A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab With or Without Platinum-Based Combination Chemotherapy Versus Chemotherapy in Subjects With Advanced or Metastatic Urothelial Carcinoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,010
- 主要终点
- Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10%
研究概览
简要总结
The purpose of this study is to determine the efficacy and safety of pembrolizumab (pembro, MK-3475) with or without chemotherapy versus chemotherapy alone in participants with advanced or metastatic urothelial carcinoma (bladder cancer).
The primary hypotheses are that pembrolizumab plus chemotherapy is superior to chemotherapy alone with respect to Progression-free Survival (PFS) and Overall Survival (OS) in all participants, and that pembrolizumab alone is superior to chemotherapy alone with respect to OS in all participants and in participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score [CPS] ≥10%).
详细描述
As specified by the protocol, the study hypotheses will be evaluated by comparing the pembro combo arm or pembro arm separately to the chemo arm.
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 or cytologically confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial carcinoma of the renal pelvis, ureter [upper urinary tract], bladder, or urethra. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.
- •Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment.
- •Has received no prior systemic chemotherapy for advanced or metastatic urothelial carcinoma, with the following exceptions:
- •Neoadjuvant platinum-based chemotherapy with recurrence >12 months from completion of therapy is permitted.
- •Adjuvant platinum-based chemotherapy following radical cystectomy with recurrence >12 months from completion of therapy is permitted.
- •Has provided tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated from a muscle invasive urothelial carcinoma or a metastatic biopsy, originally from the original tumor.
- •Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or
- •Demonstrates adequate organ function.
- •Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment.
- •Male participants of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment.
排除标准
- •Has disease that is suitable for local therapy administered with curative intent.
- •Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization.
- •Has an active autoimmune disease that has required systemic treatment in the past 2 years.
- •Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to the first dose of study drug (6 weeks for nitrosoureas or mitomycin C) or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from adverse events (AEs) due to mAbs administered more than 4 weeks earlier.
- •Has not recovered (i.e., AE ≤ Grade 1 or at Baseline) from AEs due to a previously administered agent.
- •Has a known additional malignancy that is progressing or requires active treatment within the past 5 years.
- •Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- •A history of prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤6; Prostate-specific Antigen (PSA) level undetectable.
- •Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- •Has a known history of active tuberculosis (TB).
- •Has an active infection requiring systemic therapy.
- •Has a history of severe hypersensitivity reaction (e.g. generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to pembrolizumab, gemcitabine, carboplatin, or cisplatin or their analogs and/or to any of their excipients.
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is a known regular user (including "recreational use") of any illicit drug(s) or had a recent history (within the last year) of drug or alcohol abuse.
- •Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapy treatment.
- •Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137).
- •Has a known history of human immunodeficiency virus (HIV).
- •Has known active hepatitis B or hepatitis C.
研究组 & 干预措施
Pembrolizumab + ST Chemotherapy (Pembro Combo)
Participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Pembrolizumab (Biological)
Pembrolizumab + ST Chemotherapy (Pembro Combo)
Participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Cisplatin (Drug)
Pembrolizumab + ST Chemotherapy (Pembro Combo)
Participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Carboplatin (Drug)
Pembrolizumab + ST Chemotherapy (Pembro Combo)
Participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Gemcitabine (Drug)
Pembrolizumab (Pembro)
Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses. Eligible participants who stop pembrolizumab with SD or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
干预措施: Pembrolizumab (Biological)
ST Chemotherapy (Chemo)
Participants receive ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
干预措施: Cisplatin (Drug)
ST Chemotherapy (Chemo)
Participants receive ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
干预措施: Carboplatin (Drug)
ST Chemotherapy (Chemo)
Participants receive ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
干预措施: Gemcitabine (Drug)
结局指标
主要结局
Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10%
时间窗: Up to approximately 42 months
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the CPS ≥10% subset of the pembro arm was compared to OS in the CPS ≥10% subset of the chemo arm for this endpoint as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro arm and chemo arm who were PD-L1 CPS ≥10%. Per protocol, OS in the CPS ≥10% subset of the pembro combo arm was not a pre-specified analysis of the ITT population and is not presented.
Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
时间窗: Up to approximately 42 months
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population (all randomized participants). PFS is reported here for all participants in the pembro combo arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
Pembro Combo vs Chemo: Overall Survival (OS)
时间窗: Up to approximately 42 months
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all participants in the pembro combo arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
Pembro vs Chemo: OS
时间窗: Up to approximately 42 months
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all participants in the pembro arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
次要结局
- PFS Using RECIST 1.1 as Assessed by BICR at 18 Months(18 months)
- Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score(Baseline up to approximately 25 months)
- PFS Using RECIST 1.1 as Assessed by BICR at 6 Months(6 months)
- Pembro vs Chemo: Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score(Baseline, Week 18)
- Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR(Up to approximately 42 months)
- Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR(Up to approximately 42 months)
- Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR(Up to approximately 42 months)
- Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR(Up to approximately 42 months)
- Number of Participants Who Experience an Adverse Event (AE)(Up to approximately 55 months)
- Number of Participants Who Discontinue Study Drug Due to an AE(Up to approximately 52 months)
- Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score(Baseline up to approximately 25 months)
- Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR(Up to approximately 42 months)
- Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR(Up to approximately 42 months)
- Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR(Up to approximately 42 months)
- PFS Using RECIST 1.1 as Assessed by BICR at 12 Months(12 months)
- Pembro Combo vs Chemo: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score(Baseline, Week 18)