LUCIE Localised Urothelial Carcinoma Immuno-oncology Evaluation Randomised Phase II trial, evaluating safety and efficacy of a combination therapy of Durvolumab and Tremelimumab in adjuvant setting for patients undergoing neoadjuvant chemotherapy and cystectomy for locally advanced urothelial carcinoma (pT3/pT4a or N1) A project of the Bladder Cancer Committee of the French Association of Urology(CCAFU) Vessie Nadine Houédé – Morgan Rourpret Italy - Sandro Pignata Spain – Alvaro Juarez

Goals Primary Objective: PFS of the combination of durvalumab and tremelimumab after chemotherapy and cystectomy for patients with locally advanced urothelial carcinoma (stage pT3/pT4 or N1). Secondary Objectives: Overall survival at 2 years Quality of life (EORTC QLQ-C30)

Inclusion criteria Histologically confirmed muscle invasive transitional cell carcinoma of the bladder. Treated with neoadjuvant chemotherapy based on platin combination for at least one cycle. Pathological stage T3-T4a or N>1 after radical cystectomy, whatever surgical margins (R0 ou R+). M0 disease. Karnofsky Performance Status ≥ 70%.

Treatment Durvalumab 1500 mg every 4 weeks for a maximum of 12 months or until disease progression Tremelimumab 75 mg i.v. 4 weeks for a maximum of 4 doses

Method Hypotheses : Sample size and justification : The association of durvalumab and tremelimumab will improve progression free survival from 12 to 18 months. Sample size and justification : N= 90 ; Phase II trial. Power calculation 0.80, alpha risk 5%, bilateral approach Method(-s) to analyze primary variable(-s) : survival model (Kaplan Meier Curve and Log rank test)

Calendrier 10 centers in France, 15 in Italy, 15 in Spain (must to be updated) Binome Onco / Uro 9 patients / month Recrutement over 1 year Follow up 2 years

Ancillary study To evaluate potential associations between PDL1 and CTLA4 germline variants and Response to Immune check points inhibitors Risk of MIBC progression and mortality To investigate potential biomarkers of response to durvolumab and tremelimumab combination therapy: PDL1/PDL2/CTLA4 expression in the tumor microenvironment and in tumor cells Inflammatory infiltrate, (CD8+ Tumor associated Lymphocyte, CD3, CD68…) Known bladder cancer oncogenes mutational status: FGFR3, RAS, PIK3CA The TCGA status of bladder cancer subtypes The EMT status of tumor cells.