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)

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

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. The study will establish the safety of belzutifan plus palbociclib and determine a recommended dosage of palbociclib for the combination therapy by ascending dose escalation.

Study Overview

• Status: Active, not recruiting
• Conditions: Renal Cell Carcinoma
• Intervention / Treatment: Drug: Belzutifan; Drug: Palbociclib

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Macquarie University, New South Wales, Australia, 2109
      • Macquarie University-MQ Health Clinical Trials Unit ( Site 2001)
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital ( Site 2006)
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Frankston Hospital-Oncology and Haematology ( Site 2005)
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • One Clinical Research ( Site 2008)
• Israel
  • Afula, Israel, 1834111
    • Emek Medical Center-oncology ( Site 3003)
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus-Oncology ( Site 3000)
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center-Oncology ( Site 3002)
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center-Oncology ( Site 3004)
  • Tel Aviv, Israel, 6423906
    • Sourasky Medical Center ( Site 3005)
• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University Medical Center ( Site 1002)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center ( Site 1007)
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center-Cancer Clinical Trials Office ( Site 1001)
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute-HCI Clinical Trials Office ( Site 1004)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Beltuzifan 120 mg + Palbociclib 75 mg; 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; 40 mg tablet administered orally at a dose of 120 mg.; Other Names: MK-6482; PT2977; WELIREG™; Drug: Palbociclib; 75, 100, or 125 mg tablet administered orally according to randomized dose for 21 days consecutive days followed by 7 days off.; Other Names: PD 0332991; IBRANCE®
Experimental: Beltuzifan 120 mg + Palbociclib 100 mg; 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; 40 mg tablet administered orally at a dose of 120 mg.; Other Names: MK-6482; PT2977; WELIREG™; Drug: Palbociclib; 75, 100, or 125 mg tablet administered orally according to randomized dose for 21 days consecutive days followed by 7 days off.; Other Names: PD 0332991; IBRANCE®
Experimental: Beltuzifan 120 mg + Palbociclib 125 mg; 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; 40 mg tablet administered orally at a dose of 120 mg.; Other Names: MK-6482; PT2977; WELIREG™; Drug: Palbociclib; 75, 100, or 125 mg tablet administered orally according to randomized dose for 21 days consecutive days followed by 7 days off.; Other Names: PD 0332991; IBRANCE®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to approximately 28 days
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.	Up to approximately 4 years
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.	Up to approximately 4 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 6 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 6 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 6 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 6 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 6 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 6 years

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Meiman D, Skaar TC, Shugg T, Quinney SK. Physiologically Based Pharmacokinetic Model to Assess the Drug-Drug-Gene Interaction Potential of Belzutifan in Combination With Cyclin-Dependent Kinase 4/6 Inhibitors. JCO Precis Oncol. 2025 Jul;9:e2500153. doi: 10.1200/PO-25-00153. Epub 2025 Jul 25.

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Estimated): July 21, 2026
• Study Completion (Estimated): July 21, 2026

Study Registration Dates

• First Submitted: July 18, 2022
• First Submitted That Met QC Criteria: July 18, 2022
• First Posted (Actual): July 21, 2022

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 22, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Hypoxia inducible factor 2 alpha (HIF-2 alpha); Hypoxia inducible factor 2α (HIF-2α); Renal Cell Carcinoma (RCC); Kidney Cancer; Programmed cell death ligand 1 (PD-L1)
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; palbociclib; belzutifan
• Other Study ID Numbers: 6482-024; MK-6482-024 (Other Identifier: MSD); LITESPARK-024 (Other Identifier: MSD); U1111-1290-4845 (Registry Identifier: UTN); 2023-504963-17-00 (Registry Identifier: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No