Coyle, C; (2018) Repurposing medicines for the adjuvant treatment of cancer: An evaluation of aspirin and metformin. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Introduction: Evidence from pre-clinical studies and observational data suggest that metformin and aspirin are good candidates for adjuvant therapies, though definitive phase III trials have not been completed. Prior to the initiation of this work, the Add-Aspirin trial had been conceived and funded with several potential challenges related to the implementation and design identified. Evidence to support the evaluation of metformin in a phase III adjuvant basket trial had not been systematically evaluated. Methods: I examined the implementation and conduct of the Add-Aspirin trial during its first year at individual UK research centres. Baseline clinical characteristics, and the feasibility and effect of the run-in period, in the first 500 participants was also examined. Additionally, I conducted a systematic review and meta-analysis to investigate the effect of metformin use on survival outcomes for individual tumour types in the adjuvant setting. Results: Centres recognised the efficiencies offered from a basket trial design particularly in terms of gaining approvals, staffing and data entry, though some unanticipated set-up and recruitment challenges have been identified. The baseline clinical characteristics were largely as expected. Overall, 88% of participants were randomised. The run-in period was effective in identifying, and preventing randomisation of participants who had less than 80% adherence (5.0%), and participants who developed significant aspirin related toxicities (1.2%). Other nonrandomisations were mostly due to minor toxicity and/or personal choice. A systematic review and meta-analysis found that metformin use was associated with significant benefits in recurrence-free survival, overall survival and cancer-specific survival in early-stage colorectal and prostate cancer. Conclusion: Opening a large multi-tumour type basket trial with an active run-in period was found to be feasible, but minor conduct modifications have been recommended and protocol amendments implemented. Metformin could be a useful adjuvant agent, and randomised control​ trials in colorectal and prostate cancer are advocated.

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