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

Overview[ - collapse ][ - ]

Purpose 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.
ConditionColorectal Cancer
Steatohepatitis
InterventionDrug: Metformin/Placebo
PhasePhase 2
SponsorAustrian Breast & Colorectal Cancer Study Group
Responsible PartyAustrian Breast & Colorectal Cancer Study Group
ClinicalTrials.gov IdentifierNCT01523639
First ReceivedJanuary 26, 2012
Last UpdatedMarch 7, 2014
Last verifiedMarch 2014

Tracking Information[ + expand ][ + ]

First Received DateJanuary 26, 2012
Last Updated DateMarch 7, 2014
Start DateApril 2012
Estimated Primary Completion DateMay 2014
Current Primary Outcome MeasuresReduction in the chemotherapy-associated steatosis [Time Frame: up to 24 weeks] [Designated as safety issue: Yes]Reduction in the chemotherapy-associated steatosis, as assessed by the steatosis subcore of NAFLD activity score (NAS)
Current Secondary Outcome Measures
  • Progression Free Survival [Time Frame: up to 30 months] [Designated as safety issue: No]PFS will be evaluated after final study visits. Subjects who terminate the study before their scheduled final study visits will be censored.
  • Overall Survival [Time Frame: up to 30 months] [Designated as safety issue: No]OS will be evaluated after final study visits. Subjects who terminate the study before their scheduled final study visits will be censored.
  • Safety assessment of all randomized subjects with at least one administration of study treatment [Time Frame: up to 24 weeks] [Designated as safety issue: Yes]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.
  • Occured Adverse Events of all randomized subjects with at least one administration of study treatment [Time Frame: up to 30 months] [Designated as safety issue: Yes]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.
  • Objective response rate (CR/PR) [Time Frame: up to 24 weeks] [Designated as safety issue: No]Objective response rate (CR/PR), as assessed by RECIST criteria, version 1.1
  • Reduction in chemo-therapy associated steatohepatitis (CASH) [Time Frame: up to 24 weeks] [Designated as safety issue: No]Reduction in chemo-therapy associated steatohepatitis (CASH) as assessed by NAS

Descriptive Information[ + expand ][ + ]

Brief TitleA Randomized, Placebo-controlled, Double-blind Phase II Study Evaluating if Glucophage Can Avoid Liver Injury Due to Chemotherapy Associated Steatosis
Official TitleA 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
Brief Summary
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
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 TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Condition
  • Colorectal Cancer
  • Steatohepatitis
InterventionDrug: 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
Study Arm (s)
  • Active Comparator: Metformin
    FOLFIRI + cetuximab + metformin every 2 weeks for 12 cycles
  • Placebo Comparator: Placebo
    FOLFIRI + cetuximab + placebo every 2 weeks for 12 cycles

Recruitment Information[ + expand ][ + ]

Recruitment StatusTerminated
Estimated Enrollment8
Estimated Completion DateMay 2014
Estimated Primary Completion DateNovember 2013
Eligibility Criteria
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
GenderBoth
Ages18 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesAustria

Administrative Information[ + expand ][ + ]

NCT Number NCT01523639
Other Study ID NumbersG-LUCAS
Has Data Monitoring CommitteeYes
Information Provided ByAustrian Breast & Colorectal Cancer Study Group
Study SponsorAustrian Breast & Colorectal Cancer Study Group
CollaboratorsMerck Gesellschaft mbH, Austria
Investigators Principal Investigator: Birgit Gruenberger, MD Austrian Breast & Colorectal Cancer Study Group
Verification DateMarch 2014

Locations[ + expand ][ + ]

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