(UroToday.com) The 2023 GU ASCO annual meeting included a trials in progress session for bladder cancer, featuring a presentation by Dr. Massimo Lazzeri discussing the trial design of a randomized phase III clinical trial of neoadjuvant intravesical mitomycin C treatment in patients with primary treatment naïve non-muscle invasive bladder cancer (NMIBC). Approximately 75-85% of bladder urothelial carcinomas are non-muscle invasive, for which the primary treatment is transurethral resection (TUR) followed by adjuvant intravesical therapies with immunotherapy (BCG) and/or chemotherapy agents (i.e. mitomycin C). Unfortunately, the response to intravesical treatments is variable and incomplete and there is an unmet clinical need to improve its efficacy for reducing the recurrence rate and progression to muscle invasive bladder cancer. Recently, it has been shown that mitomycin C induces immunogenic cell death, 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 immunogenic cell death as a novel immune-related mechanism of action of mitomycin C could provide opportunities to optimize bladder cancer management by proposing the use of mitomycin C in a “neoadjuvant” setting. The aim of current clinical trial is to test the hypothesis that the neoadjuvant instillation of mitomycin C in patients with NMIBC may reduce the recurrence rate and/or progression to muscle invasive bladder cancer.
This is a prospective phase III randomized clinical trial in patients with primary treatment NMIBC recruiting since March 2022. Patients are randomized 1:1 to neoadjuvant mitomycin C or standard of care. Patients enrolled in the neoadjuvant mitomycin C group receive two intravesical instillations of mitomycin C (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 neoadjuvant mitomycin C subjects, undergo adjuvant treatment, if required, based on the histological evaluation of the tumor and following EAU guidelines. The trial design is as follows:
The primary endpoint of the study is to evaluate the efficacy of mitomycin C neoadjuvant treatment in reducing the recurrence rate of bladder cancer calculated as the proportion of patients who achieve a complete response (no evidence of bladder cancer after 3, 6, 12, and 24 months). The secondary clinical endpoint will be the analysis of the rate of grade and stage progression to muscle invasive bladder cancer in case of recurrence and the correlation with specific biomarkers (i.e. expression of HMGB1). Considering 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 groups, a two-sided significance level test (α =0.05) with 80% power (β=0.2), and assuming that recruitment was to be terminated after 12 months, with a 2-year follow up, the required sample size is approximately 160 patients, 80 in each group (control / neoadjuvant mitomycin C).
Presented by: Massimo Lazzeri, IRCCS Humanitas Research Hospital, Milan, Italy
Co-Authors: Maria Rescigno, Giorgio Ferruccio Guazzoni, Paolo Casale, NicolòMaria Buffi, Giovanni Lughezzani, Stefano Mancon, Vittorio Fasulo, Alberto Saita, Rodolfo Hurle
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.
References:
- Oresta B, et al Sci Transl Med. Jan 6;13(575):eaba6110 Clinical trial information: EudraCT 2021-003751-42_studio ICH-013 (MMC).