Combination belzutifan plus zanzalintinib for recurrent clear cell renal cell carcinoma after anti‑PD‑(L)1 adjuvant therapy

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

What this trial studies

Substudy 03C enrolls participants with recurrent clear cell renal cell carcinoma after prior adjuvant anti‑PD‑(L)1 therapy and gives an oral combination of belzutifan (a HIF‑2α inhibitor) and zanzalintinib (a VEGFR‑targeted agent). The trial includes a safety lead‑in phase to establish a tolerable dose and an efficacy phase to measure clinical activity such as response and duration. Participants must provide tumor tissue, be able to take oral medication, and have controlled blood pressure among other eligibility requirements. There is no formal hypothesis testing; the focus is on safety, tolerability, and signals of anti‑tumor activity to inform further development.

Why it matters

Who can join: the full rules

The main inclusion criteria include but are not limited to the following:

* Has a histologically confirmed diagnosis of unresectable locally advanced/metastatic renal cell carcinoma (RCC) with clear cell component
* Has received no other prior systemic therapy for treatment of advanced/metastatic clear cell renal cell carcinoma (ccRCC) except for adjuvant programmed cell death ligand 1 (PD-(L)1) therapy
* Has disease recurrence during adjuvant anti- PD-(L)1 therapy or ≤24 months following the last dose of adjuvant anti-PD-(L)1 therapy
* Is able to swallow oral medication
* Submits an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
* Participants receiving bone resorptive therapy (must have therapy initiated at least 2 weeks before allocation/randomization)
* Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤140/90 mm Hg with no change in antihypertensive medications within 1 week before allocation/randomization
* Has adequate organ function

The main exclusion criteria include but are not limited to the following:

* Has clinically significant hematuria, hematemesis, or hemoptysis of (\>2.5 mL) of red blood, or other history of significant bleeding
* Has clinically significant cardiovascular disease within 12 months from first dose of study intervention
* Has deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization
* Has history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis
* Has serious wound, ulcer or bone fracture or has had major surgery within 8 weeks before first dose of study intervention
* Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage in the last 4 weeks before allocation/randomization
* Has gastrointestinal (GI) disorders, including those associated with a high risk of perforation or fistula formation
* Has malabsorption due to prior GI surgery or GI disease
* Has moderate to severe hepatic impairment
* Has received colony-stimulating factors within 28 days prior to intervention allocation/randomization
* Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids
* Is currently receiving strong inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study
* Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention
* Is currently receiving anticoagulants or platelet inhibitors that cannot be discontinued for the duration of the study
* Have been previously allocated/randomized to study intervention in any sub study of protocol MK-3475-U03
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
* Has active autoimmune disease that has required systemic treatment in the past 2 years
* Has an active infection requiring systemic therapy
* Has history of human immunodeficiency virus (HIV) infection
* Has hepatitis B or hepatitis C virus infection

Where it's running

• UCSF Medical Center at Mission Bay ( Site 5008)
  San Francisco, California, United States Recruiting
• Perlmutter Cancer Center at NYU Langone Hospital - Long Island ( Site 5026)
  Mineola, New York, United States Recruiting
• Laura and Isaac Perlmutter Cancer Center ( Site 5016)
  New York, New York, United States Recruiting
• Memorial Sloan Kettering Cancer Center ( Site 5002)
  New York, New York, United States Recruiting
• Duke Cancer Institute ( Site 5015)
  Durham, North Carolina, United States Recruiting
• UPMC Cancer Center/Hillman Cancer Center ( Site 5017)
  Pittsburgh, Pennsylvania, United States Recruiting

Study contacts

• Study coordinator: Toll Free Number
• Email: Trialsites@msd.com
• Phone: 1-888-577-8839

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.