B1

Background: Temsirolimus is an intravenous inhibitor of mammalian target of rapamycin (mTOR). Metformin has been recently observed to have anti-tumor activity in in vitro and in vivo studies, likely through activation of adenosine monophosphate kinase (AMPK). The molecular pathways targeted by these two agents both affect cellular glucose metabolism and cell proliferation. Dual inhibition of the AMPK-TSC protein-mTOR pathway by both metformin and temsirolimus would be a novel strategy to enhance the antitumour activity of temsirolimus. The additional downregulation of the involved pathways may overcome the resistance to temsirolimus that is seen in most clinical cancers. Initial in vitro evidence in support of the combination of mTOR inhibition and AMPK activation has been published by other authours.
 We have undertaken a phase I, open label dose-escalation trial to establish the maximum tolerated dose and recommended phase II dose of the combination of intravenous temsirolimus and oral metformin in patients with advanced solid cancers.
 Methods: Eligible patients include those with histologically confirmed advanced solid tumors who are either not eligible for, or have declined, further standard therapy. Patients must have adequate hematologic and biochemical parameters and measurable disease by RECIST criteria. Patients must be non-diabetic, with normal creatinine clearance and no unstable central nervous system metastases.
 Treatment: This is a standard dose-escalation phase I trial with planned dose escalation as noted below
 Patients will be monitored for clinical, hematologic and biochemical toxicity according to NCI CTCAE criteria. Radiologic response to treatment will be assessed by RECIST criteria. Dose escalation cohorts will be accrued in a standard Fibonnaci sequence until maximum tolerated dose is achieved.
 Results: Thus far, the first cohort of three patients has been enrolled on study, and one patient has actually received treatment. This one patient has experienced a grade 3 mucositis, diarrhea, and skin toxicity, without significant hematologic toxicity. Updated toxicity data will be presented.

Second AACR Centennial Conference on Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA