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

This study has been terminated.
(Prematurely due to slow recruitment (07/08/2013). Newly defined study end=LPLV=05/11/2013. ABCSG guaranteed completed treatment period for ethical reasons.)
Sponsor:
Collaborator:
Merck Gesellschaft mbH, Austria
Information provided by (Responsible Party):
Austrian Breast & Colorectal Cancer Study Group
ClinicalTrials.gov Identifier:
NCT01523639
First received: January 26, 2012
Last updated: March 7, 2014
Last verified: March 2014
  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.


Condition Intervention Phase
Colorectal Cancer
Steatohepatitis
Drug: Metformin/Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Austrian Breast & Colorectal Cancer Study Group:

Primary Outcome Measures:
  • Reduction 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)


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


Enrollment: 8
Study Start Date: April 2012
Estimated Study Completion Date: May 2014
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Glucophage

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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01523639

Locations
Austria
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
Sponsors and Collaborators
Austrian Breast & Colorectal Cancer Study Group
Merck Gesellschaft mbH, Austria
Investigators
Principal Investigator: Birgit Gruenberger, MD Austrian Breast & Colorectal Cancer Study Group
  More Information

Additional Information:
Publications:

Responsible Party: Austrian Breast & Colorectal Cancer Study Group
ClinicalTrials.gov Identifier: NCT01523639     History of Changes
Other Study ID Numbers: G-LUCAS, 200084-610, 2011-001010-34
Study First Received: January 26, 2012
Last Updated: March 7, 2014
Health Authority: Austria: Federal Office for Safety in Health Care

Keywords provided by Austrian Breast & Colorectal Cancer Study Group:
liver injury
steatosis
KRAS-Wild-Type
metastatic colorectal cancer
metformin
placebo
chemotherapy

Additional relevant MeSH terms:
Colorectal Neoplasms
Fatty Liver
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Liver Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 28, 2014