A Trial of Belzutifan (PT2977, MK-6482) in Combination With Cabozantinib in Patients With Clear Cell Renal Cell Carcinoma (ccRCC) (MK-6482-003)

Study Overview
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Brief Summary
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This is an open-label Phase 2 study which will evaluate the efficacy and safety of belzutifan in combination with cabozantinib in participants with advanced ccRCC. Belzutifan and cabozantinib will be administered orally once daily.

Official Title
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A Phase 2 Trial of PT2977 in Combination With Cabozantinib in Patients With Advanced Clear Cell Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma (RCC), Clear Cell Renal Cell Carcinoma (ccRCC), Kidney Cancer, Renal Cancer, Renal Cell Carcinoma, Renal Cell Cancer Metastatic, Renal Cell Carcinoma Recurrent, Renal Cell Cancer, Recurrent, Kidney

Intervention / Treatment
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* Drug: Belzutifan
* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has locally advanced or metastatic RCC with predominantly clear cell subtype Has at least one measurable lesion as defined by RECIST version 1.1 Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Has adequate organ function defined as follows: Absolute neutrophil count ≥ 1,000/µL, hemoglobin level ≥ 10 g/dL and platelet count ≥ 100,000/µL without transfusion or growth factor support within 2 weeks prior to obtaining the hematology values at screening; Serum creatinine level ≤ 2.0 × upper limit of normal (ULN) Transaminase levels (AST/ALT) ≤ 3.0 × upper limit of normal (ULN); total bilirubin (TBILI) ≤ 1.5 mg/dL in the absence of Gilbert's disease *Cohort 1: Participants must not have received prior systemic therapy for advanced or metastatic ccRCC Cohort 2: Participants must have received prior immunotherapy and no more than two prior treatments for advanced or metastatic ccRCC Exclusion Criteria: Has received prior treatment with belzutifan or other HIF2α inhibitors Has received prior treatment with cabozantinib Has had radiation therapy for bone metastases within two weeks of starting study drug Has a history of untreated brain metastases or history of leptomeningeal disease or spinal cord compression Has failed to recover from the reversible effects of prior anticancer therapy Has uncontrolled or poorly controlled hypertension Is receiving anticoagulant therapy Has had any major cardiovascular event within 6 months prior to study drug administration Has any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with participation in the trial or interfere with the interpretation of trial results Has had major surgery within 3 months before first study drug administration Has an active infection requiring systemic treatment Is participating in another therapeutic clinical trial

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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Belzutifan in combination with cabozantinib administered orally once daily
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belzutifan + Cabozantinib: Treatment Naïve (Cohort 1)<br>Naïve participants will receive 120 mg belzutifan and 60 mg cabozantinib orally once daily (QD) at the same time. | Drug: Belzutifan<br>* Belzutifan tablets administered orally.<br>* Other names: WELIREG™;Drug: Cabozantinib<br>* Cabozantinib tablets administered orally.<br>* Other names: CABOMETYX®;|
| Experimental: Belzutifan + Cabozantinib: Prior Immunotherapy (Cohort 2)<br>Participants who have received prior immunotherapy will receive 120 mg belzutifan and 60 mg cabozantinib orally QD at the same time. | Drug: Belzutifan<br>* Belzutifan tablets administered orally.<br>* Other names: WELIREG™;Drug: Cabozantinib<br>* Cabozantinib tablets administered orally.<br>* Other names: CABOMETYX®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with a best confirmed response of Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as determined by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the interval from the start of study treatment until the earlier of the first documentation of disease progression determined by RECIST 1.1 or death from any cause. | Up to approximately 2 years | 
| Duration of Response (DOR) | DOR is defined as the interval from the first documentation of response, as determined by RECIST 1.1, to the earlier of the first documentation of disease progression or death from any cause, and calculated for participants with a best confirmed response of CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions). | Up to approximately 2 years | 
| Time to Response (TTR) | TTR is defined as the interval from the start of study treatment to the first documentation of a response, as determined by RECIST 1.1, and calculated for participants with a best confirmed response of CR or PR. | Up to approximately 2 years | 
| Overall Survival (OS) | OS is defined as the interval from the start of treatment to the death of the participant from any cause. | Up to approximately 2 years | 
| Number of participants experiencing an Adverse Event (AE) | An AE is defined as any untoward medical occurrence in a participant regardless of its causal relationship to study treatment. An AE can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not it is considered to be study drug related. Included in this definition are any newly occurring events and any previous condition that has increased in severity or frequency since the administration of study drug. | Up to approximately 2 years | 
| Number of participants discontinuing study treatment due to an Adverse Event (AE) | An AE is defined as any untoward medical occurrence in a participant regardless of its causal relationship to study treatment. An AE can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not it is considered to be study drug related. Included in this definition are any newly occurring events and any previous condition that has increased in severity or frequency since the administration of study drug. | Up to approximately 2 years | 
| Belzutifan Plasma Concentration | Blood samples for the determination of belzutifan concentration will be collected at pre-specified timepoints before and after treatment administration. | Weeks 1 and 4: pre-dose, 2 and 6 hours post-dose | 
| Belzutifan Metabolite Plasma Concentration | Blood samples for the determination of belzutifan metabolite concentration will be collected at pre-specified timepoints before and after treatment administration. | Weeks 1 and 4: pre-dose, 2 and 6 hours post-dose | 
| Cabozantinib Plasma Concentration | Blood samples for the determination of cabozantinib concentration will be collected at pre-specified timepoints before and after treatment administration. | Weeks 1 and 4: pre-dose, 2 and 6 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypoxia-inducible factor (HIF), hypoxia-inducible factor 2 alpha (HIF-2α, HIF-2 alpha)