Enfortumab Vedotin in Combination With Pembrolizumab vs. Concurrent Chemoradiotherapy (cCRT) in People With Muscle Invasive Bladder Cancer (EV-309)

Official title

A PHASE 3, OPEN-LABEL, RANDOMIZED STUDY TO EVALUATE ENFORTUMAB VEDOTIN IN COMBINATION WITH PEMBROLIZUMAB IN ADULT PARTICIPANTS WITH MUSCLE-INVASIVE BLADDER CANCER WHO ARE INELIGIBLE FOR OR HAVE ELECTED NOT TO UNDERGO CYSTECTOMY

Overview

This study is being done to see how well two drugs (enfortumab vedotin and pembrolizumab) work together as a bladder preservation approach to treat patients with muscle invasive bladder cancer. The study will compare these drugs to concurrent chemoradiotherapy that is usually used to treat this cancer (standard of care). The study will enroll patients with muscle-invasive bladder cancer (MIBC) who have cancer that has not spread outside the bladder.

Detailed description

This study is being conducted to evaluate the combination of enfortumab vedotin + pembrolizumab versus standard of care concurrent chemoradiotherapy, in subjects with previously untreated muscle invasive bladder cancer.

Enfortumab vedotin may be administered for up to 9 cycles or a protocol defined reason for study discontinuation occurs, whichever is first. Pembrolizumab may be administered for a maximum of 17 cycles (3-week cycles) or a protocol-defined reason for study discontinuation occurs, whichever is first. Concurrent chemoradiotherapy may be administered for a maximum of 6.5 weeks.

Interventions

• Drug Enfortumab vedotin
  Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle up to cycle 9.
• Radiation Conventional Radiotherapy
  64 Gy in 32 fractions over 6.5 weeks administered to the participant's bladder only or the bladder and prophylactically to pelvic nodes.
• Radiation Hypofractionated Radiotherapy
  55 Gy in 20 fractions over 4 weeks administered to the participant's bladder only.
• Drug Cisplatin
  40 mg of cisplatin per meter squared of body surface area, administered once weekly via IV infusion during radiation OR 20 mg of cisplatin per meter squared of body surface area per day on Days 1 and 2 weekly via IV infusion during radiation.
• Drug Fluorouracil
  500 mg per meter squared of body surface area per day on Days 1-5 (week 1) and Days 22 26 (week 3) administered as continuous IV infusion during radiation in combination with mitomycin C.
• Drug Mitomycin C
  12 mg per meter squared of body surface area administered as an IV bolus on Day 1 during radiation in combination with fluorouracil.
• Drug Gemcitabine
  100 mg per meter squared of body surface area administered once weekly via IV infusion during radiation OR 27 mg per meter squared of body surface area administered twice weekly via IV infusion during radiation
• Drug Pembrolizumab
  IV infusion on Day 1 of every 3-week cycle up to cycle 17.

Primary outcome measures

• Bladder-intact Event Free Survival (BI-EFS) by Blinded Independent Central Review (BICR) [Time frame: Up to approximately 45.5 months]
• Overall Survival (OS) [Time frame: Up to approximately 60 months]

Secondary outcome measures (8)

• Bladder-intact Event Free Survival (BI-EFS) by Investigator [Time frame: Up to approximately 45.5 months]
• Complete clinical response (cCR) rate by Blinded Independent Central Review (BICR) and Investigator [Time frame: Up to approximately 60 months]
• Metastasis-Free Survival (MFS) by Blinded Independent Central Review (BICR) and Investigator [Time frame: Up to approximately 60 months]]
• Time to Cystectomy [Time frame: Up to approximately 60 months]
• Disease Free Survival (DFS) by Blinded Independent Central Review (BICR) and Investigator [Time frame: Up to approximately 60 months]
• Cystectomy Free Survival (CFS) [Time frame: Up to approximately 60 months]
• Number of Participants with Treatment Emergent Adverse Event (TEAE) [Time frame: From start of study treatment up to 30 days after last dose of study drug (approximately up to 1.1 years)]
• Number of Participants with Serious TEAEs [Time frame: From start of treatment up to 90 days after the last dose of study treatment (approximately up to 1.3 years)]

Eligibility criteria

Inclusion criteria

• Has histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology staged cT2-T4aN0M0
• Tissue comprising muscle-invasive urothelial cancer must be submitted for clinical staging at baseline
• Eligible for and agree to receive chemoradiotherapy and one of the protocol-specified radiosensitizing chemotherapy regimens
• Fit for systemic therapy and elect bladder preservation, including participants who are ineligible for or have elected not to undergo cystectomy
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Exclusion criteria

• Advanced or metastatic disease (N+, M1), non-urothelial carcinoma, diffuse or multifocal CIS, urothelial carcinoma or histological variant at any site outside the urinary bladder within previous 24 months prior to randomization except Ta/T1/CIS of the upper urinary tract including renal pelvis and ureter if the participant had undergone complete nephrectomy
• Has received any prior systemic treatment, chemoradiation, and/or radiation for MIBC or NMIBC
• Prior pelvic radiation for any reason
• Inadequate bladder function
• Other active malignancies within 3 years prior to randomization
• Previously treated with enfortumab vedotin or other MMAE-based antibody-drug conjugates (ADCs)
• Previously treated with a PD(L)-1 inhibitor, defined as a PD-1 inhibitor or PD-L1 inhibitor
• Uncontrolled diabetes
• Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted
• Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection
• Received major surgery (defined as requiring general anesthesia and >24 hour inpatient hospitalization) within 4 weeks prior to randomization
• Known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin
• Known genetic disorders associated with radiosensitivity (eg, ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi syndrome)
• Active keratitis or corneal ulcerations
• History of autoimmune disease that has required systemic treatment in the past 2 years
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Prior allogeneic stem cell or solid organ transplant
• Received a live attenuated vaccine within 30 days prior to randomization

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 12 centers

• Samsun Clinic - Ridley-Tree Cancer Center — Santa Barbara
• Rocky Mountain Cancer Center — Aurora
• Medical Oncology Hematology Consultants — Newark
• Illinois Cancer Specialists — Niles
• Fort Wayne Medical Oncology and Hematology — Fort Wayne
• Missouri Cancer Associates — Columbia
• Williamette Valley Cancer Institute and Research Center — Eugene
• Compass Oncology - West — Tigard
• … and 4 more centers

Identifiers

NCT: NCT07566156 · C5701009 · EV-309 · 2026-525612-34-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗