USPI for midazolam will be used as the reference safety information for safety reporting (see Midazolam hydrochloride syrup Prescribing Information. Padagis US, LLC). Concomitant Medication In addition to the restrictions described above, the following restrictions are required in this sub-study: Use of the following medications are not allowed from Day -3 to Day 18 a. Strong or moderate CYP2C19 or CYP3A4 inhibitors b. Strong or moderate CYP2C19 or CYP3A4 inducers c. grapefruit, grapefruit juice, pomelo, or Seville oranges (CYP3A4 inhibitors) or St. John’s wort (CYP3A4 inducer) Other herbal and complementary therapies should not be encouraged because of unknown side effects and potential drug interactions, but any taken by the patient should be documented appropriately on the eCRF. Example strong and moderate clinical CYP3A inhibitors can be found at https: / / www.fda.gov / drugs / dmg-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3. Pharmacokinetic Assessment for Compound (I) Form A Blood samples for the determination of plasma Compound (I) concentrations will be collected at multiple time points as shown in Table 11. The date and time of collection of all PK blood samples should be recorded. A validated LC-MS / MS method will be used to assay the samples for plasma concentrations of Compound (I). Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. PK parameters will be calculated based on the serial PK data following the first dose on Day 1, including but not limited to Cmax, Tmax, Ctrough, and AUC0-24, if data allow. Pharmacokinetic Assessment for Midazolam and I’-hydroxymidazolam Blood samples for the determination of plasma concentrations of midazolam and its metabolite 1’-hydroxymidazolam will be collected at multiple time points as shown Table 11. The date and time of collection of all PK blood samples should be recorded. A validated LC-MS / MS method will be used to assay the samples for plasma concentrations of midazolam and 1’-hydroxymidazolam. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. PK parameters will be calculated based on the serial PK data of midazolam and 1 hydroxymidazolam following the first dose on Day -3 and Day 15, including but not limited to Cmax, Tmax, Clast, AUCo-last, if data allow. PD Marker Assessment Blood samples for the determination of serum concentrations of pharmacodynamic (PD) biomarkers (e.g., EPO) will be collected at multiple time points as shown in Table 11. The date and time of collection of all PD blood samples should be recorded. A validated enzyme-linked immunosorbent assay (ELISA) will be used to determine the serum level of EPO. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Safety Assessments Ongoing assessment of safety for all patients in this sub-study will be determined by monitoring of symptoms, signs, and abnormal laboratory test results. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Other safety assessments will include vital signs, physical examination, ECG, and ECOG. Sample Size Up to 12 eligible patients will be enrolled to enable 10 evaluable patients. The sample size is empirically selected to allow preliminary assessments of the DDI and the FE. Drug-Drug Interaction and Food Effect Analysis Descriptive summary statistics of PK and PD concentration data will be provided and Mean (SD) PK and PD plots will be generated. Serial plasma PK data of Compound (I), midazolam, and 1’-hydroxymidazolam will be analyzed using non-compartmental methods using Phoenix® WinNonlin® software, and the results will be further analyzed to determine the FE on Compound (I) Form A and the effect of Compound (I) Form A on oral midazolam PK as the following: Food Effect Analysis C max and AUCo.24 of NK2152 will be log-transformed before statistical analysis. The 90% CI for the ratio of the population geometric means between the fed and fasted conditions will be provided. Drug-Drug Interaction Analysis Cmax and AUCs of midazolam and 1 ’-hydroxymidazolam as well as the 1 hydroxymidazolam-to-midazolam AUC ratio will be log-transformed before statistical analysis. The 90 percent CI for the ratio of the population geometric means with and without Compound (I) Form A treatment will be provided. Safety Analysis Safety analyses will be based on all patients who received at least one dose of study drug. Study drug is defined as either Compound (I) Form A or midazolam. In general, data will be summarized using descriptive statistics. Continuous data will be summarized with number of patients (n), arithmetic mean, standard deviation, median, minimum, and maximum. Categorical data will be summarized using frequency counts and percentages. A TEAE is defined as an AE with onset on or after the first dose of study drug (or that worsened from prior to the first dose of study drug). Any AE occurring after the 28-day followup period after discontinuation of study drug will be included in listings but will not be included in the summary tables of AEs. The number and percentage of patients experiencing 1 or more AEs will be summarized for the following classifications: • TEAEs by SOC and PT • TEAEs by SOC, PT and maximum toxicity grade • Compound (I) Form A-related or midazolam-related TEAEs by SOC and P • Compound (I) Form A-rclatcd or midazolam-related TEAEs by SOC, PT and maximum toxicity grade • TEAEs leading to treatment discontinuation by SOC and PT • TEAEs resulting in dose modifications by SOC and PT • CTCAE Grade > 3 TEAEs by SOC and PT • Fatal TEAEs by SOC and PT • SAEs by SOC and PT • Compound (I) Form A-related or midazolam-related SAEs by SOC and PT Additional safety analysis will be described in the statistical analysis plan. Efficacy Analysis Tumor response will be evaluated by the investigator using RECTST 1.1. Efficacy analyses as described bclowwill be summarized for the patients in the sub-study. Further details will be included in the statistical analysis plan. Table 10:    Schedule of Assesments for DDIPK and FE Sub-study Assessment Pre Treatment Period Treatment Period Post-Treatment Period Screening (Day -281 to Day -4) Week I1 (Day 1) Weeks 2, 3, 4, 5, 61 (±ld) Weeks 9, 13, 17, and every 4 weeks1 (± 2 d)through Week 49 Extended treatment every 12 weeks (± 1 week) Safety Follow-up 28 days after last dose of study drug (±7d) Long Term Follow-up (every 6 months) Midazolam administration Day -3 Week 3 (Day 15) Pre-dose high fat meal3 X Assessment Reminder Day -34 Week 1 (Day I)4 Week 3 (Day 15)4 Informed Consent (Main study) X Informed Consent (PK sub-study) X Medical History X Physical Examination5 X X X X X X Vital Signs6 X X X X X X WO 2025 / 235290                                   PCT / US2025 / 027249 <0 00 Six-minute walk21 X Weight X X X X X X Height X ECOG X X X X X X Dispense / Collect Study Drug X X X X Hematology7 X X X X X X Serum Chemistry8 X X X X X X PT / aPTT / INR X Iron Panel9 X X X X Urinalysis10 X X X X X X Pregnancy Test11 X X X X X X ECG12 X X X X Tumor Assessment13 X X X DNA Sequencing14 X Circulating Tumor DNA15 X X PK and PD Sample16 X Archival Tissue Samples17 X Image Transfer18 X X X Echocardiogram / MUGA1 9 X X WO 2025 / 235290                                   PCT / US2025 / 027249 ID <0 Study Drug Administration ____ ___ ___v   ____ ____ Adverse Events Day -3 X X X X X Concomitant Medications X X X X X Patient Status20 X 1. Assessments to be done at Screening and on Day 1 of each visit week. For the Week 2-6 Visits, all patients will return to clinic on Weeks 2, 3, 4, and 6. Patients assigned to the OW dosing schedule will have an additional clinic visit on Week 5 to obtain a single pre-dose PK sample. These assessments can be performed + 1 day. For the Week 9, 13. 17 and visits every 4 weeks thereafter through Week 49, assessments can be performed + 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test). Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit but must be done prior to the high-fat meal on WIDE In exceptional circumstances. Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. For FE / DDI sub-study. D-3 midazolam dosing should occur on Monday to ensure collection of required PK samples. PK / PD sample collection windows are included in fable 11. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Half of the FE substudy patients will eat a high-fat meal, and the rest will be dosed under fasted conditions. Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, VS, ECG, and ECOG must be done prior to high-fat meal on Week 1 Day 1. The high fat meal should be consumed within 30 minutes and prior to administration of the Compound (I) Form A dose. 4. Reminder for site staff to call the patient the day before the visit to remind of overnight fasting. 5. Physical examination to be performed before study drug administration at the Week 1, 4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through week 49. 6. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature and obtained at Day -3 and prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 7. Hematology assessments include CBC, differential, platelet count, and reticulocyte count. WO 2025 / 235290                                   PCT / US2025 / 027249 100 8. Routine serum chemistry assessments include glucose. LDH. AST, ALT, ALP. total bilirubin, albumin, electrolytes (Na. K, Cl, COj). Ca. Mg. PO4, BUN, creatinine, total protein levels, and an iron panel. BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs. 9. Iron panel assessments including Fe, ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening. Week 1, Week 4, Week 9 and every 4 weeks for the first year. 10. Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2. 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 11. Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4. 6, 9, 13. and 17 visits and visits every 4 weeks until treatment discontinuation. For female patients of child-bearing potential who discontinue treatment, home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A. 12. An ECG will be obtained before and at 1.5 hours after study drug administration at the Week 1 and Week 4 Visits. ECGs will be obtained prior to study drug administration only at Weeks 2, 3, 6, 9, and every 4 weeks, thereafter, through Week 49 (e.g., Week 13, Week, 17, Week 21, etc.). 13. Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening / baseline (within 35 days) and every 8 weeks (± 1 week) from Week 1 Day 1 for the first year. After the 1st year, anti-tumor assessments will be conducted every 12 weeks (± 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. 14. At the Week 1 visit, 2 mL of whole blood as 2 x 1 mL Paxgene blood DNA tubes should be collected for genetic sequencing of drug-metabolizing enzymes. 15. At the Week 1 and Week 9 visits, 20 mL of whole blood as 2 x 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA. 16. See Table 11 for details. 17. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin-fixed, paraffin-embedded blocks. 18. Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual. 19. An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). WO 2025 / 235290                                   PCT / US2025 / 027249 20. For consenting patients and after completion of the 28-Day post-treatment follow-up visit, long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc. Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 21. Patients enrolled under PA vlO will have a 6MWT during Screening visit. WO 2025 / 235290                                   PCT / US2025 / 027249 Table 11:    Pharmacokinetic and Pharmacodynamic Sampling Schedule for the Sub Study Day Midazolam PK Compound (I) Form A PK PD markers Day -3 Pre-dose 15 min post dose ± 5 mins 30 min post dose ± 5 mins 1 hour post dose ± 10 mins 2 hours post dose ± 10 mins 4 hours post dose ± 10 mins 6 hours post dose ± 10 mins Day -2 24 hours post dose ± 2 hrs Day -1 48 hours post dose ± 2 hrs Week 1 (Day 1) 72 hours post dose ± 2 hrs Pre-dose Pre-dose 30 min post dose ± 5 mins 1 hour post dose ± 10 mins 2 hours post dose ± 10 mins 4 hours post dose ± 10 mins 6 hours post dose ± 10 mins Week 1 (Day 2) Predose (24 hours post Day 1 dose ± 2 hrs) Pre-dose Week 2 (Day 8) Pre-dose Pre-dose Week 3 (Day 15) Pre-dose Pre-dose Pre-dose 15 min post dose ± 5 mins 30 min post dose ± 5 mins 1 hour post dose ± 5 mins 2 hours post dose ± 5 mins 4 hours post dose ± 10 mins 6 hours post dose ± 10 mins Day Midazolam PK Compound (I) Form A PK PD markers Week 3 (Day 16) 24 hours post dose ± 2 hrs Week 3 (Day 17) 48 hours post dose ± 2 hrs (optional collection) Week 3 (Day 18) 72 hours post dose + 2 hrs (optional collection) Week 5 Pre-dose Week 6 Pre-dose Pre-dose Week 9 Pre-dose Pre-dose Week 13 Pre-dose Pre-dose Week 17 Pre-dose Pre-dose Week 21 Pre-dose Pre-dose Week 25 Pre-dose Pre-dose Week 29 Pre-dose Pre-dose Week 33 Pre-dose Pre-dose Week 37 Pre-dose Pre-dose Week 41 Pre-dose Pre-dose Week 45 Pre-dose Pre-dose Week 49 Pre-dose Pre-dose Sub-study 2: Preliminary Urinary Excretion and Metabolite Profiling Sub-study Sub-Study Objectives Primary sub-study objectives: 5      • To determine plasma PK of Compound (I) after a single dose and repeated doses of Compound (I) Form A • To determine urinary clearance (CLr) of Compound (I) after repeated doses • To conduct preliminary metabolite profiling in plasma and urine samples after repeated doses 10 Secondary sub-study objective: • To assess incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Exploratory sub-study objectives: • To explore biomarkers potentially predictive of response to Compound (I) Form A Urinary Excretion and Metabolite Profiling Sub-Study Design In this sub-study, 5 eligible patients with advanced clear cell renal cell carcinoma will be enrolled. Patients will receive 200 mg Compound (I) Form A QD for Week 1 and Week 2 (Day 1 to Day 14), followed by 50 mg Compound (1) Form A QD starting on Week 3 (Day 15). Serial plasma PK samples will be collected on Day 1 and Day 22, and additional sparse pre-dose plasma samples will be collected during the treatment course. On Day 22, total 24-hour urine will be collected from each patient. Urine will be collected in 3 time periods: 0-2 hours, 26 hours, and 6-24 hours. The first 2 periods (up to 6 hours) will be collected during the clinical visit. The total volumes of urine for each period should be recorded. The third period will not be collected during the clinical visit. Patients will be instructed to collect the total urine, measure and record the volume, and store 2 aliquots of urine samples. Patients will return to the clinic with the urine samples on the second day (Day 23). The plasma and urine samples will be analyzed to determine Compound (I) concentration and urinary excretion. In addition, the Day 22 plasma samples and urine samples will be analyzed for metabolite profiling. See Fig. 8. A Schedule of Assessments for the Urinary Excretion and Metabolite Profiling Sub-Study is shown in Table 12. Inclusion Criteria In addition to the inclusion criteria above in the main protocol, the following inclusion criteria arc applicable to this sub-study: 1. Adequate hepatic and renal function a. Hepatic: normal hepatic function (total bilimbin < upper limit of normal (ULN) and aspartate aminotransferase (AST) < ULN) or mild hepatic impairment (total bilimbin < ULN and AST > ULN, or total bilimbin > 1.0 x to 1.5 x ULN) b. Renal: measured or calculated creatinine clearance (CrCL) > 60 mL / min (Cockcroft-Gault formula) Exclusion Criteria In addition to the exclusion criteria abovein the main protocol, the following exclusion criteria are required in this sub-study: 1. Use of any drags, investigational agents, fruits, or herbs that are strong or moderate CYP3A inhibitors or inducers within 14 days prior to Day -3 (or 5 times the half-life of the drug, whichever is longer). Example strong and moderate clinical CYP3A inhibitors can be found at https: / / www.fda.gov / drags / drag-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3. Study Design Rationale Compound (I) Form A dosage selection The Compound (I) Form A dosage for this sub-study is loading doses of 200 mg QD x 14 days followed by maintenance doses of 50 mg QD. The daily maintenance doses are expected to maintain relatively steady exposure levels (approximate steady state) following the loading doses. This dosage was evaluated by the Safety Review Committee (SRC) and was deemed safe and well tolerated with no dose limiting toxicity. Currently, a recommended Phase 2 dose (RP2D) hasn’t been determined. Urinary excretion design Total 24-hour urine will be collected at approximate steady state on Day 22 in 3 periods. The 24-hour urine collection is to cover the dosing interval. The design is based on practical feasibility, i.e., urine will be collected up to 6 hours (0-2 and 2-6 hours) during clinical visit and 6-24 hours at home (or off-site stay). Dosage and Administration of Study Drags Compound (I) Form A On Week 1 Day 1, loading doses of Compound (I) Form A will be given to patients at 200 mg QD x 14 days. On Week 3 (Day 15), patients will start maintenance doses of 50 mg Compound (I) Form A QD. Compound (I) Form A doses will be administered on an empty stomach at least 2 hours after the last meal and at least 1 hour before the next meal as defined in the main protocol. Concomitant Medication In addition to the restrictions above, the following restrictions are required in this substudy: Use of the following medications are not allowed from Day 1 to Day 24 a. Strong or moderate CYP2C19 or CYP3A4 inhibitors b. Strong or moderate CYP2C19 or CYP3A4 inducers c. grapefruit, grapefruit juice, pomelo, or Seville oranges (CYP3A4 inhibitors) or St. John’s wort (CYP3A4 inducer) Other herbal and complementary therapies should not be encouraged because of unknown side effects and potential drug interactions, but any taken by the patient should be documented appropriately on the eCRF. Example strong and moderate clinical CYP3A inhibitors can be found at https: / / www.fda.gov / drugs / dmg-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3. Pharmacokinetic Assessment for Compound (I) Form A Blood samples for the determination of plasma Compound (I) concentrations will be collected at multiple time points as shown in Table 13. The date and time of collection of all PK blood samples should be recorded. Similarly, the total urine samples (3 periods) should have date and time recorded for the start and end of each period with urine volumes recorded. Validated LC-MS / MS methods will be used to determine plasma and urine concentrations of Compound (I). Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. PK parameters will be calculated based on the serial PK data following the first dose on Day 1 and Day 22, including, but not limited to, Cmax, Tmax, Ctrough, AUC0-24, steady-state CL, and CLr, if data allow. A detailed sample analysis plan for plasma and urine metabolite profiling will be defined in a Metabolite Profiling Plan separately. PD Marker Assessment Blood samples for the determination of scrum concentrations of pharmacodynamic (PD) biomarkers (e.g., EPO) will be collected at multiple time points as shown in Table 13. The date and time of collection of all PD blood samples should be recorded. A validated enzyme-linked immunosorbent assay (ELISA) will be used to determine the serum level of EPO. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Safety Assessments Ongoing assessment of safety for all patients in this sub-study will be determined by monitoring of symptoms, signs, and abnormal laboratory test results. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Other safety assessments will include vital signs, physical examination, ECG, and ECOG. Sample Size Five evaluable patients will be enrolled. Unevaluable patient(s) will be replaced. The sample size is empirically selected to allow preliminary assessments of urinary excretion and metabolite profiling. Safety Analysis Safety analyses will be based on all patients who received at least one dose of Compound (I) Form A. In general, data will be summarized using descriptive statistics. Continuous data will be summarized with the number of patients (n), arithmetic mean, standard deviation, median, minimum, and maximum. Categorical data will be summarized using frequency counts and percentages. A TEAE is defined as an AE with onset on or after the first dose of study drug (or that worsened from prior to the first dose of study drug). Any AE occurring after the 28-day followup period after discontinuation of study drug will be included in listings but will not be included in the summary tables of AEs. The number and percentage of patients experiencing 1 or more AEs will be summarized for the following classifications: • TEAEs by SOC and PT • TEAEs by SOC, PT and maximum toxicity grade • Compound (I) Form A-related TEAEs by SOC and PT • Compound (I) Form A-related TEAEs by SOC, PT and maximum toxicity grade • TEAEs leading to treatment discontinuation by SOC and PT • TEAEs resulting in dose modifications by SOC and PT 5     • CTCAE Grade > 3 TEAEs by SOC and PT • Fatal TEAEs by SOC and PT • SAEs by SOC and PT • Compound (I) Form A-rclatcd SAEs by SOC and PT Additional safety analysis will be described in the statistical analysis plan. 10 Efficacy Analysis Tumor response will be evaluated by the investigator using RECIST 1.1. Efficacy analyses as described below will be summarized for the patients in the sub-study. Further details will be included in the statistical analysis plan. 109 Table 12: Schedule of Assessments for Urinary Excretion and Metabolite Profiling Assessment Pre Treatment Period Treatment Period Post-Treatment Period Screening (Day -281 to Day -1) Week I1 (Day 1) Weeks 2, 3, 4, 5, 61 (±ld) Weeks 9, 13, 17, and every 4 weeks1 (± 2 d)through Week 49 Extended treatment every 12 weeks (± 1 week) Safety Follow-up 28 days after last dose of study drug (±7d) Long Term Follow-up (every 6 months) Assessment Reminder Week 43 (Day 22) Informed Consent (Main study) X Informed Consent (PK sub-study) X Medical History X Physical Examination4 X X X X X X Vital Signs5 X X X X X X Six-minute walk20 X Weight X X X X X X Height X ECOG X X X X X X WO 2025 / 235290                                   PCT / US2025 / 027249 110 Dispense / Collect Study Drug X X X X Hematology6 X X X X X X Serum Chemistry7 X X X X X X PT / aPTT / INR X Iron Panel8 X X X X Urinalysis9 X X X X X X Pregnancy Test10 X X X X X X ECG11 X X X X Tumor Assessment12 X X X DNA Sequencing13 X Circulating Tumor DNA14 X X PK and PD Sample15 X Archival Tissue Samples16 X Image Transfer17 X X X Echocardiogram / MU GA1 8 X X Study Drug Administration ____ ___ _ V _   ____ ____ Adverse Events X X X X X Concomitant Medications X X X X X WO 2025 / 235290                                   PCT / US2025 / 027249 Patient Status19 X 1. Assessments to be done at Screening and on Day 1 of each visit week. For the Week 2-6 Visits, patients will return to clinic on Weeks 2, 3, 4, and 6. These assessments can be performed + 1 day. For the Week 9, 13, 17 and visits every 4 weeks thereafter, assessments can be performed + 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. PK7PD samples collection windows are included in Table 13. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Site to remind patient that serial urine collection is required at Week 4 visit. 4. Physical examination to be performed before study drug administration at the Week 1,4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through week 49. 5. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature, and obtained only prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 6. Hematology assessments include CBC, differential, platelet count, and reticulocyte count. 7. Routine serum chemistry assessments include glucose. LDH. AST, ALT, ALP. total bilirubin, albumin, electrolytes (Na. K, Cl. CO2), Ca. Mg, PO4. BUN. creatinine, total protein levels, and an iron panel. BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs. 8. Iron panel assessments including Fe, ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening. Week 1. Week 4, Week 9 and every 4 weeks for the first year. 9. Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2. 4. 6, 9, 13. and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 10. Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4. 6, 9, 13. and 17 visits and visits every 4 weeks until treatment discontinuation. For female patients of childbearing potential who discontinue treatment, home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and WO 2025 / 235290                                   PCT / US2025 / 027249 112 contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A. 11. An ECG will be obtained before and at 1.5 hours after study drug administration at the Week 1 and Week 4 Visits. ECGs will be obtained prior to study drug administration only at Weeks 2, 3, 6, 9. and every 4 weeks, thereafter, through Week 49 (e.g., Week 13, Week, 17, Week 21. etc.). 12. Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening / baseline (within 35 days) and every 8 weeks (+ 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (+ 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. 13. At week 1 visit. 2ml of whole blood as 2 x 1 mL Paxgene blood DNA tubes should be collected for the genotyping of drug metabolizing enzymes. 14. At the Week 1 and Week 9 visits, 20ml of whole blood as 2 x 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA. 15. See Table 13 for details. 16. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin-fixed, paraffin-embedded blocks. 17. Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual. 18. An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). 19. For consenting patients and after completion of the 28-day post-treatment follow-up visit, long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc. Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 20. Patients enrolled under PA vlO will have a 6MWT during Screening visit. WO 2025 / 235290                                   PCT / US2025 / 027249 113 Table 13: Pharmacokinetic and Pharmacodynamic Sampling Schedule for the Sub-Study Day Compound (I) Form A PK1 PD markers1 Urine2 Week 1 (Day 1) Pre-dose Pre-dose 30 min post dose ± 5 mins 1 hour post dose ±10 mins 2 hours post dose ± 10 mins 4 hours post dose ±10 mins 6 hours post dose ± 10 mins Week 1 (Day 2) Predose (24 hours post the Day 1 dose ± 2 hrs) Pre-dose (24 hours post the Day 1 dose ± 2 hrs) Week 2 (Day 8) Pre-dose Pre-dose Week 3 (Day 15) Pre-dose Pre-dose Week 4 (Day 22) Pre-dose Pre-dose 0-2 hr total urine 30 min post dose ± 5 mins 1 hour post dose ±10 mins 2 hours post dose ±10 mins 2-6 hr total urine 4 hours post dose ± 10 mins 6 hours post dose ±10 mins 6-24 hr total urine Week 4 (Day 23) Prcdosc (24 hours post the Day 1 dose ± 2 hrs) WO 2025 / 235290                                   PCT / US2025 / 027249 114 Day Compound (I) Form A PK1 PD markers1 Urine2 Week 5 Pre-dose Pre-dose Week 6 Pre-dose Pre-dose Week 9 Pre-dose Pre-dose Week 13 Pre-dose Pre-dose Week 17 Pre-dose Pre-dose Week 21 Pre-dose Pre-dose Week 25 Pre-dose Pre-dose Week 29 Pre-dose Pre-dose Week 33 Pre-dose Pre-dose Week 37 Pre-dose Pre-dose Week 41 Pre-dose Pre-dose Week 45 Pre-dose Pre-dose Week 49 Pre-dose Pre-dose 1. Predose samples will be collected within 2 hours prior to the dose. Refer to the Laboratory Manual for details. 2. The 0-2 hr total urine and the 2-6 hr total urine will be collected during Day 22 clinical visit. The 6-24 hr total urine will be collected at home or off-site and returned to the clinic at Week 4 Day 23. Refer to the Laboratory Manual for details. WO 2025 / 235290                                   PCT / US2025 / 027249 Sub-study 3: Phase 2 Expansion: Belzutifan Pre-treated Cohort Exploratory Sub-study Sub-Study Objectives The same study objectives noted for the main study apply to this exploratory sub-study of belzutifan pre-treated patients; however, due to the limited sample size (N=10), all objectives in this cohort are considered exploratory. Sub-Study Design Approximately 10 evaluable patients who have had prior treatment with the HIF2a inhibitor belzutifan will be enrolled. Patients in the belzutifan pre-treated cohort will receive Compound (I) Form A at the highest of the selected RDEs. The overall study design described for Phase 1 and Phase 2 and the schedule of events in Table 3 and Table 4 apply to this exploratory sub-study. Inclusion Criteria In addition to the 13 inclusion criteria in the main protocol, the following inclusion criteria are applicable to this sub-study: 1. Relapse or progressive disease following prior treatment with belzutifan a. Patient must have received at least 28 days of treatment with belzutifan 2. Willingness to undergo a pretreatment and post-treatment biopsy of the tumor. Note: Study patients who are found after initiation of protocol therapy to have inadequate biopsy tissue will not be considered to have deviated from the protocol enrollment criteria if the presence or adequacy of biopsy tissue is the only enrollment criterion that is not fulfilled. However, patients who, after informed consent, are considered to have tumors amenable to pretreatment biopsy will be considered screen failures. Exclusion Criteria Exclusion criteria #1-14 in the main study apply to this exploratory sub-study. Exclusion criterion #15 is not applicable to this exploratory sub-study which includes patients who have received prior treatment with belzutifan (a HIF2a inhibitor). In addition to the 14 exclusion criteria in the main protocol, the following exclusion criteria are applicable to this sub-study: 1. History of toxicity or intolerance to treatment with belzutifan or other HIF2a inhibitor. 2. Known presence of HIF2a mutation G323E or HIF-1B mutation F446L. Study Design Rationale Hypoxia-inducible factor 2 alpha (HIF2a) has emerged as a critical oncogenic driver in ccRCC, which often constitutively expresses high levels of HIF2a due to the high frequency of VHL functional deficiency. Belzutifan (trade name) targets HIF2a and is currently marketed and indicated for VHL disease who require therapy for associated RCC. Disease response rates to belzutifan treatment have been limited and resistance mechanisms to treatment are largely unknown. In this substudy, the antitumor activity of Compound (I) Form A, a potent and more selective HIF2a inhibitor, will be investigated in a subset of patients who have had a previous relapse after treatment with belzutifan. The rationales for selecting the RDEs are provided above. Dosage and Administration of Study Drugs See below. Concomitant Medication See below. Pharmacokinetic Assessment for Compound (I) Form A Blood samples for the determination of plasma concentrations of Compound (I) will be collected at multiple time points as shown in the PK and PD sampling schedule (Table 5). PD Marker Assessment Blood samples for the determination of serum concentrations of PD biomarkers (e.g., EPO) will be collected at multiple time points as shown in the PK and PD sampling schedule (Table 5). Safety Assessments Ongoing assessment of safety for all patients in this sub-study will be determined by monitoring of symptoms, signs, and abnormal laboratory test results. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Other safety assessments will include vital signs, physical examination, ECG, and ECOG. Sample Size Approximately 10 evaluable patients will be enrolled. The sample size is empirically selected to allow assessments of the exploratory objectives of this sub-study. Safety Analysis See below. Efficacy Analysis See below. Treatment of Patients Study Procedures Informed Consent Written informed consent must be obtained from the patient before any study-related procedures are performed and whenever the study procedures change, or new safety information becomes available that may affect the patient’s willingness to participate. Procedures conducted as part of the patient’s routine clinical management (e.g., blood count, imaging study) and obtained before signing of informed consent may be used for screening or baseline purposes provided the procedure meets the Protocol-defined criteria and has been performed in the timeframe of the study (i.e., within 21 days of Week 1 Day 1). All information associated with eligibility requirements must be entered into the appropriate electronic case report form (eCRF) pages. Inclusion / Exclusion Inclusion and exclusion criteria should be reviewed during the time period indicated for Screening in Table 3 and Table 4, Schedule of Assessments. Patients must meet all of the inclusion and none of the exclusion criteria for study entry. Demographics and Medical History Demographic data include gender, age, race, and ethnicity will be collected during the time period indicated for Screening in Table 3 and Table 4. Medical and surgical history will be obtained during Screening and will include documentation of the date / year of advanced solid tumor diagnosis, documentation of prior anti-cancer therapies, prior radiation therapy, prior nephrectomy, and documentation of all currently active and relevant medical and surgical conditions. Vital Signs Vital signs (systolic and diastolic blood pressure, pulse, respirations, temperature, and oxygen saturation) will be assessed as noted in Table 3 and Table 4. All blood pressure measurements should be taken after the patient has rested in a seated or semi-recumbent position. Oxygen saturation should be measured by pulse oximetry at pre-dose and 6-hour timepoints on Week 1 Day 1 and Week 4 (Day 22) visits and at any time a patient presents with any new or worsening respiratory symptoms. If a patient shows changes on pulse oximetry or other pulmonary-related signs (e.g., hypoxia, fever) or symptoms (e.g., dyspnea, cough, fever) consistent with possible pulmonary AEs, the patient should be immediately evaluated to rule out pulmonary toxicity. Physical Examination The physical examination will include evaluation of the head, eyes, ears, nose and throat, and cardiovascular, dermatological, musculoskeletal, respiratory, GI, and neurological systems. Height will be assessed during Screening only. Physical examinations should be performed according to the Schedule of Assessments (Table 3 and Table 4). Before administration of the first dose of study drug, any new or worsened abnormalities (other than those due to protocol-required procedures) should be recorded as medical history. After the initiation of study drug administration, any clinically significant new or worsened abnormalities noted on the physical examination will be recorded as AEs. No rectal or pelvic examination is required. Eastern Cooperative Oncology Group Performance Status Eastern Cooperative Oncology Group (ECOG) performance status will be assessed using the grading system shown in Table 14, at the time points indicated in Table 3 and Table 4. Table 14: ECOG Performance Status Grade ECOG 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 Dead See Oken, et al. Am J Clin Oncol 5: 649-655, 1982. Electrocardiogram During Phase 1, a 12-lcad ECG will be obtained after 5-15 minutes of rest in the supine or semi-recumbent positions using equipment at the site and according to the schedule in Table 3 and Table 4. The investigator or designee will evaluate the ECG for abnormalities. In addition, ECGs will be collected in triplicate at selected timepoints in Phase 2 Expansion (Table 5). Echocardiogram / MUGA An echocardiogram or multigated acquisition (MUGA) for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). Laboratory Assessments Clinically significant abnormal laboratory findings identified during the screening period should be recorded as medical history in the CRF. Laboratory samples will be obtained according to the schedule in Table 3 and Table 4. Clinically significant abnormal laboratory test results that are considered to be drug related should be followed. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Hematology Hematology tests will include RBC count, white blood cell (WBC) count, Hgb, HCT, WBC differential count (neutrophils, lymphocytes, eosinophils, monocytes, and basophils), mean corpuscular Hgb concentration (MCHC), mean corpuscular Hgb (MCH), mean corpuscular volume (MCV), mean platelet volume (MPV), red blood cell distribution width (RDW), platelet count (Pit), and reticulocyte count (retie). Blood Chemistry Routine serum chemistry tests will include sodium (Na), potassium (K), chloride (Cl), bicarbonate (CO2), calcium (Ca), magnesium (Mg), phosphate (PO4), blood urea nitrogen (BUN), creatinine, total protein, glucose, lactate dehydrogenase (LDH), AST, ALT, ALP, TBILI, and albumin. B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) are required at W1D1. The same lab test will be repeated as needed when a grade 3 or higher hypoxia adverse event occurs. Activated Partial Thromboplastin Time Blood samples collected during screening will be used to determine the prothrombin time (PT), the activated partial thromboplastin time (aPTT), and the INR (international normalized ratio) to assess coagulation. Iron Panel Blood samples will be collected for an iron panel to include: iron (Fe), ferritin, transferrin saturation, total iron binding capacity. Urinalysis Urinalysis will include appearance, glucose, ketones, blood, protein, nitrite, bilirubin, specific gravity, pH, urobilinogen, and leukocytes. If the results are positive for blood or protein, a microscopic examination should be included. Pregnancy Test A serum pregnancy test must be performed within 7 days before the first study drug administration. Urine or serum pregnancy tests will be performed according to the Schedule of Assessments in Table 3 and Table 4 for females of child-bearing potential. Response Assessments Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening / baseline (within 35 days), within 7 days before the Week 9 Visit, and every 8 weeks (± 1 week) thereafter for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (+ 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4). When the last scan in the 8-week interval ends at Week 49, the next week starts the 12-week interval. Response will be assessed using RECIST v 1.1 (Table 15 and Table 16). After one year, assessments of the patient’s tumor will be made every 12 weeks. Investigators must ensure that original images (or high-quality copies) of all CT / MRI scans of disease areas are filed and available for transmission for a future possible central reading by an independent review depending on preliminary efficacy results and upon request. If possible, bone lesions should not be selected as target lesions. If brain metastases are found at baseline, brain scan or MRIs will be repeated with response assessment scans. For patients discontinuing the study treatment before documented radiographic progression, tumor assessments should continue on schedule approximately every 8 weeks or at the current scan interval at the time of treatment discontinuation until radiographic evidence of disease progression, the start of a subsequent anticanccr therapy, withdrawal of consent, or decision to no longer treat (e.g., supportive care only), whichever is first. 5 Table 15: RECIST 1.1 Summary Time Point Response: Patients with Target (± Non target) Disease Target lesions Non-target lesions New lesions Overall response CR CR No CR CR Non-CR / non-PD No PR CR Not evaluated No PR PR Non-PD or not all evaluated No PR SD Non-PD or not all evaluated No SD Not all evaluated Non-PD No NE PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD CR = complete response, PR = partial response, SD = stable disease. PD = progressive disease, and NE = not evaluable; Abstracted from Eisenhauer, et al. Eur J Cancer 45: 228-247, 2009. 10 Table 16: Time Point Response: Patients with Non-target Disease Only Non-target lesions New lesions Overall response CR No CR Non-CR / non-PD No Non-CR / non-PD Not all evaluated No NE Unequivocal PD Yes or No PD Any Yes PD CR = complete response, PD = progressive disease and NE = not evaluable A ‘Non-CR / non-PD is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint for assessment of efficacy in some studies so to assign this category when no lesions can be measured is not advised. 15 Quality of Life For Phase 2, quality of life will be self-assessed using EORTC-QLQ-C30 in the clinic at the specified time points prior to dosing. Patients will be instructed to complete the assessment without any help from friends or family members. It is recommended that assessments are completed in the morning. All scheduled assessments of the EORTC-QLQ-C30 cannot be taken home and must be completed in the clinic prior to any other study or medical procedure. Six-Minute Walk Test (6MWT) A six-minute walk test (6MWT) (see ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories, Am J Respir Crit Care Med 166:111-7, 2002; Holland, et al. Eur Respir J. 44:1428-46, 2014) and pulse oximetry measurement are required during screening. Inclusion criterion #13 and exclusion criterion #2 provide guidance for a subject’s eligibility. Test procedures are summarized below: PATIENT PREPARATION 1. Comfortable clothing should be worn. 2. Appropriate shoes for walking should be worn. 3. Patients should use their usual walking aids during the test (cane, walker, etc.). 4. The patient’s usual medical regimen should be continued. 5. A light meal is acceptable before early morning or early afternoon tests. 6. Patients should not have exercised vigorously within 2 hours of beginning the test. MEASUREMENTS 1. A “warm-up” period before the test should not be performed. 2. The patient should sit at rest in a chair, located near the starting position, for at least 10 minutes before the test starts. During this time, check for contraindications, measure pulse and blood pressure, and make sure that clothing and shoes are appropriate, 3. Pulse oximetry is required for this study. If it is performed, measure and record baseline heart rate and oxygen saturation (SpO2) and follow manufacturer’s instructions to maximize the signal and to minimize motion artifact. Make sure the readings are stable before recording. Note pulse regularity and whether the oximeter signal quality is acceptable. 4. Have the patient stand and rate their baseline dyspnea and overall fatigue using the Borg scale. 5. Set the lap counter to zero and the tinier to 6 minutes. Assemble all necessary equipment (lap counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point. 6. Instruct the patient as follows: “The object of this test is to walk as far as possible for 6 minutes. You will walk back and forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. You will probably get out of breath or become exhausted. You are permitted to slow down, to stop, and to rest as necessary. You may lean against the wall while resting, but resume walking as soon as you are able. You will be walking back and forth around the cones. You should pivot briskly around the cones and continue back the other way without hesitation. Now I’m going to show you. Please watch the way I turn without hesitation.” Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly. “Are you ready to do that? I am going to use this counter to keep track of the number of laps you complete. I will click it each time you turn around at this starting line. Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog. Stall now, or whenever you are ready.” 7. Position the patient at the starting line. You should also stand near the starting line during the test. Do not walk with the patient. As soon as the patient starts to walk, start the timer. 8. Do not talk to anyone during the walk. Use an even tone of voice when using the standard phrases of encouragement. Watch the patient. Do not get distracted and lose count of the laps. Each time the participant returns to the starting line, click the lap counter once (or mark the lap on the worksheet). Let the participant see you do it. Exaggerate the click using body language, like using a stopwatch at a race. After the first minute, tell the patient the following (in even tones): “You are doing well. You have 5 minutes to go.” When the timer shows 4 minutes remaining, tell the patient the following: “Keep up the good work. You have 4 minutes to go.” When the timer shows 3 minutes remaining, tell the patient the following: “You are doing well. You are halfway done.” When the timer shows 2 minutes remaining, tell the patient the following: “Keep up the good work. You have only 2 minutes left.” When the timer shows only 1 minute remaining, tell the patient: “You are doing well. You have only 1 minute to go.” Do not use other words of encouragement (or body language to speed up). If the patient stops walking during the test and needs a rest, say this: “You can lean against the wall if you would like; then continue walking whenever you feel able.” Do not stop the timer. If the patient stops before the 6 minutes are up and refuses to continue (or you decide that they should not continue), wheel the chair over for the patient to sit on, discontinue the walk, and note on the worksheet the distance, the time stopped, and the reason for stopping prematurely. When the timer is 15 seconds from completion, say this: “In a moment I’m going to tell you to stop. When I do, just stop right where you are and I will come to you.’’When the timer rings (or buzzes), say this: “Stop!” Walk over to the patient. Consider taking the chair if they look exhausted. Mark the spot where they stopped by placing a bean bag or a piece of tape on the floor. 9. Post-test: Record the postwalk Borg dyspnea and fatigue levels and ask this: “What, if anything, kept you from walking farther?” 10. This study uses a pulse oximeter. Please measure SpO2 and pulse rate from the oximeter and then remove the sensor. 11. Record the number of laps from the counter (or tick marks on the worksheet). 12. Record the additional distance covered (the number of meters in the final partial lap) using the markers on the wall as distance guides. Calculate the total distance walked, rounding to the nearest meter, and record it on the worksheet. 13. Congratulate the patient on good effort and offer a drink of water. Absolute contraindications The following absolute contraindications for the 6MWT are noted by the ATS Committee 2002 and Holland et al. 2014. The absolute contraindications include acute myocardial infarction (within 30 days), unstable angina, uncontrolled arrhythmias causing symptoms or haemodynamic compromise, syncope, active endocarditis, acute myocarditis or pericarditis, symptomatic severe aortic stenosis, uncontrolled heart failure, acute pulmonary embolus or pulmonary infarction, thrombosis of lower extremities, suspected dissecting aneurysm, uncontrolled asthma, pulmonary oedema, room air SpO2 at rest <85%, acute respiratory failure, acute noncardiopulmonary disorder that may affect exercise performance or be aggravated by exercise (i.e., infection, renal failure, thyrotoxicosis), and mental impairment leading to inability to cooperate. Patients with any of the findings below should be referred to the physician for individual clinical assessment and a decision about the conduct of the test. Stable exertional angina patients should perform the test after using their anti-angina medication, and rescue nitrate medication should be readily available. All comorbidities and medication use should be recorded prior to the test. Relative Contradictions The following relative contraindications were noted by the ATS Committee 2002 and Holland et al. 2014. Left main coronary stenosis or its equivalent, stable exertional angina, moderate stenotic valvular heart disease, severe untreated arterial hypertension at rest (180 mmHg systolic, 100 mmHg diastolic), tachyarrhythmias or bradyarrhythmias, high-degree atrioventricular block, hypertrophic cardiomyopathy, significant pulmonary hypertension, advanced or complicated pregnancy, electrolyte abnormalities, and orthopaedic impairment that prevents walking. Concomitant Medications Patients may not receive systemic anti-neoplastic therapy including chemotherapy, hormonal therapy, or any investigational anti-neoplastic agent during the course of this study. Chronic systemic corticosteroid use (prednisone > 12.5 mg / day or dexamethasone >2 mg / day) for palliative or supportive purpose is not permitted (unless administered for adrenal insufficiency). Acute emergency administration, topical application, inhaled sprays, eyedrops or local injections are permitted. Anti-convulsant therapies at a stable dose are allowed. Patients may receive limited-fraction palliative radiotherapy after first 3 weeks of Compound (I) Form A dosing to control local tumor-related symptoms if irradiation is unlikely to induce major organ toxicity and only if, in the opinion of the treating investigator, the patient does not have progressive disease. The radiation field cannot encompass a target lesion. Radiation to a target lesion is considered to be a treatment decision for progressive disease, and patients who receive radiation for a target lesion should be removed from study treatment unless, in the opinion of the investigator, the patient would continue to benefit from study treatment in discussion with the Sponsor medical monitor. Administration of prophylactic anti-emetics are not allowed prior to the first dose of study drug but may be given if needed during study treatment. During the first 21 days of treatment, granulocyte colony stimulating factor (G-CSF) should be administered only for severe or prolonged neutropenia or for neutropenic sepsis. There will be no constraint on the use of growth factors during subsequent treatment; however, prophylactic use is discouraged and adherence to the American Society of Clinical Oncology (ASCO) guidelines is recommended. Erythropoietin should not be administered during the first 21 days of study drug treatment. Patients should receive all necessary supportive care, including blood products, transfusions, antibiotics, pain medications, bisphosphonates, and replacement hormonal therapies (insulin, thyroid hormones, estrogen / progesterone). Herbal and complementary therapies should not be encouraged because of unknown side effects and potential drug interactions, but any taken by the patient should be documented appropriately on the eCRF. The preclinical data indicated that Compound (I) Form A is metabolically stable with CYPs; however, the amount of Compound (I) Form A oxidative metabolite formed with CYP2C19 was much higher than with other CYPs. As a precaution, it is recommended that strong inhibitors of CYP2C19 be avoided in patients receiving Compound (I) Form A. Given the abundant expression levels of CYP3As, clinically significant contributions of CYP3As to Compound (I) Form A metabolism cannot be excluded. Examples of strong clinical CYP2C19 and CYP3A4 perpetrators can be found at the following websites: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2 and https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3. Hormone-based contraceptives regardless of dosing route are not considered effective as Compound (I) Form A could induce CYP3A4 and reduce efficacy of such drugs. See below for requirements on effective birth control. In vitro results indicate that Compound (I) Form A is an inducer of CYP3A4 and CYP2B6. In addition, CYP3A4 induction occurs via activation of nuclear PXR, which may result in co-induction of CYP2C8, CYP2C9 and CYP2C19. Compound (I) Form A may, therefore, decrease the exposure of concomitant medications that are substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9 or CYP2C19; however, the clinical relevance of these effects is not yet clear. If Compound (I) Form A is taken with sensitive substrates of these enzymes, additional monitoring of the concomitant medication’s effectiveness may be needed. Example sensitive clinical substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 can be found at the following website: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-l. In vitro results indicate that Compound (I) Form A may mildly inhibit liver CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As at clinically relevant concentrations. Compound (I) Form A may also inhibit CYP3As in the gut. Cautions should be used if Compound (I) Form A is taken with sensitive substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As as Compound (I) Form A could potentially increase the exposures of these drugs. Example sensitive clinical substrates of these CYPs can be found at the following website: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-l. In addition, Compound (I) Form A could inhibit BCRP in the gut and MATE2-K in the kidney at clinically relevant dose levels. No inhibition of other transporters is expected at clinically relevant clinical dose levels. Example substrates for BCRP and MATE2-K can be found at the following website: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table4-l. All concomitant medication(s) used during the study and within 28 days before the start of study drug administration will be reported on the appropriate CRF page. Treatment Compliance The investigator or his / her designated and qualified representatives will dispense study drug only to patients enrolled in the study in accordance with the protocol. The study drug must not be used for reasons other than that described in the protocol. The number of capsules returned at a visit will be used to assess compliance; any discrepancy from the expected number of returned capsules will be discussed with the patient. Patients who fail to comply with the requirements of the study will be withdrawn from the study. Patients who have not received at least 80% of the planned doses of study drug or missed more than one Compound (I) Form A maintenance weekly dose in the 21-day DLT observation period for reasons other than treatment related toxicity will not be considered DLT evaluable and may be replaced in dose escalation. Randomization and Blinding In the phase 1 dose-escalation part of the trial, no randomization or blinding will be performed. In the phase 2 dose expansion part, following confirmation of eligibility at Day 1, 40 patients with no prior treatment with a HIF2a inhibitor will be randomized (1:1) via an Interactive Response Technology (IRT) system to either RDE-w (100 mg QD x 7 then 100 mg QW) or RDE-d (200 mg QD x 14 then 50 mg QD). No blinding will be performed. Study Drug Materials and Management Study Drug Compound (I) Form A Capsules are supplied as immediate-release capsules in 3 dose strengths, 10 mg (oblong), 50 mg (oblong), and 200 mg (oblong), for oral administration. Study Drug Packaging and Labeling Compound (I) Form A capsules will be packaged in 5-, 15-, and 30-count high-density polyethylene (HDPE) bottles with induction-seal liners and a child-resistant closure. Each bottle will be labeled per local regulatory requirements. Study drug will be provided to each site pharmacy, and the investigator or designee will provide capsules to each patient, with clear instructions on the number and dose strength of capsules to be taken each day until the next study visit. Study Drug Storage Compound (I) Form A must be stored in a secure location in accordance with the study drug label. Study Drug Administration Following confirmation of eligibility, patients will be sequentially assigned to the next open dose cohort. Study drug should be taken at least 2 hours after the last meal, and patients should refrain from eating for at least 1 hour after taking each dose. For Phase 1 Dose Escalation, the initial dose cohort will begin treatment at a dosage of 200 mg orally, once daily. Dose escalation will be in 100% increments until the second Grade 2 or greater toxicity or DLT that is at least possibly related to study drug is reported. Thereafter, sequential dose levels will increase by increments of up to 50% as determined by an SRC. Intermediate dose levels may be studied as appropriate based on the available safety and PK profiles of Compound (I) Form A. Increments of dose escalation will be adjusted as needed to accommodate available capsule strengths. Every effort should be made to have patients take their study drug at the same time each day. For Phase 2 Dose Expansion, patients will be randomized to receive Compound (I) Form A at RDE-w or RDE-d. For patients assigned to the RDE-w, study drug will be administered once daily during the first study week on study days 1-7. Then the weekly maintenance dose will start on Week 2, Study Day 8. For patients assigned to the RDE-d, study drug will be administered once daily during the first 14 days. Then the daily maintenance dose will start on Week 3, Study Day 15. For patients receiving daily dosing, missed doses may be made up if taken within 4 hours after the scheduled administration time. Study drug may not be taken within 8 hours before the scheduled time for administration of the next dose. Patients who vomit after study drug administration should not retake that study drug dose but should resume taking study drug at the next scheduled administration time. For patients receiving weekly dosing, missed doses may be made up as long as the next scheduled dose is more than 3 days (72 hours) away. Patients should not take a missed dose of Compound (I) Form A if it is within 3 days (72 hours) of the next scheduled dose. For patients that consume more than their prescribed dose, consideration should be given as to whether dose administration should be temporarily interrupted. Observation for any symptomatic side effects should be instituted, and safety laboratory parameters should be followed closely (consistent with the protocol or more frequently, as needed). Appropriate supportive management to mitigate adverse effects should be initiated. The occurrence of a dose deviation does not preclude further protocol therapy as long as the patient appears to be safely benefiting from treatment and the circumstances that led to the initial deviation are unlikely to recur. Study Drug Accountability, Handling and Disposal The dispensing pharmacist or designated qualified individual will write the date dispensed, dose strength dispensed, and the patient’s identification number or initials on the Drug Accountability Source Documents. Study medication will be dispensed at appropriate intervals to ensure each patient has adequate supply between study visits. All medication supplied will be accounted for on the Drug Accountability Record. All partially used or unused study drug supplies will be destroyed at the site in accordance with approved written site procedures or returned as described in the pharmacy manual. The investigator will maintain a record of the amount and dates when unused supplies were either destroyed or returned for destruction. All records will be retained as noted below. Pharmacokinetic Assessments Blood Sample Collection and Analysis Blood samples for the determination of plasma Compound (I) concentrations will be collected at multiple time points throughout the study as noted in Table 3 and Table 4. The date and time of collection of all PK blood samples should be recorded. Validated liquid chromatography / mass spectrometry (LC-MS / MS) methods will be used to assay the samples for plasma concentrations of Compound (I). Additional blood and urine samples will be collected for determination of plasma concentrations of Compound (I) and midazolam and for Compound (I) metabolite profiling in the sub-studies 1 and 2, as described above. Refer to Table 5 for PK sample collection schedule in Phase 2 Expansion. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Pharmacokinetic Analysis The following PK parameters of Compound (I) Form A will be calculated for all patients by non-compartmental analysis in Phase 1 Dose Escalation: • Time to maximum observed plasma concentration (tmax) • Maximum observed plasma concentration (Cmax) • Area under the plasma concentration-time curve from 0 to last measurable concentration (AUCo-t), computed using the linear up / log down trapezoidal rule • Area under the plasma concentration-time over the dose interval (0-24 hours) (AUC0-24) computed, using the linear up / log down trapezoidal rule assuming plasma concentrations can be quantified over this time interval • Accumulation ratio (Rauc), calculated by AUCo-tau after multiple doses / AUCo-tau after the first dose • Accumulation ratio (Rcmax), calculated by Cmax after multiple doses / Cmax after the first dose Pharmacodynamic and Biomarker Assessments Blood Sample Collection Samples for analysis of PD effects (biomarkers) for Phase 1 Dose Escalation will be collected at multiple time points throughout the study as noted in Table 3 and Table 4. Pharmacodynamic biomarkers to be assessed may include EPO and other biomarkers of the HIF pathway and ccRCC. Scrum EPO level will be determined using a validated ELISA method. Whole blood samples will be collected for sequencing of genes encoding proteins that may be involved in regulating Compound (I) Form A metabolism. Whole blood samples will be collected for the analysis of circulating tumor DNA at the Week 1 and Week 9 visits. Details for the collection, processing, storage, and shipment of samples for these biomarker studies can be found in the study laboratory manual. Refer to Table 5 for PD sample collection schedule for Phase 2 Expansion. Tissue Sample Collection A formalin-fixed paraffin-embedded tumor tissue block or unstained slides of tumor sample (archival or recent) for biomarker evaluation will be requested for all patients at study entry. In the case of unstained slides, 20 slides will be requested to conduct biomarker analyses. Tumor tissue samples may be analyzed for HIF2a and HIFla expression, and for other biomarkers that may be predictive of benefit of treatment with Compound (I) Form A. Details for the collection, processing, storage, and shipment of tissue samples for these biomarkers can be found in the study laboratory manual. Analysis Biomarker analyses are dependent on the availability of appropriate biomarker assays and clinical response. Biomarker analysis may be deferred or not performed, if during or at the end of the study, it becomes clear that i) the analysis will not have sufficient scientific justification for the planned biomarker evaluation or ii) there are not enough samples and / or responses to allow for adequate biomarker assessment. In the scenario of study being terminated early or lack of sufficient clinical benefit, completion of biomarker evaluation will be based on scientific justification and the intended utility of the data. Additional Collection If it is determined at any time before the study completion that additional material is needed from a FFPE sample for the successful completion of the protocol specified analyses, the sponsor may request additional material to be retrieved from existing samples. Assessment of Safety Safety Parameters Safety and tolerability will be determined by symptoms, signs, and abnormal laboratory test results. The investigator will monitor the laboratory test findings. Abnormalities of laboratory test results may or may not, in the opinion of the investigator, be considered clinically significant. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Abnormal laboratory values that require intervention must be reported on the Adverse Event CRF. Any laboratory test result that is abnormal during the course of the study but not considered clinically significant will be followed at the discretion of the investigator. Adverse and Serious Adverse Events Definition of Adverse Events Adverse Event An AE is defined as any untoward medical occurrence in a patient regardless of its causal relationship to study treatment. An AE can be any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug, whether or not it is considered to be study drug related. Included in this definition are any newly occurring events and any previous condition that has increased in severity or frequency since the administration of study drug. Disease progression is a study endpoint and consequently, should not be reported as an AE. However, if a patient dies from disease progression with no other immediate causes, “disease progression” should be reported as a serious adverse event (SAE). All AEs that are observed or reported by the patient during the study (from the time of administration of the first dose of study drug until the final visit indicated in Table 3 and Table 4) must be reported, regardless of their relationship to study drug or their clinical significance. Serious Adverse Event An SAE is any AE occurring at any dose and regardless of causality that meets any of the following criteria. • Results in death • Is life-threatening • Requires in-patient hospitalization or prolongation of existing hospitalization • Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions • Is a congenital anomaly or birth defect in an offspring of a patient taking study drug • Is an important medical event • The term “life-threatening” refers to an event in which the patient is at immediate risk of death at the time of the event. The term docs not refer to an event that hypothetically might cause death if it were more severe. Important medical events are those that may not meet any of the criteria defined above; however, they may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the SAE definition. Pregnancy is not considered an AE; however, information will be collected for any pregnancies that occur during the study (from the time the first dose of study drug is administered until 6 months after the last dose of study drug). Certain pregnancy outcomes will require submission as an SAE. The investigator is responsible for reporting all SAEs that are observed or reported by the patient during the study (from the time of administration of the first dose of study drug until the final visit indicated in Table 3 and Table 4), regardless of their relationship to study drug or their clinical significance. All SAEs reported or observed during the study must be followed to resolution or until the investigator deems the event to be chronic or the patient to be stable. The investigator may be contacted to obtain additional information on any SAE that has not resolved at the time the patient completes the study. Eliciting Adverse Event Information At every study visit, patients must be asked a standard, non-directed question, such as, “How do you feel?” or “How have you been feeling since your last visit?” to elicit any medically related changes in their well-being. They may also be asked if they have been hospitalized, had any accidents, used any new medications, or changed concomitant medication regimens (including prescription drugs, over-the-counter medications, vitamins, herbal products, and minerals). Responses should be recorded in the source documents. In addition to patient observations, AEs must be documented for any clinically significant diagnosis resulting from abnormal laboratory test values, physical examination findings, or ECG abnormalities, or from other documents that are relevant to patient safety. Assessment of Causality The investigator must use the following classifications and criteria to characterize the relationship or association of the study drug in causing or contributing to the AE: Unrelated: This relationship suggests that there is no association between the study drug and the reported event. Unlikely: This relationship suggests that the temporal sequence of the event with study drug administration makes a causal relationship improbable and / or other factors also provide plausible explanations. Possible: This relationship suggests that treatment with the study drug caused or contributed to the AE. That is, the event follows a reasonable temporal sequence from the time of study drug administration, and / or, follows a known response pattern to the study drug, but could have been produced by other factors. Probable: This relationship suggests that a reasonable temporal sequence of the event with study drug administration exists and, based upon the known pharmacological action of the study drug, known or previously reported adverse reactions to the study drug or class of drugs, or judgment based on the investigator’s clinical experience, the association of the event with study drug administration seems likely. Assessment of Severity The investigator will grade the severity of the AEs as Grades 1, 2, 3, 4, or 5 based on NCI CTCAE, version 5.0 or subsequent versions released during the study. If the CTCAE do not apply, severity should be defined as shown in Table 17. Table 17: Adverse Event Severity Grades Grade Description 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 4 Life-threatening consequences; urgent intervention indicated. Grade Description 5 Death related to AE. The NCI CTCAE, version 5.0 (https: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / docs / CTCAE_v5_Quick_ Reference_5x7.pdf), will be provided to the investigator. Recording Adverse Events All conditions present before administration of the first dose of study drug should be documented as medical history. All drug-related AEs and abnormal laboratory test results reported or observed during the study must be followed to resolution (either return to baseline or within normal limits). All other AEs will be followed through the final visit indicated in Table 3 and Table 4. Information to be collected includes type of event, date of onset, date of resolution, investigator-specified assessment of severity and relationship to study drug, seriousness, action taken, and outcome. While an AE is ongoing, changes in the severity (e.g., worsening and improving) for a reporting period (e.g., between visits), each change in severity will be reported as a separate AE until the event resolves. Adverse events characterized as intermittent require documentation of onset and duration. Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent medications, or progression of disease states must also be reported. Preexisting conditions (present before the start of the AE collection period) are considered concurrent medical conditions and should NOT be recorded as AEs. However, if the patient experiences a worsening or complication of such a concurrent condition, the worsening or complication (except disease progression) should be recorded as an AE. Investigators should ensure that the AE term recorded captures the change in the condition (e.g., “worsening of...”). Each AE should be recorded to represent a single diagnosis. Accompanying signs (including abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an AE(s). Changes in laboratory test values or ECG parameters are only considered to be AEs if they are judged to be clinically significant (i.e., if some action or intervention is required or if the investigator judges the change to be beyond the range of normal physiologic fluctuation). If abnormal laboratory test values or ECG findings are the result of pathology for which there is an overall diagnosis (c.g., increased creatinine levels in renal failure), only the diagnosis should be reported as an AE. Elective procedures (surgeries or therapies) that were scheduled before the start of AE collection are not considered AEs. These elective procedures should not be recorded as AEs but should be documented in the patient’s source documents as elective (e.g., elective periodontal surgery). However, if a pre-planned procedure is performed early (e.g., as an emergency) because of a worsening of the pre-existing condition, the worsening of the condition should be captured as an AE. Reporting Serious Adverse Events Any AE that meets the previously described criteria for “serious” must be reported to the sponsor’s designee within 24 hours from the time when site personnel first learn about the event. All SAEs occurring from the time of administration of the first dose of study drug until the final visit indicated in Table 3 and Table 4 must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the occurrence. After the final visit, any SAE that the Investigator considers related to study drug must be reported to the Medpace Clinical Safety or the Sponsor / designee. The investigator must continue to follow the patient until the SAE has subsided or until the condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient dies. Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form electronically in the EDC system for the study and submit any supporting documentation (e.g., patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. Expedited Reporting Regulatory agencies will be notified of any fatal or life-threatening unexpected events associated with the use of the study drug as soon as possible but no later than 7 calendar days after the initial receipt of the information. Initial notification will be followed by a written report within the timeframe established by the appropriate regulatory agency. For other SAEs that do not meet the fatal or life-threatening unexpected criteria but are deemed by the investigator to be associated with the use of the study drug (that is, “possible” or “probable” in causality assessment), the appropriate regulatory agencies will be notified in writing within the timeframe established by those regulatory agencies.copies of any reports will be provided to regulatory agencies regarding serious and unexpected SAEs to the investigators for their information and submission to their institutional review board (IRB), as appropriate. Principal investigators are responsible for informing their IRB of any SAEs at their site, as appropriate. SAE correspondence with regulatory authorities or IRBs must be submitted to for recording in the study file. Pregnancy Female patients of child-bearing potential are defined as patients who are not surgically sterile (no history of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), do not have fallopian inserts with confirmed blockage, have not had reproductive potential terminated by radiation, and have not been postmenopausal for at least 1 year. Methods of Birth Control During screening, while taking study drug, and until 6 months (approximately 5 x ti / 2) after taking the final dose of study drug, female patients of child-bearing potential and male patients who have female partners of child-bearing potential must practice one of the following methods of birth control: • Total abstinence (defined as refraining from heterosexual intercourse during the entire period outlined above), • Male or female sterilization • Placement of an intrauterine device • Use of a condom In vitro and preliminary clinical data suggested that Compound (I) Form A is a CYP3A4 inducer and can render some hormonal contraceptives ineffective during Compound (I) Form A treatment and up to 6 months after Compound (I) Form A treatment. Established use of oral, inserted, injected or implanted hormonal methods of contraception are allowed provided one of the above four effective methods is used in combination with the hormonal method. Suspected Pregnancy During the study, all females of child-bearing potential must be instructed to contact the investigator immediately if they suspect they might be pregnant (e.g., late or missed menstrual period). Male patients must be instructed to contact the investigator if a sexual partner suspects she may be pregnant. If a patie...

Claims

What is Claimed:

1. A method of treating cancer comprising administering to a patient in need thereof:(a) one or more loading doses during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of Compound (1):or Compound (I) Form A polymorph of Compound (I) having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2° 20 as measured using an X-ray wavelength of 1.5418 A; and(b) one or more maintenance doses during a maintenance period, wherein each maintenance dose comprises less than or the same amount of Compound (I) or the Compound (I) Form A present in each of the one or more loading doses in (a); provided that, when the amount of Compound (I) or the Compound (I) Form A in each of the one or more maintenance doses is the same as in each of the one or more loading doses in (a), the one or more maintenance doses are administered to the patient less frequently than the one or more loading doses are administered during the loading period.

2. The method of claim 1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2° 20.

3. The method of claim 1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2° 20.

4. The method of claim 1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 11.4, 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2° 0.

5. The method of claim 1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions substantially as shown in Fig. 4.

6. The method of any one of claims 1 to 5, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered once daily (QD).

7. The method of any one of claims 1 to 6, wherein each of the one or more loading doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 consecutive days.

8. The method of any one of claims 1 to 5, wherein each of the one or more loading doses comprise about 200 mg Compound (1) or the Compound (1) Form A and wherein the one or more loading dose is administered QD.

9. The method of any one of claims 1 to 5 and 8, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 7 consecutive days.

10. The method of any one of claims 1 to 5 and 8, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD 14 consecutive days.

11. The method of any one of claims 1 to 5 and 8, wherein each of the one or more loading doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more loading dose is administered QD for 28 consecutive days.

12. The method of any one of claims 1 to 7, wherein each of the one or more maintenance doses comprise about 100 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered once weekly (QW).

13. The method of any one of claims 1 to 5, 8, and 9, wherein each of the one or more maintenance doses comprise about 200 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QW.

14. The method of any one of claims 1 to 5, 8, 10, and 11, wherein each of the one or more maintenance doses comprise about 50 mg Compound (I) or the Compound (I) Form A and wherein the one or more maintenance dose is administered QD.

15. The method of any one of claims 1 to 14, wherein the Compound (I) or the Compound (I) Form A is administered in combination with at least one other anticancer agent.

16. The method of any one of claims 1 to 15, wherein the cancer is selected from a renal cancer, a glioblastoma, a neuroblastoma, a paraganglioma, a pheochromocytoma, a somatostatinoma, a hemangioblastoma, a gastrointestinal stromal tumor, a pituitary tumors, a bladder cancer, a liver cancer, a leiomyoma, a leiomyosarcoma, a polycythaemia, and a retinal cancer.

17. The method of any one of claims 1 to 16, wherein the at least one other anticancer agent is selected from abemaciclib, cemiplimab-rwlc, nivolumab, pembrolizumab, dostarlimab, atezolizumab, durvalumab, and avelumab.

18. The method of any one of claims 1 to 17, wherein the Compound (I) Form A is5 administered.

19. The method of any one of claims 1 to 18, wherein the Compound (I) Form A is micronized having a D90 value of 14 + 4 pm.

20. The method of any one of claims 1 to 18, wherein the Compound (I) Form A is micronized having a D90 value of 14 + 2 pm.10         21. The method of any one of claims 1 to 20, wherein the Compound (I) Form A ismicronized having a D50 value of 6 + 3 pm.

22. The method of any one of claims 1 to 20, wherein the Compound (I) Form A is micronized having a D50 value of 6 ± 1 pm.

23. The method of any one of claims 1 to 22, wherein the Compound (I) Form A is15 micronized having a D10 value of 3 + 2 pm.

24. The method of any one of claims 1 to 22, wherein the Compound (I) Form A is micronized having a D10 value of 3 + 0.5 pm.

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