Enfortumab Vedotin, Pembrolizumab and Quemliclustat for the Treatment of Unresectable Locally Advanced and Metastatic Urothelial Cancer

NCT07667335 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: RG1125912NCI-2026-03972
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib/II trial tests the safety, side effects, and best dose of quemliclustat in combination with enfortumab vedotin and pembrolizumab, and to see how well the combination works for the treatment of bladder, renal pelvis, or ureter urothelial cancer that cannot be removed by surgery (unresectable), 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). Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Quemliclustat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving quemliclustat in combination with enfortumab vedotin and pembrolizumab and may be safe, tolerable and/or effective in treating patients with unresectable locally advanced and metastatic urothelial cancer.

Conditions

Locally Advanced Bladder Urothelial Carcinoma; Locally Advanced Renal Pelvis Urothelial Carcinoma; Locally Advanced Ureter Urothelial Carcinoma; Metastatic Bladder Giant Cell Urothelial Carcinoma; Metastatic Renal Pelvis Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; Stage IIIB Bladder Cancer AJCC v8; Stage IV Bladder Cancer AJCC v8; Stage IV Renal Pelvis Cancer AJCC v8; Stage IV Ureter Cancer AJCC v8; Unresectable Bladder Urothelial Carcinoma; Unresectable Renal Pelvis Urothelial Carcinoma; Unresectable Ureter Urothelial Carcinoma

Outcome Measures

Primary Outcomes (2)

• Incidence of treatment related adverse events (Phase Ib)

  As measured by Common Terminology Criteria for Adverse Events version (v) 6.

  From baseline, up to 21 days after last dose of investigational product

• Overall response rate (ORR) (Phase II)

  Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Will calculate the count and percentage with a 95% confidence interval (CI).

  From baseline, up to disease progression or unacceptable side effects, up to 3 years after completion of study treatment

Secondary Outcomes (5)

• ORR (Phase Ib)

  From baseline, up to disease progression or unacceptable side effects, up to 3 years after completion of study treatment

• Complete response rate (Phase II)

  From baseline, up to disease progression or unacceptable side effects, up to 3 years after completion of study treatment

• Duration of response (Phase II)

  From response (ORR) until disease progression or unacceptable side effects or death which occurs earlier, up to 3 years after completion of study treatment

• Progression free survival (Phase II)

  From date of registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, up to 3 years after completion of study treatment

• Rate of consolidative therapy with cystectomy or chemoradiation with stage 3b (Phase II)

  Up to 6 months

Study Arms (1)

Treatment (enfortumab vedotin, pembrolizumab, quemliclustat)

EXPERIMENTAL

Patients receive quemliclustat IV on day 1, enfortumab vedotin IV on days 1 and 8 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients may undergo tumor biopsy during screening and optionally undergo throughout the study. Patients also undergo CT/MRI and blood sample collection throughout the study.

Drug: Quemliclustat; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Enfortumab Vedotin; Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Procedure: Biopsy Procedure

Interventions

Quemliclustat DRUG

Given IV

Also known as: AB 680, AB-680, AB680, CD73 Inhibitor AB680

Treatment (enfortumab vedotin, pembrolizumab, quemliclustat)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

Treatment (enfortumab vedotin, pembrolizumab, quemliclustat)

Computed Tomography PROCEDURE

Undergo CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (enfortumab vedotin, pembrolizumab, quemliclustat)

Enfortumab Vedotin DRUG

Given IV

Also known as: AGS 22ME, AGS-22M6E, Anti-Nectin 4 ADC ASG-22CE, Anti-nectin-4 Monoclonal Antibody-Drug Conjugate AGS-22M6E, ASG 22CE, ASG-22CE, ASG22CE, Enfortumab Vedotin-ejfv, Padcev

Treatment (enfortumab vedotin, pembrolizumab, quemliclustat)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (enfortumab vedotin, pembrolizumab, quemliclustat)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: BCD-201, GME 751, GME751, Keytruda, Lambrolizumab, MK 3475, MK-3475, MK3475, Pembrolizumab Biosimilar BCD-201, Pembrolizumab Biosimilar GME751, Pembrolizumab Biosimilar QL2107, Pembrolizumab Biosimilar RPH-075, Pembrolizumab Biosimilar SB27, QL2107, RPH 075, RPH-075, RPH075, SB 27, SB-27, SB27, SCH 900475, SCH-900475, SCH900475

Treatment (enfortumab vedotin, pembrolizumab, quemliclustat)

Biopsy Procedure PROCEDURE

Undergo tumor biopsy

Also known as: Bx, BIOPSY_TYPE

Treatment (enfortumab vedotin, pembrolizumab, quemliclustat)

Eligibility Criteria

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

You may qualify if:

• Participants must be at least 18 years of age on the day of signing informed consent. Participant (or legally authorized representative if applicable) provides written informed consent for trial
• Participants must have previously untreated locally advanced or metastatic bladder cancer including bladder cancer \[stage IIIB: T1-T4N2-3M0, stage IVa: T4bAnyNM0 or AnyTAnyNM1a, and stage IVB: AnyTAnyNM1b clinical stage per American Joint Commission on Cancer (AJCC)\] or renal pelvis or ureter cancer \[stage IV: T4Nx-0M0, AnyTN1-2M0, AnyTAnyNM1 clinical stage per AJCC\]. Lymph node with ≥ 15 mm short axis or biopsy-positive for carcinoma will be considered pathologically enlarged and measurable
• Participants must have either conventional urothelial carcinoma or urothelial carcinoma variants. A review of pathology by a local expert genitourinary (GU) pathologist is required to confirm the diagnosis. Any component (%) of non-conventional urothelial noted on tumor specimen is allowed for only histologic subtypes listed below in up to 20% of participants enrolled in this study.
• Urothelial carcinoma with squamous differentiation
• Urothelial carcinoma with glandular differentiation
• Urothelial carcinoma with trophoblastic differentiation
• Nested urothelial carcinoma
• Tubular and microcystic urothelial carcinoma
• Micropapillary urothelial carcinoma
• Lymphoepithelioma-like urothelial carcinoma
• Plasmacytoid urothelial carcinoma
• Sarcomatoid urothelial carcinoma
• Giant cell urothelial carcinoma
• Lipid-rich urothelial carcinoma
• Clear cell (glycogen rich) urothelial carcinoma

You may not qualify if:

• Participants who are receiving any other investigational agents or concurrent anticancer treatment. Participants must have adequate treatment washout period before treatment, defined as: Major surgery (≥ 4 weeks), palliative radiation therapy (≥ 1 weeks from completion of treatment if they have recovered from the acute toxic effect of radiotherapy), prior adjuvant immunotherapy (≥ 4 weeks)
• Participants whose tumors have any % neuroendocrine or small cell histology, glandular neoplasms, urachal carcinomas, tumor of mullerian type, mesenchymal tumors or urothelial tract hematopoietic and lymphoid tumors
• Participants considered to be medically unfit for EV-P regimen as per Investigator discretion
• Participants with concurrent use of systemic steroids (within 10 days of enrollment), except for physiologic doses of systemic steroid replacement or local (topical, nasal, intraarticular or inhaled) steroid use
• Participants who have experienced disease progression following neoadjuvant or adjuvant systemic therapy within 12 months prior to enrollment will not be eligible
• Patients with Fridericia's corrected QT interval (QTcF) interval at screening of \> 480 milliseconds.
• Note: For any QTcF \> 480 milliseconds on initial electrocardiogram (ECG), a follow-up ECG will be performed to confirm QTcF interval prolongation and exclude the patient from this study
• Participants with active systemic autoimmune disease (e.g., lupus erythematosus, rheumatoid arthritis, Addison's disease, autoimmune disease associated with lymphoma, inflammatory bowel disease). Participants with autoimmune endocrine disorders controlled by medical management (e.g. thyroid disorders, type 1 diabetes, or adrenal insufficiency) will not be excluded
• Participants who are known to be serologically positive for human immunodeficiency virus (HIV) and a CD4 count \< 350 cells/microliter
• Participants with known active hepatitis (i.e. Hepatitis B or C). Prior hepatitis (Hep) C infection is allowed as long as polymerase chain reaction (PCR) test is negative
• Participants with clinically inactive brain metastases may be included. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole-brain radiation therapy and study treatment
• Participants with new or progressive brain metastases (less or equal of 1 cm of larger diameter) are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required for at least 4 weeks (or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis (discussion) by the participant and the investigator favors participation in the clinical trial. Patients with leptomeningeal disease will be excluded
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy of assessment of the investigational regimen are eligible for this trial

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• Bench to Bedside (B2B): collaborator
• Arcus Biosciences, Inc.: collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Urinary Bladder Neoplasms; Ureteral Neoplasms

Interventions

quemliclustat; Specimen Handling; enfortumab vedotin; Magnetic Resonance Spectroscopy; pembrolizumab; Biopsy

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Ureteral Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative

Study Officials

• Rosa Nadal Rios, MD, PhD

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rosa Nadal Rios, MD, PhD

CONTACT

206-598-3300; rnadalri@fredhutch.org

Study Design

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

Study Record Dates

• First Submitted: June 18, 2026
• First Posted: June 25, 2026
• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): July 16, 2029
• Study Completion (Estimated): July 16, 2029
• Last Updated: June 25, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)