The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients

Abstract

BackgroundEpidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials.Methods/designThis is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin 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 are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC 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 measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year.DiscussionA favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC.Trial registrationEudraCT Number: 2015–004824-77; ClinicalTrial.gov Identifier: NCT03047837. Registered on February 1, 2017.

Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects

“…Nonetheless, there were insignificant different in OS and disease free survival (DFS) among the metformin, non-metformin, and non-diabetic patients. Currently, an ongoing randomized, phase II, double-blind, placebo-controlled trial aims to determine the effect of low-dose aspirin and metformin in stage I-III CRC patients since the single use of both drugs exhibited beneficial use in reducing adenoma recurrence and CRC mortality rates [102]. The CRC patients ( n = 160) are divided in four arms; aspirin (100 mg/day), metformin (850 mg/bis in die), aspirin and metformin combination, or placebo for a duration of 12 months.…”

Aspirin inhibits colon cancer cell line migration through regulating epithelial‑mesenchymal transition via Wnt signaling

“…Firstly, it was proposed that aspirin affects the nuclear transport of Slug. Previous studies have demonstrated that aspirin can downregulate the expression of Slug in aggressive K-ras-expressing cancer cells (26,27). A previous study has also implicated aberrant nuclear transport of Snail family member transcription factors in tumor formation (28).…”

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“…73 In another randomized, Phase II, double-blind, placebocontrolled, multicenter, ASAMET trial, the combination of aspirin and metformin was assessed for their potential synergistic interaction on a set of biomarkers associated with colon carcinogenesis. 74 Here, the patient trial administered metformin at 850 mg BID (twice a day) and aspirin at 100mg QD (once a day) for one year.…”