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

Phase 3RecruitingNCT07566156

Astellas Pharma Global Development, Inc.390 enrolled

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

390

Conditions

Urothelial Cancer Urinary Bladder Neoplasms

Interventions

Enfortumab vedotinDRUG

Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle up to cycle 9.

Conventional RadiotherapyRADIATION

64 Gy in 32 fractions over 6.5 weeks administered to the participant's bladder only or the bladder and prophylactically to pelvic nodes.

Hypofractionated RadiotherapyRADIATION

55 Gy in 20 fractions over 4 weeks administered to the participant's bladder only.

CisplatinDRUG

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.

FluorouracilDRUG

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.

Mitomycin CDRUG

12 mg per meter squared of body surface area administered as an IV bolus on Day 1 during radiation in combination with fluorouracil.

GemcitabineDRUG

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

PembrolizumabDRUG

IV infusion on Day 1 of every 3-week cycle up to cycle 17.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (14)

Samsun Clinic - Ridley-Tree Cancer Center

Santa Barbara, California, United States

RECRUITING

Rocky Mountain Cancer Center

Aurora, Colorado, United States

RECRUITING

Medical Oncology Hematology Consultants

Newark, Delaware, United States

RECRUITING

Illinois Cancer Specialists

Niles, Illinois, United States

RECRUITING

Fort Wayne Medical Oncology and Hematology

Fort Wayne, Indiana, United States

RECRUITING

Missouri Cancer Associates

Columbia, Missouri, United States

RECRUITING

Oncology Hematology Care Clinical Trials, LLC

Fairfield, Ohio, United States

RECRUITING

Williamette Valley Cancer Institute and Research Center

Eugene, Oregon, United States

RECRUITING

Compass Oncology - West

Tigard, Oregon, United States

RECRUITING

SCRI Oncology Partners

Nashville, Tennessee, United States

RECRUITING

...and 4 more locations

Outcomes

Primary Outcomes

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.

Time frame: Up to approximately 45.5 months

Overall Survival (OS)

Time from randomization to death due to any cause.

Time frame: Up to approximately 60 months

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: Up to approximately 60 months]

Time to Cystectomy

The time from randomization to cystectomy.

Time frame: 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.

Time frame: Up to approximately 60 months

Cystectomy Free Survival (CFS)

The time from randomization to cystectomy or death due to any cause, whichever occurs first.

Time frame: 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.

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

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.

Time frame: From start of treatment up to 90 days after the last dose of study treatment (approximately up to 1.3 years)

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

Overview

Conditions

Interventions

Eligibility

Locations (14)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts