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

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

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.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer; Steatohepatitis
• Intervention / Treatment: Drug: Metformin/Placebo

Detailed Description

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
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1021
    • KH BHB Vienna
  • Vienna, Austria, 1090
    • Med. Univ. Vienna, General Hospital Vienna
  • Vienna, Austria, 1130
    • KH St. Josef KH
  • Styria
    • Graz, Styria, Austria, 8036
      • Medical University Graz, Oncology
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Medical University Innsbruck, Internal Medicine
    • Zams, Tyrol, Austria, 6511
      • Hospital St. Vinzenz
  • Upper Austria
    • Ried, Upper Austria, Austria, 4910
      • Hospital BHS Ried

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin; FOLFIRI + cetuximab + metformin every 2 weeks for 12 cycles	Drug: Metformin/Placebo; 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; Other Names: Glucophage
Placebo Comparator: Placebo; FOLFIRI + cetuximab + placebo every 2 weeks for 12 cycles	Drug: Metformin/Placebo; 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; Other Names: Glucophage

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Austrian Breast & Colorectal Cancer Study Group
• Collaborators: Merck Gesellschaft mbH, Austria
• Investigators: Principal Investigator: Birgit Gruenberger, MD, Austrian Breast & Colorectal Cancer Study Group

Publications and helpful links

General Publications

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• Sasaki M, Itatsu K, Minato H, Takamura H, Ohta T, Nakanuma Y. Flare-up of nonalcoholic steatohepatitis after hepatectomy resulted in hepatic failure in a patient with type 2 diabetes mellitus. Dig Dis Sci. 2007 Dec;52(12):3473-6. doi: 10.1007/s10620-006-9662-7. Epub 2007 Apr 3. No abstract available.
• Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003 May;37(5):1202-19. doi: 10.1053/jhep.2003.50193. Erratum In: Hepatology. 2003 Aug;38(2):536.
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Helpful Links

• Click here for more information about this study: open studies

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: January 26, 2012
• First Submitted That Met QC Criteria: January 30, 2012
• First Posted (Estimate): February 1, 2012

Study Record Updates

• Last Update Posted (Actual): December 19, 2018
• Last Update Submitted That Met QC Criteria: December 17, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: chemotherapy; placebo; liver injury; metastatic colorectal cancer; metformin; steatosis; KRAS-Wild-Type
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Liver Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Fatty Liver; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: G-LUCAS; 200084-610 (Other Identifier: Merck); 2011-001010-34 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No