Randomized phase III clinical trial of neoadjuvant intravesical mitomycin C (MMC) treatment in patients with primary treatment-naïve non-muscle invasive bladder cancer (NMIBC).
Authors: Lazzeri Massimo , Rescigno Maria , Guazzoni Giorgio Ferruccio , Casale Paolo , Buffi NicolòMaria , Lughezzani Giovanni , Mancon Stefano , Fasulo Vittorio , Saita Alberto , Hurle Rodolfo 
Published: March 2023

TPS578 Background: Approximately 75-85% of vesical urothelial carcinomas are non-muscle invasive bladder cancers (NMIBC). The primary treatment is transurethral resection (TUR) followed by adjuvant intravesical therapies with immunotherapy (BCG) and/or chemotherapy agents (i.e. mitomycin C - MMC). Unfortunately, the response to intravesical treatments is variable and incomplete and there is a un-met clinical need to improve its efficacy for reducing the recurrence rate and progression to muscle invasive BC (MIBC). Recently, has been showed that MMC induces immunogenic cell death (ICD), determining the expression of specific damage signals, like HMGB1 molecule, that favors the phagocytosis of dying tumor cells, the activation of innate immune cells and the presentation of tumor antigens to T lymphocytes [1]. The identification of ICD as a novel immune-related mechanism of action of MMC could provide opportunities to optimize bladder cancer management by proposing the use of MMC in a “neoadjuvant” setting. The aim of current clinical trial is to test the hypothesis that the neoadjuvant instillation of MMC in patients with NMIBC may reduce the recurrence rate and/or progression to MIBC. Methods: This is a prospective phase III randomized clinical trial in patients with primary treatment-naïve NMIBC recruiting since March 2022 (EudraCT 2021-003751-42_studio ICH-013-MMC). Patients are randomized 1:1 to neo-adjuvant MMC or standard of care. Patients enrolled in the neo-MMC group receive two intravesical instillations of MMC (40 mg/40 ml saline) in the 2 weeks before (days: -14 and -7) the scheduled TUR (day: 0). After TUR, as for clinical practice, both controls and neoMMC subjects, undergo adjuvant treatment, if required, based on the histological evaluation of the tumor and following EAU/PMID: 33040478 guidelines. The primary endpoint of the study is to evaluate the efficacy of MMC neoadjuvant treatment in reducing the recurrence rate of BC calculated as the proportion of patients who achieve a complete response (no evidence of BC after 3, 6, 12 and 24 mo.). The secondary clinical endpoint will be the analysis of the rate of grade and stage progression to MIBC in case of recurrence and the correlation with specific biomarker (i.e. expression of HMGB1). Consider that the primary aim of the study is to see a reduction of relapse, leading to an HR of 0.6, estimating on the control group a 30% relapse free at 12 months. With equal-sized group, a two-sided significance level test (α =0.05) with power 80% power (β=0.2), and assume that recruitment was to be terminated after 12 months, with a 2-year follow up, the required sample size is approximate 160 patient, 80 in each group (control / neoMMC). References: 1. Oresta B, et al Sci Transl Med. Jan 6;13(575):eaba6110 Clinical trial information: EudraCT 2021-003751-42_studio ICH-013 (MMC) .