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

NCT07579195 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: RG1126354NCI-2026-02920FHIRB0021260
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Muscle Invasive Bladder Carcinoma; Stage III Bladder Cancer AJCC v8; Stage IV Bladder Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Progression-free survival

  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

  Up to 18 months since start of EV + pembrolizumab

• Change in patient-reported quality of life

  From baseline to each follow-up assessment (every 3 months up to 1 year)

• Time to progression in the bladder (local control)

  At 1 year

• Time to progression in the pelvis (pelvic control)

  At 1 year

Study Arms (1)

Local consolidative therapy

EXPERIMENTAL

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.

Radiation: Intensity-Modulated Radiation Therapy; Radiation: Volume Modulated Arc Therapy; Drug: Cisplatin; Drug: Gemcitabine; Drug: Fluorouracil; Drug: Mitomycin; Procedure: Radical Cystectomy; Procedure: Pelvic Lymphadenectomy; Radiation: Stereotactic Body Radiation Therapy; Procedure: Computed Tomography; Procedure: Positron Emission Tomography; Procedure: Magnetic Resonance Imaging; Procedure: Transurethral Resection of Bladder Tumor; Procedure: Cystoscopy; Procedure: Biospecimen Collection; Other: Questionnaire Administration

Interventions

Intensity-Modulated Radiation Therapy RADIATION

Undergo IMRT

Also known as: IMRT, Intensity modulated radiation therapy (procedure), Intensity Modulated RT

Local consolidative therapy

Cisplatin DRUG

Given IV

Also known as: Platinol, Cisplatinum

Local consolidative therapy

Gemcitabine DRUG

Given IV

Local consolidative therapy

Mitomycin DRUG

Given mitomycin

Also known as: MITO, MITO-C

Local consolidative therapy

Radical Cystectomy PROCEDURE

Undergo radical cystectomy

Local consolidative therapy

Computed Tomography PROCEDURE

Undergo CT and/or PET/CT

Also known as: CT, CT Scan, CAT Scan

Local consolidative therapy

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: MRI

Local consolidative therapy

Cystoscopy PROCEDURE

Undergo cystoscopy

Also known as: CS

Local consolidative therapy

Questionnaire Administration OTHER

Ancillary studies

Local consolidative therapy

Positron Emission Tomography PROCEDURE

Undergo PET/CT

Also known as: PET, PET scan

Local consolidative therapy

Transurethral Resection of Bladder Tumor PROCEDURE

Undergo TURBT

Also known as: TURBT

Local consolidative therapy

Pelvic Lymphadenectomy PROCEDURE

Undergo pelvic lymph node dissection

Also known as: Excision Pelvic Lymph Nodes, Pelvic Lymph Node Dissection

Local consolidative therapy

Stereotactic Body Radiation Therapy RADIATION

Undergo SBRT

Also known as: SBRT, SABR, Stereotactic Ablative Body Radiation Therapy

Local consolidative therapy

Fluorouracil DRUG

Given fluorouracil

Also known as: 5-Fluorouracil, 5-Fu, Ribofluor

Local consolidative therapy

Volume Modulated Arc Therapy RADIATION

Undergo VMAT

Also known as: VMAT, Volumetric Modulated Arc Therapy (procedure)

Local consolidative therapy

Biospecimen Collection PROCEDURE

Undergo collection of blood and urine samples

Also known as: Biological Sample Collection

Local consolidative therapy

Eligibility Criteria

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

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Washington: lead
• Lopker Family Foundation: collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

Radiotherapy, Intensity-Modulated; Cisplatin; Gemcitabine; Fluorouracil; Mitomycin; Cystectomy; Radiosurgery; Magnetic Resonance Spectroscopy; Transurethral Resection of Bladder; Cystoscopy

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

Intervention Hierarchy (Ancestors)

Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Uracil; Pyrimidinones; Mitomycins; Indolequinones; Quinones; Organic Chemicals; Azirines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Urologic Surgical Procedures; Urogenital Surgical Procedures; Surgical Procedures, Operative; Stereotaxic Techniques; Neurosurgical Procedures; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Endoscopy; Diagnostic Techniques, Surgical; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Urological; Minimally Invasive Surgical Procedures

Study Officials

• T. Martin Ma, MD, PhD

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Central Study Contacts

T. Martin Ma, MD, PhD

CONTACT

206-606-7318; mma1@uw.edu

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: May 4, 2026
• First Posted: May 12, 2026
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: May 14, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)