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Platelet Aggregation Inhibitors

Metformin

Aspirin

placebo Aspirin (1 tablet daily) + placebo Metformin (1 tablet BID) for 12 months

placebo Aspirin (1 tablet daily) + active Metformin (850 mg, 1 tablet BID), for 12 months

active Aspirin (100 mg, 1 tablet daily) + placebo Metformin (1 tablet BID), for 12 months

active Asprin (100 mg, 1 tablet daily) + active Metformin (850 mg, 1 tablet BID), for 12 months

Arm C (experimental arm) Treatment: active ASA + placebo MET Dose: 100 mg, 1 tablet daily + 1 tablet twice a day (BID) Duration: 12 months

Arm B (experimental arm) Treatment: placebo ASA + active MET Dose: 1 tablet daily+ 850 mg, 1 tablet twice a day (BID) Duration: 12 months

Arm A (control arm) Treatment: placebo ASA + placebo MET Doses: 1 tablet daily +1 tablet twice a day (BID) Duration: 12 months

Placebo

Andrea De Censi, MD

It has been shown that Aspirin (ASA) as well as Metformin (Met) can inhibit the incidence and mortality of colorectal cancer (CRC). In this randomized, placebo controlled clinical trial we compare the effect of these two drugs alone and their combination to prevent recurrent CRC after surgery.

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 trials.

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 colon cancer will randomly be assigned in a four-arm trial to either ASA, 100 mg day, MET 850 mg bid, their combination, or placebo for one year. The primary endpoint biomarker is the change, defined as the difference between pre- and post-treatment expression of nuclear factor kappa-B (NFκB), in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two 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 next generation sequencing 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 Randomized, 2x2 Factorial Design Biomarker Prevention Trial of Low-dose ASA and Metformin in Stage I-III Crc Patients

A Randomized, Phase II, Double-blind, Placebo-controlled, Multicenter, 2x2 Factorial Design Biomarker Tertiary Prevention Trial of Low-dose Aspirin and Metformin in Stage I-III Colorectal Cancer Patients. The ASAMET Trial

It will be measured the change, defined as the difference between post- and pre-treatment levels, in NFκB expression in normal colonic tissue. The NFκB transcription factor family is composed of the p65, RelB, c-Rel, p105, andt p100 subunits, and activation of the NFκB pathway is defined by the nuclear translocation of the p65 subunit. Therefore, cytoplasmic and nuclear localization of p65 will be immunohistochemically assessed as an indicator of NFκB activity. The analysis of expression will be performed by semi quantitative assessment: NFκB expression will be measured primarily as the percentage of positive nuclear areas for NFkB over the total nuclear areas in 10 section fields.

It will be measured the change (defined as above) in IHC expression levels of pS6K, p53, beta-catenin, PI3K (from colon unaffected biopsy specimen). These biomarkers will be measured as described above for NFκB.

The change in circulating biomarkers IL-6, CRP, VEGF and HOMA index\[homeostasis model assessment (fasting blood glucose (mmol/L)\*insulin (mU/L))/22.5\] will be measured in plasma and serum at two time points, pre- and post-intervention, using monoclonal ELISA kits.

Gene expression levels of candidate genes and pathways, in normal colonic tissue, will be measured on a genome-wide basis using Illumina HumanHT-12 Expression BeadChips targeting more than 47,000 transcripts including known splice variants across the human transcriptome.

The blood and tissue MET levels will be measured. LC-MS/MS system will be used for the drug level determinations to be correlated with biomarker modulation and toxicity

Spots Global Cancer Trial Database for tertiary prevention in colon cancer