A Phase 1/2 Randomized, Umbrella Study to Evaluate the Safety and Efficacy of Pembrolizumab Plus Enfortumab Vedotin (EV) in Combination With Investigational Agents Versus Pembrolizumab Plus EV, as First-Line Treatment for Participants With Advanced Urothelial Carcinoma (KEYMAKER-U04): Substudy 04B
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 390
- 试验地点
- 47
- 主要终点
- Part 1: Objective Response Rate (ORR)
研究概览
简要总结
This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the efficacy and safety of coformulated favezelimab/pembrolizumab plus EV and coformulated vibostolimab/pembrolizumab plus EV relative to pembrolizumab plus EV. There will be no comparison of coformulated favezelimab/pembrolizumab plus EV versus coformulated vibostolimab/pembrolizumab plus EV. If ORR and/or DRR are substantially better on coformulated favezelimab/pembrolizumab plus EV and/or coformulated vibostolimab/pembrolizumab plus EV compared with pembrolizumab plus EV, after evaluation of the totality of data, the sponsor might consider Part 2 (expansion) to further characterize the efficacy and safety of the treatment arms under study.
详细描述
The master study for this substudy is MK-3475-U04/KEYMAKER-U04. The master study will not be screening any participants and will not be registered.
With Amendment 2, participants will discontinue treatment with coformulated vibostolimab/pembrolizumab (Arm B) and be transitioned to pembrolizumab only. Per protocol, no analysis of Part 2 primary or secondary outcome measures (including efficacy or safety) will occur since Part 2 of the study will no longer take place.
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
- •Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).
- •Participants with mixed histology are eligible provided the urothelial component is ≥50% (and <10% plasmacytoid component)
- •Participants whose tumors contain any neuroendocrine component are not eligible (variant histology to be confirmed locally)
- •Must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease setting (eg, muscle-invasive urothelial carcinoma (MIUC)) are permitted:
- •Participants that received neoadjuvant or adjuvant chemotherapy are permitted.
- •Participants who received anti- programmed cell death 1 protein (PD-1) or programmed cell death ligand 1 (PD-L1) therapy for an earlier disease stage (eg, NMIBC, MIUC) with progression/recurrence >12 months from completion of therapy are permitted.
- •Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.
- •Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement or with <Grade 2 neuropathy are eligible.
排除标准
- •Has a known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
- •Central nervous system (CNS) metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease.
- •Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
- •Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
- •Has active keratitis or corneal ulcerations. Superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
- •Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy.
- •Has a history of uncontrolled diabetes.
- •Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
- •Has an active infection (viral, bacterial, or fungal) requiring systemic therapy.
- •Has a known history of human immunodeficiency virus (HIV) infection.
- •Has hepatitis B or hepatitis C virus infection.
- •Has had major surgery within 4 weeks prior to first dose of study intervention.
- •Has had an allogenic tissue/solid organ transplant
研究组 & 干预措施
Arm A: Coformulated favezelimab/pembrolizumab plus EV
Participants will receive coformulated favezelimab/pembrolizumab (800 mg/200 mg) as an intravenous (IV) infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.
干预措施: Coformulated favezelimab/pembrolizumab (Biological)
Arm A: Coformulated favezelimab/pembrolizumab plus EV
Participants will receive coformulated favezelimab/pembrolizumab (800 mg/200 mg) as an intravenous (IV) infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.
干预措施: EV (Combination Product)
Arm B: Coformulated vibostolimab/pembrolizumab plus EV
Participants will receive coformulated vibostolimab/pembrolizumab (200 mg/200 mg) as an IV infusion on Day 1 of every 3-week cycle, for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.
干预措施: Coformulated vibostolimab/pembrolizumab (Biological)
Arm B: Coformulated vibostolimab/pembrolizumab plus EV
Participants will receive coformulated vibostolimab/pembrolizumab (200 mg/200 mg) as an IV infusion on Day 1 of every 3-week cycle, for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.
干预措施: EV (Combination Product)
Arm C: Pembrolizumab plus EV
Participants will receive 200 mg pembrolizumab as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle, until disease progression, intolerable toxicity, or investigator decision.
干预措施: EV (Combination Product)
Arm C: Pembrolizumab plus EV
Participants will receive 200 mg pembrolizumab as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle, until disease progression, intolerable toxicity, or investigator decision.
干预措施: Pembrolizumab (Biological)
结局指标
主要结局
Part 1: Objective Response Rate (ORR)
时间窗: Up to ~4 years
ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). ORR will be reported for participants in Part 1.
Part 1: Percentage of Participants experiencing an Adverse Event (AE)
时间窗: Up to ~4 years
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 1 will be reported.
Part 2: Progression Free Survival (PFS)
时间窗: Up to ~4 years
PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. PFS will be reported for participants in Part 2.
Part 1: Percentage of Participants who Discontinue study interventions due to an AE
时间窗: Up to ~4 years
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study interventions due to an AE in Part 1 will be reported.
Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)
时间窗: Up to 21 days
A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0). The number of participants who experience a DLT in Part 1 will be reported.
次要结局
- Part 1: Duration of Response (DOR)(Up to ~4 years)
- Part 2: Overall Survival (OS)(Up to ~4 years)
- Part 1: PFS(Up to ~4 years)
- Part 2: ORR(Up to ~4 years)
- Part 2: DOR(Up to ~4 years)
- Part 2: Mean Change from baseline in the global health status/quality of life of the EORTC QLC-C30 (Items 29 and 30)(Baseline and up to ~4 years)
- Part 2: TTD for the global health status/quality of life of the EORTC QLQ-C30 (Items 29 and 30)(Up to ~4 years)
- Part 2: Mean Change from Baseline in the EQ-5D-5L visual analog score (VAS)(Baseline and up to ~4 years)
- Part 1: Time-to-Deterioration (TTD) for the global health status/quality of life of the EORTC QLQ-C30 (Items 29 and 30)(Up to ~4 years)
- Part 1: TTD for the EQ-5D-5L VAS(Up to ~4 years)
- Part 2: TTD for the EQ-5D-5L VAS(Up to ~4 years)
- Part 2: Percentage of Participants experiencing an Adverse Event (AE)(Up to ~4 years)
- Part 2: Percentage of Participants who Discontinue study interventions due to an AE(Up to ~4 years)
- Part 1: Mean Change from baseline in the global health status/quality of life of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLC-C30) (Items 29 and 30)(Baseline and up to ~4 years)
- Part 1: TTD for the physical functioning scale of the EORTC QLQ-C30(Up to ~4 years)
- Part 2: Percentage of Participants with Dose-limiting toxicities (DLT)(Up to 21 days)
- Part 1: Mean Change from baseline in the physical functioning scale of the EORTC QLQ-C30(Baseline and up to ~4 years)
- Part 1: Mean Change from Baseline in the European Quality of Life 5 Dimensions, 5-level Questionnaire (EQ-5D-5L) visual analog score (VAS)(Baseline and up to ~4 years)
- Part 2: Mean Change from baseline in the physical functioning scale of the EORTC QLQ-C30(Baseline and up to ~4 years)
- Part 2: TTD for the physical functioning scale of the EORTC QLQ-C30(Up to ~4 years)