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A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, Versus Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)

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ClinicalTrials.gov Identifier: NCT04736706
Recruitment Status : Recruiting
First Posted : February 3, 2021
Last Update Posted : March 30, 2023
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:

The goal of this study is to evaluate the efficacy and safety of pembrolizumab plus belzutifan plus lenvatinib or pembrolizumab/quavonlimab plus lenvatinib versus pembrolizumab plus lenvatinib as first-line treatment in participants with advanced clear cell renal cell carcinoma (ccRCC).

The primary hypotheses are (1) pembrolizumab plus belzutifan plus lenvatinib is superior to pembrolizumab plus lenvatinib with respect to progression-free survival (PFS) and overall survival (OS), in advanced ccRCC participants; and (2) pembrolizumab/quavonlimab plus lenvatinib is superior to pembrolizumab plus lenvatinib with respect to PFS and OS, in advanced ccRCC participants.


Condition or disease Intervention/treatment Phase
Carcinoma, Renal Cell Biological: Pembrolizumab Drug: Belzutifan Biological: Pembrolizumab/Quavonlimab Drug: Lenvatinib Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1653 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Randomized Phase 3 Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or MK-1308A in Combination With Lenvatinib, Versus Pembrolizumab and Lenvatinib, as First-Line Treatment in Participants With Advanced Clear Cell Renal Cell Carcinoma (ccRCC)
Actual Study Start Date : April 14, 2021
Estimated Primary Completion Date : October 29, 2026
Estimated Study Completion Date : October 29, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Pembrolizumab + Belzutifan + Lenvatinib
Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 18 administrations (up to ~2 years). Belzutifan and lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation.
 Biological: Pembrolizumab
Pembrolizumab 400 mg administered Q6W via IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: Belzutifan
Belzutifan 120 mg administered QD via oral tablet
Other Names:
  • MK-6482
  • PT2977
  • WELIREG™

Drug: Lenvatinib
Lenvatinib 20 mg administered QD via oral capsule
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®
Experimental: Pembrolizumab/Quavonlimab + Lenvatinib
Participants will receive pembrolizumab/quavonlimab (co-formulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered IV Q6W for up to 18 administrations (up to ~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.
 Biological: Pembrolizumab/Quavonlimab
Pembrolizumab/quavonlimab is a co-formulated product composed of pembrolizumab 400 mg in combination with quavonlimab 25 mg, administered Q6W via IV infusion
Other Name: MK-1308A

Drug: Lenvatinib
Lenvatinib 20 mg administered QD via oral capsule
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®
Active Comparator: Pembrolizumab + Lenvatinib
Participants will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 18 administrations (up to ~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.
 Biological: Pembrolizumab
Pembrolizumab 400 mg administered Q6W via IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: Lenvatinib
Lenvatinib 20 mg administered QD via oral capsule
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®


Outcome Measures
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Primary Outcome Measures :
  1. Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 46 months ]
    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 BICR based on RECIST 1.1 will be presented.

  2. Overall Survival (OS) [ Time Frame: Up to approximately 66 months ]
    OS is defined as the time from randomization to death due to any cause.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 46 months ]
    ORR is defined as the percentage of participants who have a complete response (CR: disappearance of all target lesions) or 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 BICR based on RECIST 1.1 will be presented.

  2. Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 66 months ]
    For participants who demonstrate a confirmed CR (disappearance of all target lesions) or confirmed 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 PD or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as at least a 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. The DOR as assessed by BICR based on RECIST 1.1 will be presented.

  3. Number of Participants Who Experienced At least One Adverse Event (AE) [ Time Frame: Up to approximately 66 months ]
    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 presented.

  4. Number of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: Up to approximately 66 months ]
    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 discontinue study treatment due to an AE will be presented.


Eligibility Criteria
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Information from the National Library of Medicine

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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 histologically confirmed diagnosis of RCC with clear cell component.
  • Has received no prior systemic therapy for advanced ccRCC
  • Male participants are abstinent from heterosexual intercourse or agree to use contraception during and for at least 7 days after last dose of study intervention with belzutifan and lenvatinib.
  • Female participants are not pregnant or breastfeeding and are either not a woman of child-bearing potential (WOCBP) or use a contraceptive method that is highly effective or are abstinent from heterosexual intercourse during the intervention period and for at least 120 days after pembrolizumab or pembrolizumab/quavonlimab or for at least 30 days after last dose of lenvatinib or belzutifan, whichever occurs last
  • Has adequately controlled blood pressure with or without antihypertensive medications
  • Has adequate organ function.
  • Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks prior to randomization/allocation

Exclusion Criteria:

  • Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
  • Has had major surgery, other than nephrectomy within 4 weeks prior to randomization
  • Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Has received prior radiotherapy within 2 weeks prior to first dose of study intervention
  • Has hypoxia or requires intermittent supplemental oxygen or requires chronic supplemental oxygen
  • Has clinically significant cardiac disease within 12 months from first dose of study intervention
  • Has a history of interstitial lung disease
  • Has symptomatic pleural effusion; a participant who is clinically stable following treatment of this condition is eligible
  • Has preexisting gastrointestinal or non-gastrointestinal fistula
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
  • Has a known psychiatric or substance abuse disorder that would interfere with requirements of the study
  • Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug; killed vaccines are allowed
  • Has an active autoimmune disease that has required systemic treatment in the past 2 years
  • Has a history of noninfectious pneumonitis that required steroids or has current pneumonitis
  • Has an active infection requiring systemic therapy
  • Has a known history of human immunodeficiency virus (HIV) infection
  • Has a known history of Hepatitis B
  • Has radiographic evidence of intratumoral cavitation, encasement or invasion of a major blood vessel
  • Has clinically significant history of bleeding within 3 months prior to randomization
  • Has had an allogenic tissue/solid organ transplant
Contacts and Locations
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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): NCT04736706


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

Locations
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Sponsors and Collaborators
Merck Sharp & Dohme LLC
Eisai Inc.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
More Information
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Additional Information:

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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT04736706    
Other Study ID Numbers: 6482-012
MK-6482-012 ( Other Identifier: Merck )
jRCT2031210435 ( Registry Identifier: jRCT(Japan Registry of Clinical Trials) )
PHRR210911-003887 ( Registry Identifier: Philippine Health Research Registry (PHRR) )
2020-002216-52 ( EudraCT Number )
First Posted: February 3, 2021    Key Record Dates
Last Update Posted: March 30, 2023
Last Verified: March 2023
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-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Hypoxia inducible factor (HIF)
Hypoxia inducible factor 1B (HIF-1B)
Hypoxia inducible factor 2 alpha (HIF-2 alpha)
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
Pembrolizumab
Lenvatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action