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Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04626479
Recruitment Status : Recruiting
First Posted : November 12, 2020
Last Update Posted : May 18, 2023
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:

Substudy 03A is part of a larger research study that is testing experimental treatments for renal cell carcinoma (RCC). The larger study is the umbrella study (U03).

The goal of substudy 03A is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced first line (1L) clear cell renal cell carcinoma (ccRCC).

This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to demonstrate a tolerable safety profile for the combination of investigational agents. There will be no hypothesis testing in this study.


Condition or disease Intervention/treatment Phase
Carcinoma, Renal Cell Biological: Pembrolizumab Biological: Favezelimab/Pembrolizumab Drug: Belzutifan Drug: Lenvatinib Biological: Pembrolizumab/Quavonlimab Drug: Vibostolimab/Pembrolizumab Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (U03): Substudy 03A
Actual Study Start Date : December 16, 2020
Estimated Primary Completion Date : May 31, 2026
Estimated Study Completion Date : May 31, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib
Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to ~2 years). Lenvatinib will be administered orally once-daily (QD) until progressive disease or discontinuation.
 Drug: Lenvatinib
Administered via oral capsule at a dose of 20 mg QD
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®

Biological: Pembrolizumab/Quavonlimab
Administered via IV infusion at a dose of 400 mg/25 mg Q6W
Other Name: MK-1308A
Experimental: Coformulation Favezelimab/Pembrolizumab+ Lenvatinib
Participants will receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg) PLUS lenvatinib 20 mg. Favezelimab/Pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.
 Biological: Favezelimab/Pembrolizumab
Administered via IV infusion at a dose of 800 mg/200 mg Q3W
Other Name: MK-4280A

Drug: Lenvatinib
Administered via oral capsule at a dose of 20 mg QD
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®
Experimental: Pembrolizumab + Belzutifan + Lenvatinib
Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~2 years). Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation.
 Biological: Pembrolizumab
Administered via IV infusion at a dose of 400 mg Q6W
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: Belzutifan
Administered via oral tablet at a dose of 120 mg QD
Other Names:
  • MK-6482
  • WELIREG™

Drug: Lenvatinib
Administered via oral capsule at a dose of 20 mg QD
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®
Experimental: Pembrolizumab + Lenvatinib
Participants will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~ 2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.
 Biological: Pembrolizumab
Administered via IV infusion at a dose of 400 mg Q6W
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: Lenvatinib
Administered via oral capsule at a dose of 20 mg QD
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®
Experimental: Coformulation Vibostolimab/Pembrolizumab+Belzutifan
Participants will receive vibostolimab/pembrolizumab (coformulation of 200 mg vibostolimab and pembrolizumab 200 mg). Vibostolimab/pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Belzutifan will be administered orally QD until progressive disease or discontinuation.
 Drug: Belzutifan
Administered via oral tablet at a dose of 120 mg QD
Other Names:
  • MK-6482
  • WELIREG™

Drug: Vibostolimab/Pembrolizumab
Administered via IV infusion at a dose of 200 mg/200 mg Q6W
Other Name: MK-7684A


Outcome Measures
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Primary Outcome Measures :
  1. Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs) [ Time Frame: Up to ~21 days ]
    DLTs are defined as one or more of the following toxicities: (1) grade (gr) 4 nonhematologic toxicity (2) gr 4 hematologic toxicity lasting >7 days OR gr 4 platelet count decreased of any duration OR gr 3 platelet count decreased if associated with bleeding (3) gr 3 nonhematologic toxicity except gr 3 fatigue (lasting ≤3 days), diarrhea, nausea, vomiting or rash without standard of care (4) gr 3 or 4 nonhematologic abnormality if medical intervention is required or if it leads to hospitalization or persists for >1 week (5) gr 3 or 4 febrile neutropenia (6) gr 3 or 4 alanine aminotransferase, aspartate aminotransferase and/or bilirubin laboratory value (7) treatment related adverse event (AE) causing study intervention discontinuation during the first 21 days (8) treatment related AE causing intervention administration delay for >14 days during the first 21 days (9) gr 5 toxicity. The number of participants who experience one or more DLTs in the safety lead-in phase will be presented.

  2. Safety Lead-in Phase: Number of participants who experience one or more adverse events (AEs) [ Time Frame: Up to ~21 days ]
    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 one or more AEs in the safety lead-in phase will be presented.

  3. Safety Lead-in Phase: Number of participants who discontinue study treatment due to an AE [ Time Frame: Up to ~21 days ]
    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 in the safety lead-in phase will be presented.

  4. Efficacy Phase: Number of participants who experience one or more DLTs [ Time Frame: Up to ~21 days ]
    DLTs are defined as one or more of the following toxicities: (1) grade (gr) 4 nonhematologic toxicity (2) gr 4 hematologic toxicity lasting >7 days OR gr 4 platelet count decreased of any duration OR gr 3 platelet count decreased if associated with bleeding (3) gr 3 nonhematologic toxicity except gr 3 fatigue (lasting ≤3 days), diarrhea, nausea, vomiting or rash without standard of care (4) gr 3 or 4 nonhematologic abnormality if medical intervention is required or if it leads to hospitalization or persists for >1 week (5) gr 3 or 4 febrile neutropenia (6) gr 3 or 4 alanine aminotransferase, aspartate aminotransferase and/or bilirubin laboratory value (7) treatment related adverse event (AE) causing study intervention discontinuation during the first 21 days (8) treatment related AE causing intervention administration delay for >14 days during the first 21 days (9) gr 5 toxicity. The number of participants who experience one or more DLTs in the efficacy phase will be presented.

  5. Efficacy Phase: Number of participants who experience one or more AEs [ Time Frame: Up to ~43 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 one or more AEs in the efficacy phase will be presented.

  6. Efficacy Phase: Number of participants who discontinue study treatment due to an AE [ Time Frame: Up to ~43 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 in the efficacy phase will be presented.

  7. Efficacy Phase: Objective response rate (ORR) [ Time Frame: Up to ~43 months ]
    ORR is defined as the percentage of participants in the analysis population 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, taking as reference the baseline sum of diameters). Responses are according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).


Secondary Outcome Measures :
  1. Efficacy Phase: Duration of response (DOR) [ Time Frame: Up to ~43 months ]
    For participants in the analysis population 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, taking as reference the baseline sum of diameters), DOR is defined as the time from first documented evidence of CR or PR until progressive disease or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 by BICR.

  2. Efficacy Phase: Progression-free survival (PFS) [ Time Frame: Up to ~43 months ]
    PFS is defined as the time from randomization to the first documented progressive disease or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 by BICR.

  3. Efficacy Phase: Overall survival (OS) [ Time Frame: Up to ~43 months ]
    OS is defined as the time from randomization to death due to any cause.

  4. Efficacy Phase: Clinical benefit rate (CBR) [ Time Frame: Up to ~43 months ]
    CBR is defined as the percentage of participants who have achieved CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) of ≥6 months. Responses are according to RECIST 1.1 by BICR.


Eligibility Criteria
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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 to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
  • Has received no prior systemic therapy for advanced RCC; prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed ≥12 months before randomization/allocation.
  • Is able to swallow oral medication
  • Has adequate organ function
  • Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks before randomization/allocation
  • Has resolution of toxic effects of the most recent prior therapy to ≤Grade 1
  • Has adequately controlled blood pressure (BP ≤150/90 mm Hg) with no change in hypertensive medications within 1 week before randomization/allocation
  • Male participants are abstinent from heterosexual intercourse or agree to use contraception during treatment with and for at least 7 days after the last dose of lenvatinib and /or belzutifan; 7 days after lenvatinib and/or belzutifan is stopped, if the participant is only receiving pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab or a combination of the aforementioned drugs, no contraception is needed
  • Female participants must not be pregnant and not be a woman of childbearing potential (WOCBP) or is a WOCBP abstinent from heterosexual intercourse or using contraception during the intervention period and for at least 120 days after the last dose of pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab for 30 days after the last dose of lenvatinib or belzutifan, whichever occurs last and must abstain from breastfeeding during the study intervention period and for at least 120 days after study intervention

Exclusion Criteria:

  • Has urine protein ≥1 g/24 hours and has any of the following: (a) a pulse oximeter reading <92% at rest, or (b) requires intermittent supplemental oxygen, or (c) requires chronic supplemental oxygen (d) active hemoptysis within 3 weeks prior to the first dose of study intervention
  • Has clinically significant cardiovascular disease within 12 months from the first dose of study intervention administration
  • Has had major surgery within 3 weeks before first dose of study interventions
  • Has a history of lung disease
  • Has a history of inflammatory bowel disease
  • Has preexisting gastrointestinal (GI) or non-GI fistula
  • Has malabsorption due to prior GI surgery or disease
  • Has received prior radiotherapy within 2 weeks of start of study intervention
  • Has received a live or live attenuated vaccine within 30 days before the first dose of study drug; killed vaccines are allowed
  • Has received more than 4 previous systemic anticancer treatment regimens
  • Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
  • Has 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 an active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is not considered a form of systemic treatment and is allowed
  • 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 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): NCT04626479


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
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: NCT04626479    
Other Study ID Numbers: 3475-03A
MK-3475-03A ( Other Identifier: Merck )
2019-003609-84 ( EudraCT Number )
First Posted: November 12, 2020    Key Record Dates
Last Update Posted: May 18, 2023
Last Verified: May 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:
receptor tyrosine kinase inhibitor
programmed cell death 1 (PD-1, PD1)
programmed cell death ligand 1 (PD-L1, PDL1)
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
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
 Kidney Diseases
Urologic Diseases
Male Urogenital Diseases
Pembrolizumab
Lenvatinib
Belzutifan
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors