A Pharmacodynamic Study of Sirolimus and Metformin in Patients With Advanced Solid Tumors

Objectives: This is a descriptive study to evaluate the pharmacodynamic markers of dual sirolimus and metformin therapy. Primary Objective: i. To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone. Secondary Objectives: i. To compare the changes in pharmacodynamic biomarkers p4EBP1 and pAKT in peripheral blood T cells with the combination of metformin XR and sirolimus to those with sirolimus alone. ii. To assess the tolerability of the combination of metformin XR plus sirolimus at the selected doses. iii. To compare fasting serum glucose and triglycerides on sirolimus before and after the addition of metformin XR. Study Design: This will be an open-label, randomized study in which all eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days (lead-in period); cycle 1, days 1-8. Before starting the sirolimus the investigators will obtain previous pathology (if available) and collect blood lymphocytes for baseline testing of biomarkers as is shown in study calendar. The pharmacodynamic biomarkers will be collected again on cycle 1, day 8 to assess the effect of sirolimus alone on these biomarkers. In the previous study, the effect of sirolimus on p70S6K was observed within 48 hours of the first dose9. On day 8, patients will be randomized 1:1 to metformin XR (500 mg daily with the evening meal) or no metformin for two weeks (through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop \> grade 2 toxicity will be taken off study. A repeat biomarkers evaluation will be done on cycle 1, day 22 to assess the effect of adding metformin on these pharmacodynamic biomarkers. From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks. CT scans will be obtained after every 2 cycles to assess the response by RECIST version 1.140. Metformin will be temporarily held on the day of CT scan and resumed 48 hours after CT scan. This is due to increased risk of lactic acidosis with iodinated contrast agent and is a standard procedure for contrast enhanced CT scan at the University of Chicago.