Consolidative Therapy After EV + Pembrolizumab in Muscle Invasive Bladder Cancer, REINFORCE Trial

Consolidative Radiation Therapy or Cystectomy After Initial Favorable Response Succeeding Enfortumab Vedotin Plus Pembrolizumab (REINFORCE)--- A Phase I/II Pilot Feasibility Trial

This phase I/II clinical trial is evaluating a novel treatment strategy for patients with advanced bladder cancer that is unresectable, has spread to nearby lymph nodes or a limited number of distant sites (oligometastatic disease), and has responded to initial treatment with enfortumab vedotin and pembrolizumab. Although this combination has significantly improved outcomes compared to traditional chemotherapy, many patients are left with residual cancer in the bladder or other sites, and there is currently no established standard approach for managing this remaining disease or determining the optimal duration of systemic therapy. Prolonged treatment can lead to cumulative side effects and negatively impact quality of life.

This study investigates whether adding consolidative treatment-such as radiation therapy to the bladder and metastatic sites or surgical removal of the bladder (radical cystectomy)-can safely eliminate residual disease and delay cancer progression. Radiation therapy uses high-energy x-rays to precisely target and destroy cancer cells while minimizing exposure to surrounding normal tissues. In selected patients, surgery may be used to remove remaining tumor in the bladder. Targeted radiation techniques, such as stereotactic body radiation therapy (SBRT), may also be used to treat small metastatic sites. This approach may allow for safe discontinuation of systemic therapy, potentially reducing long-term treatment-related side effects.

A key component of this trial is the integration of biomarker testing using circulating tumor DNA (ctDNA) from blood and urine tumor DNA (utDNA). These tests detect small amounts of tumor-derived genetic material and may help identify patients most likely to benefit from consolidative treatment, as well as guide decisions about ongoing therapy. By combining response to systemic therapy with personalized local treatment and biomarker-driven monitoring, this study aims to improve cancer control, reduce complications from untreated local disease, and inform future treatment strategies for patients with advanced bladder cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Stage III Bladder Cancer AJCC v8; Stage IV Bladder Cancer AJCC v8; Muscle Invasive Bladder Carcinoma
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Magnetic Resonance Imaging; Drug: Cisplatin; Drug: Gemcitabine; Radiation: Intensity-Modulated Radiation Therapy; Radiation: Stereotactic Body Radiation Therapy; Procedure: Positron Emission Tomography; Procedure: Radical Cystectomy; Procedure: Cystoscopy; Procedure: Computed Tomography; Procedure: Transurethral Resection of Bladder Tumor; Radiation: Volume Modulated Arc Therapy; Procedure: Biospecimen Collection; Drug: Fluorouracil; Procedure: Pelvic Lymphadenectomy; Drug: Mitomycin

Detailed Description

OUTLINE: This is a single arm, phase I/II study of consolidative therapy after initial favorable response after enfortumab vedotin and pembrolizumab. For patients with a complete response (cCR) in the bladder, local consolidative therapy (radiation or cystectomy) as described below is encouraged but not required. They will participate in a discussion with the treating physician regarding the limitations of a cCR. For patients with residual tumor in the bladder (not achieving a cCR), local consolidative therapy, either in the form of radiation or cystectomy will be delivered, per shared decision-making with their treating physician. Concurrent radiosensitizing chemotherapy will be delivered with radiation therapy to the bladder, whenever feasible. Regardless of the disease status in the bladder, patients with residual disease outside the bladder receive metastasis-directed therapy (MDT), as described below.

RADIATION TO THE BLADDER/PELVIS: Patients undergo radiation therapy to the bladder with intensive-modulated radiation therapy (IMRT)/volume modulated arc therapy (VMAT) daily for a total of 20 fractions over 4 weeks. Patients may undergo pelvic lymph node-directed radiation therapy with simultaneous integrated boost to the bladder daily for 20 fractions, if indicated. Patients also receive radiosensitizing chemotherapy (weekly cisplatin intravenously [IV] and weekly or twice weekly gemcitabine IV or fluorouracil and mitomycin, per physician discretion and according to standard of care) concurrently with radiation therapy.

CYSTECTOMY: Patients undergo radical cystectomy with pelvic lymph node dissection on study.

MDT: Patients undergo metastasis-directed radiation therapy with stereotactic body radiation therapy (SBRT) for 3-5 fractions, as determined by the treating physician.

Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET)/CT and collection of blood and urine samples throughout the trial, undergo transurethral resection of bladder tumor (TURBT) on study, and undergo cystoscopy during follow-up.

After completion of study treatment, patients are followed up every 3 months for up to 12 months (1 year) on study.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: T. Martin Ma, MD, PhD; Phone Number: 206-606-7318; Email: mma1@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: T. Martin Ma, MD, PhD; Phone Number: 206-606-7318; Email: mma1@uw.edu
      • Principal Investigator: T. Martin Ma, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age >= 18 at the time of screening
• Ability to understand and willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of potential study participants
• Histopathologically confirmed cTxN1-3M0, cTxNxM1 or cT4bNxM0 muscle invasive bladder cancer at initial diagnosis
• Achieved a radiographic complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria and at the determination of treating physicians) after 3-9 cycles of induction EV + pembro

• If M1 after completion of EV + pembro, patients need to have =< 5 sites of metastasis and all sites of metastasis should be extracranial

  • Note: when counting the number of oligometastatic lesions, each lymph node lesion, whether pelvic or extrapelvic, is counted (for example, 2 distinct lymph nodes in the right external iliac basin count as 2 oligometastatic lesions; one extrapelvic and one pelvic node count as 2 oligometastatic lesions, etc). Five or fewer sites of metastasis applies after the completion of EV + pembro, not at initial diagnosis
• Be a candidate for consolidative radiation therapy (RT) to the pelvis (if indicated) or cystectomy (if indicated), and all sites of metastasis are amenable to RT
• Life expectancy > 6 months
• Eastern Cooperative Oncology Group (ECOG) performance 0-2
• Absolute neutrophil count (ANC) >= 1500 /mcL (within 180 days of trial registration)
• Platelets >= 100,000/mcL (within 180 days of trial registration)
• Hemoglobin > 9 g/dL (within 180 days of trial registration)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min (within 180 days of trial registration)
• Total bilirubin =< 1.5 ULN OR direct bilirubin =< ULN if total bilirubin > 1.5 x ULN (within 180 days of trial registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR < 5 x ULN if patient has live metastasis (within 180 days of trial registration)
• Albumin >= 2.5 g/dL (within 180 days of trial registration)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless on anticoagulation therapy, in which case PT or partial thromboplastin time (PTT) should be in the therapeutic range (within 180 days of trial registration)
• PTT =< 1.5 x ULN unless on anticoagulation therapy, in which case PT or PTT should be in the therapeutic range (within 180 days of trial registration)
• Participants of child-bearing potential must be willing to employ two highly effective and acceptable forms of contraception during, and for at least 90 days after the end of radiation therapy. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours of treatment initiation
• HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are included in this trial

Exclusion Criteria:

• Prior radiation therapy with field overlapping with current proposed radiation field, precluding delivery of meaningful dose of radiation
• Intracranial metastasis
• Any small cell component, or predominant (> 50%) sarcomatoid or plasmacytoid histology
• Other active malignancy or clinically relevant malignancy within past 2 years, per discussion with the principal investigator
• Genetic conditions that increase sensitivity to radiation, such as Fanconi syndrome, ataxia telangiectasia, and Nijmegen breakage syndrome
• Active human immunodeficiency virus (HIV) not adequately controlled, active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Any other medical condition that may interfere with trial therapy delivery

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: Local consolidative therapy; Following a complete re-TURBT, participants with residual bladder disease will receive either concurrent chemoradiation (IMRT/VMAT, 55 Gy in 20 fractions) to bladder +/- pelvic nodes or cystectomy, based on shared decision-making. For patients with a clinical complete response, bladder-directed consolidation is encouraged but optional. Patients with disease outside the true pelvis will receive metastasis-directed therapy (preferably SBRT) following primary chemoradiation to all site of metastasis. Participants then proceed to observation or maintenance pembrolizumab until progression, unacceptable toxicity, or clinical discretion. The study includes longitudinal imaging, cystoscopy, biospecimen collection, and quality-of-life assessments.

Other: Questionnaire Administration; Ancillary studies; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Drug: Cisplatin; Given IV; Other Names: Cisplatinum; Platinol; Drug: Gemcitabine; Given IV; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT; Intensity Modulated RT; Intensity modulated radiation therapy (procedure); Radiation: Stereotactic Body Radiation Therapy; Undergo SBRT; Other Names: SBRT; SABR; Stereotactic Ablative Body Radiation Therapy; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: PET; PET scan; Procedure: Radical Cystectomy; Undergo radical cystectomy; Procedure: Cystoscopy; Undergo cystoscopy; Other Names: CS; Procedure: Computed Tomography; Undergo CT and/or PET/CT; Other Names: CT; CAT Scan; CT Scan; Procedure: Transurethral Resection of Bladder Tumor; Undergo TURBT; Other Names: TURBT; Radiation: Volume Modulated Arc Therapy; Undergo VMAT; Other Names: VMAT; Volumetric Modulated Arc Therapy (procedure); Procedure: Biospecimen Collection; Undergo collection of blood and urine samples; Other Names: Biological Sample Collection; Drug: Fluorouracil; Given fluorouracil; Other Names: 5-Fluorouracil; 5-Fu; Ribofluor; Procedure: Pelvic Lymphadenectomy; Undergo pelvic lymph node dissection; Other Names: Excision Pelvic Lymph Nodes; Pelvic Lymph Node Dissection; Drug: Mitomycin; Given mitomycin; Other Names: MITO; MITO-C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Completion rate of protocol-defined treatment (feasibility)	Feasibility will be assessed through the completion rate of protocol-defined treatment. Primary endpoint is met if the completion rate of protocol-defined treatment is > 70%. Descriptive statistics will be provided.	Up to 18 months from start of enfortumab vedotin (EV) + pembrolizumab

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	The Kaplan-Meier method will be used.	From date of EV + pembrolizumab start to date of first documentation of progression assessed by local review, or death due to any cause, assessed up to 1 year
Incidence of treatment-related grade 3 or higher adverse events	Safety of consolidative radiation therapy will be assessed by the incidence of treatment-related grade 3 or higher toxicities per Common Terminology Criteria for Adverse Events version 6 that is possibly, probably, or definitely related to radiation treatment or chemoradiation therapy. Descriptive statistics will be provided.	Up to 18 months since start of EV + pembrolizumab
Time to progression in the bladder (local control)	The Kaplan-Meier method will be used.	At 1 year
Time to progression in the pelvis (pelvic control)	The Kaplan-Meier method will be used.	At 1 year
Overall survival	The Kaplan-Meier method will be used.	From first date of EV + pembrolizumab to death from any cause, assessed up to 1 year
Change in patient-reported quality of life	Changes in patient-reported quality of life will be measured by the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) assessment. Will measure change in total FACT-Bl score from baseline to each follow-up assessment as well as changes in individual domain subscale scores (physical, social/family, emotional, functional well-being, and bladder-specific concerns). Each question is scored 0-4 and higher score indicates better quality of life (for negatively worded items [e.g., symptoms, distress], scores are reversed). Clinically meaningful deterioration or improvement will be defined using established minimally important difference thresholds for FACT-Bl.	From baseline to each follow-up assessment (every 3 months up to 1 year)

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Lopker Family Foundation
• Investigators: Principal Investigator: T. Martin Ma, MD, PhD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: May 4, 2026
• First Submitted That Met QC Criteria: May 4, 2026
• First Posted (Actual): May 12, 2026

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 11, 2026
• Last Verified: May 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; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Indoles; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Diagnostic Techniques, Surgical; Endoscopy; Chemistry Techniques, Analytical; Spectrum Analysis; Uracil; Pyrimidinones; Platinum Compounds; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Quinones; Azirines; Urologic Surgical Procedures; Urogenital Surgical Procedures; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Diagnostic Techniques, Urological; Mitomycins; Indolequinones; Gemcitabine; Fluorouracil; Cisplatin; Mitomycin; Magnetic Resonance Spectroscopy; Radiosurgery; Transurethral Resection of Bladder; Radiotherapy, Intensity-Modulated; Cystoscopy; Cystectomy
• Other Study ID Numbers: RG1126354; NCI-2026-02920 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); FHIRB0021260 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

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