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

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ClinicalTrials.gov Identifier: NCT05468697
Recruitment Status : Recruiting
First Posted : July 21, 2022
Last Update Posted : November 25, 2022
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Renal Cell Carcinoma Drug: Belzutifan Drug: Palbociclib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 10, 2022
Estimated Primary Completion Date : March 16, 2027
Estimated Study Completion Date : March 16, 2027


Arm Intervention/treatment
Experimental: Part 1 - 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:
  • WELIREG™
  • MK-6482
  • PT2977

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:
  • IBRANCE®
  • PD 0332991

Experimental: Part 1 - 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:
  • WELIREG™
  • MK-6482
  • PT2977

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:
  • IBRANCE®
  • PD 0332991

Experimental: Part 1 - 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:
  • WELIREG™
  • MK-6482
  • PT2977

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:
  • IBRANCE®
  • PD 0332991

Experimental: Part 2 - Beltuzifan 120 mg + Palbociclib
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
40 mg tablet administered orally at a dose of 120 mg.
Other Names:
  • WELIREG™
  • MK-6482
  • PT2977

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:
  • IBRANCE®
  • PD 0332991

Experimental: Part 2 - Beltuzifan 120 mg
Participants receive beltuzifan 120 mg orally QD until progressive disease or discontinuation.
Drug: Belzutifan
40 mg tablet administered orally at a dose of 120 mg.
Other Names:
  • WELIREG™
  • MK-6482
  • PT2977




Primary Outcome Measures :
  1. Part 1 - Number of Participants Who Experience at Least One Dose-limiting Toxicity (DLT) [ Time Frame: Up to approximately 28 days ]
    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.

  2. Part 1 - Number of Participants Who Experience at Least One Adverse Event (AE) [ Time Frame: Up to approximately 4.5 years ]
    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.

  3. Part 1 - Number of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: Up to approximately 4.5 years ]
    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.

  4. Part 2 - Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator [ Time Frame: Up to approximately 4.5 years ]
    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.


Secondary Outcome Measures :
  1. Part 2 - Clinical Benefit Rate (CBR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator [ Time Frame: Up to approximately 4.5 years ]
    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.

  2. Part 2 - Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator [ Time Frame: Up to approximately 4.5 years ]
    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.

  3. Part 2 - Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator [ Time Frame: Up to approximately 4.5 years ]
    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.

  4. Part 2 - Overall Survival (OS) [ Time Frame: Up to approximately 4.5 years ]
    OS is defined as the time from randomization to death due to any cause. OS will be reported for Part 2.

  5. Part 2 - Number of Participants Who Experience at Least One Adverse Event (AE) [ Time Frame: Up to approximately 4.5 years ]
    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.

  6. Part 2 - Number of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: Up to approximately 4.5 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05468697


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
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United States, District of Columbia
Georgetown University Medical Center ( Site 1002) Recruiting
Washington, District of Columbia, United States, 20007
Contact: Study Coordinator    617-797-5460      
Australia, New South Wales
Macquarie University-MQ Health Clinical Trials Unit ( Site 2001) Recruiting
Macquarie University, New South Wales, Australia, 2109
Contact: Study Coordinator    +61298122956      
Israel
Rambam Health Care Campus-Oncology ( Site 3000) Recruiting
Haifa, Israel, 3109601
Contact: Study Coordinator    +972-4-7776400      
Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
Additional Information:
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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT05468697    
Other Study ID Numbers: 6482-024
MK-6482-024 ( Other Identifier: Merck )
LITESPARK-024 ( Other Identifier: Merck )
First Posted: July 21, 2022    Key Record Dates
Last Update Posted: November 25, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme LLC:
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
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Palbociclib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action