N-803 in Combination With Pembrolizumab and Enfortumab Vedotin for Treatment of Urothelial Cancer

NCT07217496 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 25525NCI-2025-07330
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib trial will investigate the effect of N-803 in combination with pembrolizumab and enfortumab vedotin in treating participants with urothelial cancer that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic).

Conditions

Metastatic Urothelial Carcinoma; Urothelial Carcinoma; Locally Advanced Urothelial Carcinoma; Urothelial Cancer

Outcome Measures

Primary Outcomes (3)

• Proportion of participants with reported Treatment-Emergent Adverse Events

  Treatment emergent adverse events will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version (v) 5.0.

  Up to 2 years

• Number of participants with reported Dose-limiting toxicities (DLTs)

  Safety will be evaluated by assessing for DLTs in the first 6 participants treated with the study drug combination. If \>33% or \>2 of the first six participants experiences a DLT, the dose will be reviewed, and study will be considered for modification.

  Up to 28 days

• Percentage of participants alive and progression free at 12 months (PFS12)

  The percentage of participants alive and progression free at 12 months is defined from the date of first dose of study drugs (C1D1) to the date of disease progression or death (any cause), whichever occurs first, by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. If disease progression or death from any cause is not observed prior to initiating subsequent anti-cancer therapy or completing study participation, the PFS will be censored as the last available disease assessment. Kaplan Meier analyses will be used to estimate 12 month PFS with 90% confidence interval.

  12 months

Secondary Outcomes (6)

• Complete Response (CR) Rate

  Up to 2 years

• Clinical Benefit Rate (CBR)

  Up to 24 weeks

• Objective Response Rate (ORR)

  Up to 2 years

• Median Overall Survival (OS)

  Up to 5 years

• Median Duration of Response (DOR)

  Up to 5 years

Study Arms (1)

Treatment (EV, N-803, pembrolizumab)

EXPERIMENTAL

Participants with unresectable locally advanced (LA) or metastatic urothelial carcinoma (mUC) will receive N-803 plus Enfortumab Vedotin (EV) and Pembrolizumab on Day 1 and EV on Day 8 in a repeated 3-week cycle until disease progression or unacceptable toxicity. EV treatment is provided up to 12 cycles. Participants with confirmed clinical benefit based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at the second or third scan (between 8 to 12 cycles on treatment) will discontinue EV treatment at investigator discretion. After participants discontinue EV treatment, participants may continue to receive N-803 and Pembrolizumab treatment up to 2 years.

Drug: Nogapendekin Alfa Inbakicept (N803); Drug: Enfortumab Vedotin (EV); Drug: Pembrolizumab; Procedure: Research Biospecimen Collection; Procedure: Radiographic Imaging; Procedure: Tumor Biopsy

Interventions

Enfortumab Vedotin (EV) DRUG

Given intravenously (IV)

Also known as: Enfortumab Vedotin

Treatment (EV, N-803, pembrolizumab)

Nogapendekin Alfa Inbakicept (N803) DRUG

Given subcutaneously (SC)

Also known as: Nogapendekin Alfa Inbakicept, N803

Treatment (EV, N-803, pembrolizumab)

Pembrolizumab DRUG

Given intravenously (IV)

Also known as: Keytruda

Treatment (EV, N-803, pembrolizumab)

Research Biospecimen Collection PROCEDURE

Undergo blood collection for research purposes

Treatment (EV, N-803, pembrolizumab)

Radiographic Imaging PROCEDURE

Undergo radiographic imaging for disease assessment

Also known as: Magnetic Resonance Imaging (MRI), Computed tomography (CT)

Treatment (EV, N-803, pembrolizumab)

Tumor Biopsy PROCEDURE

Undergo tumor biopsy

Treatment (EV, N-803, pembrolizumab)

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 years
• Histologically or cytologically confirmed locally advanced (LA)/ metastatic urothelial carcinoma (mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as \> 50% urothelial component is present (mixed histology other than small cell/ neuroendocrine are allowed).
• No prior systemic treatment for LA/mUC.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) \<= 2.
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
• Prior perioperative systemic therapy including neoadjuvant or adjuvant chemotherapy, immune checkpoint inhibitors, and EV is allowed if treatment was completed \> 12 months before trial enrollment.
• Participants enrolling in the trial must agree with discontinuing EV upon demonstrating confirmed CR/PR/SD at the second or third scan timepoint on treatment (after 5.5 to 8 months of intended EV treatment).
• Leukocytes ≥ 3,000/microliter (uL).
• Absolute neutrophil count (ANC) ≥ 1,500/uL.
• Platelets ≥ 100,000/uL.
• Total bilirubin \< 1.5 x institutional upper limit of normal (ULN) (if previously abnormal due to non-malignant causes such as Gilbert's disease bilirubin ≤ 2 x ULN will be permitted.)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT))/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal (ULN).
• Creatinine clearance ≥ 30 mL/min/1.73 m\^2 calculated using the Cockcroft-Gault equation.
• Must have archival tumor tissue available or have disease amenable to a fresh biopsy for diagnosis confirmation and correlative studies.
• Human immunodeficiency virus (HIV)-infected individuals with undetectable viral load within 6 months are eligible for this trial. Trial participants who are on antiretroviral therapy (ART) should be on established ART for at least four weeks and have an HIV viral load less than 400 copies/mL prior to enrollment.

You may not qualify if:

• Symptomatic or untreated central nervous system (CNS) metastases.
• \* Note: Participants with previously treated brain or CNS metastases are eligible if the participant has recovered from any acute effects of surgery or radiotherapy and do not require steroids (prednisone equivalent ≥ 10 mg daily), and any whole brain radiation therapy or any stereotactic radiosurgery was completed at least 2 weeks prior to initiation of therapy.
• Participants with a history of active autoimmune disease and on active management with immunosuppressive agents within the past 2 years
• Participants with a history of interstitial lung disease
• Participants with congestive heart failure (New York Heart Association class III or IV)
• Participants on systemic intravenous or oral corticosteroid therapy (prednisone equivalent ≥ 10 mg daily) or other immunosuppressive agents such as azathioprine or cyclosporin A are excluded. For these participants, these excluded treatments must be discontinued at least 1 week prior to enrollment for recent short course use (≤ 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (\> 14 days).
• \* Note: The use of corticosteroids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study. participants requiring hormone replacement with corticosteroids if the steroids are administered only for the purpose of hormonal replacement or participants treated at doses ≤ 10 mg of prednisone or equivalent per day are allowed.
• History of uncontrolled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 8%.
• Grade ≥ 2 peripheral neuropathy at baseline.
• Radiotherapy or major surgery within 2 weeks prior to treatment start.
• History of another significant life-limiting malignancy within 2 years prior to the first dose of study drug. Participants with non-melanoma skin cancer, curatively treated localized prostate cancer, or carcinoma in situ of any type (if complete resection was done) are allowed.
• History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to EV and/or pembrolizumab and/or N-803.
• Participants who have received hematopoietic stem cell transplantation or solid organ transplantation.
• Known active keratitis or corneal ulcerations.
• Received or will receive a live vaccine within 30 days prior to the first administration of study intervention.

Sponsors & Collaborators

• Vadim S Koshkin: lead
• ImmunityBio, Inc.: collaborator

MeSH Terms

Conditions

Carcinoma, Transitional Cell

Interventions

ALT-803; enfortumab vedotin; pembrolizumab; Phantoms, Imaging; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Equipment and Supplies; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Vadim Koshkin, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 14, 2025
• First Posted: October 16, 2025
• Study Start: February 15, 2026
• Primary Completion (Estimated): May 30, 2027
• Study Completion (Estimated): May 30, 2027
• Last Updated: March 17, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)