A Phase 3, Randomized, Comparator-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Bacillus Calmette-Guerin (BCG) in Participants With High-risk Non-muscle Invasive Bladder Cancer (HR NMIBC) That is Either Persistent or Recurrent Following BCG Induction or That is Naïve to BCG Treatment (KEYNOTE-676)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 1,397
- 试验地点
- 415
- 主要终点
- Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) (Cohort A)
研究概览
简要总结
Researchers are looking for new ways to treat high-risk non muscle invasive bladder cancer (HR NMIBC). NMIBC is cancer in the tissue that lines the inside of the bladder but has not spread to the bladder muscle or outside of the bladder. High-risk means NMIBC may have a high chance of getting worse or coming back after treatment.
The goals of this study are to learn: 1. If more people who receive pembrolizumab with Bacillus Calmette-Guerin (BCG) have no signs of cancer in their body and live longer without the cancer growing, spreading, or coming back compared to people who receive BCG alone. 2. About the safety and how well people tolerate BCG alone or in combination with pembrolizumab.
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
- •Have locally and blinded independent central review (BICR)-confirmed histological diagnosis of high-risk non-muscle invasive (T1, high grade Ta and/or CIS) UC of the bladder
- •Has undergone cystoscopy/ transurethral resection of bladder tumor (TURBT) to remove all resectable disease
- •Has provided tissue for biomarker analysis
- •Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- •Has adequate organ function
- •During the treatment period and for ≥7 days after the last dose of BCG, male participants are EITHER abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent, OR, must agree to use contraception unless confirmed to be azoospermic
- •Female participants who are not pregnant, not breastfeeding, and either not a woman of child bearing potential (WOCBP); or are a WOCBP who agrees to use a contraception method that is highly effective or remains abstinent from heterosexual intercourse during the treatment period and for ≥7 days after the last dose of BCG or 120 days after the last dose of pembrolizumab, whichever comes last
- •BCG Post-induction Cohort (Cohort A) Only
- •Has been treated with one adequate course of BCG induction therapy for the treatment of HR NMIBC
- •Following adequate BCG induction therapy, must have persistent or recurrent HR NMIBC
排除标准
- •Has a history of or concurrent locally advanced (i.e., T2, T3, T4) or metastatic UC
- •Has concurrent extra-vesical (i.e, urethra, ureter, renal pelvis) non-muscle invasive urothelial carcinoma or a history of extra-vesical non-muscle invasive UC
- •Has received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
- •Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks of start of study treatment
- •Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of start of study treatment
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of start of study treatment
- •Has a known additional malignancy that is progressing or requires active treatment within the past 3 years
- •Has an active autoimmune disease that has required systemic treatment in past 2 years
- •Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
- •Has one or more of the following contraindications to BCG: prior BCG sepsis or systemic infection, total bladder incontinence, or an adverse experience to a previous BCG instillation that resulted in treatment discontinuation and precludes retreating with BCG
- •Has an active infection or diagnosis requiring systemic antimicrobial therapy
- •Has a known history of human immunodeficiency virus (HIV) infection
- •Has a known history of Hepatitis B or known active Hepatitis C virus infection
- •Has current active tuberculosis
- •Has had an allogenic-tissue/solid organ transplant
- •Has any contraindication(s) to IV contrast or is otherwise unable to have screening imaging with IV contrast performed
- •BCG Post-induction Cohort (Cohort A) Only - Has persistent T1 disease following an induction course of BCG
- •BCG Naïve Cohort (Cohort B) Only
- •- Has received any prior treatment with BCG for their NMIBC within the past 2 years prior to study entry
研究组 & 干预措施
BCG plus Pembrolizumab: Post-induction Cohort A (Arm A-1)
Participants receive BCG (Induction and Maintenance) in combination with 200 mg pembrolizumab administered intravenously (IV) every 3 weeks (Q3W) for 35 doses (~2 years).
干预措施: Pembrolizumab (Biological)
BCG plus Pembrolizumab: Post-induction Cohort A (Arm A-1)
Participants receive BCG (Induction and Maintenance) in combination with 200 mg pembrolizumab administered intravenously (IV) every 3 weeks (Q3W) for 35 doses (~2 years).
干预措施: BCG (Biological)
BCG Monotherapy: Post-induction Cohort A (Arm A-2)
Participants receive BCG monotherapy (Induction and Maintenance).
干预措施: BCG (Biological)
BCG plus Pembrolizumab: BCG Naïve Cohort B-Reduced Maintenance (Arm B-1)
Participants receive BCG (Induction and reduced Maintenance) in combination with 400 mg pembrolizumab administered IV every 6 weeks (Q6W) for 9 doses (~1 year).
干预措施: Pembrolizumab (Biological)
BCG plus Pembrolizumab: BCG Naïve Cohort B-Full Maintenance (Arm B-2)
Participants receive BCG (Induction and full Maintenance) in combination with 400 mg pembrolizumab administered IV Q6W for 9 doses (~1 year).
干预措施: Pembrolizumab (Biological)
BCG plus Pembrolizumab: BCG Naïve Cohort B-Reduced Maintenance (Arm B-1)
Participants receive BCG (Induction and reduced Maintenance) in combination with 400 mg pembrolizumab administered IV every 6 weeks (Q6W) for 9 doses (~1 year).
干预措施: BCG (Biological)
BCG plus Pembrolizumab: BCG Naïve Cohort B-Full Maintenance (Arm B-2)
Participants receive BCG (Induction and full Maintenance) in combination with 400 mg pembrolizumab administered IV Q6W for 9 doses (~1 year).
干预措施: BCG (Biological)
BCG Monotherapy: BCG Naïve Cohort B (Arm B-3)
Participants receive BCG monotherapy (Induction and Maintenance).
干预措施: BCG (Biological)
结局指标
主要结局
Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) (Cohort A)
时间窗: Up to ~3.5 years
CRR is defined as the percentage of participants with carcinoma in situ (CIS) achieving a complete response (CR).
Event-Free Survival (EFS) (Cohort B)
时间窗: Up to ~5 years
EFS is defined as the time from randomization until urothelial carcinoma (UC)-defined event, or death due to any cause.
次要结局
- Disease Specific Survival (DSS) (Cohorts A and B)(Up to ~5 years)
- EFS (Cohort A)(Up to ~5 years)
- Recurrence-Free Survival (RFS) (Cohorts A and B)(Up to ~5 years)
- Overall Survival (OS) (Cohorts A and B)(Up to ~5 years)
- Time to Cystectomy (Cohorts A and B)(Up to ~5 years)
- 12-Month EFS Rate (Cohort A)(12 months after EFS (up to ~5 years))
- Duration of Response (DOR) (Cohorts A and B)(Up to ~5 years)
- 12-Month DOR Rate (Cohorts A and B)(12 months after CR (up to ~4.5 years))
- Percentage of Participants Experiencing Adverse Events (AEs) (Cohorts A and B)(Up to ~5 years)
- Percentage of Participants Discontinuing Study Drug Due to AEs (Cohorts A and B)(Up to ~5 years)
- Change from Baseline 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 (Cohorts A and B)(Baseline, time of last PRO assessment (up to ~2 years))
- Change from Baseline in EORTC-QLQ-C30 Physical Functioning (Items 1-5) Combined Score (Cohorts A and B)(Baseline, time of last PRO assessment (up to ~2 years))
- Change from Baseline in EORTC-QLQ-Non-muscle Invasive Bladder Cancer Module 24 (NMIBC24) Total Score (Cohorts A and B)(Baseline, time of last PRO assessment (up to ~2 years))
- Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) (Cohorts A and B)(Baseline, time of last PRO assessment (up to ~2 years))
- Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score (Cohorts A and B)(Time of last PRO assessment (up to ~2 years))
- TTD in the EQ-5D-5L VAS (Cohorts A and B)(Time of last PRO assessment (up to ~2 years))
- CRR by BICR (Cohort B)(Up to ~3.5 years)
- 24-Month EFS Rate (Cohort B)(24 months after EFS (Up to ~5 years))