Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4–78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.
Molenaar, R. J., van de Venne, T., Weterman, M. J., Mathot, R. A., Klümpen, H-J., Richel, D. J., & Wilmink, J. W. (2018). A phase Ib study of everolimus combined with metformin for patients with advanced cancer. Investigational New Drugs, 36(1), 53-61. https://doi.org/10.1007/s10637-017-0478-4