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

A Phase Ib/II Study to Evaluate the Safety and Efficacy of Enfortumab Vedotin Plus Pembrolizumab in Combination With Quemliclustat in Unresectable Locally Advanced and Metastatic Urothelial Carcinoma

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Renal Pelvis Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; 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; Locally Advanced Bladder Urothelial Carcinoma; Locally Advanced Renal Pelvis Urothelial Carcinoma; Locally Advanced Ureter Urothelial Carcinoma; Stage IIIB Bladder Cancer AJCC v8; Metastatic Bladder Giant Cell Urothelial Carcinoma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Enfortumab Vedotin; Procedure: Biopsy Procedure; Drug: Quemliclustat

Detailed Description

OUTLINE:

Patients receive quemliclustat intravenously (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 computed tomography (CT)/magnetic resonance imaging (MRI) and blood sample collection throughout the study.

After completion of study treatment, patients are followed up within 30 days and then every 12 weeks for 3 years.

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Rosa Nadal Rios, MD, PhD; Phone Number: 206-598-3300; Email: rnadalri@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium
      • Principal Investigator: Rosa Nadal Rios, MD, PhD
      • Contact: Rosa Nadal Rios, MD, PhD; Phone Number: 206-598-3300; Email: rnadalri@fredhutch.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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
  • Poorly differentiated urothelial carcinoma
  • Squamous cell neoplasms including pure squamous cell carcinomas, verrucous carcinomas and squamous cell papilloma
• Measurable disease by RECIST v 1.1
• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
• Available baseline fresh biopsy tissue sample obtained in the protocol RG1712006 though clinically indicated procedures or participants must be willing to undergo a baseline research biopsy when safe and feasible
• Participant must have an estimated life expectancy of at least 3 months
• Hemoglobin ≥ 9 gr/dl
• Absolute neutrophil count: ≥ 1500/ µL
• White blood cell count: ≥ 3000/µL
• Absolute lymphocyte count: ≥ 1000/µL
• Platelet count: ≥ 100.000/µL (without transfusion support)
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 2.5 x upper limit of normal (ULN)
• Total bilirubin: ≤ 1.5 mg/dl except for patients with Gilbert's syndrome who must have a total bilirubin ≤ 3 mg/dl
• Creatinine clearance: ≥ 30 ml/min/1.73m^2 by the method of Chronic Kidney Disease Epidemiology Collaboration (CKI-EPI) or ≥ 30 ml/min by the method of 24 hour (h) clearance of creatinine calculation
• International Normalized Ratio (INR): < 1.5

Exclusion Criteria:

• 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
• Woman of childbearing potential with positive serum pregnancy test within 72 hours prior to enrollment. Active lactation is an exclusion criterion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (enfortumab vedotin, pembrolizumab, quemliclustat); 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.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; MK3475; SCH-900475; BCD-201; Pembrolizumab Biosimilar BCD-201; Pembrolizumab Biosimilar QL2107; QL2107; GME 751; GME751; Pembrolizumab Biosimilar GME751; MK 3475; SCH900475; Pembrolizumab Biosimilar RPH-075; RPH 075; RPH-075; RPH075; Pembrolizumab Biosimilar SB27; SB 27; SB-27; SB27; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Enfortumab Vedotin; Given IV; Other Names: ASG-22CE; Padcev; AGS 22ME; AGS-22M6E; Anti-Nectin 4 ADC ASG-22CE; Anti-nectin-4 Monoclonal Antibody-Drug Conjugate AGS-22M6E; Enfortumab Vedotin-ejfv; ASG 22CE; ASG22CE; Procedure: Biopsy Procedure; Undergo tumor biopsy; Other Names: Bx; BIOPSY_TYPE; Drug: Quemliclustat; Given IV; Other Names: AB680; AB 680; AB-680; CD73 Inhibitor AB680

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR (Phase Ib)	Assessed by RECIST v 1.1. Will calculate the count and percentage with a 95% CI.	From baseline, up to disease progression or unacceptable side effects, up to 3 years after completion of study treatment
Complete response rate (Phase II)	Assessed by RECIST v 1.1. Will calculate the count and percentage with a 95% CI.	From baseline, up to disease progression or unacceptable side effects, up to 3 years after completion of study treatment
Duration of response (Phase II)	Will use Kaplan Meier method to estimate the survival curve, median and its corresponding 95% CI.	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)	Will use Kaplan Meier method to estimate the survival curve, median and its corresponding 95% CI.	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)	Will calculate the count and percentage with a 95% CI.	Up to 6 months

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Arcus Biosciences, Inc.; Bench to Bedside (B2B)
• Investigators: Principal Investigator: Rosa Nadal Rios, MD, PhD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): July 16, 2029
• Study Completion (Estimated): July 16, 2029

Study Registration Dates

• First Submitted: June 18, 2026
• First Submitted That Met QC Criteria: June 18, 2026
• First Posted (Actual): June 25, 2026

Study Record Updates

• Last Update Posted (Actual): June 25, 2026
• Last Update Submitted That Met QC Criteria: June 18, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Ureteral Diseases; Urinary Bladder Diseases; Ureteral Neoplasms; Urinary Bladder Neoplasms; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Biopsy; Specimen Handling; pembrolizumab; Magnetic Resonance Spectroscopy; enfortumab vedotin; quemliclustat
• Other Study ID Numbers: RG1125912; NCI-2026-03972 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No