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A Study of Belzutifan and Zanzalintinib Compared to Cabozantinib in Patients with Advanced Kidney Cancer that Returned After Previous Treatment

Verified siteRegistered drugNo placebo
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What is this trial about?

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

This study involves people with advanced Renal Cell Carcinoma, which is a type of kidney cancer. The study will include people whose cancer came back either while they were receiving a specific type of treatment after surgery called adjuvant anti-programmed cell death therapy, or within 24 months after finishing that treatment. The study will test two different treatment approaches. One group of people will receive a combination of two medications called belzutifan (also known as MK-6482) and zanzalintinib (also known as XL092), while another group will receive a single medication called cabozantinib. All of these medications are taken by mouth in tablet form.

The purpose of this study is to compare how well the combination of belzutifan and zanzalintinib works against cabozantinib in treating advanced kidney cancer. The study will look at how long people live without their cancer getting worse and how long they live overall. The study will also measure how many people respond to treatment, meaning their cancer shrinks or disappears, and how long that response lasts.

During the study, people will be randomly assigned to receive either the combination treatment or cabozantinib alone. The study will track any unwanted effects that occur and whether people need to stop treatment because of these effects. The study will also measure quality of life and how well people are able to carry out daily activities using questionnaires that ask about physical health, ability to perform usual activities, and symptoms related to kidney cancer. The study will continue to follow people over time to gather information about how the treatments affect their cancer and overall health.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Random assignment to treatment group

    Upon joining the study, you will be randomly assigned to one of two treatment groups. This process is similar to flipping a coin and ensures fairness in the study.

    You will receive either the combination of belzutifan and zanzalintinib, or cabozantinib alone.

  2. Step 2

    Start of treatment

    You will begin taking your assigned medication by mouth in the form of tablets.

    If you are assigned to the combination group, you will take both belzutifan and zanzalintinib tablets.

    If you are assigned to the single medication group, you will take cabozantinib tablets.

    All medications are taken orally as tablets or film-coated tablets.

  3. Step 3

    Regular imaging assessments

    Throughout the study, you will undergo regular imaging scans to evaluate how your kidney cancer is responding to treatment.

    These assessments will follow standardized criteria called RECIST 1.1, which is a method used to measure changes in tumor size.

    Independent radiologists will review your scans to determine if the disease is stable, improving, or progressing.

  4. Step 4

    Safety monitoring

    Your health will be monitored regularly for any side effects or adverse events related to the treatment.

    If you experience any concerning symptoms or side effects, your treatment may be adjusted or stopped.

  5. Step 5

    Quality of life assessments

    You will be asked to complete questionnaires at regular intervals to assess your quality of life and how you are feeling.

    These questionnaires include the EORTC QLQ-C30, which evaluates your overall health, physical functioning, and ability to perform daily activities.

    You will also complete the FKSI-DRS questionnaire, which focuses on symptoms specifically related to kidney cancer.

    Your responses will help determine how the treatment affects your daily life and well-being.

  6. Step 6

    Continuation of treatment

    You will continue taking your assigned medication as long as the treatment is working and you are not experiencing unacceptable side effects.

    The study will monitor how long you remain without disease progression, which is called progression-free survival.

    The study will also track overall survival, which measures how long participants live during and after the study.

  7. Step 7

    Response evaluation

    Your medical team will assess whether your cancer responds to treatment, including whether tumors shrink or disappear.

    If your cancer responds to treatment, the duration of that response will be measured to understand how long the benefit lasts.

  8. Step 8

    Study completion or discontinuation

    You will remain in the study until your disease progresses, you experience side effects that require stopping treatment, or the study ends.

    The study is expected to continue until December 2031, though your individual participation may be shorter depending on your response to treatment.

Who can join the trial?

5 criteria

  • You must have a confirmed diagnosis through tissue examination of renal cell carcinoma, which is a type of kidney cancer, that cannot be removed by surgery and has spread to other parts of the body. The cancer must have a clear cell component, which is a specific type of kidney cancer cell, and it may or may not have sarcomatoid features, which means certain aggressive cell characteristics.
  • You must have cancer that can be measured using imaging scans according to specific medical guidelines called RECIST 1.1, which are standards used to measure tumor size and response to treatment.
  • Your cancer must have returned either while you were receiving a specific type of preventive treatment called adjuvant anti-PD-1/L1 therapy, which is a type of immunotherapy given after initial treatment to prevent cancer from coming back, or your cancer must have returned within 24 months after finishing this preventive treatment.
  • You must not have received any other treatments for your kidney cancer except for the preventive anti-PD-1/L1 therapy mentioned above.
  • You must be an adult aged 18 years or older.

Who cannot join the trial?

1 criterion

  • No specific exclusion criteria have been provided for this clinical trial in the available information.
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Investigated drugs

  • Belzutifan

    is a medicine being tested in this study. It works by blocking a protein that helps cancer cells grow and survive when oxygen levels are low. In this trial, it is being given together with another medication to treat kidney cancer that has come back after previous treatment.

  • Zanzalintinib

    is a medicine being tested in combination with belzutifan. It works by blocking certain proteins that help cancer cells grow and form new blood vessels that feed the tumor. This medication is being studied to see if it can help stop kidney cancer from getting worse.

  • Cabozantinib

    is a medication used to treat advanced kidney cancer. It works by blocking proteins that help cancer cells grow and spread, and also blocks the formation of new blood vessels that tumors need to grow. In this study, it is being compared to the combination of belzutifan and zanzalintinib to see which treatment works better.

What is already known about the treatment

  • Belzutifan

    Belzutifan is a medication taken by mouth in tablet form that is used to treat certain types of kidney cancer, including advanced renal cell carcinoma. It works by blocking a protein called HIF-2 alpha, which helps cancer cells grow and survive by allowing them to adapt to low oxygen conditions. This medication is approved for use in several countries and is being studied in combination with other cancer treatments to help slow down or stop the growth of kidney tumors. Belzutifan belongs to a class of drugs called HIF-2 alpha inhibitors, which represent a newer approach to targeting cancer cells.

  • Zanzalintinib

    Zanzalintinib is an investigational medication given by mouth that is currently being studied in clinical trials for the treatment of advanced kidney cancer. It works by blocking multiple proteins called tyrosine kinases that help cancer cells grow, form new blood vessels, and spread to other parts of the body. This medication is not yet approved for general use and is being tested in combination with other cancer drugs to determine if it can effectively treat renal cell carcinoma. Zanzalintinib belongs to a group of medicines known as multi-targeted tyrosine kinase inhibitors, which interfere with several pathways that cancer cells use to survive and multiply.

  • Cabozantinib

    Cabozantinib is an oral medication in tablet form that is approved for treating advanced kidney cancer and other types of cancer. It works by blocking several proteins called tyrosine kinases, including VEGF receptors and MET, which cancer cells need to grow, create new blood vessels, and spread throughout the body. This medication is widely used in clinical practice and has been shown to help slow the progression of renal cell carcinoma in patients whose disease has advanced or spread. Cabozantinib is classified as a multi-targeted tyrosine kinase inhibitor, which means it attacks cancer through multiple pathways at once.

Investigated diseases

Renal Cell Carcinoma – Renal cell carcinoma is a type of kidney cancer that begins in the lining of the small tubes within the kidneys. These tubes help filter waste from the blood and produce urine. The disease occurs when cells in the kidney grow abnormally and form a mass or tumor. As the condition progresses, the cancerous cells can multiply and the tumor may increase in size. In advanced stages, the cancer cells may spread beyond the kidney to other parts of the body through the bloodstream or lymphatic system. The progression of the disease can affect kidney function and cause various symptoms as it advances.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2024-517136-21-00Protocol codeMK-6482-033Estimated enrolment904 patientsSponsorMerck Sharp & Dohme LLC

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