Condition(s):Carcinoma, Renal Cell
Principal Investigator:Choueiri, Toni, K
Site Investigator(s):Gao, Xin,
McDermott, David, F.
Site Research Nurse(s):Bretta, Katherine, v.
Cash, Hanna, Marie
Gotthardt, Susan, Jean
Markt, Denise, A.
The primary objective of this study is to compare belzutifan to everolimus with respect to
progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1
(RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) and to compare
everolimus with respect to overall survival (OS). The hypothesis is that belzutifan is
superior to everolimus with respect to PFS and OS.
- Has unresectable, locally advanced or metastatic clear cell renal cell carcinoma (RCC)
- Has had disease progression on or after having received systemic treatment for locally
advanced or metastatic RCC with both Programmed cell death 1 ligand 1 (PD-1/L1)
checkpoint inhibitor and a vascular endothelial growth factor - tyrosine kinase
inhibitor (VEGF-TKI) in sequence or in combination.
- Has received no more than 3 prior systemic regimens for locally advanced or metastatic
- A male participant is eligible to participate if he is abstinent from heterosexual
intercourse or agrees to use contraception during the intervention period and for at
least 7 days after the last dose of study intervention
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least 1 of the following conditions applies: Not a (woman of
childbearing potential) WOCBP OR A WOCBP who agrees to follow the contraceptive
guidance during the intervention period and for at least 30 days after the last dose
of study intervention for those randomized to belzutifan and for at least 8 weeks
after the last dose of study intervention for those randomized to everolimus.
- The participant (or legally acceptable representative if applicable) has provided
documented informed consent for the study.
- Has adequate organ function
- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. (Participants with basal cell carcinoma of the skin, squamous
cell carcinoma of the skin, or carcinoma in situ [e.g., breast carcinoma, cervical
cancer in situ] that have undergone potentially curative therapy are not excluded.)
- Has known central nervous system (CNS) metastases and/or carcinomatous meningitis.
(Participants with previously treated brain metastases may participate provided they
are radiologically stable for at least 4 weeks (28 days) by repeat imaging.)
- Has clinically significant cardiac disease, including unstable angina, acute
myocardial infarction within 6 months from Day 1 of study medication administration,
or New York Heart Association Class III or IV congestive heart failure. (Medically
controlled arrhythmia stable on medication is permitted.)
- Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg
and/or diastolic blood pressure (DBP) ≥90 mm Hg.
- Has moderate to severe hepatic impairment (Child-Pugh B or C).
- Has a known psychiatric or substance abuse disorder that would interfere with
cooperation with the requirements of the study.
- Is unable to swallow orally administered medication or has a gastrointestinal disorder
affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption).
- Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any
component of the study intervention (belzutifan or everolimus) formulations.
- Has received prior treatment with belzutifan or another hypoxia inducible factor 2α
- Has received prior treatment with everolimus or any other specific or selective target
of rapamycin complex 1 (TORC1)/ phosphatidylinositol 3-kinase (PI3K)/ protein kinase B
(AKT) inhibitor (e.g., temsirolimus) in the advanced disease setting.
- Has received any type of systemic anticancer antibody (including investigational
antibody) within 4 weeks before randomization.
- Has received prior radiotherapy within 2 weeks prior to randomization.
- Has had major surgery within 3 weeks prior to randomization.
- Has received a live vaccine within 30 days prior to randomization. Examples of live
vaccines include, but are not limited to, the following: measles, mumps, rubella,
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG),
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed
virus vaccines and are allowed; however, intranasal influenza vaccines are live
attenuated vaccines and are not allowed.
- Is currently receiving either strong (e.g., itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin,
erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 3A4
(CYP3A4) that cannot be discontinued for the duration of the study.
- Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be
discontinued for the duration of the study.
- Is currently participating in a study of an investigational agent or is currently
using an investigational device.
- Has an active infection requiring systemic therapy.
- Has active bacillus tuberculosis (TB).
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to randomization.
- Has a known history of human immunodeficiency virus (HIV) infection. (Testing for HIV
at screening is only required if mandated by local health authority.
- Has a known history of Hepatitis B virus (HBV) (defined as Hepatitis B surface antigen
[HBsAg] reactive) or known active Hepatitis C virus (HCV) (defined as HCV ribonucleic
acid [RNA] [qualitative] is detected) infection.
Protocol #: 19-897