Background: Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Metformin has shown anti-cancer activity through its cellular (e.g., AMPK activation) and systemic effects (e.g., inhibition of IGF-1). We conducted a pilot study to test the hypothesis that metformin may potentiate mTOR inhibition by sirolimus. Methods: An open-label, randomized study was conducted in which eligible patients with advanced solid tumors were started on sirolimus (3mg daily) alone for the first 7 days. On day 8, patients were randomized to either receive metformin XL (500 mg daily) plus sirolimus (Arm A) or sirolimus alone (Arm B) for until day 21. From day 22 onwards, all patients recieved metformin XL plus sirolimus. The pharmacodynamic (PD) biomarkers were collected at baseline, day 8 and day 22 of cycle 1. The primary endpoint was to compare the change in PD biomarker phospho-p70S6K, using a two-sample t test (log ratio D22/D8 in arm A vs. arm B). The phospho-p70S6K was measured in peripheral blood T cells using Western blot. The secondary endpoints were to assess objective response rate (RECIST 1.1), toxicity (CTCAE V4.0) and changes in the serum levels of PD biomarkers: fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, leptin and adiponectin using two-sample t tests. Results: 24 patients were enrolled, at which time an interim futility analysis was conducted. 18 patients were evaluable for the primary endpoint (8 in arm A; 10 in arm B). The mean log ratios D22/D8 in phospho-p70S6K in arms A and B were -0.12 (SD = 0.13) and -0.16 (SD = 0.29), respectively (P = 0.64). Of the 17 pts evaluable for response, the best response was stable disease in 9 patients and progressive disease in 8 patients. There were no dose-limiting or unexpected toxicities. Of the 21 patients evaluable for serum PD biomarkers, there were no significant differences between arms A and B in fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-BP1, IGF-BP3, leptin and adiponectin (P > 0.05 for all). Conclusions: The addition of metformin to sirolimus, although well-tolerated, was not associated with significant changes in phospho-p70S6k and other PD biomarkers. Based on the results of the interim analysis, the trial was terminated. Clinical trial information: NCT02145559