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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Urinary Bladder Neoplasms; Urothelial Cancer
• Intervention / Treatment: Drug: Enfortumab vedotin; Drug: Pembrolizumab; Radiation: Conventional Radiotherapy; Radiation: Hypofractionated Radiotherapy; Drug: Cisplatin; Drug: Fluorouracil; Drug: Mitomycin C; Drug: Gemcitabine

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.

• Study Type: Interventional
• Enrollment (Estimated): 390
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Pfizer CT.gov Call Center; Phone Number: 1-800-718-1021; Email: ClinicalTrials.gov_Inquiries@pfizer.com

Study Locations

• United States
  • California
    • Santa Barbara, California, United States, 93105
      • Recruiting
      • Samsun Clinic - Ridley-Tree Cancer Center
  • Delaware
    • Newark, Delaware, United States, 19713
      • Recruiting
      • Medical Oncology Hematology Consultants
  • Illinois
    • Niles, Illinois, United States, 60714
      • Recruiting
      • Illinois Cancer Specialists
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Recruiting
      • Williamette Valley Cancer Institute and Research Center
    • Tigard, Oregon, United States, 97223
      • Recruiting
      • Compass Oncology - West
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • SCRI Oncology Partners
  • Texas
    • Austin, Texas, United States, 78705
      • Recruiting
      • Texas Oncology
    • Tyler, Texas, United States, 75702
      • Recruiting
      • Texas Oncology - Northeast Texas
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Recruiting
      • Virginia Oncology Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Enfortumab vedotin + pembrolizumab (EV + P)	Drug: Enfortumab vedotin; Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle up to cycle 9.; Other Names: • Padcev; • ASG-22CE; • ASG-22Me; Drug: Pembrolizumab; IV infusion on Day 1 of every 3-week cycle up to cycle 17.; Other Names: Keytruda
Active Comparator: Arm B; Concurrent Chemoradiotherapy (cCRT)	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.; Other Names: • 5-Fluorouracil; • 5-FU; 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.; Other Names: • MMC; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bladder-intact Event Free Survival (BI-EFS) by Blinded Independent Central Review (BICR)	BI-EFS is defined as the time from randomization to any of the following events: histologically confirmed persistent or residual MIBC post-treatment confirmed by BICR, histologically confirmed recurrent MIBC by BICR, disease progression by BICR, cystectomy, or death from any cause.	Up to approximately 45.5 months
Overall Survival (OS)	Time from randomization to death due to any cause.	Up to approximately 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bladder-intact Event Free Survival (BI-EFS) by Investigator	BI-EFS is defined as the time from randomization to any of the following events: histologically confirmed persistent or residual MIBC post-treatment, histologically confirmed recurrent MIBC, disease progression, cystectomy, or death from any cause.	Up to approximately 45.5 months
Complete clinical response (cCR) rate by Blinded Independent Central Review (BICR) and Investigator	cCR is defined as no radiographic evidence of residual or metastatic disease on imaging, negative cystoscopy, negative pathology except for low-grade Ta, and negative urine cytology.	Up to approximately 60 months
Metastasis-Free Survival (MFS) by Blinded Independent Central Review (BICR) and Investigator	Time from randomization to radiologically or pathologically confirmed distant metastasis, or death due to any cause, whichever occurs first.	Up to approximately 60 months]
Time to Cystectomy	The time from randomization to cystectomy.	Up to approximately 60 months
Disease Free Survival (DFS) by Blinded Independent Central Review (BICR) and Investigator	The time from cCR to local recurrence or distant metastases, a second primary bladder cancer, or death due to any cause, whichever occurs first.	Up to approximately 60 months
Cystectomy Free Survival (CFS)	The time from randomization to cystectomy or death due to any cause, whichever occurs first.	Up to approximately 60 months
Number of Participants with Treatment Emergent Adverse Event (TEAE)	An AE is any untoward medical occurrence in a participant who receives a study treatment without regard to possibility of causal relationship. Treatment-emergent are events between the first dose of study treatment and up to 30 days after the last dose that were absent before treatment or that worsened relative to pretreatment state.	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	An SAE is any AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/ incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 90 days after last dose that were absent before treatment or that worsened relative to pretreatment state.	From start of treatment up to 90 days after the last dose of study treatment (approximately up to 1.3 years)

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Pfizer
• Investigators: Study Director: Zejing Wang, MD/PhD, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2026
• Primary Completion (Estimated): March 31, 2030
• Study Completion (Estimated): February 29, 2032

Study Registration Dates

• First Submitted: April 29, 2026
• First Submitted That Met QC Criteria: April 29, 2026
• First Posted (Actual): May 4, 2026

Study Record Updates

• Last Update Posted (Actual): June 8, 2026
• Last Update Submitted That Met QC Criteria: June 5, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Gemcitabine; Neoplasms; Urinary Bladder Neoplasms; Urothelial Carcinoma; Cisplatin; Pembrolizumab; Fluorouracil; Complications; Urologic Diseases; Urothelial Cancer; Enfortumab vedotin; Urogenital Neoplasms; Neoplasms by Site; Urologic Neoplasms; Female Urogenital Diseases; Male Urogenital Diseases; Muscle Invasive Bladder Cancer; Mitomycin; Urinary Bladder Diseases; Bladder Preservation; Urogenital Diseases; Female Urogenital Diseases and Pregnancy; Bladder-sparing
• Additional Relevant MeSH Terms: Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Urogenital Diseases; Neoplasms; Urologic Diseases; Urinary Bladder Neoplasms; Urologic Neoplasms; Carcinoma, Transitional Cell; Urogenital Neoplasms; Neoplasms by Site; Male Urogenital Diseases; Urinary Bladder Diseases; Female Urogenital Diseases; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Therapeutics; Indoles; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Uracil; Pyrimidinones; Platinum Compounds; Radiotherapy; Quinones; Azirines; Dose Fractionation, Radiation; Radiotherapy Dosage; Mitomycins; Indolequinones; Gemcitabine; Fluorouracil; Cisplatin; Mitomycin; pembrolizumab; enfortumab vedotin; Radiation Dose Hypofractionation
• Other Study ID Numbers: C5701009; EV-309 (Other Identifier: Alias Study Number); 2026-525612-34-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No