This multicenter randomized, placebo-controlled phase II study will enroll 132 first-line palliative treated subjects with metastatic KRAS wild type CRC. Subjects with histologically confirmed, KRAS wild-type CRC without previous chemo-therapy for metastatic disease will be screened for this study. Approximately 10 sites in Austria will participate in the study. Subjects will be randomized in a ratio of 1:1 into two groups.
This multicenter randomized, placebo-controlled phase II study will enroll 132 first-line palliative treated subjects with metastatic KRAS wild type CRC. Wild-type KRAS is required for study entry. Further target-related parameters, based on current scientific knowledge may be assessed. Subjects are randomized to Arm A or Arm B Arm A: FOLFIRI in combination with cetuximab and metformin Arm B: FOLFIRI in combination with cetuximab and placebo A liver biopsy of hepatic metastasis and normal liver tissue is planned before the first cycle and at the end of treatment; with regard to the primary study objective, these subjects are evaluable. Both efficacy and safety data will be collected. The investigators will assess response to treatment every 8 weeks based on imaging. Following permanent treatment cessation, subjects will be followed-up for survival. One interim analysis for futility (54 evaluable patients) and in addition two safety analysis for evaluation of reported adverse events between the two treatment groups will be performed at two different timepoints (20 evaluable patients/54 evaluable patients).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
8
The starting dose of Metformin/Placebo is 500 mg p.o. twice daily for 7 days (daily dose 1000 mg p.o.). Dose will be increased to 1000 mg p.o. twice daily at day 8 (daily dose 2000 mg p.o.) unless no toxicity ≥ 2 due to IMP occurs. Duration of treatment: 24 weeks
Medical University Graz, Oncology
Graz, Styria, Austria
Medical University Innsbruck, Internal Medicine
Innsbruck, Tyrol, Austria
Hospital St. Vinzenz
Zams, Tyrol, Austria
Hospital BHS Ried
Ried, Upper Austria, Austria
KH BHB Vienna
Vienna, Austria
Med. Univ. Vienna, General Hospital Vienna
Vienna, Austria
KH St. Josef KH
Vienna, Austria
Reduction in the chemotherapy-associated steatosis
Reduction in the chemotherapy-associated steatosis, as assessed by the steatosis subcore of NAFLD activity score (NAS)
Time frame: up to 24 weeks
Progression Free Survival
PFS will be evaluated after final study visits. Subjects who terminate the study before their scheduled final study visits will be censored.
Time frame: up to 30 months
Overall Survival
OS will be evaluated after final study visits. Subjects who terminate the study before their scheduled final study visits will be censored.
Time frame: up to 30 months
Safety assessment of all randomized subjects with at least one administration of study treatment
All subjects who received at least one dose of IMP. Additional safety analyses of reported AEs will be performed after the evaluation of 20 and 54 patients (between the 2 treatment groups) at the time of interim analysis.
Time frame: up to 24 weeks
Occured Adverse Events of all randomized subjects with at least one administration of study treatment
All subjects who received at least one dose of IMP. Additional safety analyses of reported AEs will be performed after the evaluation of 20 and 54 patients (between the 2 treatment groups) at the time of interim analysis.
Time frame: up to 30 months
Objective response rate (CR/PR)
Objective response rate (CR/PR), as assessed by RECIST criteria, version 1.1
Time frame: up to 24 weeks
Reduction in chemo-therapy associated steatohepatitis (CASH)
Reduction in chemo-therapy associated steatohepatitis (CASH) as assessed by NAS
Time frame: up to 24 weeks
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