Results of safety run-in part in Metal (METformin in Advanced Lung cancer) trial

Abstract

Background: The combination of metformin (M) with gefitinib (G) reduced the anchorage-independent colony forming ability and proliferation and exerted a great proapoptotic effect in NSCLC cell lines, which harbored wild type LKB1 gene. Of interest such effects was shown also in those NSCLC cell lines resistant to the EGFR TKI, suggesting that M can revert resistance to G in some cancer cell lines. Material and methods: The METAL (METformin in Advanced Lung cancer) trial (EudraCT number: 2014-000349-59) is a multicenter, open label phase II study, designed to evaluate the safety and activity of M combined with erlotinib (E) as II line therapy in non-diabetic patients (PTS) with stage IV NSCLC.We report results form the safety run-in part designed to detect acute toxicities, to study pharmacokinetics (PK) and to identify the recommended phase II dose to be used for the phase II of the study. In the run-in phase, M treatment was administered according to a dose escalation scheme, starting with a dose of 500 mg twice a day, and, subsequently, combined with E 150 mg daily. Cohort of 3 to 6 PTS has been treated at each dose level. If DLT occurs in two or more PTS treated at the same dose level, this dose level will be declared the maximally administered dose. Results: Twelve PTS were enrolled.We carried timed withdrawals of peripheral venous blood to time 0, 2 hours (T2h) and 5 hours (T5h) after taking the first dose of M. The collected data were used for Therapeutic Drug Monitoring (TDM) and for PK evaluation. Additional blood samples for TDM were carried out while increasing the dose of M and in case of adverse events (AE). Results showed that serum concentration of M undergoes a rapid increase at T2h with a subsequent decrease at T5h. In the 3 PTS treated with M 1500 mg/day, serum concentrations at day 4, 8 and 12 remained in the therapeutic range of 1-2 mg/L. In 2 of 3 pts treated with M 2000 mg/day serum concentration increased more than 3 mg/L and they developed DLT (G3 gastrointestinal toxicity). AE were mostly represented by G1 gastrointestinal toxicity. Full-body CT scan was performed every 10 weeks with stable disease in 5 PTS after 30 weeks of combination treatment. Conclusions: In accordance with the primary objective, the tolerated M dose was of 1500 mg/day. To define the setting of patients who best respond to the combination of M plus TKIs, underway is the identification of predictors of response to treatment as the state of LKB1 expression.