A Phase I/II open-label, dose-escalation, and dose-expansion study of mRNA-4194 in participants with Lynch syndrome
Lynch syndrome (LS)
The INTERCEPT-Lynch trial is an open-label, multicentre, Phase I/II trial of mRNA-4194 administered by intramuscular (IM) injection to participants with LS who are not known to have active cancer but are at high risk of developing MSI-H cancer due to inheritance of a germline pathogenic variant in one of the DNA MMR genes. The trial will include two parts: Part 1 consists of dose-escalation/de-escalation cohorts. Part 1 will enrol participants with confirmed LS. Participants will receive doses (cycles) of mRNA-4194. Part 2 consists of dose-expansion cohort(s). Part 2 will enrol participants with confirmed LS and at least one baseline adenomatous colorectal polyp measuring ≥2 mm and <10 mm identified at SOC surveillance colonoscopy. Participants will receive doses (cycles) of mRNA-4194 administered at the dose level(s) determined from Part 1. A follow-up colonoscopy will be conducted 28 weeks after the start of priming treatment to remove retained polyps and evaluate biological endpoints, with a further colonoscopy performed at 24 months to align with the interval of surveillance colonoscopies in LS. Part 1: Dose range: 50 μg, 125 μg (starting dose), 250 μg, 500 μg, 1000 μg Safety follow-up: 30 days after last dose Immunogenicity follow-up: 28 weeks after first dose Part 2: Dose range: Dose(s) to be selected based on assessment of safety, immunogenicity and other translational data from participants in Part 1 Safety follow-up: 30 days after last dose Long-term follow-up: Week 104 Randomisation process (Part 2) – if two recommended doses for expansion (RDEs) are selected Participants will be randomised in a 1:1 ratio Randomisation Form completed via REDCap EDC Central CTU team to review and confirm participant eligibility In the event of being unable to access REDCap, randomisation may be performed over the telephone with a member of the central CTU team
1. ≥18 years of age (inclusive) at the time of signing the informed consent. 2. Known LS, i.e., previously confirmed to be a carrier of a germline pathogenic variant in MLH1, MSH2, MSH6, PMS2, or EPCAM by genetic testing through a UKAS-accredited (or equivalent international agency) laboratory setting. 3. For Part 2 only: Participants must have at least one colorectal polyp with an adenomatous appearance measuring ≥2 mm and <10 mm in diameter identified on the screening colonoscopy (i.e., within 28 days prior to the planned first dose of study intervention). 3.1. Polyp size will be based on measurements taken during the screening colonoscopy by the gastroenterologist performing the procedure. Polyp measurements will be performed in one dimension (transverse plane) under standard conditions as outlined in the Laboratory Manual using endoscopic tools as a reference (e.g., closed biopsy forceps [2.5 mm], open biopsy forceps [7 mm], and standard cold snare [9 mm]). 3.2. The participant must agree to allow adenomatous polyps ≥2 mm and <10 mm to be left in situ for longitudinal evaluation. The participant must agree to an additional colonoscopy at 28 weeks for resection of all polyps identified, including those identified at baseline and left in situ and any new polyps. 3.3. The retained polyp(s) must be absent of features suspicious for advanced neoplasia, as determined by internationally validated endoscopic methods (see Appendix 2). Participants with adenomatous polyps meeting the following morphological endoscopic criteria are eligible: 3.3.1. Kudo pit pattern type III-IV 3.3.2. JNET (Japan Expert NBI Team) classification type 2A 3.3.3. Paris polyp type 0-Ip, 0-Isp, 0-Is, 0-IIa, or 0-IIb, provided there is no visible depression within the polyp (0-IIc or mixed 0-IIa+IIc) 3.4. All adenomatous polyps <2 mm or ≥10 mm will be resected at the time of the screening colonoscopy, as will all polyps with non-adenomatous morphology. 4. For Part 2 Only: Predicted to be fit and e
1. Active cancer or pre-malignant condition, other than superficial non-melanoma skin cancers (e.g., basal cell carcinoma and squamous cell carcinoma), at time of enrolment. 2. Received treatment, including surgical resection, for cancer within the preceding 3 years for LS-related cancers or within the preceding 5 years for non-LS-related cancer. 3. Toxicities from prior cancer therapy that have not recovered to Grade 1 or baseline with the exceptions of alopecia, vitiligo, and, if approved by the Chief Investigator or designated clinician , other toxicities not reasonably expected to recover. 4. For Part 2 only: A diagnosis of active inflammatory bowel disease which would compromise identification of polyps at baseline or week 28 colonoscopy 5. For Part 2 only: Prior total or subtotal resection of the colon or another prior surgical procedure preventing colonoscopy. 6. Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors (eg, ibuprofen, naproxen, celecoxib), defined as ≥3 doses per week for a duration of ≥4 weeks within the past 6 months, unless discontinued at least 4 weeks prior to Screening. Use of aspirin is permitted but must be documented (note that for subjects in Part 2 on anti-platelet and anticoagulant therapy, Exclusion Criterion #15 must be followed. 7. Immunosuppressive doses of systemic steroids or absorbed topical steroids (doses >10 mg prednisolone (prednisone) daily equivalent) within 2 weeks before study intervention administration or currently requiring maintenance doses of >10 mg prednisolone (prednisone) or equivalent per day. 8. History of primary immunodeficiency or solid organ transplantation. 9. Any history of live or live attenuated vaccinations within 28 days prior to cycle 1 day 1 (C1D1), i.e., the first dose of study treatment. Recent non-live vaccines (including mRNA vaccines) are permitted but should not be administered within 14 days prior to study dose. 10. History of anaphylaxis