Abstract CT252: COLO-PREVENT: A platform for developing colorectal cancer prevention therapies

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the U.K. with modifiable risk factors significantly contributing to its incidence. By 2030, the global CRC burden is predicted to increase by 60%, emphasizing the need for prevention strategies. Metformin and aspirin are repurposed oral medications that have shown preventive potential. Resveratrol, a natural compound found in red wine, grapes, and peanuts, has shown promise in early phase CRC prevention trials. In England, the bowel cancer screening program (BCSP) invites individuals aged 54-74 to complete a fecal immunochemical test (FIT) at home, followed by colonoscopy if positive. High-risk polyp findings (≥2 premalignant polyps including ≥1 advanced colorectal polyp; or ≥5 premalignant polyps) lead to a surveillance colonoscopy after 3 years. Protocol-driven care pathways, coupled with rigorous endoscopic and histological quality assurance, make the BCSP ideal for prevention studies. Polyps are precursors to most CRC and have been used as a validated surrogate endpoint, including in seAFOod, a polyp prevention trial embedded within the BCSP that evaluated aspirin and eicosapentaenoic acid in over 700 high-risk individuals (ISRCTN05926847). The COLO-PREVENT trial platform evaluates the efficacy of aspirin, aspirin plus metformin, and resveratrol in preventing colorectal polyps in high-risk individuals identified via the BCSP. Ultimately, it is intended to provide long-term infrastructure, beyond these initial studies, for developing various preventive interventions for CRC. Methods: COLO-PREVENT is the first trial platform enabling simultaneous assessment of multiple preventive therapies; it includes a phase III interventional open-label parallel randomized control trial (RCT) comparing three years of aspirin (75mg daily) with aspirin (75mg daily) plus metformin (500mg twice daily). Additionally, there is a parallel phase II interventional double-blinded RCT with 3 treatment arms comparing: 5mg resveratrol, 1g resveratrol, and placebo, taken once daily for one year. The planned sample sizes are 862 and 477 participants, respectively. Key eligibility criteria include high-risk polyp findings on BCSP colonoscopy, adequate renal function (GFR ≥35ml/min/1.73m), within the preceding 4 weeks, and informed consent. Additional specific eligibility criteria apply to each study. The primary outcome for both studies is the mean number of polyps per participant (MPP). Safety, tolerability, adverse events, and gastrointestinal symptoms will also be assessed. Furthermore, a large integrated translational program with a focus on metabolic phenotyping and microbiome analysis will provide mechanistic insights and identify biomarkers to inform future precision prevention strategies. Recruitment to the COLO-PREVENT main trial began in November 2022, with the resveratrol sub-trial opening in April 2024 (ISRCTN13526628). Citation Format: Frankie Fan, Ajay Verma, Mark Hull, Ruth Langley, Philip Quirke, Matthew Rutter, Colin Rees, Nafisa Boota, Cassey Brookes, Louise Brown, Lynne Howells, Anne Thomas, Barry Sandwell, Karen Brown. COLO-PREVENT: A platform for developing colorectal cancer prevention therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT252.