Background: The integration of immune checkpoint inhibitors (ICI) in the perioperative setting of localized muscle-invasive bladder cancer (MIBC) is extensively investigated and several results from phase 2 trials have been published. While promising, the pathological complete remission rate (pCR, ypT0 ypN0) achieved with ICI-containing regimens appears similar to cisplatin-based chemotherapy alone. Further improvement is needed. Intravesical BCG has successfully been used for decades for non-muscle invasive bladder cancer (NMIBC) in patients (pts) with carcinoma in situ (CIS) and as adjuvant treatment for high-risk papillary tumors. Intravesical BCG induces a local inflammation leading to induction of the innate immune system, probably followed by a tumor-specific adaptive immune response. Recently, a novel recombinant BCG vaccine (VPM1002BC) has been developed and a clinical study in BCG-refractory NMIBC (SAKK 06/14, Eur Urol Oncol. 2022 Apr;5(2):195-202.) has demonstrated good safety with low local toxicity and promising efficacy. We hypothesize that induction therapy with intravesical VPM1002BC improves the efficacy of systemic perioperative chemo-immunotherapy in pts with operable MIBC. Methods: SAKK 06/19 is an open-label single arm phase II trial for pts with operable pT2 or cT2-T4a cN0-1 MIBC without contraindication for cisplatin. Prior intravesical BCG is excluded as are pts unable to keep BCG instillation for less than 1 hour. Intravesical VPM1002BC is administered weekly for 3 instillations. Atezolizumab (atezo) 1200mg is given on day 1 and then every 3 weeks (q3w) for four times. Chemotherapy with cisplatin (70mg/m2 day 1) and gemcitabine (1000mg/m2 day 1 & 8) q3w is started on day 22 and given for four cycles followed by radical cystectomy and lymphadenctomy. Atezo is continued after surgery for 13 cycles in case of residual muscle invasive disease (≥ypT2) or positive lymph nodes (ypN+) only. pCR at cystectomy is the primary endpoint. A total of 46 pts is needed (including 15% dropout rate) using Simon’s minimax two-stage design with type I error 5%, power 80%, a null hypothesis of ≤35% pCR and an alternative hypothesis of ≥55% pCR. Secondary endpoints include pathological response rate (<ypT2N0), event-free survival, recurrence-free survival, overall survival, feasibility and toxicity. An interim safety analysis will be performed after the first 12 pts have completed neoadjuvant treatment specifically assessing toxicity possibly associated with intravesical BCG application. An interim efficacy analysis will be performed after the first 21 pts have undergone surgery. Accrual to the study is currently ongoing (NCT04630730). Clinical trial information: NCT04630730.