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

NCT07643519 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: UF-GU-014
• Study Type: interventional
• Target: 39
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Urothelial Carcinoma (UC)

Keywords

bladder cancer; cystectomy; enfortumab vedotin; muscle invasive bladder cancer; pembrolizumab; urothelial carcinoma; upper tract urothelial carcinoma

Outcome Measures

Primary Outcomes (2)

• Clinical complete response rate

  Determine the percent of subjects in Cohort A that achieve a clinical complete response following completion of neoadjuvant EV-P. A clinical complete response is defined as having all three of the following: * A negative ctDNA result, * Imaging of the pelvis with negative lymph nodes and no distant metastasis on CT scans, AND * A TURBT showing T0 or low-grade Ta only, and a negative urinary cytology.

  3 weeks following completion of neoadjuvant therapy

• Pathologic complete response rate

  Determine the percent of subjects in Cohort B who achieve a pathologic complete response at the time of surgery. A pathologic complete response is defined as having disease staging of pT0N0 at time of surgery.

  8 weeks following completion of neoadjuvant therapy

Secondary Outcomes (11)

• Event-free survival

  1 year from the start of EV-P

• Event-free survival

  2 years from the start of EV-P

• Overall survival

  1 year from the start of EV-P

• Overall survival

  2 years from the start of EV-P

• Bladder-intact survival

  1 year from the start of EV-P

Study Arms (2)

Cohort A (neoadjuvant EV-P + response-adapted management)

EXPERIMENTAL

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.

Drug: enfortumab vedotin and pembrolizumab (EV/P)

Cohort B (neoadjuvant EV-P + surgery + adjuvant EV-P)

EXPERIMENTAL

Drug: enfortumab vedotin and pembrolizumab (EV/P)

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.

Cohort A (neoadjuvant EV-P + response-adapted management); Cohort B (neoadjuvant EV-P + surgery + adjuvant EV-P)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults ≥ 18 years of age.
• ECOG Performance Status of 0-2
• For Cohort A, a clinical or pathological diagnosis consistent with muscle-invasive urothelial carcinoma of the bladder (locoregional), with a clinical staging of T2 or higher, N0 to N2, and M0.
• For Cohort B, a clinical or pathological diagnosis of upper tract urothelial carcinoma, with high-intermediate risk or higher per NCCN guidelines, planned for definitive surgery.
• High-intermediate: High grade + Unifocal \<1.5 cm

You may not qualify if:

• Eligible to receive enfortumab vedotin plus pembrolizumab (EV-P) in the opinion of the investigators.
• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.
• Subjects must not have more than one active malignancy at the time of enrollment.
• Note: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen or primary endpoint (as determined by the treating physician) are eligible for this trial.
• \- Subjects of childbearing potential (SOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 months after the last dose of EV-P to minimize the risk of pregnancy. Prior to study enrollment, subjects of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.
• SOCBP includes any subject who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:
• Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
• For subjects with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
• Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 4 months following the last dose of EV-P.
• Histology that contains any component of neuroendocrine carcinoma.
• Any known contraindications to enfortumab vedotin plus pembrolizumab.
• Subjects who are confirmed to be pregnant or breastfeeding.
• History of any other disease, metabolic dysfunction, clinical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician.
• Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose.
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.

Sponsors & Collaborators

• University of Florida: lead

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms

Interventions

enfortumab vedotin; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Daniel Araujo, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 3, 2026
• First Posted: June 11, 2026
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): October 1, 2030
• Last Updated: June 11, 2026

Record last verified: 2026-06