A Randomized Phase 3 Study Evaluating Cystectomy With Perioperative Pembrolizumab and Cystectomy With Perioperative Enfortumab Vedotin and Pembrolizumab Versus Cystectomy Alone in Participants Who Are Cisplatin-Ineligible or Decline Cisplatin With Muscle-Invasive Bladder Cancer (KEYNOTE-905/EV-303)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 595
- 试验地点
- 484
- 主要终点
- Event-Free Survival (EFS) between Arm C and Arm B
研究概览
简要总结
This is a study of perioperative pembrolizumab or enfortumab vedotin in combination with pembrolizumab in participants who are cisplatin-ineligible or decline cisplatin with muscle-invasive bladder cancer (MIBC).
The primary hypothesis is that perioperative pembrolizumab plus radical cystectomy (RC) plus pelvic lymph node dissection (PLND) and perioperative enfortumab vedotin in combination with pembrolizumab plus RC+PLND will achieve superior event-free survival (EFS) compared with RC+PLND alone.
With Amendment 5, outcome measures for programmed cell death ligand 1 (PD-L1) combined positive score (CPS) were removed.
With Amendment 8, the primary outcome measure of pathologic complete response (pCR) rates was changed to a secondary outcome measure.
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 a histologically confirmed diagnosis of urothelial carcinoma/muscle-invasive bladder cancer [MIBC] (cT2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology to be confirmed by Blinded Independent Central Review (BICR) (central pathology and/or imaging).
- •Clinically nonmetastatic bladder cancer determined by imaging
- •Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND), and agreement to undergo curative intent standard RC + PLND (including prostatectomy if applicable)
- •Ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria OR be eligible for treatment with cisplatin but decline treatment with cisplatin-based chemotherapy:
- •Impaired renal function with measured or calculated creatinine clearance (CrCl) 30 to 59 mL/min (calculated by Cockcroft-Gault method, Modification of Diet of Renal Disease [MDRD] equations, or measured by 24-hour urine collection)
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 2
- •Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric hearing loss
- •New York Heart Association (NYHA) Class III heart failure
- •Transurethral resection (TUR) of a bladder tumor that is submitted for central pathology assessment and adequate to determine urothelial histology and PD-L1 expression assessment
- •ECOG performance status of 0, 1, or 2
- •Adequate organ function
- •A male participant is eligible to participate if he agrees to use contraception and refrain from donating sperm during the intervention period and for at least 180 days after the last dose of enfortumab vedotin. If the male participants are receiving pembrolizumab only or undergoing surgery only, there are no contraception requirements
- •A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a (woman of childbearing potential) WOCBP or a WOCBP who agrees to use a highly effective contraceptive method or be abstinent from heterosexual intercourse (as their preferred and usual lifestyle) during the intervention period and for at least 120 days after the last dose of pembrolizumab and at least 180 days after the last dose of enfortumab vedotin; whichever comes last. A female participant must agree not to donate eggs during this period as well
- •A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention
排除标准
- •Known additional nonurothelial malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization, with certain exceptions
- •Has ≥ N2 or metastatic disease (M1) as identified by imaging
- •Received any prior systemic treatment, chemoradiation, and/or radiation therapy for muscle-invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMIBC)
- •Received prior therapy with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2 (PD-L2), or with an agent directed to another stimulatory or coinhibitory T-cell receptor
- •Received prior systemic anticancer therapy including investigational agents within 3 years prior to randomization
- •Received any prior radiotherapy to the bladder
- •Received a partial cystectomy of the bladder to remove any non-muscle-invasive bladder cancer (NMIBC) or MIBC
- •Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
- •Current participation in or participation in a study of an investigational agent or use of an investigational device within 4 weeks prior to the first dose of study intervention
- •Ongoing sensory or motor neuropathy Grade 2 or higher
- •Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
- •Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
- •Severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient contained in the drug formulation of enfortumab vedotin
- •Active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator
- •Active autoimmune disease that has required systemic therapy in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic therapy and is allowed
- •Has uncontrolled diabetes
- •History of (noninfectious) pneumonitis that required steroids, or current pneumonitis
- •Active infection requiring systemic therapy
- •Has had an allogeneic tissue/solid organ transplant
研究组 & 干预措施
Arm A: Pembrolizumab + Surgery
Participants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by 14 cycles of postoperative pembrolizumab. Each cycle is 21 days.
干预措施: Pembrolizumab (Drug)
Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery
Participants receive 3 preoperative cycles of enfortumab vedotin + pembrolizumab, followed by standard of care surgery, followed by 6 cycles of postoperative enfortumab vedotin + pembrolizumab, followed by 8 cycles of pembrolizumab alone. Each cycle is 21 days.
干预措施: Enfortumab Vedotin (Drug)
Arm A: Pembrolizumab + Surgery
Participants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by 14 cycles of postoperative pembrolizumab. Each cycle is 21 days.
干预措施: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND]) (Procedure)
Arm B: Surgery alone
Participants receive standard of care surgery alone.
干预措施: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND]) (Procedure)
结局指标
主要结局
Event-Free Survival (EFS) between Arm C and Arm B
时间窗: Up to approximately 6.75 years
EFS is defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes RC surgery or failure to undergo RC surgery in participants with residual disease (biopsy-proven muscle-invasive bladder cancer \[MIBC\] will be considered an event regardless of radiographic findings), gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy, or death due to any cause.
Event-Free Survival (EFS) Between Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery and Arm B: Surgery Alone
时间窗: Up to approximately 53 months
EFS is defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy + pelvic lymph node dissection (RC + PLND) surgery, failure to undergo RC + PLND surgery in participants with residual disease and any radiographic disease present (biopsy-proven muscle-invasive bladder cancer \[MIBC\] will be considered an event regardless of radiographic findings), gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy, or death due to any cause.
次要结局
- Overall Survival (OS) between Arm C and Arm B(Up to approximately 7.6 years)
- OS between Arm A and Arm B(Up to approximately 7.6 years)
- EFS between Arm A and Arm B(Up to approximately 6.75 years)
- Pathologic Complete Response (pCR) Rate between Arm C and Arm B(Up to approximately 5.7 years)
- pCR Rate between Arm A and Arm B(Up to approximately 5.7 years)
- Disease-Free Survival (DFS)(Up to approximately 6.75 years)
- Pathologic Downstaging (pDS) Rate between Arm A and Arm B(Up to approximately 5.7 years)
- pDS Rate between Arm C and Arm B(Up to approximately 5.7 years)
- Number of Participants Experiencing Adverse Events (AEs)(Up to approximately 7.6 years)
- Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs)(Up to approximately 1 year)
- Number of Participants Experiencing Perioperative Complications(Up to approximately 1 year)
- EFS Between Arm A and Arm B(Up to approximately 6.75 years)
- Overall Survival (OS) Between Arm C and Arm B(Up to approximately 7.6 years)
- OS Between Arm A and Arm B(Up to approximately 7.6 years)
- Pathologic Complete Response (pCR) Rate Between Arm C and Arm B(Up to approximately 53 monhts)
- pCR Rate Between Arm A and Arm B(Up to approximately 5.7 years)
- Pathologic Downstaging (pDS) Rate Between Arm A and Arm B(Up to approximately 5.7 years)
- Pathologic Downstaging {pDS) Rate Between Arm C and Arm B(Up to approximately 53 months)