A Study of Belzutifan (MK-6482) in Combination With Palbociclib Versus Belzutifan Monotherapy in Participants With Advanced Renal Cell Carcinoma (MK-6482-024/LITESPARK-024)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of belzutifan monotherapy and belzutifan plus palbociclib combination therapy in participants with advanced clear-cell renal cell carcinoma (ccRCC) who experienced disease progression on or after receiving prior therapy. Part 1 will establish the safety of belzutifan plus palbociclib and determine a recommended dosage of palbociclib for the combination therapy by ascending dose escalation. Part 2 will evaluate the efficacy and safety of belzutifan plus palbociclib at the dosage level determined in Part 1.

Official Title
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A Multicenter, Open-label, Randomized, Phase 1/2 Study of Belzutifan in Combination With Palbociclib Versus Belzutifan Monotherapy in Participants With Advanced Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Belzutifan
* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically confirmed diagnosis of unresectable Stage IV (per American Joint Committee on Cancer [AJCC], 8th Edition) RCC with clear-cell component Has had disease progression on or after having received at least 2 systemic treatments for unresectable Stage IV RCC with prior anti-programmed cell death 1 ligand 1 (PD-1/L1) and a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) in sequence or in combination Has measurable disease per RECIST 1.1 as assessed by the investigator and verified by blinded independent central review (BICR) Has recovered from all AEs due to previous therapies Exclusion Criteria: Has hypoxia, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen Has a known additional malignancy that is progressing or has required active treatment within the past 3 years Has known central nervous system (CNS) metastases and/or carcinomatous meningitis Has clinically significant cardiac disease Has moderate to severe hepatic impairment Has a known history of human immunodeficiency virus (HIV) infection Has a history of hepatitis B (HBV) or known active hepatitis C (HCV) infection Has received prior treatment of belzutifan or palbociclib Has received prior radiotherapy ≤2 weeks prior to first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids Has had major surgery ≤3 weeks prior to first dose of study intervention Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin [EPO]) ≤28 days prior to the first dose of study intervention

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - Beltuzifan 120 mg + Palbociclib 75 mg<br>Participants receive beltuzifan 120 mg orally once per day (QD) and palbociclib 75 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. | Drug: Belzutifan<br>* 40 mg tablet administered orally at a dose of 120 mg.<br>* Other names: PT2977;Drug: Palbociclib<br>* 75, 100, or 125 mg tablet administered orally according to randomized dose for 21 days consecutive days followed by 7 days off.<br>* Other names: PD 0332991;|
| Experimental: Part 1 - Beltuzifan 120 mg + Palbociclib 100 mg<br>Participants receive beltuzifan 120 mg orally QD and palbociclib 100 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. | Drug: Belzutifan<br>* 40 mg tablet administered orally at a dose of 120 mg.<br>* Other names: PT2977;Drug: Palbociclib<br>* 75, 100, or 125 mg tablet administered orally according to randomized dose for 21 days consecutive days followed by 7 days off.<br>* Other names: PD 0332991;|
| Experimental: Part 1 - Beltuzifan 120 mg + Palbociclib 125 mg<br>Participants receive beltuzifan 120 mg orally QD and palbociclib 125 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. | Drug: Belzutifan<br>* 40 mg tablet administered orally at a dose of 120 mg.<br>* Other names: PT2977;Drug: Palbociclib<br>* 75, 100, or 125 mg tablet administered orally according to randomized dose for 21 days consecutive days followed by 7 days off.<br>* Other names: PD 0332991;|
| Experimental: Part 2 - Beltuzifan 120 mg + Palbociclib<br>Participants receive beltuzifan 120 mg orally QD and palbociclib orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. Palbociclib will be administered at a dosage level determined in Part 1. | Drug: Belzutifan<br>* 40 mg tablet administered orally at a dose of 120 mg.<br>* Other names: PT2977;Drug: Palbociclib<br>* 75, 100, or 125 mg tablet administered orally according to randomized dose for 21 days consecutive days followed by 7 days off.<br>* Other names: PD 0332991;|
| Experimental: Part 2 - Beltuzifan 120 mg<br>Participants receive beltuzifan 120 mg orally QD until progressive disease or discontinuation. | Drug: Belzutifan<br>* 40 mg tablet administered orally at a dose of 120 mg.<br>* Other names: PT2977;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 - Number of Participants Who Experience at Least One Dose-limiting Toxicity (DLT) | A DLT consists of one or more of the following toxicities: Grade (Gr) 3 or 4 hypoxia or dyspnea; Gr 3 or 4 nausea, vomiting, or diarrhea if persistent for >48 hours despite therapy; Gr 3 or 4 cardiovascular, vascular, or thrombotic events; Nonhematologic AE ≥Gr 3 in severity with exceptions; Gr 3 rash that does not resolve within 2 weeks; Gr 3 nonhematologic toxicity if persisting despite optimal medical treatment; Gr 3 or 4 hematologic toxicities; Gr 3 or 4 febrile neutropenia; Gr 3 or 4 nonhematologic laboratory value; Any aspartate aminotransferase or alanine aminotransferase >8x the upper limit of normal (ULN) or 5 to 8x ULN persisting for >2 weeks; >2 weeks delay in dosing due to intervention-related toxicity; Intervention-related toxicity causing intervention discontinuation in the first 28 days of dosing; Missing >20% of intervention doses due to drug-related AEs; Gr 5 toxicity. The number of participants who experience at least one DLT will be reported for Part 1. | Up to approximately 28 days | 
| Part 1 - 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. The number of participants who experience at least one AE will be reported for Part 1. | Up to approximately 4.5 years | 
| Part 1 - Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. The number of participants who discontinued from the study treatment due to an AE will be reported for Part 1. | Up to approximately 4.5 years | 
| Part 2 - Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator | ORR is defined as the percentage of participants who have a complete response (CR: Disappearance of all target lesions) or a partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience a CR or PR as assessed by the investigator based on RECIST 1.1 will be presented for Part 2. | Up to approximately 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2 - Clinical Benefit Rate (CBR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator | CBR is defined as the percentage of participants who have a complete response (CR: Disappearance of all target lesions) or a partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD: Neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study) for ≥6 months per RECIST 1.1. The percentage of participants with CBR will be presented for Part 2. | Up to approximately 4.5 years | 
| Part 2 - Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator | For participants who demonstrate a confirmed complete response (CR: Disappearance of all target lesions) or confirmed partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR as assessed by the investigator will be presented for Part 2. | Up to approximately 4.5 years | 
| Part 2 - Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by the investigator will be presented for Part 2. | Up to approximately 4.5 years | 
| Part 2 - Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. OS will be reported for Part 2. | Up to approximately 4.5 years | 
| Part 2 - 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. The number of participants who experience at least one AE will be reported for Part 2. | Up to approximately 4.5 years | 
| Part 2 - Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. The number of participants who discontinued from the study treatment due to an AE will be reported for Part 2. | Up to approximately 4.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed cell death ligand 1 (PD-L1), Hypoxia inducible factor 2 alpha (HIF-2 alpha), Hypoxia inducible factor 2α (HIF-2α), Renal Cell Carcinoma (RCC), Kidney Cancer