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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)

NCT04626479

Description:

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.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A)
  • Official Title: A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (U03): Substudy 03A

Clinical Trial IDs

  • ORG STUDY ID: 3475-03A
  • SECONDARY ID: 2019-003609-84
  • SECONDARY ID: MK-3475-03A
  • NCT ID: NCT04626479

Conditions

  • Carcinoma, Renal Cell

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Pembrolizumab + Belzutifan + Lenvatinib
Favezelimab/PembrolizumabMK-4280ACoformulation Favezelimab/Pembrolizumab+ Lenvatinib
BelzutifanMK-6482Pembrolizumab + Belzutifan + Lenvatinib
LenvatinibMK-7902, E7080, LENVIMA®Coformulation Favezelimab/Pembrolizumab+ Lenvatinib
Pembrolizumab/QuavonlimabMK-1308ACoformulation Pembrolizumab/Quavonlimab + Lenvatinib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Coformulation Pembrolizumab/Quavonlimab + LenvatinibExperimentalParticipants 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.
  • Lenvatinib
  • Pembrolizumab/Quavonlimab
Coformulation Favezelimab/Pembrolizumab+ LenvatinibExperimentalParticipants 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.
  • Favezelimab/Pembrolizumab
  • Lenvatinib
Pembrolizumab + Belzutifan + LenvatinibExperimentalParticipants 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.
  • Pembrolizumab
  • Belzutifan
  • Lenvatinib
Pembrolizumab + LenvatinibExperimentalParticipants 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.
  • Pembrolizumab
  • Lenvatinib

Eligibility 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

          -  If participants receive major surgery or radiation therapy, they must have recovered
             from complications from the intervention

          -  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 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 for 30
             days after the last dose of lenvatinib or belzutifan, whichever occurs last

        Exclusion Criteria:

          -  Has urine protein ≥1 g/24 hours and has any of the following: (a) hypoxia defined as a
             pulse oximeter reading <92% at rest, or (b) requires intermittent supplemental oxygen,
             or (c) requires chronic supplemental oxygen

          -  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
      
Maximum Eligible Age:120 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)
Time Frame:Up to ~21 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Efficacy Phase: Duration of response (DOR)
Time Frame:Up to ~43 months
Safety Issue:
Description: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.
Measure:Efficacy Phase: Progression-free survival (PFS)
Time Frame:Up to ~43 months
Safety Issue:
Description: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.
Measure:Efficacy Phase: Overall survival (OS)
Time Frame:Up to ~43 months
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause.
Measure:Efficacy Phase: Clinical benefit rate (CBR)
Time Frame:Up to ~43 months
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • receptor tyrosine kinase inhibitor
  • programmed cell death 1 (PD-1, PD1)
  • programmed cell death ligand 1 (PD-L1, PDL1)

Last Updated

May 27, 2021