Neoadjuvant chemotherapy followed by watchful waiting versus immediate bladder treatment for muscle-invasive bladder cancer

Active Surveillance Versus Definitive Local Therapy for Patients Showing Clinical Complete Response Following Neoadjuvant Therapy for Muscle Invasive Bladder Cancer

This trial will test whether people whose cancer appears to be gone after chemotherapy can safely skip immediate bladder removal or chemo-radiation and be followed with active surveillance instead.

Quick facts

• Phase: PHASE2; PHASE3
• Study type: Interventional
• Enrollment: 688 (estimated)
• Ages: 19 Years and up
• Sex: All
• Sponsor: University of British Columbia (other)
• Drugs / interventions: chemotherapy, immunotherapy, radiation, methotrexate
• Locations: 1 site (Vancouver, British Columbia)
• Trial ID: NCT06537154 on ClinicalTrials.gov

What this trial studies

Patients with muscle-invasive urothelial bladder cancer receive standard cisplatin-based neoadjuvant therapy and are then re-staged using pelvic MRI, repeat bladder biopsy (TURBT), and circulating tumor DNA (ctDNA) testing. Participants who have no detectable cancer by all three methods (clinical complete response) are randomized to either active surveillance or standard definitive bladder treatment (radical cystectomy or chemo-radiation). The initial phase is a pilot randomized trial to test feasibility and safety, with a planned transition to a larger phase 3 randomized trial if results support it. The goal is to determine whether combined imaging, tissue sampling, and molecular testing can reliably identify patients who may safely avoid immediate definitive bladder therapy.

Who should consider this trial

Good fit: Adults with primary muscle-invasive urothelial bladder carcinoma (clinical stage T2–T4a N0 M0) who are eligible for cisplatin-based neoadjuvant therapy and achieve negative MRI, negative repeat TURBT biopsy, and undetectable ctDNA after treatment are ideal candidates.

Not a fit: Patients with residual disease on MRI or biopsy, detectable ctDNA, multifocal carcinoma in situ, those unfit for MRI or cisplatin-based chemotherapy, or those with metastatic disease are unlikely to benefit from the surveillance approach.

Why it matters

Potential benefit: If successful, the approach could spare a substantial subset of patients from bladder removal or chemo-radiation, preserving bladder function and quality of life.

How similar studies have performed: Retrospective series and small prospective phase 2 studies have reported promising outcomes with selective active surveillance after neoadjuvant therapy, but randomized trial evidence is not yet available.

Eligibility criteria

Inclusion Criteria:

* Male or female \>18 years
* Primary urothelial or predominantly (\>50%) urothelial carcinoma of the bladder with histologic evidence of muscularis propria invasion.
* Clinical stage T2-T4aN0M0 (Radiographic lymphadenopathy greater than 1.5 cm in short axis by imaging must be proven by biopsy to be free of cancer)
* No concomitant multifocal carcinoma in situ; a single focus is allowed.
* ECOG performance status 0, 1, or 2.
* Participants must be able to undergo pelvis MRI.
* Medically appropriate candidate for radical cystectomy (assessed by uro-oncologist) or chemo-radiation (assess by radiation-oncologist and medical-oncologist)
* Participants must be candidate to received standard of care (SOC) neoadjuvant systemic treatment at time of enrolment (assessed by medical-oncologist): 4 or more cycles of cisplatin-based chemotherapy (gemcitabine/cisplatin (GC) or methotrexate/vinblastine/Adriamycin/cisplatin (MVAC) or dose-dense MVAC (ddMVAC). If SOC evolves from the time of trial design and enrolment, eligibility to any SOC NAT (for example immunotherapy and/or antibody drug conjugate, as per NCCN guideline) will be allowed.
* Adequate bladder function and/or absence of significant urethral stricture to allow cystoscopic surveillance, as evaluate by urologist.

Exclusion Criteria:

* Any component of small cell or plasmacytoid histology.
* Prior systemic chemotherapy or immunotherapy (an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) or antibody-drug conjugate (NECTIN-4, HER2 or other) : Participants who have received any previous systemic therapy for urothelial carcinoma or cytotoxic chemotherapy, immunotherapy or other targeted therapy for another malignancy within 2 year of study entry are ineligible.
* No available bladder tumor tissue from prior TURBT for tumor sequencing.
* Prior or concurrent malignancy of any other site EXCEPT for non-melanoma skin cancer OR low risk malignancy not requiring treatment (such as prostate cancer Grade Group 1 under adequate surveillance, carcinoma in situ of the breast, cervix, etc.) AND unless free of disease for ≥ 5 years. Other cancers at low risk of recurrence may be allowed after review by principal investigator.
* Prior radiation therapy for bladder cancer.
* Participants who have received experimental agents within 4 weeks of study entry.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined by current oral or intravenous antibiotic therapy), symptomatic congestive heart failure (NYHA \>2), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnancy. People of childbearing potential must have a negative serum pregnancy test before general anesthesia procedure and MRI
* No concurrent treatment on another clinical trial; supportive care trials or non-therapeutic trials (e.g., quality of life) are allowed.

Where this trial is running

Vancouver, British Columbia

• Vancouver Prostate Centre — Vancouver, British Columbia, Canada (RECRUITING)

Study contacts

• Principal investigator: Peter Black, MD — University of British Columbia
• Study coordinator: Marie-Pier St-Laurent, MD

Conditions: Muscle-Invasive Bladder Carcinoma, Muscle invasive bladder urothelial carcinoma, Bladder Cancer