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Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B)

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ClinicalTrials.gov Identifier: NCT04626518
Recruitment Status : Recruiting
First Posted : November 12, 2020
Last Update Posted : September 10, 2022
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Tracking Information
First Submitted Date  ICMJE November 10, 2020
First Posted Date  ICMJE November 12, 2020
Last Update Posted Date September 10, 2022
Actual Study Start Date  ICMJE December 17, 2020
Estimated Primary Completion Date May 29, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 22, 2021)
  • 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.
  • 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.
  • 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.
  • Efficacy Phase: Number of participants who experienced 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.
  • Efficacy Phase: Number of participants who experience one or more AEs [ Time Frame: Up to ~37 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.
  • Efficacy Phase: Number of participants who discontinue study treatment due to an AE [ Time Frame: Up to ~37 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.
  • Efficacy Phase: Objective response rate (ORR) [ Time Frame: Up to ~37 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).
Original Primary Outcome Measures  ICMJE
 (submitted: November 10, 2020)
  • 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.
  • 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.
  • 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.
  • Efficacy Phase: Number of participants who experience one or more AEs [ Time Frame: Up to ~35 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.
  • Efficacy Phase: Number of participants who discontinue study treatment due to an AE [ Time Frame: Up to ~35 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.
  • Efficacy Phase: Objective response rate (ORR) [ Time Frame: Up to ~35 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).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 2, 2021)
  • Efficacy Phase: Duration of response (DOR) [ Time Frame: Up to ~37 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.
  • Efficacy Phase: Progression-free survival (PFS) [ Time Frame: Up to ~37 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.
  • Efficacy Phase: Overall survival (OS) [ Time Frame: Up to ~37 months ]
    OS is defined as the time from randomization to death due to any cause.
  • Efficacy Phase: Clinical benefit rate (CBR) [ Time Frame: Up to ~37 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 10, 2020)
  • Efficacy Phase: Duration of response (DOR) [ Time Frame: Up to ~35 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.
  • Efficacy Phase: Progression-free survival (PFS) [ Time Frame: Up to ~35 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.
  • Efficacy Phase: Overall survival (OS) [ Time Frame: Up to ~35 months ]
    OS is defined as the time from randomization to death due to any cause.
  • Efficacy Phase: Clinical benefit rate (CBR) [ Time Frame: Up to ~35 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B)
Official Title  ICMJE A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (U03): Substudy 03B
Brief Summary

Substudy 03B 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 03B is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced second line plus (2L+) 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Carcinoma, Renal Cell
Intervention  ICMJE
  • Biological: Pembrolizumab
    Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W
    Other Names:
    • MK-3475
    • KEYTRUDA®
  • Biological: MK-4830
    Administered via IV infusion at a dose of 800 mg Q3W
  • 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®
  • Biological: Pembrolizumab/Quavonlimab
    Administered via IV infusion at a dose of 400 mg/25 mg Q6W
    Other Name: MK-1308A
  • Biological: Favezelimab/Pembrolizumab
    Administered via IV infusion at a dose of 800 mg/200 mg Q3W
    Other Name: MK-4280A
Study Arms  ICMJE
  • Experimental: Coformulation Pembrolizumab/Quavonlimab
    Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg). Pembrolizumab/quavonlimab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to ~2 years).
    Intervention: Biological: Pembrolizumab/Quavonlimab
  • Experimental: Coformulation Favezelimab/Pembrolizumab
    Participants will receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg). Favezelimab/Pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years).
    Intervention: Biological: Favezelimab/Pembrolizumab
  • Experimental: Pembrolizumab + MK-4830
    Participants will receive pembrolizumab 200 mg PLUS MK-4830 800 mg. Both pembrolizumab and MK-4830 will be administered IV Q3W for up to 35 administrations (up to ~2 years).
    Interventions:
    • Biological: Pembrolizumab
    • Biological: MK-4830
  • Experimental: Pembrolizumab + Belzutifan
    Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~ 2 years). Belzutifan will be administered orally once-daily (QD) until progressive disease or discontinuation.
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Belzutifan
  • Experimental: Belzutifan + Lenvatinib
    Participants will receive Belzutifan 120 mg PLUS lenvatinib 20 mg. Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation.
    Interventions:
    • Drug: Belzutifan
    • Drug: Lenvatinib
  • 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.
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Lenvatinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 10, 2020)
370
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 29, 2025
Estimated Primary Completion Date May 29, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
  • Has experienced disease progression on or after having received systemic. treatment for locally advanced or metastatic RCC with a PD-(L)1 checkpoint inhibitor (in sequence or in combination with a vascular endothelial growth factor. - tyrosine kinase inhibitor [VEGF-TKI]) where PD-(L)1 checkpoint inhibitor treatment progression is defined by meeting ALL of the following criteria: (a) has received ≥2 doses of an anti-PD-(L)1 monoclonal antibody (mAb) (b) has shown radiographic disease progression during or after an anti-PD-(L)1 mAb as defined by RECIST 1.1 by investigator (c) disease progression has been documented within 12 weeks from the last dose of an anti-PD-(L)1 mAb
  • Has experienced disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with a VEGF-TKI (in sequence or in combination with a PD-[L]1 checkpoint inhibitor) where VEGF-TKI treatment progression is defined by meeting the following criterion: has shown radiographic disease progression during or after a treatment with a VEGF-TKI as defined by RECIST 1.1 by investigator.
  • 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 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, MK-4830 or a combination of the aforementioned drugs, no contraception is needed
  • Female participant is not pregnant or breastfeeding and is not 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, MK-4830 or 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 previously received treatment with a combination of pembrolizumab plus lenvatinib
  • Has received prior treatment with belzutifan
  • 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 intervention; 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 120 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE Australia,   Canada,   France,   Israel,   Korea, Republic of,   New Zealand,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04626518
Other Study ID Numbers  ICMJE 3475-03B
MK-3475-03B ( Other Identifier: Merck )
2019-003610-13 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Current Responsible Party Merck Sharp & Dohme LLC
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Merck Sharp & Dohme LLC
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme LLC
PRS Account Merck Sharp & Dohme LLC
Verification Date September 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP