Neoadjuvant Enfortumab Vedotin Plus Pembrolizumab in Muscle-Invasive Bladder Cancer and Upper Tract Urothelial Carcinoma

Sponsor
University of Florida
Study ID
NCT07643519
Phase
PHASE2
Status
Not Yet Recruiting

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Conditions

  • Urothelial Carcinoma (UC)

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • enfortumab vedotin and pembrolizumab (EV/P) — DRUG
    Participants in both cohorts will first receive neoadjuvant enfortumab vedotin + pembrolizumab (EV-P) for 4 cycles. Each cycle is 21 days. Participants will be given 1.25 mg/kg enfortumab vedotin intravenously on days 1 and 8 and 200 mg pembrolizumab intravenously on day 1 of each cycle. Participants in Cohort A may then choose to receive 5 more cycles of EV-P followed by pembrolizumab alone to complete 1 year of study therapy if they have a composite complete clinical response. Participants in Cohort B will then receive 5 more cycles of EV-P followed by pembrolizumab alone to complete 1 year of study therapy following their definitive surgery.

Study Details

Radical cystectomy remains the standard curative-intent treatment for most patients with muscle-invasive bladder cancer, but it is associated with significant morbidity and long-term quality-of-life implications. Trimodality therapy is an accepted standard-of-care alternative for carefully selected patients who wish to preserve their bladder; however, optimal patient selection remains challenging. The combination of enfortumab vedotin plus pembrolizumab (EV-P) has demonstrated remarkable activity in urothelial carcinoma, including in the perioperative setting, with pathologic complete response rates of approximately 50-60%. These results generate the hypothesis that a subset of patients may achieve sufficiently deep responses to allow selective deferral of cystectomy. Cohort A of this trial prospectively evaluates the use of multimodal response assessment (pelvic MRI and TURBT, ctDNA) to guide individualized decisions regarding cystectomy versus bladder preservation. Radical nephroureterectomy (RNU) remains the standard curative-intent treatment for high-risk upper tract urothelial carcinoma (UTUC), but recurrence rates after surgery alone are high. Neoadjuvant cisplatin-based chemotherapy improves pathologic outcomes and is supported by phase II data, but its delivery is constrained by baseline renal dysfunction and the further decline in glomerular filtration that follows RNU - historically, only about 20% of patients remain cisplatin-eligible postoperatively, which is the principal rationale for delivering platinum in the neoadjuvant rather than adjuvant setting. A large fraction of patients with UTUC are cisplatin-ineligible at baseline, and no level 1 evidence supports a specific neoadjuvant regimen in this population. EV-P is not constrained by renal function and has produced unprecedented activity in urothelial carcinoma. In the EV-302 upper tract subgroup, EV-P achieved an objective response rate of 67.7% and a complete response rate of 28.6%, with survival benefit preserved relative to platinum-based chemotherapy. In the perioperative bladder cancer setting, EV-P has yielded pathologic complete response rates of approximately 50-60%. However, available data on EV-P in UTUC are restricted to the metastatic setting, and prospective evaluation in the neoadjuvant setting is lacking. Cohort B of this trial addresses this gap by prospectively evaluating neoadjuvant EV-P followed by RNU in patients with high-risk UTUC, with pathologic complete response as the primary endpoint.

Key Dates

Start date
Oct 31, 2026
Status verified
Jun 2026
Primary completion
Feb 28, 2029
Completion
Oct 31, 2030

Study Design

Enrollment
39 participants (estimated)
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: Cohort A (neoadjuvant EV-P + response-adapted management)
    Following neoadjuvant EV-P, participants in this cohort will have response-adapted management based on if they achieved a composite clinical complete response (cCR) to determine the next step in their treatment on this study. A participant has achieved cCR if ALL the following are met: 1. ctDNA is negative, 2. Imaging are negative for lymph nodes and distant metastases, and 3. TURBT shows T0 or Ta low-grade only, and a negative urinary cytology. If a participant achieves cCR, they will have a choice between: * receive 5 more cycles of EV-P, followed by pembrolizumab alone to complete 1 year of therapy. * Alternatively, if participant wishes, partial or radical cystectomy. If a participant does not achieve cCR, they will have cystectomy.
  • Experimental: Cohort B (neoadjuvant EV-P + surgery + adjuvant EV-P)

Primary Outcome Measure

Clinical complete response rate [ Time Frame: 3 weeks following completion of neoadjuvant therapy ]

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