Metformin Combined With Chemotherapy for Pancreatic Cancer

Summary

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.

Conditions

• Locally Advanced Pancreatic Cancer
• Metastatic Pancreatic Cancer

Interventions

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

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

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.

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.

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  lead OTHER

Principal Investigators

• Hanneke Wilmink, MD, PhD · Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2010-08-31

Primary Completion

2014-02-28

Completion

2014-04-30

Countries

• Netherlands

Study Locations