ABCSG C09/ASAMET Details
- 04/2017 (international), 10/2018 (national)
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Randomized, phase II, double-blind, placebo-controlled, multicenter, 2×2 factorial design clinical trial.
To test the synergistic effect of the combined treatment with low dose ASA plus MET given for 1 year to reduce the expression of NFκB (primary endpoint) in unaffected colonic tissue in patients with removed CRC.
- To test the effect of treatment with ASA and MET, in combination and independently, on the following secondary endpoints:
- The change (defined as above) in IHC expression levels of pS6K, p53, beta-catenin, PI3K (from colon unaffected biopsy specimen);
- The change in the circulating biomarkers IL-6, CRP, VEGF and HOMA index [homeostasis model assessment (fasting blood glucose (mmol/L)*insulin (mU/L))/22.5];
- The gene expression levels of candidate genes (PTGS1-COX1, PTGS2-COX2, VEGF, TNFα, EGFR, NFκB), pathways (mTOR signaling – KEGG04150, NFκB signaling – KEGG04064, VEGF signaling – 04370, FoxO signaling KEGG04068, Regulation of autophagy – KEGG04140), and genome-wide expression profile in colon unaffected biopsy tissue.
- To define the blood and tissue drug levels of metformin, considering the genetic variability of specific membrane-bound drug transporters which may affect the pharmacokinetics.
- To genetically characterize the primary colorectal carcinomas using next generation sequencing (NGS) on a panel comprising 180 amplicons of 30 genes (including KRAS, BRAF, NRAS, APC, PIK3CA, TP53,CTNNB1 and EGFR) and determine their association with treatment response
- To study the treatment tolerability comparing incidence and grade of toxicities (safety endpoint) among arms (categorized using the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4 (CTCAE v4).
- To study the serum concentrations of thromboxane B2 (TxB2), as a biomarker of treatment adherence, to be correlated with biomarker modulation and toxicity.
- To evaluate the effect of treatment on psychological variables (distress, anxiety, depression) and cancer related fatigue and to explore their interactions with treatment on the endpoint biomarkers.
- To evaluate the occurrence of adenoma (low, intermediate and/or high grade intraepithelial neoplasia) at baseline and 12 months after randomization according to the Vienna classification of gastrointestinal epithelial neoplasia.
- Patients aged > 18 and ≤ 80 years
- Patients with completely resected stage I, II, or III primary colorectal cancer within 24 months prior to randomization, regardless of (neo-)adjuvant chemotherapy. Patients with pT1 CRC treated with endoscopic polypectomy.
- Adjuvant chemotherapy and (neo)adjuvant radiotherapy terminated at least 3 months before randomization.
- ECOG performance status ≤ 1
- Satisfactory hematological and biochemical functions:
- Platelets ≥ 100 x 10^9/L
- Creatinine clearance estimated with the Cockcroft – Gault formula ≥ 60 mL/min. Patients with Gault formula ≥ 30 – ≤ 59 ml/min are eligible but they will receive a single (evening) tablet of MET, 850 mg
- AST and ALT ≤ 2.5 times ULN
- Females of childbearing potential/males with partners of childbearing potential participating in the study are to use effective methods of birth control during study participation. Female participants must provide a pregnancy test, according to local national guidelines.
- Able to understand and sign an informed consent (or have a legal representative who is able and willing to do so)
- Patients who are not able to undergo colonoscopy
- Patients who are allergic or intolerant to ibuprofen or naproxen, or who have MET-, or ASA-, or salicylate intolerance or more generalized drug intolerance to non-steroidal anti-inflammatory drugs (NSAIDs)
- Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing or participating in the study and/or comply with study procedures
- Chronic treatment with ASA or other NSAIDs or MET or patients who are on current long term treatment (≥ 4 consecutive weeks) with ASA, NSAID or COX -2 inhibitors or MET
- Diabetic patients on drug treatment are excluded
- Anticoagulant therapy (dicumarol, heparin, fondaparinux, apixaban, dabigatran etexilate, rivaroxaban) or active current treatment with antiplatelet agents (e.g. off-study ASA, clopidogrel, prasugrel, ticagrelor, or ticlopidine)
- Any other invasive malignancies (with the exclusion of basal cell carcinoma or cutaneous squamous cell carcinoma) diagnosed during the last 5 years before randomization
- Past history of any other invasive CRC than the one the patient is currently being treated for
- Alcohol or drug abuse, defined according to Investigators discretion
- Prior history of gastro-intestinal bleeding to ASA or hemorrhagic diathesis (e.g. hemophilia).
- Erosive-ulcerative lesions in the gastrointestinal tract
- History of erosive GERD or active erosive GERD on gastroscopy
- Concomitant corticosteroid treatment
- Known hypersensitivity or intolerance to MET or ASA or NSAID
- Deficiency of glucose-6-phosphate dehydrogenase (G6PD)
- Treatment with another investigational drug < 28 days prior to study entry
- Concurrent participation in a clinical trial with the same endpoints
- History of hemorrhagic stroke
- Lynch Syndrome (HNPCC)
- Crohn’s disease (CD) and Ulcerative Colitis (UC)
- Pregnant or lactating females
- History of lactic acidosis
- Liver dysfunction including chronic active hepatitis and cirrhosis not compensated
- History of vitamin B12 deficiency or megaloblastic anemia
- Uncontrolled coronary syndrome or symptomatic congestive heart failure (e.g. Class III or IV New York Heart Association’s Functional Classification)
- Inability or unwillingness to swallow tablets