Overview
Multicenter, multinational, randomized, 2-arm, double-blind, phase II clinical study with 2000mg mesalamine, or placebo for prevention of colorectal neoplasia in Lynch Syndrome patients during and following daily intake for 2 years.
Description
This is a multicenter, multinational, randomized, 2-arm, double-blind, phase II clinical study with 2000mg mesalamine (5-ASA) or placebo in LS patients for a 2-year treatment. 260 tumor free carriers of a known genetic mutation in a major MMR gene (including patients in which the polyps are endoscopically removed) will be randomized 1:1 to receive 2000mg mesalamine or placebo. Patients will be identified through local or national registries and through collaboration with sites. Tumor free patients, assessed by white light high resolution colonoscopy, will be randomized to the study. Blood and stool samples will be collected for analysis of microbiota, ctDNA and potential biomarkers. Biopsies of the normal tissue of ascending colon and rectum will be taken at the first and the last colonoscopy.
The aim of the study is to investigate the effect of regular treatment with mesalamine (5-ASA) on the occurrence of any colorectal neoplasia, tumor multiplicity (the number of detected adenomas/carcinomas) and tumor progression in LS patients.
Tumor multiplicity and tumor progression (severity of the neoplastic lesions) will be investigated.
Eligibility
Inclusion Criteria:
- Proven tumor-free (including patients in which the polyps are removed endoscopically) carriers of a germline pathologic mutation in one of the MMR genes including MLH1, MSH2 (including EpCAM) and MSH6
- Male or female subjects with the age of 30 years or older
- Females who have been post-menopausal more than one (1) year or females of childbearing potential using a highly efficient method of contraception with less than 1% failure rate (i.e. oral hormonal contraceptives, hormone implants, hormone injections, sterilization, hormonal or copper intrauterine device, sterilized/vasectomized partner, or diaphragm in combination with a condom, spermicide or birth control pills) or should agree to abstain from heterosexual activity during treatment period. Females of childbearing potential must have a negative pregnancy test at screening and before randomization.
- Signed written informed consent prior to inclusion in the study
Exclusion Criteria:
- Presence of colorectal endoscopically non-removable benign neoplasia (patient can be included if the adenoma is removed)
- Carriers of germline mutations in PMS2
- Patients with history of stage 3 and 4 CRC are excluded
- Presence of metastatic disease
- Regular use of aspirin/ASA: daily use of ≥100mg in more than 3 continuous months within the last year
- Regular use of NSAIDs or COX-2 inhibitors: daily use in more than 3 continuous months within the last year
- Hypersensitivity to 5-ASA
- Patients after any subtotal or total colectomy
- Colorectal surgery within the previous 6 months
- Unwillingness to participate or who is considered incompetent to give an informed consent
- Pregnant or breastfeeding women
- Participation in another clinical study investigating another IMP within 1 month prior to screening
- Renal insufficiency (GFR <30ml/min/1.73m2)
- Severe liver disease or liver failure (elevation of liver enzymes above 3xULN)
- Current or history of serious psychiatric disorder or alcohol/drug abuse that in the opinion of the investigator may impact the assessment of IMP safety and efficacy or protocol adherence
- Prior history of myocarditis or pericarditis. Other severe acute or chronic medical condition such as severe chronic lung (COPD, including asthma, kidney and heart diseases) or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or ability to comply with study procedures, investigational product administration and, in the judgment of the investigator, would make the subject inappropriate for entry into this study