John Burn research projects
CRUK/12/039: CaPP3 - a double blind randomised controlled dose inferiority trial of aspirin prevention in people with Lynch syndrome: high risk of cancer due to mutations in the mismatch repair genes (supported by Stand Up To Cancer)Funding period: 01 September 2013 to 31 August 2020
Funding scheme: Phase III Clinical Trial Grants
Funding committee: Clinical Trials Awards and Advisory Committee
Background: CAPP2 recruited worldwide 1009 people with the Lynch syndrome (LS) who are at high risk of hereditary cancer due to being carriers of mismatch repair gene defects; it showed, in a randomised placebo controlled trial format that 600mg daily aspirin for 2 years results in 63% reduction in colorectal cancer and similar reduction in other related cancers, apparent from 4 years (Burn et al Lancet 2011). It is important to establish whether this protective effect can be achieved with lower doses of aspirin and, consequently, fewer adverse events and to support translational studies of underlying mechanism. Aims: CaPP3 will be a double blind randomised dose inferiority trial (RCT) designed to compare the degree of cancer prevention resulting from three daily doses of enteric coated aspirin; 600mg, 300mg and 100mg. Methods:Recruits will be adults of 60 or under who have been shown to have a constitutional pathological variant in one of the mismatch repair genes (hMSH2, hMLH1, hMSH6 or PMS2), who are not known to be sensitive to aspirin. The UK regional genetics centres have identified approximately 6500 adult LS gene carriers (based on 2011 audits) and all are under 1 to 2 yearly followup colonoscopy. Gene carriers will be consented and blood/ saliva biobanking samples collected before blinded dose allocation via secure website: www.capp3.org, regular review and cancer registry data will be combined to assess impact on new cancers and adverse events related to medication for at least 5 years. Sample size calculation used CAPP2 observed "survival probability" for all Lynch related cancers and colorectal cancer: 0.889 and 0.949 after 5 years respectively. The null hypothesis is that 600 mg aspirin as active control is superior to the new treatments (300 mg and 100 mg aspirin). We have estimated that all Lynch syndrome cancers will be reduced by 50% using 600mg while 100mg will result in a 25% reduction. If 300mg results in a 30% reduction, the target would be to follow 1000 participants in each group. Parallel studies in other countries using the same randomisation are under development and will provide greater power. Application: This trial will establish a new international standard of care in hereditary cancer and inform the debate about more widespread use of aspirin to prevent cancer, especially in people with a personal or family history of cancer.