ASAMET: A randomized, 2x2 biomarker prevention trial of low-dose aspirin and metformin in colorectal cancer.

Abstract

TPS1591 Background: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin (ASA) can inhibit colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin (MET) has also been associated with decreased CRC incidence and mortality in meta-analyses of epidemiological studies in diabetics and has been shown to decrease by 40% colorectal adenoma recurrence in a randomized trial. Recent studies have shown that ASA is an inhibitor of mTOR/S6K1 and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism, and that the combination of ASA and MET, another AMPK activator and S6K1 inhibitor, has a striking additive effect on AMPK activation and mTOR inhibition, with increased autophagy and decreased cell growth in CRC cell lines. While both drugs are being tested as single agents, their combination has not been tested in clinical trials. Methods: This is a randomized, placebo-controlled, double-blind, 2x2 biomarker trial of ASA and MET to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC will randomly be assigned in a 4-arm trial to either ASA, 100mg qd, MET 850mg bid, their combination, or placebo for 1 year. The primary endpoint is the change, defined as the difference between pre- and post-treatment expression, of NFκBin the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in paired colonoscopies one year apart. Additional biomarkers will include: 1) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome-wide gene expression arrays; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of mutations and SNPs with treatment response by NGS of primary tumors; 4) the measurement of circulating IL-6, CRP and VEGF, and 5) plasma and colonic MET concentrations and their correlation with biomarker profiles. A favorable biomarker modulation may provide important clues for a subsequent phase III adjuvant trial. Clinical trial information: EudraCT Number: 2015-004824-77.