Mesalamine for Colorectal Cancer Prevention in Lynch Syndrom (MesaCapp)

Colorectal cancer (CRC) is the second most common cause of cancer deaths. The most common inherited syndrome of colorectal tumors is the so called Lynch syndrome (LS). This autosomal dominant disorder leads to the formation of CRC at a young age (generally before age 50) and the occurrence of numerous colonic, metachronous and extracolonic tumor formations. This means an increased lifetime risk with increasing age for CRC in affected persons. Approximately 3% of all CRC are caused by the LS. The cause of the development of carcinoma in LS is an inherited or spontaneously aquired mutation in sequence alteration of the mismatch repair genes (MLH1, MSH2, MSH6, PMS2), which leads to rapid development of CRC by defective DNA replication. Thus the characteristic of the tumors from LS patients result in microsatellite instability (MSI). Mutation carriers carry an approximately 80% lifetime risk for the development of CRC. After successful treatment, the risk of developing further tumors in the remaining colon is approximately 30% and thus remains extremely high compared to the normal population. Annual colonoscopies, often with removal of adenomas, represent the obligatory screening- and follow-up strategy for mutation carriers. So far there is no evidence-based and generally applicable way of chemoprevention in LS patients and mutation carriers. Mesalazine (5-ASA), is a well-tolerated drug that is used for over 30 years for the treatment of ulcerative colitis. It reduces MSI by improving replication fidelity in vitro. In ulcerative colitis 5- ASA appears to reduce the risk for CRC. In a genetic mouse model of LS, 5-ASA reduced the tumor incidence, tumor multiplicity, and MSI. In this application we propose a multicenter, multinational, randomized, 3-arm, double-blind, phase 2 trial with 5-ASA 2400mg, 1200mg 5-ASA or placebo in LS patients for 2 years. The applicant has the field of responsibility of national project management of the study in Austria. A total of 540 patients from Austria, Germany, Netherlands, Poland and Israel will be randomized for the study. Only tumor-free patients, as assessed by colonoscopy, will be included in the study. After a two-year intervention period, patients will be assessed for the presence of colorectal tumors again by colonoscopy.