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 metastastatic 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, cetuximab and bevacizumab are adding some benefit to the
conventional cytotoxic agents. Unfortunately, these agents all failed to show
any significant superiority over gemcitabine except the combination of
erlotinib plus gemcitabine; however, the clinical impact of this combination
remains controversial until now.
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 ramamycin (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 versa. 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, we want to determine the activity and safety of concurrent interruption
of the MAPK and PI3K pathways by the EGFR tyrosine kinase inhibitor erlotinb
and metformin, combined with gemcitabine in patients with metatastatic
pancreatic cancer.

In this study we want to determine the activity and safety of concurrent
interruption of the MAPK and PI3K pathways by the EGFR tyrosine kinase
inhibitor erlotinb and metformin, combined with gemcitabine in patients with
metatastatic pancreatic cancer.

This is a phase II randomized, placebo controlled study. Eligible subjects
will be randomized to treatment with gemcitabine and erlotinib or gemcitabine,
erlotinib and metformin or placebo.

Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for
3 weeks, followed by one week treatment holiday.
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.

Each cycle contains 4 weeks, in which the patients take erlotinib and
metformin/ placebo daily. Gemcitabine will be administred via an infusion pump
weekly, during 3 weeks followed by one week treatment holiday. At various days
during treatment the patient will come to the hospital for blood investigations
and evaluation of the toxicity profile. After 3 cycles (12 weeks) during the
treatment fase a scan will be performed to establish response.
Gemcitabine has been used in a wide variety of malignancies, both as single
agent and in combination with other cytotoxic drugs. Myelosuppression is the
principal dose-limiting toxicity. Side effects that appear frequently (>10%)
are oedema, neuropathy, fever, flu-like symptoms and somnolence. Dermatologic
side effects are rash, alopecia and pruritus. Gastrointestinal:
nausea/vomiting, constipation, diarrhoea and stomatitis. As written before,
myelosuppression is the dose limiting toxicity. Finally, liver function
disturbance can occur.
Erlotinib is a human epidermal growth factor receptor type 1/epidermal growth
factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Side effects that appear
frequently (>10%) are fatigue and dermatologic toxicity (e.g rash, dry skin and
pruritus), diarrhoea, nausea and stomatitis. Other side effects are
pneumonitis, dyspnoea, cough and increased liver enzymes.
One of the most serious adverse events that can occur prescribing metformin is
lactic acidosis. Other side effects are primarily gastrointestinal, including
abdominal pain, bloating, nausea, diarrhoea and anorexia.