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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)

NCT04626518

Description:

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.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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: A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (U03): Substudy 03B

Clinical Trial IDs

  • ORG STUDY ID: 3475-03B
  • SECONDARY ID: 2019-003610-13
  • SECONDARY ID: MK-3475-03B
  • NCT ID: NCT04626518

Conditions

  • Carcinoma, Renal Cell

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Coformulation MK-1308A
MK-1308Coformulation MK-1308A
MK-4280Coformulation MK-4280A
MK-4830Pembrolizumab + MK-4830
MK-6482MK-6482 + Lenvatinib
LenvatinibMK-7902, E7080, LENVIMA®MK-6482 + Lenvatinib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Coformulation MK-1308AExperimentalParticipants will receive MK-1308A (coformulation of MK-1308 25 mg and pembrolizumab 400 mg). MK-1308A will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to ~2 years).
  • Pembrolizumab
  • MK-1308
Coformulation MK-4280AExperimentalParticipants will receive MK-4280A (coformulation of MK-4280 800 mg and pembrolizumab 200 mg). MK-4280A will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years).
  • Pembrolizumab
  • MK-4280
Pembrolizumab + MK-4830ExperimentalParticipants 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).
  • Pembrolizumab
  • MK-4830
Pembrolizumab + MK-6482ExperimentalParticipants will receive pembrolizumab 400 mg PLUS MK-6482 120 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~ 2 years). MK-6482 will be administered orally once-daily (QD) until progressive disease or discontinuation.
  • Pembrolizumab
  • MK-6482
MK-6482 + LenvatinibExperimentalParticipants will receive MK-6482 120 mg PLUS lenvatinib 20 mg. Both MK-6482 and lenvatinib will be administered orally QD until progressive disease or discontinuation.
  • MK-6482
  • 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 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 demonstrated 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 demonstrated 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 prior to 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 prior to randomization/allocation

          -  Male participants are abstinent from heterosexual intercourse or agree to use
             contraception during treatment with and for at least 5 days after the last dose of
             lenvatinib and /or MK-6482; for male participants receiving only pembrolizumab,
             MK-1308A, MK-4280A, 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, MK-1308A, MK-4280A, MK-4830 or 30 days after the last dose of
             lenvatinib or MK-6482, 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 cardiac disease within 12 months from the first day of
             study intervention administration

          -  Has had major surgery within 3 weeks prior to 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 MK-6482

          -  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
      
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 ~35 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 ~35 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 ~35 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 ~35 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:Not yet 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

November 12, 2020