Background: In addition to clinical data from retrospective observational studies, there is a strong preclinical rationale for a beneficial effect of metformin in cancer treatment. Therefore we conducted a randomized phase II, placebo controlled study to assess the clinical effects of metformin in pancreatic cancer. Methods: Patients with locally advanced or metastatic pancreatic cancer were randomly assigned to gemcitabine at 1000 mg/m² on day 1, 8 and 15 q 4 weeks plus erlotinib 100 mg once daily in combination with metformin or placebo. Metformin was administered at a dose of 500 mg twice daily during the first week. If tolerated well, the dose was increased to 1000 mg twice daily. Patients were stratified according to stage of disease and the presence of diabetes. The primary endpoint was survival at 6 months. Secondary endpoints were overall survival (OS), progression free survival (PFS), objective response rate(ORR), toxicity profile, pharmacodynamics, and biomarker research. Results: A total of 121 patients were included. Baseline characteristics were well balanced. Median follow-up is 23.6 months (95%CI: 17.5-29.6). Survival at 6 months was 55% (95% CI: 42-68) for the metformin arm versus 66% (95% CI: 54-78) for the placebo arm (p=0.23). Median OS and PFS were 6.8 (95%CI: 5.3-8.3)and 4.4 (95%CI: 2.0-6.7) months for the metformin arm versus 7.6 (95%CI: 6.3-9.0) and 5.4 (95%CI: 4.7-6.1) months for the placebo arm (p=0. 62 and p=0.45), respectively. The objective response rate was 9% in both groups. The addition of metformin was well tolerated with no significant differences in grade ≥3 toxicity between treatment arms. Baseline insulin and glucose levels were not predictive for outcome. Conclusion: The addition of metformin to gemcitabine and erlotinib does not improve the outcome of patients with locally advanced or metastatic pancreatic cancer. Additional data on predictive biomarkers, including IGF1 and IGF binding protein-3 and pharmacodynamics will be presented at the meeting. Clinical trial information: NCTO1210911.