ABCSG C09/ASAMET Details

Start:
04/2017 (international), 10/2018 (national)
Randomizing:
open

Contact ABCSG-Trial office

E-mail: info@abcsg.at
Phone: +43 1 408 92 30
Fax: +43 1 409 09 90

Design

Randomized, phase II, double-blind, placebo-controlled, multicenter, 2×2 factorial design clinical trial.

ABCSG C09/ASAMET
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Objectives:

Primary:

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.

Secondary:

  1. 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.
  2. 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.
  3. 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
  4. 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).
  5. To study the serum concentrations of thromboxane B2 (TxB2), as a biomarker of treatment adherence, to be correlated with biomarker modulation and toxicity.
  6. 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.
  7. 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.

Inclusion criteria:

  1. Patients aged > 18 and ≤ 80 years
  2. 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.
  3. Adjuvant chemotherapy and (neo)adjuvant radiotherapy terminated at least 3 months before randomization.
  4. ECOG performance status ≤ 1
  5. 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
  6. 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.
  7. Able to understand and sign an informed consent (or have a legal representative who is able and willing to do so)

Exclusion criteria:

  1. Patients who are not able to undergo colonoscopy
  2. 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)
  3. 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
  4. 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
  5. Diabetic patients on drug treatment are excluded
  6. 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)
  7. Any other invasive malignancies (with the exclusion of basal cell carcinoma or cutaneous squamous cell carcinoma) diagnosed during the last 5 years before randomization
  8. Past history of any other invasive CRC than the one the patient is currently being treated for
  9. Alcohol or drug abuse, defined according to Investigators discretion
  10. Prior history of gastro-intestinal bleeding to ASA or hemorrhagic diathesis (e.g. hemophilia).
  11. Erosive-ulcerative lesions in the gastrointestinal tract
  12. History of erosive GERD or active erosive GERD on gastroscopy
  13. Concomitant corticosteroid treatment
  14. Known hypersensitivity or intolerance to MET or ASA or NSAID
  15. Deficiency of glucose-6-phosphate dehydrogenase (G6PD)
  16. Treatment with another investigational drug < 28 days prior to study entry
  17. Concurrent participation in a clinical trial with the same endpoints
  18. History of hemorrhagic stroke
  19. Lynch Syndrome (HNPCC)
  20. Crohn’s disease (CD) and Ulcerative Colitis (UC)
  21. Pregnant or lactating females
  22. History of lactic acidosis
  23. Liver dysfunction including chronic active hepatitis and cirrhosis not compensated
  24. History of vitamin B12 deficiency or megaloblastic anemia
  25. Uncontrolled coronary syndrome or symptomatic congestive heart failure (e.g. Class III or IV New York Heart Association’s Functional Classification)
  26. Inability or unwillingness to swallow tablets