Novel sequential treatment strategy for patients with muscle-invasive bladder cancer (MIBC): intravesical recombinant BCG, followed by neoadjuvant chemoimmunotherapy, radical cystectomy plus pelvic lymphadenectomy and adjuvant immunotherapy – protocol of a multicentre, single arm phase 2 trial (SAKK

Introduction The combination of checkpoint inhibition and cisplatin-based chemotherapy is investigated in muscle invasive bladder cancer (MIBC) and results from phase 2 trials have been presented. Intravesical BCG has been used for non-MIBC (NMIBC) in patients with carcinoma in situ and high-grade Ta/T1 tumours. BCG induces innate and adapted immune response and upregulation of PD-L1 in preclinical models. The proposed trial is intended to implement a new immuno-immuno-chemotherapy induction therapy for MIBC. The combination of BCG and checkpoint inhibition with chemotherapy aims at higher intravesical responses and better local and systemic control of disease. Methods and analysis SAKK 06/19 is an open-label single-arm phase II trial for patients with resectable MIBC T2-T4a cN0-1. Intravesical recombinant BCG (rBCG: VPM1002BC) is applied weekly for three instillations followed by four cycles of neoadjuvant cisplatin/gemcitabine every 3 weeks. Atezolizumab 1200 mg every 3 weeks is started together with rBCG and given for four cycles. All patients then undergo restaging and radical cystectomy and pelvic lymphadenectomy. Atezolizumab is continued as maintenance therapy after surgery every 3 weeks for 13 cycles. Pathological complete remission is the primary endpoint. Secondary endpoints include pathological response rate (<ypT2 N0), event-free survival, recurrence-free survival, overall survival, feasibility and toxicity. An interim safety analysis will be performed after the first 12 patients have completed neoadjuvant treatment specifically assessing toxicity possibly associated with intravesical rBCG application. The study has received approval by ethical committee Zurich, Switzerland, BASEC-No. 2021–01872. Results will be made available by publication. Trial registration number NCT04630730.