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

Primary Purpose

Colorectal Cancer, Steatohepatitis

Status

Terminated

Phase

Phase 2

Locations

Austria

Study Type

Interventional

Intervention

Metformin/Placebo

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring liver injury, steatosis, KRAS-Wild-Type, metastatic colorectal cancer, metformin, placebo, chemotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Medical University Graz, Oncology
Medical University Innsbruck, Internal Medicine
Hospital St. Vinzenz
Hospital BHS Ried
KH BHB Vienna
Med. Univ. Vienna, General Hospital Vienna
KH St. Josef KH

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Metformin

Placebo

Arm Description

FOLFIRI + cetuximab + metformin every 2 weeks for 12 cycles

FOLFIRI + cetuximab + placebo every 2 weeks for 12 cycles

Outcomes

Primary Outcome Measures

Reduction in the chemotherapy-associated steatosis

Reduction in the chemotherapy-associated steatosis, as assessed by the steatosis subcore of NAFLD activity score (NAS)

Secondary Outcome Measures

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.

Overall Survival

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

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

Objective response rate (CR/PR)

Objective response rate (CR/PR), as assessed by RECIST criteria, version 1.1

Reduction in chemo-therapy associated steatohepatitis (CASH)

Reduction in chemo-therapy associated steatohepatitis (CASH) as assessed by NAS

Full Information

NCT ID

NCT01523639

First Posted

January 26, 2012

Last Updated

December 17, 2018

Sponsor

Austrian Breast & Colorectal Cancer Study Group

Collaborators

Merck Gesellschaft mbH, Austria

1. Study Identification

Unique Protocol Identification Number

NCT01523639

Brief Title

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

Acronym

G-LUCAS

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2018

Overall Recruitment Status

Terminated

Why Stopped

Prematurely due to slow recruitment (07/08/2013). Newly defined study end=LPLV=05/11/2013. ABCSG guaranteed completed treatment period for ethical reasons.

Study Start Date

April 2012 (undefined)

Primary Completion Date

November 2013 (Actual)

Study Completion Date

April 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Austrian Breast & Colorectal Cancer Study Group

Collaborators

Merck Gesellschaft mbH, Austria

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Cancer, Steatohepatitis

Keywords

liver injury, steatosis, KRAS-Wild-Type, metastatic colorectal cancer, metformin, placebo, chemotherapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Metformin

Arm Type

Active Comparator

Arm Description

FOLFIRI + cetuximab + metformin every 2 weeks for 12 cycles

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

FOLFIRI + cetuximab + placebo every 2 weeks for 12 cycles

Intervention Type

Drug

Intervention Name(s)

Metformin/Placebo

Other Intervention Name(s)

Glucophage

Intervention Description

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

Primary Outcome Measure Information:

Title

Reduction in the chemotherapy-associated steatosis

Description

Reduction in the chemotherapy-associated steatosis, as assessed by the steatosis subcore of NAFLD activity score (NAS)

Time Frame

up to 24 weeks

Secondary Outcome Measure Information:

Title

Progression Free Survival

Description

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

Title

Overall Survival

Description

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

Title

Safety assessment of all randomized subjects with at least one administration of study treatment

Description

Time Frame

up to 24 weeks

Title

Occured Adverse Events of all randomized subjects with at least one administration of study treatment

Description

Time Frame

up to 30 months

Title

Objective response rate (CR/PR)

Description

Objective response rate (CR/PR), as assessed by RECIST criteria, version 1.1

Time Frame

up to 24 weeks

Title

Reduction in chemo-therapy associated steatohepatitis (CASH)

Description

Reduction in chemo-therapy associated steatohepatitis (CASH) as assessed by NAS

Time Frame

up to 24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Birgit Gruenberger, MD

Organizational Affiliation

Austrian Breast & Colorectal Cancer Study Group

Official's Role

Principal Investigator

Facility Information:

Facility Name

Medical University Graz, Oncology

City

Graz

State/Province

Styria

ZIP/Postal Code

8036

Country

Austria

Facility Name

Medical University Innsbruck, Internal Medicine

City

Innsbruck

State/Province

Tyrol

ZIP/Postal Code

6020

Country

Austria

Facility Name

Hospital St. Vinzenz

City

Zams

State/Province

Tyrol

ZIP/Postal Code

6511

Country

Austria

Facility Name

Hospital BHS Ried

City

Ried

State/Province

Upper Austria

ZIP/Postal Code

4910

Country

Austria

Facility Name

KH BHB Vienna

City

Vienna

ZIP/Postal Code

1021

Country

Austria

Facility Name

Med. Univ. Vienna, General Hospital Vienna

City

Vienna

ZIP/Postal Code

1090

Country

Austria

Facility Name

KH St. Josef KH

City

Vienna

ZIP/Postal Code

1130

Country

Austria

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Links:

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http://www.abcsg.at

Description

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Learn more about this trial

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

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