Abstract 378: Exploring intermittent dosing schedules for the Pan PI3K/mTor inhibitor PQR309

Abstract

Abstract Introduction PQR309 is a novel oral balanced dual pan-PI3K and mTOR inhibitor currently in clinical development for the treatment of solid tumors and hematological malignancies. Eighty mg PQR309 given once daily (q.d.) has been established as the MTD in patients with advanced solid cancers. This dose and regimen was associated with plasma concentrations that were pharmacologically active in pre-clinical experiments. However, there is emerging evidence that continuous inhibition of PI3K/mTOR may not be needed to achieve the full effect of PQR309 on tumor growth inhibition and therefore further intermittent dosing regimens will be explored. Methods In vivo xenograft studies in nude male rats bearing PC3-derived tumors were conducted with continuous and intermittent dosing schedules to estimate effective plasma concentrations. Pharmacokinetic (PK) data from cancer patients were used to establish a 2-compartment PK model with first order absorption. The model was applied to simulate PK profiles after various intermittent dosing schedules including 2 daily administrations followed by a 5 day wash-out period in a 7 day cycle (2 days ON/5 days OFF) and a regimen with administrations on days 1 and 4 in a 7 day cycle (eg MON/THUR). Results A maximum plasma concentration (Cmax) of 800-1200ng/mL PQR309 and an impulse interval of 72 hours or less was associated with maximum effect in the rat xenograft model. In rats PQR309 is rapidly eliminated from plasma but in humans the compound has an elimination half-life of about 40 hours and accumulates upon multiple dosing. The applied model predicts that PQR309 administration given 2 days ON/5 days OFF will build up drug exposure to reach levels that strongly inhibit the targeted signalling pathways. During the 5 day wash-out period, PQR309 levels will decrease significantly, thereby reducing the probability of adverse events. For the alternative dosing regimen MON/THUR, the model predicts a sharp Cmax lasting for a few hours followed by a decrease in drug levels over the following 3 or 4 days, thus minimizing accumulation and drug exposure that could lead to adverse events. Conclusions Both intermittent regimens are expected to strongly inhibit the targeted signalling pathways with high transient concentrations around Cmax followed by wash-out periods for healthy tissue recovery to optimize the benefit/risk of the compound. These regimens are currently being explored in clinical studies. Citation Format: Karin Jorga, Debora Schmitz, Natasa Cmiljanovic, Doriano Fabbro, Sasa Dimitrijevic. Exploring intermittent dosing schedules for the Pan PI3K/mTor inhibitor PQR309. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 378.