Metformin Combined With Chemotherapy for Pancreatic Cancer
Condition: Locally Advanced Pancreatic Cancer; Metastatic Pancreatic Cancer
MeSH terms: Pancreatic Neoplasms
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): gemcitabine; erlotinib; metformin; placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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 for the first week. If tolerated well, the dose will be increased up to 1000 mg twice daily in the second week.; 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.
Other intervention name(s): gemzar; Tarceva; Glucophage
Intervention MeSH terms: Metformin; Gemcitabine; Erlotinib Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: pancreatic cancer; metformin; MAPK pathway; PI3K/Akt pathway; gemcitabine