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 Pilot Feasibility Trial

This pilot feasibility 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.

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, 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 re-transurethral resection of bladder tumor (re-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.

Inclusion Criteria:

• Age >= 18 at the time of screening

• Ability to understand and willingness to sign a written informed consent document

• 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), as determined by standard of care testing
• 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
• Adults with impaired decision-making capacity, as determined by the treating physician