Metformin Combined With Chemotherapy for Pancreatic Cancer (GEM)

A Phase II, Randomized, Placebo Controlled Study to Evaluate the Efficacy of the Combination of Gemcitabine, Erlotinib and Metformin in Patients With Locally Advanced and Metastatic Pancreatic Cancer

Pancreatic cancer patients have one of the worst prognoses among all cancer types with a 5 year survival rate of less than 5%. Despite significant changes during the last decade in our molecular knowledge on this disease, the prognosis and management of pancreatic cancer have remained unchanged. With the advances in molecular biology, newer biologic agents such as erlotinib, are adding some benefit to the conventional cytotoxic agents. There is a growing body of literature suggesting that type 2 diabetes mellitus (DM) may be associated with the development of pancreatic cancer, but this association is complex. Because various DM medications can affect directly the key factors mediating the association between DM and pancreatic cancer, understanding the effect of anti-diabetic therapies on pancreatic cancer is a critical step in fully characterizing the role of type 2 DM in the development of pancreatic cancer. Indeed, two epidemiologic studies have found that diabetic patients treated with metformin were less likely to develop cancer, but those treated with insulin were more likely to die of various kinds cancer. Not only does metformin ameliorate hyperglycemia and hyperinsulinemia, both of which are associated with the adverse impact of DM on cancer, metformin also has direct metabolic effects through activation of adenosine monophosphate-activated protein kinase (AMPK). AMPK regulates many metabolic enzymes and also inhibits the mammalian target of rapamycin (mTOR) pathway via phosphorylation and stabilization of the tumor suppressor gene TSC2. But there is an intensive cross-talk between various pathways. Inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway, of which mTOR is one of the effector proteins, for instance may result in escape via the mitogen-activated protein kinase (MAPK) pathway and vice verse. Indeed, epidermal growth factor receptor (EGFR) activation leads to activation of the MAPK pathway and the PI3K pathway. Thus, since it is clear that blocking one pathway will not always be sufficient to produce a response in the presence of other activated pathways, the best change of success will be realized when using a combination of agents that inhibit separate pathways known to be critical to the survival of the tumour. In line with these observations, combining a small molecule against the EGFR and inhibition of the PI3K pathway by metformin might account for potential candidates of the above combinatorial approach. Therefore, in this study, the investigators want to determine the activity and safety of concurrent interruption of the MAPK and PI3K pathways by the EGFR tyrosine kinase inhibitor erlotinib and metformin, combined with gemcitabine in patients with metastatic pancreatic cancer.

Study Overview

• Status: Completed
• Conditions: Metastatic Pancreatic Cancer; Locally Advanced Pancreatic Cancer
• Intervention / Treatment: Drug: gemcitabine; Drug: erlotinib; Drug: metformin; Drug: placebo

Detailed Description

In this phase II randomized, placebo controlled study, patients with locally advanced or metastatic pancreatic cancer will be randomized to treatment with gemcitabine, erlotinib and metformin, or gemcitabine, erlotinib and placebo.

Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for 3 weeks, followed by one week without treatment. Erlotinib will be administered at a daily dose of 100 mg at least one hour before or 2 hours after the ingestion of food. Metformin/ placebo will be administered at a dose of 500 mg twice daily. If well tolerated the dose will be increased to 1000 mg twice daily in the second week.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Academic Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed content obtained prior to treatment
• Cytological or histological confirmed carcinoma of the pancreas
• Metastatic cancer
• Measurable lesion according to RECIST criteria
• ECOG/ WHO performance 0-2
• Age > 18 years
• Adequate renal function (creatinine < 150 µmol/L and/ or a creatinine clearance > 60 ml/ L)
• Adequate liver function (bilirubin < 1.5 times upper limit of normal, ALAT or ASAT < 5.0 times upper limit of normal in case of liver metastases and < 2.5 the upper limit of normal in absence of liver metastases).
• Adequate bone marrow function (WBC > 3.0 x 10 9/L, platelets > 100 x 10 9/L)
• Mentally, physically, and geographically able to undergo treatment and follow up

Exclusion Criteria:

• Clinical or radiological evidence of CNS metastases
• Pregnancy (positive serum pregnancy test) and lactation
• Serious concomitant systemic disorder that would compromise the safety of the patient, at the discretion of the investigator

• Patients who have any severe and/or uncontrolled medical conditions:

  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to randomization, serious uncontrolled cardiac arrhythmia
  • uncontrolled diabetes as defined by fasting serum glucose >2X ULN.
  • active or uncontrolled severe infection.
  • cirrhosis, chronic active hepatitis or chronic persistent hepatitis
  • severely impaired lung function
• Previous treatment with erlotinib
• Previous treatment with gemcitabine for metastatic disease
• Previous treatment with gemcitabine combined with radiotherapy for locally advanced pancreatic cancer within 6 months prior to study entry
• Patients with a known hypersensitivity to metformin
• Use of metformin in the previous 6 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gemcitabine, erlotinib and metformin; Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for 3 weeks, followed by one week without gemcitabine. Erlotinib will be administered at a daily dose of 100 mg at least one hour before or 2 hours after the ingestion of food. Metformin will be administered at a dose of 500 mg twice daily. If well tolerated the dose will be increased to 1000 mg twice daily in the second week.	Drug: gemcitabine; Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for 3 weeks, followed by one week without gemcitabine; Other Names: gemzar; Drug: erlotinib; Erlotinib will be administered at a daily dose of 100 mg at least one hour before or 2 hours after the ingestion of food; Other Names: Tarceva; Drug: metformin; Metformin will be administered at a dose of 500 mg twice daily for the first week. If tolerated well, the dose will be increased up to 1000 mg twice daily in the second week.; Other Names: Glucophage
Placebo Comparator: Gemcitabine, erlotinib and placebo; Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for 3 weeks, followed by one week without gemcitabine. Erlotinib will be administered at a daily dose of 100 mg at least one hour before or 2 hours after the ingestion of food. PLacebo will be administered at a dose of 500 mg twice daily. If well tolerated the dose will be increased to 1000 mg twice daily in the second week.	Drug: gemcitabine; Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for 3 weeks, followed by one week without gemcitabine; Other Names: gemzar; Drug: erlotinib; Erlotinib will be administered at a daily dose of 100 mg at least one hour before or 2 hours after the ingestion of food; Other Names: Tarceva; Drug: placebo; Placebo will be administered at a dose of 500 mg twice daily for the first week. If tolerated well, the dose will be increased up to 1000 mg twice daily in the second week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Survival after 6 months	6 months after completion of the study

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression free survival	6 months after the completion of the study
Objective response rate	expected treatment duration 2- 6 months
toxicity profile	during study and 4 weeks after stop study medication

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Hanneke Wilmink, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• Kordes S, Pollak MN, Zwinderman AH, Mathot RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. doi: 10.1016/S1470-2045(15)00027-3. Epub 2015 Jun 8.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: September 28, 2010
• First Submitted That Met QC Criteria: September 28, 2010
• First Posted (Estimate): September 29, 2010

Study Record Updates

• Last Update Posted (Actual): April 21, 2021
• Last Update Submitted That Met QC Criteria: April 19, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: pancreatic cancer; metformin; gemcitabine; MAPK pathway; PI3K/Akt pathway
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; Erlotinib Hydrochloride; Metformin
• Other Study ID Numbers: AMCmedonc10/003