A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors

Abstract

Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis.

Methods: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin).

Results: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (- 0.12 vs. - 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities.

Conclusions: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers.

Impact: Combining metformin with sirolimus did not improve mTOR inhibition.

Keywords: Metformin; P70S6K and mTOR; Pharmacodynamics; Sirolimus; Solid tumors.

Figure 1:

Potential mechanisms of action of sirolimus and metformin. Sirolimus directly inhibits mTOR whereas metformin mainly leads to mTOR inhibition through activation of AMPK, although metformin can also directly inhibit mTOR. mTOR inhibition ultimately leads to decrease in p70S6K.

Figure 2:

Study design showing screening phase (day −7 to 0), initial lead-in phase (day 1–7), randomized phase (day 8–21) and post-randomization phase (day 22–28). The pharmacodynamic (PD) biomarkers were collected at baseline (day −7 to 0), day 8 and day 22. ¹ Sirolimus 3 mg daily, oral tablet ² Metformin XL started at 500 mg daily for day 8–14 and increased to 1000 mg daily on day 15 if there is no metformin related toxicity ≥ grade 2. If a patient had a grade 2 toxicity due to metformin they were maintained on metformin XL 500 mg daily for the remainder of the study. If the patient develops toxicity ≥ grade 3 they were taken off study. ³ Sirolimus 3 mg daily and metformin XL 1000 mg daily; metformin XL started at 500 mg daily for those not previously receiving it and titrated up to 1000 mg daily after one week (as above).

Figure 3:

Western blots showing pp70S6K, pERK, and Beta-actin expression in a patient treated with sirolimus alone left panel (A) and a patient treated with sirolimus plus metformin group in the right panel (B). Reduced level of pp70S6K can be seen in both left (A) and right (B) panel. Abbreviations: P, phorbol 12-myristate 13-acetate (PMA); I, ionomycin; C, cycle; D, day

Figure 4:

Phospho-p70S6K levels detected by Western blotting in each patient (shown as solid black circle) from sirolimus plus metformin and sirolimus group on cycle (C) 1, day (D) 1, C1D8 and C1D22. Marked decrease in the average level of pp70S6K can be seen from C1D1 to C1D8 which was not as dramatic from C1D8 to C1D22.