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.
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
Interventions
Drug | Synonyms | Arms |
---|
Pembrolizumab | MK-3475, KEYTRUDA® | Pembrolizumab + Belzutifan |
MK-4830 | | Pembrolizumab + MK-4830 |
Belzutifan | MK-6482, WELIREG™ | Belzutifan + Lenvatinib |
Lenvatinib | MK-7902, E7080, LENVIMA® | Belzutifan + Lenvatinib |
Pembrolizumab/Quavonlimab | MK-1308A | Coformulation Pembrolizumab/Quavonlimab |
Favezelimab/Pembrolizumab | MK-4280A | Coformulation Favezelimab/Pembrolizumab |
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
Name | Type | Description | Interventions |
---|
Coformulation Pembrolizumab/Quavonlimab | Experimental | 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). | - Pembrolizumab/Quavonlimab
|
Coformulation Favezelimab/Pembrolizumab | Experimental | 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). | - Favezelimab/Pembrolizumab
|
Pembrolizumab + MK-4830 | Experimental | 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). | |
Pembrolizumab + Belzutifan | Experimental | 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. | |
Belzutifan + Lenvatinib | Experimental | Participants will receive Belzutifan 120 mg PLUS lenvatinib 20 mg. Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation. | |
Pembrolizumab + Lenvatinib | Experimental | 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. | |
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 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 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, 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
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 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
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 ~37 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 ~37 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 ~37 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 ~37 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
September 1, 2021