Background and Rationale:~The outcome for patients with muscle-invasive bladder cancer treated with surgery alone remains dismal with a 5 year survival rate between 25% to 80% depending on the tumor stage and lymph node status. Cisplatin-based chemotherapy regimens (Methotrexate, Vinblastine, Doxorubicin, Cisplatin ; Cisplatin, Methotrexate, Vinblastine; Gemcitabine/Cisplatin) have demonstrated a modest but absolute benefit in overall survival of 5-8% when administered in the neoadjuvant setting. Therefore, neoadjuvant Cisplatin-based regimens are regarded as a standard of care in treating patients with muscle-invasive bladder cancer. However, bladder cancer is a disease of the elderly and due to age-associated factors (e.g. hearing impaired ≥ grade 2), peripheral neuropathy (≥ grade 2), disease associated impairment of renal function (Glomerular filtration rate < 60 mL/min) and performance status (ECOG ≥ 2) 30 to 50% are ineligible for cisplatin-based chemotherapy regimens. Several combinations with Carboplatin have been tested in single arm, phase II trials in patients ineligible for Cisplatin but no standard regimen has been established for this patient population thus far. The Guidelines of the European association of Urology (EAU) do not recommend any neoadjuvant treatment for Cisplatin-ineligible patients.~The advent of immune checkpoint inhibitors like Durvalumab or Azetolizumab, both antibodies blocking the PD1/PD-L1 interaction, have shown promising results as single agents in terms of response (15-46%) and tolerability in the metastatic setting of bladder cancer.~A trial evaluating the safety, tolerability and antitumor activity of the combination of the immune-checkpoint inhibitors Durvarlumab and the anti-CTLA4 antibody Tremelimumab in various solid tumors, including urothelial carcinoma of the bladder is ongoing (protocol D4190C0010). Blocking the PD1/PD-L1 pathway in combination with an anti-CTLA4 antibody has shown greater antitumor activity than each antibody alone in malignant melanoma trials and showed a promising antitumor activity (17% overall response rate, irrespective of the PD-L1 expression status on tumor cells) in a phase Ib study of metastatic non-small-cell lung cancer. The safety profile was acceptable (42% grade 3-4 treatment related adverse events across all dosing cohorts, most common were diarrhea, colitis and increase lipase), however, the rate of adverse events (e.g. autoimmune phenomena) and treatment interruptions was higher as compared to single agent use.~Objective:~The Primary objective of the trial is to assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab.~Study Duration:~Trial study duration encompassed the time from when the participant signs the informed consent until the last protocol-specific procedure has been completed (Cystectomy between week 17 to 23). All patients will be followed up for up to 78 weeks after end of treatment.~This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP as well as all national legal and regulatory requirements.
The trial assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab.