INTRODUCTION: Molecular alterations in the PI3K/AKT and Ras/Raf/MEK/ERK pathways are frequently observed in patients with endometrial cancers. However, mTOR inhibitors, such as temsirolimus, have modest clinical benefits. In addition to inducing metabolic changes in cells, metformin activates AMPK, which in turn inhibits the mTOR pathway. In this phase 1 clinical trial we hypothesized that combining metformin with temsirolimus would potentiate the antitumor activity against advanced or recurrent endometrial cancer. METHODS: The dose-expansion cohort used a Simon Minimax two-stage design. The objectives of the endometrial cancer expansion cohort were to evaluate the clinical tumor response, as indicated by the objective response and clinical benefit rates, as well as an ongoing safety assessment of the combination treatment. RESULTS: Forty patients were enrolled in this study. The most common treatment-related adverse events (reported in 32 patients) were hypertriglyceridemia (n = 14), diarrhea (n = 13), mucositis (n = 13), anorexia (n = 12), and anemia (n = 10). The grade 3 adverse events were 2 instances each of anemia and thrombocytopenia and 1 instance each of mucositis, fatigue, weight loss, hypokalemia, hypophosphatemia, and increased aspartate aminotransferase and alanine transaminase levels. Among the 33 patients evaluable for response, objective response was seen in two (6 %
both partial responses), and 13 (39 %) patients had stable disease, including 11 for ≥4 months, representing a clinical benefit rate of 39 %. CONCLUSIONS: The results of this single-center clinical trial showed that, in patients with advanced or recurrent endometrial cancer, metformin can be safely added to temsirolimus providing limited response without added safety concerns. CLINICAL TRIAL REGISTRATION NUMBER: NCT01529593.