Lynch syndrome (LS) Genetic Diseases
Conditions
Interventions
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
Sponsors
University of Oxford
Eligibility
Sex/Gender
All
Age
18 Years to 100 Years
Inclusion criteria
Inclusion criteria: 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 1 × ULN) at baseline, AST must also be measured and must be =2.5 × ULN. 6.2.2. Total bilirubin =1.5 × ULN (<3.0 × ULN if the participant has Gilbert’s disease). 6.3. Renal function: 6.3.3. Creatinine clearance of =30 ml/min (using the Cockcroft-Gault formula). 6.4. Coagulation function: 6.4.1. Prothrombin time/international normalised ratio and activated partial thromboplastin time =1.5 × ULN. 7. Participants who are assigned male at birth or can produce sperm must agree to the following during the study intervention administration period and for at least 30 days after the last dose of study intervention: 7.1. Refrain from donating sperm PLUS either: 7.2. Be abstinent from reproductive sexual intercourse as their preferred and usual lifestyle (abstinent on a long te
Exclusion criteria
Exclusion criteria: 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 or severe hypersensitivity reaction requiring medical intervention after receipt of any mRNA vaccine or therapeutic, or any components of an mRNA vaccine or therapeutic. 11. Major surgical procedures =28 days or non-study-related minor procedures =7 days prior to C1D1. In all cases, the participant must be sufficiently recovered and stable before treatment administration. 12. Any of the following cardiac abnormalities: 12.1. Medically uncontrolled hypertension 12.2. New York Heart Association Class III or IV cardiac disease 12.3. Myocardial infarction within prior 6 months 12.4. Unstable angina pectoris 12.5. Unstable arrhythmias or prolonged corrected QT interval (QTc) >450 ms in males or >470 ms in females (unless a pacemaker is in place) 13. Has an active bacterial infection requiring use of systemic antibiotics or an active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBsAg result), or hepatitis C. Participants with a past or resolved hepatitis B virus (HBV) infection (defined as the presence of anti HBc and absence of HBsAg) are eligible. Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Human immunodeficiency virus (HIV)-positive participants with CD4 count =350 cells/mm3 and an undetectable HIV viral load within the past
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1: Safety and tolerability of mRNA-4194 is assessed via the incidence and severity of Dose-Limiting Toxicities (DLTs), Adverse Events (AEs), Adverse Events of Special Interest (AESIs), and Serious Adverse Events (SAEs) at screening and weeks 0, 3, 6, 8, 12 and the safety follow-up visit Part 1: One or more RDE(s) for mRNA-4194 will be determined via the incidence and severity of DLTs, AEs, AESIs, and SAEs at screening, weeks 0, 3, 6, 8, 12 and the safety follow-up visit Part 2: Safety and tolerability of mRNA-4194 is assessed via the incidence and severity of DLTs, AEs, AESIs, and SAEs at screening, weeks 0, 3, 6, 8, 12, 16, 24, 28, 52 and the safety follow-up visit | — |
Secondary
| Measure | Time frame |
|---|---|
| The effect of mRNA-4194 on MSI-H adenomatous colorectal polyp burden after priming treatment will be assessed using the percent change in the sum of MSI-H adenomatous polyp diameter(s) pre- and post-treatment by colonoscopy per central read, at the initial (screening) colonoscopy and follow-up colonoscopy (week 28) | — |
Countries
England, United Kingdom
Contacts
Public ContactOCTO INTERCEPT-Lynch Trial Team
Outcome results
None listed