A Randomized, 2x2 Factorial Design Biomarker Prevention Trial of Low-dose Aspirin and Metformin in Stage I-III Colorectal Cancer Patients. (ASAMET)
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|ClinicalTrials.gov Identifier: NCT03047837|
Recruitment Status : Recruiting
First Posted : February 9, 2017
Last Update Posted : February 15, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Tertiary Prevention in Colon Cancer||Drug: Aspirin (ASA) + Metformin (MET) Drug: ASA Drug: MET Drug: Placebos||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||160 participants|
|Intervention Model:||Factorial Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||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|
|Actual Study Start Date :||March 15, 2017|
|Estimated Primary Completion Date :||September 15, 2019|
|Estimated Study Completion Date :||March 15, 2020|
Placebo Comparator: Arm A
placebo Aspirin (1 tablet daily) + placebo Metformin (1 tablet BID)
Arm A (control arm) Treatment: placebo ASA + placebo MET Doses: 1 tablet daily +1 tablet twice a day (BID) Duration: 12 months
Experimental: Arm B
placebo Aspirin (1 tablet daily) + active Metformin (850 mg, 1 tablet BID)
Arm B (experimental arm) Treatment: placebo ASA + active MET Dose: 1 tablet daily+ 850 mg, 1 tablet twice a day (BID) Duration: 12 months
Other Name: Metformin
Experimental: Arm C
active Aspirin (100 mg, 1 tablet daily) + placebo Metformin (1 tablet BID)
Arm C (experimental arm) Treatment: active ASA + placebo MET Dose: 100 mg, 1 tablet daily + 1 tablet twice a day (BID) Duration: 12 months
Other Name: Cardioaspirin
Experimental: Arm D
active Asprin (100 mg, 1 tablet daily) + active Metformin (850 mg, 1 tablet BID)
Drug: Aspirin (ASA) + Metformin (MET)
Arm D (experimental arm) Treatment: active ASA + active MET Dose: 100 mg, 1 tablet daily + 850 mg,1 tablet twice a day (BID) Duration: 12 months
- NFκB [ Time Frame: 1 year ]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.
- pS6K, p53, beta-catenin, PI3K [ Time Frame: 1 year ]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.
- IL-6, CRP, VEGF and HOMA index [ Time Frame: 1 year ]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 [ Time Frame: 1 year ]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.
- Metformin concentration [ Time Frame: 1 Year ]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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03047837
|Contact: Alessandra Argusti, PhDemail@example.com|
|Contact: Silvia Caviglia, M.Scfirstname.lastname@example.org|
|Principal Investigator:||Andrea De Censi, MD||E.O. Ospedali Galliera|