Abstract LB125: Pharmacokinetics of paxalisib in phase 2 clinical study in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status
Authors: Wen Patrick Y. , de Groot John , Battiste James D. , Goldlust Samuel A. , Damek Denise , Garner James S. , Simpson Jeremy A. , Olivero Alan , Cloughesy Timothy 
Published: July 2021

Abstract
Introduction: Paxalisib is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. Paxalisib is taken daily on a continuous basis in 28-day cycles. A phase I study (NCT01547S46) in recurrent high-grade gliomas identified an MTD of 45mg daily and is complete. This phase II study (NCT03522298) in patients with newly diagnosed GBM and an unmethylated MGMT promotor identified an MTD of 60mg daily and is now fully recruited and in follow-up. The phase I study showed paxalisib was rapidly absorbed (Tmax approx 2 hours) and displayed an approximately linear and dose proportional increase in Cmax and AUC0-24, with a half-life of approximately 18.7 hours, which is supportive of once-daily dosing. This study explores pharmacokinetics in a slightly different patient population, at an increased dose, and explores the effect of food. Methods: For all patients, on Day 1 of Cycle 1, plasma samples were collected at least 15 minutes prior to the visit dose, and then at 30 minutes, 1, 2, 3, 4, 6, 8, 24 hours post dose. In the escalation portion of the study (Stage 1), patients fasted for 10 hours pre-dose on PK days. In the expansion portion of this study (Stage 2), subjects were randomized to be fasted for 10 hours pre-dose or consume a high-fat, high-calorie meal approximately 30 minutes prior to dosing, on PK days. All samples were analyzed by a central laboratory using a validated LC/MS-MS method. Analysis was non-compartmental. Results: A total of 30 patients were dosed and PK analysis performed, 24 at the 60 mg dose (14 fasted/10 fed) and 6 at the 75mg dose (all fasted). Paxalisib was rapidly and steadily absorbed at the 60 mg and 75 mg dose levels in the fasted state, with median Tmax values of 3.50 (2-8) and 2.50 (2-4) hours post-dose respectively. The geometric mean (range) of t1/2 values for the 60 mg fasted , 60 mg fed , and 75 mg fasted dose levels were 21.3 hours (6.0-54.6), 19.6 hours (7.7-30.0), and 29.2 hours (15.0-88.2), respectively. Mean systemic exposure to paxalisib at fasted state based on AUC0-∞ increased in a manner that was slightly less than dose proportional between 60 mg and 75 mg dose levels. This is probably indicative of a saturation effect at the 75 mg dose. Systemic exposure to paxalisib increased for the 60 mg fed status compared to 60 mg fasted status. Geometric mean ratios for Cmax, AUClast, and AUC0-∞ were 1.40, 1.38, and 1.12, respectively. Conclusion: The pharmacokinetics of paxalisib in newly-diagnosed patients are similar to those in recurrent patients, and remain compatible with daily oral dosing. There is evidence that PK parameters begin to show saturation at doses higher than 60 mg, likely representing the limit of solubility of the molecule. Paxalisib demonstrates a mild food effect, which is unlikely to necessitate fasted administration in clinical practice. These data inform further ongoing studies with paxalisib and have just commenced recruitment into the pivotal GBM AGILE study (NCT03970447).
Citation Format: Patrick Y. Wen, John de Groot, James D. Battiste, Samuel A. Goldlust, Denise Damek, James S. Garner, Jeremy A. Simpson, Alan Olivero, Timothy Cloughesy. Pharmacokinetics of paxalisib in phase 2 clinical study in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB125.