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Belzutifan and Zanzalintinib in Adults with Advanced Renal Cell Carcinoma After PD-1/L1 and VEGF-TKI Therapy

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is studying renal cell carcinoma, a type of kidney cancer that is advanced and has gotten worse after previous treatment. The study compares two treatment approaches: belzutifan taken by mouth together with zanzalintinib, or belzutifan taken by mouth together with placebo. Zanzalintinib is also known by the code name XL092. The purpose of the study is to see which treatment helps people live longer and keeps the cancer from getting worse for a longer time.

People in the study are assigned by chance to one of the two treatment groups, and neither the study team nor the participants know which treatment is being given. The treatment is taken as tablets over time, with regular study visits during the trial. During these visits, the study team checks for side effects and overall health, and asks about symptoms and daily well-being.

The trial is looking at adults with advanced kidney cancer who have already received treatment with PD-1/L1 and VEGF-TKI medicines, either one after the other or together. PD-1/L1 and VEGF-TKI are types of cancer medicines that act in different ways to slow tumor growth. The study follows participants while they receive treatment and for some time afterward to understand the effects of the medicine combination over time.

The research process

The trial runs in 4 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Study treatment begins

    After joining the study, your treatment starts with belzutifan taken by mouth at a dose of 120 mg.

    You also receive a second tablet by mouth. This is either zanzalintinib (XL092) or placebo. A placebo is a tablet that looks like the study drug but does not contain active medicine.

    The study is randomized, which means the treatment group is assigned by chance.

    The study is double-blind, which means the study treatment is not identified to the patient during the trial.

  2. Step 2

    Daily tablet use during the trial

    You take belzutifan 120 mg by mouth during the treatment period.

    You take zanzalintinib (XL092) by mouth if that treatment is assigned to you, or you take placebo if that is assigned to you.

    The source data lists XL092 as an oral tablet, but it does not provide a dose amount in milligrams.

    The source data does not state the exact daily schedule, timing, or total duration of each medicine, so only the medicines and doses listed above can be described.

  3. Step 3

    Study follow-up and measurement of results

    During the trial, your disease is checked for signs of worsening or improvement. The main measure is progression-free survival (PFS), which means the length of time you live without the cancer getting worse.

    Another main measure is overall survival (OS), which means the length of time from study treatment start until death from any cause.

    The study also measures objective response rate (ORR), which means how many participants have their cancer shrink.

    The study measures duration of response (DOR), which means how long a response lasts after the cancer shrinks.

    The study records adverse events (AEs), which are unwanted medical problems or side effects.

    The study records whether any adverse events lead to stopping study treatment.

    The study checks changes in quality of life using the EORTC QLQ-C30. This is a questionnaire about health and daily functioning. The global health status and quality of life items ask about overall health and overall quality of life.

    The study checks physical functioning using the EORTC QLQ-C30 items about physical activity, and role functioning using the items about daily roles and activities.

    The study checks disease symptoms using the FKSI-DRS. This is a questionnaire about symptoms related to kidney cancer.

    The study also measures time to deterioration, which means how long it takes before symptoms or quality of life get worse on these questionnaires.

  4. Step 4

    End of study treatment period

    At the end of the treatment period, study treatment stops.

    The trial continues to assess the main outcomes of PFS and OS as part of the study design.

Who can join the trial?

5 criteria

  • Has a confirmed diagnosis based on tissue testing of unresectable advanced renal cell carcinoma with a clear cell component, with or without sarcomatoid features. This means the cancer has been proven by examining a sample of tissue, cannot be removed with surgery, and is at an advanced stage.
  • Has Stage IV renal cell carcinoma, which means the cancer has spread beyond the kidney.
  • Has measurable disease, meaning the tumors can be seen and measured on scans using a standard method called RECIST 1.1 (Response Evaluation Criteria In Solid Tumors, version 1.1).
  • Has received no more than 3 prior systemic treatment regimens for renal cell carcinoma. A systemic treatment regimen is a cancer treatment that works throughout the body, such as medicine given by mouth or through a vein.
  • Has received only 1 prior anti-PD-1 or anti-PD-L1 therapy. These are treatments that help the immune system attack cancer by blocking certain proteins called Programmed Cell Death-1 and Programmed Cell Death-Ligand 1.

Who cannot join the trial?

12 criteria

  • Has an oxygen level below 92% at rest, as measured by a finger oxygen monitor.
  • Needs oxygen treatment from time to time or has needed long-term oxygen treatment.
  • Has had a solid organ transplant, such as a transplant of the kidney, liver, heart, or lung.
  • Has not recovered well enough from major surgery, or still has problems caused by surgery.
  • Has had a serious heart or blood vessel problem within 12 months before starting the study.
  • Has had a deep vein thrombosis within 3 months before randomization, unless it has been stable, caused no symptoms, and has been treated with therapeutic anticoagulation for at least 4 weeks before randomization. Deep vein thrombosis means a blood clot in a deep vein, usually in a leg.
  • Has a left ventricular ejection fraction of 50% or less, or below the normal range for the local hospital or laboratory. Left ventricular ejection fraction means how well the main pumping chamber of the heart pushes blood out.
  • Has had major surgery within 8 weeks before randomization.
  • Has pneumonitis or interstitial lung disease now. Pneumonitis means inflammation of the lungs, and interstitial lung disease means long-term lung scarring or inflammation.
  • Has a history of HIV infection.
  • Has hepatitis B or hepatitis C infection. These are viral infections that affect the liver.
  • Has another cancer that is getting worse or has needed active treatment within the past 3 years.
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Investigated drugs

  • XL092 (zanzalintinib)

    is an oral tablet being tested in this study. It is the experimental medicine being added to belzutifan to see if the two drugs together can better slow or stop kidney cancer from growing after earlier treatments have stopped working.

  • Belzutifan

    is an oral medicine already being used in the trial as part of both treatment groups. It is given to participants to help treat advanced kidney cancer, and the study is checking whether adding zanzalintinib improves the results compared with belzutifan alone plus placebo.

What is already known about the treatment

  • XL092 (zanzalintinib)

    XL092, also known as zanzalintinib, is an oral tablet taken by mouth, and it is still an investigational medicine in clinical studies rather than an approved standard treatment. It is being studied for advanced kidney cancer, especially renal cell carcinoma, often in combination with other cancer medicines. It belongs to the class of targeted cancer drugs called tyrosine kinase inhibitors, and it works by blocking several signals that cancer cells and tumor blood vessels use to grow and survive, helping slow tumor growth and reduce blood supply to the tumor.

  • Belzutifan

    Belzutifan is an oral medicine taken by mouth, usually as a tablet, and it is an approved cancer treatment that is also widely discussed in medical literature for kidney cancer and some related conditions. It is used mainly for renal cell carcinoma and certain tumors linked to low oxygen control problems in the body. It belongs to a group of targeted cancer medicines called HIF-2 alpha inhibitors, and it works by blocking a protein that helps cancer cells respond to low oxygen, which can reduce signals that support tumor growth and new blood vessel formation.

Investigated diseases

Renal Cell Carcinoma - Renal cell carcinoma is a cancer that starts in the kidney, most often in the cells that line the small tubes inside the kidney. It usually grows slowly at first, but over time it can increase in size and spread into nearby tissue or to other parts of the body. Some forms may stay confined to the kidney for a long time, while others develop more quickly.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2024-516993-31-00Protocol codeMK-6482-034Estimated enrolment748 patientsSponsorMerck Sharp & Dohme LLC

sourced from the EU Clinical Trials Register and site verification

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