A phase III randomised control clinical trial of radiotherapy with radiosensitisation versus intravesical bacillus Calmette-Guerin therapy for high-risk non-muscle invasive bladder cancer: TRAIN.

TPS880 Background: High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) is typically treated with surgery (TURBT; Trans Urethral Resection of Bladder Tumour) followed by intravesical BCG (Bacillus Calmette-Geurin), or radical cystectomy. Induction BCG is given weekly for six weeks, followed by maintenance for up to 3 years. However, up to 50% of patients experience recurrence or progression, and 25% discontinue due to toxicity. Global BCG shortages have further increased recurrence rates and costs. There is a clear need for alternative treatments to reduce recurrence, progression, cystectomy rates, and mitigate supply issues. The NIHR funded the TRAIN trial (ISRCTN: 16345179) will assess radiotherapy with radiosensitisation drugs as an alternative treatment option. Methods: Co-ordinated by the Cancer Research UK Southampton Clinical Trials Unit, TRAIN is a multicentre, two arm, open-label UK randomised phase III trial comparing usual care (BCG) with radiotherapy (55Gy/20#) and a radiosensitiser in HR-NMIBC patients who have undergone maximal TURBT and are BCG naïve. Treatment allocation ratio is 1:1, stratified by disease stage and age. Radiotherapy arm participants receive Investigator choice of radiosensitiser (gemcitabine, mitomycin C/fluorouracil or carbogen/nicotinamide) and will receive radiotherapy 55Gy in 20 fractions treating once daily Monday to Friday over 4 weeks. Participants randomised to BCG (control) will be treated following EAU (European Association of Urology) guidelines. All participants will be followed for a minimum of two years. The primary endpoint is event-free survival defined as time from randomisation to any of CIS or high-risk G3 non-muscle invasive papillary tumour recurrence, continued presence of HR-NMIBC even after treatment completion, progression to muscle-invasive disease, distant metastatic bladder cancer, cystectomy (for any reason) or death from any cause. Treatment will continue until the patient has either had an event or unacceptable toxicity or withdrawn. Accounting for 5% drop out, the total sample size of 328 patients (90 events) was calculated using alpha = 0.025 (one-sided), power = 0.9, hazard ratio = 0.5, and a piecewise exponential survival distribution with event rate in the control arm of 10, 20, 25 and 30% at 3, 6, 12 and 24 months. An interim analysis for futility is planned for when 50% of events have occurred. The study will stop if the observed hazard ratio is greater than 0.924. Secondary endpoints include recurrence-free survival, cancer specific survival, cystectomy-free survival, progression-free survival, metastasis-free survival, overall survival, treatment fidelity, cost-effectiveness and safety/tolerability. TRAIN will be run in approximately 12-20 UK secondary care hospitals. Clinical trial information: 16345179.