A Study of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab in Participants With Clear Cell Renal Cell Carcinoma Post Nephrectomy (MK-6482-022)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of oral belzutifan (MK-6482) plus intravenous (IV) pembrolizumab (MK-3475) compared to placebo plus pembrolizumab, in the adjuvant treatment of Clear Cell Renal Cell Carcinoma (ccRCC) post nephrectomy. The primary study hypothesis is that belzutifan plus pembrolizumab is superior to placebo plus pembrolizumab with respect to disease-free survival (DFS).

Official Title
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A Multicenter, Double-blind, Randomized Phase 3 Study to Compare the Efficacy and Safety of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab in the Adjuvant Treatment of Clear Cell Renal Cell Carcinoma (ccRCC) Post Nephrectomy (MK-6482-022)

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Drug: Belzutifan
* Biological: Pembrolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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The main inclusion and exclusion criteria include but are not limited to the following: Inclusion Criteria: Has a histologically or cytologically confirmed diagnosis of RCC with clear cell component per American Joint Committee on Cancer (AJCC) (8th Edition), with or without sarcomatoid features Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as defined by the following pathological tumor-node metastasis and tumor grading: Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0 High risk RCC: pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0 M1 NED RCC participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following: the time of nephrectomy (synchronous) or, ≤2 years from nephrectomy (metachronous) Has undergone complete resection of the primary tumor (partial or radical nephrectomy) and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants Must have undergone a nephrectomy and/or metastasectomy ≤12 weeks prior to randomization Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days before randomization. Male participants must agree to continue contraception at least 7 days after the last dose of belzutifan/placebo Female participants of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of pembrolizumab or at least 30 days after last dose of belzutifan/placebo, whichever occurs last Has adequate organ function Exclusion Criteria: Has had a major surgery, other than nephrectomy plus resection of preexisting metastases for M1 NED participants, within 4 weeks prior to randomization Has a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen Has clinically significant cardiovascular disease within 6 months from first dose of study intervention Has other clinically significant disorders such as: serious active nonhealing wound/ulcer/bone fracture; requirement for hemodialysis or peritoneal dialysis Has preexisting brain or bone metastatic lesions Has received prior systemic therapy for RCC Has received prior radiotherapy for RCC Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention; administration of killed vaccines are allowed Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy Has a known additional malignancy (other than RCC treated with nephrectomy and/or metastasectomy) that is progressing or has required active treatment within the past 3 years Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy is allowed Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Has an active infection, requiring systemic therapy Has a known history of human immunodeficiency virus (HIV) infection, a known history of Hepatitis B or known active Hepatitis C virus infection Has had an allogenic tissue/solid organ transplant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belzutifan + Pembrolizumab<br>Participants receive belzutifan 120 mg orally once daily (QD) for up to approximately 54 weeks PLUS pembrolizumab 400 mg via intravenous (IV) infusion once every 6 weeks (Q6W) for up to 9 administrations (up to approximately 54 weeks). | Drug: Belzutifan<br>* Three 40 mg tablets given as a single oral 120 mg dose.<br>* Other names: WELIREG™;Biological: Pembrolizumab<br>* 400 mg via IV infusion<br>* Other names: Keytruda®;|
| Experimental: Placebo + Pembrolizumab<br>Participants receive placebo orally QD for up to approximately 54 weeks PLUS pembrolizumab 400 mg via IV infusion once Q6W for up to 9 administrations (up to approximately 54 weeks). | Biological: Pembrolizumab<br>* 400 mg via IV infusion<br>* Other names: Keytruda®;Drug: Placebo<br>* Oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS) | DFS is defined as the time from randomization to the first documented local recurrence, or occurrence of distant kidney cancer metastasis(es) as assessed by investigator, or death due to any cause, whichever occurs first. The DFS for all participants will be presented. | Up to approximately 54 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 89 months | 
| Number of Participants Who Experience at Least One Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE will be reported. | Up to approximately 66 weeks | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued the study due to an AE will be reported. | Up to approximately 54 weeks | 
| Disease Recurrence-Specific Survival 1 (DRSS1) | DRSS1 is defined as the time from randomization to the first documented local recurrence of RCC as assessed by the investigator. For DRSS1, only local recurrence is counted as an event. | Up to approximately 54 months | 
| Disease Recurrence-Specific Survival 2 (DRSS2) | DRSS2 is defined as the time from randomization to the first documented local recurrence with visceral lesion or occurrence of distant kidney cancer metastasis(es) with visceral lesion, whichever occurs first, as assessed by investigator. | Up to approximately 54 months | 
| Change From Baseline in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of participants with cancer. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined scores will be presented. | Baseline (Day 1) and up to approximately 36 months | 
| Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score | The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Higher scores indicate a worse level of function. Change from baseline in the score of EORTC QLQ-C30 Items 1-5 will be presented. | Baseline (Day 1) and up to approximately 36 months | 
| Change From Baseline in Role Functioning Using the EORTC QLQ-C30 Items 6 and 7 Score | The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to questions about their role functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Higher score indicate a worse level of function. Change from baseline in the score of EORTC QLQ-C30 Items 6-7 will be presented. | Baseline (Day 1) and up to approximately 36 months | 
| Change From Baseline in Disease Symptoms Using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) Items 1-9 Score | The FKSI-DRS index consists of a 9-item questionnaire that assesses the extent of participant symptoms from kidney cancer. Responses are scored on a 5-point scale (0=Not at all to 4=Very much) and summed to generate an index symptom score. These scores can range from 0 to 36, with a higher score indicating more favorable kidney cancer symptom status. Change from baseline in the score of FKSI-DRS Items 1-9 will be presented. | Baseline (Day 1) and up to approximately 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1(PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2), Hypoxia inducible factor 2 alpha (HIF-2 alpha), Hypoxia inducible factor 2α (HIF-2α)