A Randomized, Placebo-controlled, Double-blind Phase II Study Evaluating if Glucophage Can Avoid Liver Injury Due to Chemotherapy Associated Steatosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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A Randomized, Placebo-controlled, Double-blind Multicenter Phase II Study to Investigate the Protectivity and Efficacy of Metformin Against Steatosis in Combination With FOLFIRI and Cetuximab in Subjects With First-line Palliative Treated, KRAS-Wild-Type, Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer, Steatohepatitis

Intervention / Treatment
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* Drug: Metformin/Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Male or female >= 18 years of age Diagnosis of histologically confirmed, KRAS wild-type adenocarcinoma of the colon or rectum Non-resectable metastatic colorectal carcinoma Either presence of at least one liver lesion measurable unidimensionally by CT scan or MRI or at least one resectable liver metastasis with non-resectable extrahepatic disease (as assessed within 3 weeks prior to randomisation) Subjects scheduled to receive cetuximab and FOLFIRI ECOG performance status of 0 - 1 at study entry Leukocytes >= 3.0 x 10^9/L and neutrophils >= 1.5 x 10^9/L, platelets >= 100 x 10^9/L, and hemoglobin >= 8 g/dL Bilirubin <= 1.5 x ULN ASAT and ALAT <= 5 x ULN Exclusion Criteria: Brain metastasis (if suspected, brain scan indicated) Previous chemotherapy for the currently existing metastatic disease Known or newly diagnosed diabetes Patients with ACS within the last three months Stage 3 or 4 heart failure defined according to the NYHA criteria Uncontrolled angina Contraindications to metformin (renal impairment [eGFR <45 mL/min/1.73m^2], known hypersensitivity to metformin, acute illness [dehydration, severe infection, shock, acute cardiac failure]), and suspected tissue hypoxia Surgery (excl. diagnostic biopsy, central venous catheter) or irradiation within 2 weeks prior to study entry defined as given written informed consent Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the study protocol Administration of any investigational agent(s) within 4 weeks prior to study entry, Previous exposure to EGFR-pathway targeting therapy Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease Known grade 3 or 4 allergic reaction to any of the components of the treatment Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix. (Subjects with a previous malignancy but without evidence of disease for >= 5 years will be allowed to enter the trial) Pregnancy or lactation Inadequate contraception (male or female patients) if of childbearing or procreative potential Known drug abuse/ alcohol abuse Legal incapacity or limited contractual capacity Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin<br>FOLFIRI + cetuximab + metformin every 2 weeks for 12 cycles | Drug: Metformin/Placebo<br>* 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<br>* Other names: Glucophage;|
| Placebo Comparator: Placebo<br>FOLFIRI + cetuximab + placebo every 2 weeks for 12 cycles | Drug: Metformin/Placebo<br>* 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<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in the chemotherapy-associated steatosis | Reduction in the chemotherapy-associated steatosis, as assessed by the steatosis subcore of NAFLD activity score (NAS) | up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | up to 30 months | 
| Objective response rate (CR/PR) | Objective response rate (CR/PR), as assessed by RECIST criteria, version 1.1 | up to 24 weeks | 
| Reduction in chemo-therapy associated steatohepatitis (CASH) | Reduction in chemo-therapy associated steatohepatitis (CASH) as assessed by NAS | up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver injury, steatosis, KRAS-Wild-Type, metastatic colorectal cancer, metformin, placebo, chemotherapy