Introduction: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase II study (NCT03522298) aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: This study has a 2-part design: an open-label, dose-escalation phase to assess the safety, tolerability and MTD (Part 1), followed by an expansion cohort (Part 2) at the MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 recruits 20 patients who are randomised to administration in fed or fasted states. Results: Part 1 is complete. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis, with toxicity and patterns of AEs consistent with prior experience and other PI3K-targeting agents. For eight response-evaluable patients in Part 1, the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing.

Citation Format: Patrick Y. Wen, John de Groot, James D. Battiste, Samuel A. Goldlust, James S. Garner, Jeremy A. Simpson, Jelle Kijlstra, Alan Olivero, Timothy Cloughesy. Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT205.