A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (KEYMAKER-U03): Substudy 03B in Second-Line Metastatic Participants
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 370
- 试验地点
- 102
- 主要终点
- Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has a histologically confirmed diagnosis of locally advanced/metastatic clear cell renal cell carcinoma (ccRCC)
- •Has experienced disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with a programmed cell death ligand 1 (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 Response Evaluation Criteria in Solid Tumors version 1.1 (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
排除标准
- •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
研究组 & 干预措施
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).
干预措施: Pembrolizumab/Quavonlimab (Biological)
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).
干预措施: MK-4830 (Biological)
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).
干预措施: Pembrolizumab (Biological)
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).
干预措施: Favezelimab/Pembrolizumab (Biological)
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.
干预措施: Pembrolizumab (Biological)
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.
干预措施: Belzutifan (Drug)
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.
干预措施: Belzutifan (Drug)
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.
干预措施: Lenvatinib (Drug)
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.
干预措施: Pembrolizumab (Biological)
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.
干预措施: Lenvatinib (Drug)
结局指标
主要结局
Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)
时间窗: 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)
时间窗: 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.
Efficacy Phase: Number of participants who experience one or more AEs
时间窗: Up to ~56 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
时间窗: Up to ~56 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.
Safety Lead-in Phase: Number of participants who discontinue study treatment due to an AE
时间窗: 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
时间窗: 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: Objective response rate (ORR)
时间窗: Up to ~56 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).
次要结局
- Efficacy Phase: Progression-free survival (PFS)(Up to ~56 months)
- Efficacy Phase: Duration of response (DOR)(Up to ~56 months)
- Efficacy Phase: Overall survival (OS)(Up to ~56 months)
- Efficacy Phase: Clinical benefit rate (CBR)(Up to ~56 months)