Pembrolizumab Maintenance After Enfortumab Vedotin (EV)/Pembro Induction in Front-Line Metastatic Urothelial Carcinoma

NCT07221942 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 25-1029GU-229
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-arm, open-label, non-randomized Phase II trial evaluating the efficacy of induction therapy with enfortumab vedotin (EV) plus pembrolizumab (P) for 18 weeks (6 cycles), followed by maintenance pembrolizumab in treatment-naïve patients with metastatic urothelial carcinoma (mUC). Approximately 97 patients will be enrolled. Induction consists of EV (1.25 mg/kg IV on Days 1 and 8 of each 21-day cycle; starting dose of 1 mg/kg allowed) and P (200 mg IV on Day 1 of each cycle). Radiographic assessments occur after 3 and 6 cycles. Patients achieving complete or partial response transition to maintenance P (400 mg IV every 6 weeks or 200 mg IV every 3 weeks) for up to 2 years. Dose modifications for EV are permitted per protocol; no dose adjustments for P. Treatment continues until disease progression, unacceptable toxicity, or completion of maintenance therapy. Patients will enter long-term or survival follow-up as applicable.

Conditions

Metastatic Urothelial Carcinoma; Unresectable Urothelial Carcinoma; Advanced Urothelial Carcinoma

Keywords

Urothelial carcinoma

Outcome Measures

Primary Outcomes (1)

• 18-month progression-free survival (PFS)

  radiographic progression or death from any cause within 18 months of initiating treatment

  18 months

Secondary Outcomes (7)

• Overall Survival (OS)

  4 years

• Duration of Response (DoR)

  4 years

• PFS 2 after EV rechallenge

  4 years

• Treatment-free interval

  4 years

• Incidence of Peripheral neuropathy

  4 years

Study Arms (1)

Induction EV + Pembrolizumab Followed by Maintenance Pembrolizumab

EXPERIMENTAL

Participants will receive induction therapy with enfortumab vedotin (EV) plus pembrolizumab (P) for 6 cycles (approximately 18 weeks). EV will be administered at 1.25 mg/kg IV on Days 1 and 8 of each 21-day cycle (starting dose of 1 mg/kg allowed), and pembrolizumab at 200 mg IV on Day 1 of each cycle. Patients achieving complete or partial response will transition to maintenance pembrolizumab at 400 mg IV every 6 weeks or 200 mg IV every 3 weeks for up to 2 years. Dose modifications for EV are permitted per protocol; no dose adjustments for pembrolizumab. Treatment continues until disease progression, unacceptable toxicity, or completion of maintenance therapy.

Drug: Enfortumab vedotin; Drug: Pembrolizumab

Interventions

Pembrolizumab DRUG

Pembrolizumab will be administered at 200 mg IV on Day 1 of each 21-day cycle

Induction EV + Pembrolizumab Followed by Maintenance Pembrolizumab

Enfortumab vedotin DRUG

EV will be administered at 1.25 mg/kg IV on Days 1 and 8 of each 21-day cycle

Induction EV + Pembrolizumab Followed by Maintenance Pembrolizumab

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically and radiographically confirmed locally advanced, unresectable urothelial carcinoma.
• Patients should not have received prior systemic therapy for metastatic disease.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v1.1
• Patients may have received prior neoadjuvant or adjuvant immune checkpoint inhibitor therapy for localized disease and are eligible if they completed the treatment ≥12 months prior to initiating treatment on this clinical trial.
• ECOG performance status 0-2
• Ability to understand and willingness to sign a written informed consent and HIPAA consent document
• Archival tumor biospecimen (when available) must be procured for correlative evaluation. If tumor tissue is not available or accessible despite good faith efforts, patient may still be treated on study. Formalin fixed, paraffin embedded (FFPE) tissue block(s) or at least 25 unbaked, unstained slides are required. Tissue samples taken from a metastatic lesion prior to the start of screening are acceptable.
• Normal organ and marrow function as defined below.
• Absolute neutrophil count \> 1,000/mm3 unless patient has constitutional neutropenia
• Platelets \> 100,000/µl
• Hemoglobin \> 8.0 g/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<2.5 x upper limit of normal (ULN) or \<3.5 x ULN if liver metastases
• Creatinine Clearance \>20 ml/min

You may not qualify if:

• Patients who have received prior monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) for urothelial cancer.
• Grade 2 or higher baseline sensory or motor neuropathy.
• Uncontrolled diabetes (HbA1c \>8%)
• Patients with uncontrolled and untreated central nervous system (CNS) metastases.
• Prior radiation to CNS metastases is permitted.
• Prior history of CNS disease that has responded to previous systemic therapy is permitted only if no recurrence.
• Patient should not have leptomeningeal disease
• CNS metastases have been clinically stable for at least 6 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis.
• If requiring steroid treatment for CNS metastases, the patient is on stable dose \< 10 mg/day of prednisone or equivalent for at least 2 weeks prior to starting treatment
• Subjects with a history of another invasive malignancy within 3 years before the first dose of study drug that cannot be watched and requires treatment, or any evidence of residual disease from a previously diagnosed malignancy that cannot be watched and requires treatment. Adjuvant hormonal therapy for breast cancer is allowed.
• Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of first dose of enfortumab vedotin. Routine antimicrobial prophylaxis is permitted.
• Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with enfortumab vedotin.
• History of idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
• Prior allogeneic stem cell or solid organ transplant.
• Other underlying medical condition that, in the opinion of the investigator, would impair the ability of the patient to receive or tolerate the planned treatment and follow-up; any known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.

Sponsors & Collaborators

• Fox Chase Cancer Center: lead
• United States Department of Defense: collaborator

Study Sites (1)

Fox Chase Cancer Center - Philadelphia

Philadelphia, Pennsylvania, 19111-2497, United States

RECRUITING

MeSH Terms

Conditions

Carcinoma, Transitional Cell

Interventions

enfortumab vedotin; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Study Officials

• Pooja Ghatalia, MD

  Fox Chase Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ryan Romasko, MBA

CONTACT

215-214-1515; ryan.romasko@fccc.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 17, 2025
• First Posted: October 29, 2025
• Study Start: January 23, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 3, 2029
• Last Updated: February 19, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)