NEO-BLAST: Neoadjuvant Therapy for Bladder Cancer Followed by Active Surveillance vs Treatment

Purpose To assess the feasibility to randomize patients with muscle-invasive bladder cancer (MIBC) who experience a complete clinical response (cCR) following neoadjuvant therapy (NAT), as defined by negative ctDNA, negative bladder MRI and negative repeat TURBT to active surveillance vs standard of care (SOC) with definitive bladder treatment.

Hypothesis The hypothesize is that the combination of bladder re-staging with MRI, repeat biopsy and the use of ctDNA will markedly enhance the ability to identified participant who achieve an excellent response to NAT (cCR) and who could safely be offered AS.

Justification:

Cisplatin-based neoadjuvant therapy (NAT) followed by radical cystectomy (RC), or alternatively in selected patient, a combination of chemo-radiation (trimodal therapy, TMT), are the current standards of care for treatment of MIBC. However, both have significant potential toxicity that can impact quality of life. Clinical trials have demonstrated that up to 38% of patients have a pathologic complete response (pCR) to NAT. Those patients could potentially avoid RC or TMT. Unfortunately, the clinical tools to predict pCR are still considered inadequate and definitive local therapy is advised. Retrospective data and now prospective phase 2 trials have reported promising outcomes in selected patients undergoing active surveillance. A prospective randomized trial is still lacking to ensure non-inferiority of active surveillance over the standard of care.

Primary Objectives:

• Phase 2 (pilot RCT): To determine the feasibility of randomizing patients with MIBC who experience a complete clinical response (cCR) following neoadjuvant treatment, as defined by negative ctDNA, negative bladder MRI and negative repeat TURBT, to active surveillance (AS) or definitive bladder treatment (DBT; consisting of radical cystectomy (RC) or trimodal therapy (TMT)).
• Phase 3: To estimate the metastasis-free survival rate at 2 years among patients with MIBC who experience a complete clinical response (cCR) following NAT, as defined by negative ctDNA, negative bladder MRI and negative repeat TURBT and who are managed with active surveillance.

Research design:

Multi-center, phase II/III, open label randomized clinical trial

After enrolment, participants will received SOC NAT. Blood and urine specimens will be collected before or at cycle 1 day 1 of NAT. Participants will undergo conventional restaging during NAT, recommended to be done at the end of cycle 2. Conventional imaging consists of computerized tomography (CT) scan of chest/abdomen/pelvis to rule-out local or distant progression on treatment. Participants who have successfully completed the full regimen of SOC NAT, and have not been found to have progression and/or metastasis on their SOC CT scan, will then undergo the following intervention for the "clinical restaging" (CRS) (must be completed within 4 weeks after last dose of NAT):

• ctDNA from blood samples collected before and after completion of NAT.
• Restaging bladder MRI
• Urine Cytology and Cystoscopy with template bladder biopsy under anesthesia with or without site-directed bladder biopsies.

Definition of clinical complete response (cCR):

• Absence of metastasis on conventional imaging.
• Negative MRI completed within 4 weeks of last dose of systemic treatment showing absence of VI-RADS 3, 4 or 5 lesion.
• Transurethral bladder tumor resection (TURBT) with or without site-directed bladder biopsies showing absence of high-grade carcinoma ≥cT1 and/or extensive and multifocal CIS. Focal CIS and/or completely resected Ta will be included in the definition of cCR and offered randomization.
• Negative ctDNA

Participants with cCR will then be randomized to either active surveillance or definitive bladder treatment (DBT) (RC or TMT, according to patient/physician choice). Participants who do not meet all criteria of cCR will proceed with SOC and have RC or TMT under the treating investigator's care.

Participants will adhere to the following schedule of surveillance:

Cystoscopy with urine cytology (for those with preserved bladder) every 3 months for 2 years. After 2 years, follow up schedule is at the discretion of the treating physician.

Repeat chest-abdomen-pelvis imaging with CT/MRI and ctDNA at 3, 6, 12, 18 and 24 months. After 2 years, follow up schedule is at the discretion of the treating physician.

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.