Phase 2 Open‑Label Single‑Arm Study of Enfortumab Vedotin Plus Pembrolizumab for Bladder Preservation in Patients with Muscle‑Invasive Bladder Cancer
- Trial ID
- 2025-524488-18-00
- Protocol
- 7465-CL-0209
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to assess the overall complete clinical response (cCR) rate following treatment with enfortumab vedotin combined with pembrolizumab in participants with muscle‑invasive bladder cancer, and to determine the 2‑year bladder‑intact event‑free survival (BI‑EFS) rate among those who achieve a cCR. Secondary objectives include:
- Evaluation of the overall cCR rate after four treatment cycles and the 2‑year BI‑EFS rate in participants with a cCR after four cycles.
- Assessment of additional efficacy measures for the combination therapy in participants who have achieved a cCR.
- Evaluation of the safety and tolerability profile of enfortumab vedotin plus pembrolizumab.
Participants
The trial enrolled 152 participants diagnosed with muscle‑invasive bladder cancer. Eligible individuals were adults aged 18 years or older, including both male and female patients. Enrollment required histologically confirmed disease at stage cT2–T4aN0M0 or T1–T4aN1M0 with ≥50 % urothelial carcinoma histology, suitability for radical cystectomy and pelvic lymph‑node dissection as assessed by the treating urologist or oncologist, and an ECOG performance status of 0 to 2. Participants also needed accessible archival tumor tissue (or a pre‑treatment biopsy) and a transurethral resection of bladder tumor performed within approximately 60 days of screening. Selection was based on these clinical and pathological criteria; no specific lifestyle restrictions such as diet or physical activity were stipulated. The cohort represented a general adult population in overall good functional condition suitable for the investigational treatment regimen.
Plans and Procedures
The study is an open-label, single‑arm Phase 2 investigation of enfortumab vedotin in combination with pembrolizumab in participants with muscle‑invasive bladder cancer. After a screening visit to confirm histologic stage (cT2–T4aN0M0 or T1‑T4aN1M0), performance status, and availability of tumor tissue, eligible participants receive enfortumab vedotin 125 mg IV and pembrolizumab 400 mg IV on day 1 of each 3‑week cycle for up to four cycles; pembrolizumab may continue as maintenance until disease progression or up to two years. Follow‑up visits occur every 12 weeks for imaging, cystoscopy, and safety assessments, with the primary efficacy assessment of clinical complete response (cCR) after the induction phase and a secondary assessment of 2‑year bladder‑intact event‑free survival (BI‑EFS). The end‑of‑study visit is scheduled approximately two years after the last study drug administration. Overall participant involvement is expected to be about 30 months, encompassing screening, treatment, and follow‑up. Early termination may occur for unacceptable toxicity, disease progression, withdrawal of consent, or major protocol non‑compliance. The recruitment period is planned from 31 July 2026 to 30 April 2032.
Treatment
Padcev 30 mg powder for concentrate for solution for infusion contains the antibody‑drug conjugate enfortumab vedotin. The product is supplied as a sterile powder that is reconstituted to a solution for infusion and administered intravenously. Each participant receives a dose of 125 mg, delivered as an infusion according to the schedule defined in the protocol, with dosing intervals recorded in the infusion log to support compliance monitoring.
KEYTRUDA 395 mg solution for injection provides the immune‑checkpoint inhibitor pembrolizumab. It is presented as a sterile solution for injection and is administered intravenously. The assigned dose is 400 mg per administration, given on the days specified by the study protocol. Administration times and any deviations are documented to ensure adherence to the dosing regimen.
The study does not include a placebo, standard‑of‑care therapy, or any other comparator treatment; participants receive only the combination of the two investigational agents described above.
Efficacy
Efficacy will be evaluated using a set of predefined clinical endpoints. The primary efficacy parameters are the overall complete clinical response (cCR) rate after the full course of enfortumab vedotin combined with pembrolizumab, and the 2‑year bladder‑intact event‑free survival (BI‑EFS) rate as assessed by the investigator in the full analysis set (FAS1). Secondary efficacy assessments include the cCR rate after four treatment cycles, the 2‑year BI‑EFS rate in the FAS2 analysis set, as well as overall survival (OS), disease‑free survival (DFS) and metastasis‑free survival (MFS), all evaluated by the investigator.
Endpoints will be measured at specified time points: the cCR rate will be determined after completion of the treatment regimen and again after four cycles of therapy; survival endpoints (BI‑EFS, OS, DFS, MFS) will be tracked longitudinally with a minimum follow‑up of two years. Efficacy assessments will be performed by the investigators using standard clinical and radiologic evaluation methods appropriate for muscle‑invasive bladder cancer, with data collection aligned to the treatment schedule and follow‑up visits. Analyses will be conducted on the predefined analysis sets (FAS1, FAS2) according to the protocol‑specified statistical plan.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant is ≥ 18 years of age at the time of signing the ICF.
- Participant has histologically-confirmed MIBC, stage cT2–T4aN0M0 or T1-T4aN1M0.
- Participant has predominant UC histology (≥ 50%).
- Participant is deemed eligible for RC and PLND by a urologist and/or oncologist.
- Participant has accessible archival tumor tissue from the primary tumor, for which source and availability have been confirmed prior to study intervention. If no archival tumor tissue is available, the participant will have a biopsy to obtain tumor tissue prior to study intervention.
- Participant has ECOG performance status of 0 to 2.
- Have a TUR of a bladder tumor within 60 days (+14 days) prior to screening (from the date of ICF signature).
Exclusion Criteria
- Participant has preexisting sensory or motor neuropathy Grade ≥ 2
- Participant has ≥ N2 disease or metastatic disease (M1) as identified by imaging.
- Participant has a history of uncontrolled diabetes mellitus within 3 months prior to screening. Uncontrolled diabetes (within 3 months before first dose) is defined as HbA1c ≥ 8% or HbA1c between 7% and < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. The lowest HbA1c during the screening period will be used to determine eligibility.
- Participant has a second malignancy diagnosed within 3 years before first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. Participant with non-melanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
- Participant has known active keratitis or corneal ulcerations. Participant with superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator
- Participant has a history of (non-infectious) pneumonitis/ILD that required steroids or has current pneumonitis/ILD.
- Participant has a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
- Participant has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency."
- Participant has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
- Participant has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
- Participant has received prior systemic anti-cancer therapy for MIBC/NMIBC, or received prior systemic anti-cancer therapy including investigational agents (including enfortumab vedotin or other MMAE-based ADCs) within 3 years prior to screening
- Participant has received a partial cystectomy of the bladder to remove any NMIBC or MIBC.
- Participant has received any prior radiotherapy to the bladder.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 31 Jul 2026 | 18 |
 Germany | Not Yet Recruiting | 31 Jul 2026 | 24 |
 Italy | Not Yet Recruiting | 31 Jul 2026 | 18 |
 Poland | Not Yet Recruiting | 31 Jul 2026 | 10 |
 Spain | Not Yet Recruiting | 31 Jul 2026 | 18 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Padcev 30 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 125 | 28 | PRD9634494 |
KEYTRUDA 395 mg solution for injection | Test | SOLUTION FOR INJECTION | SOLUTION FOR INJECTION | 400 | 52 | PRD13198947 |