Escalation portion of phase II 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.

Authors

null

Patrick Y. Wen

Dana-Farber Cancer Institute, Boston, MA

Patrick Y. Wen , John Frederick De Groot , James D. Battiste , Samuel Aaron Goldlust , James Stuart Garner , Jeremy Andrew Simpson , Jelle Kijlstra , Alan Olivero , Timothy Francis Cloughesy

Organizations

Dana-Farber Cancer Institute, Boston, MA, The University of Texas, MD Anderson Cancer Center, Department of Neuro-Oncology, Houston, TX, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, Kazia Therapeutics Limited, Sydney, NSW, Australia, Kazia Therapeutics Limited, Barangaroo, Australia, Covance Inc, Seattle, WA, Olivero Consulting, Half Moon Bay, CA, Ronald Reagan UCLA Medical Center, Los Angeles, CA

Research Funding

Pharmaceutical/Biotech Company
Kazia Therapeutics Limited

Background: 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 Il study 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: Part 1 of this study is an open-label, dose-escalation phase to assess the safety, tolerability and MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 is an expansion cohort recruiting 20 patients randomized to administration in fed or fasted states at the MTD. Results: Part 1 is complete and reported here. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis. AEs were generally reversible and consistent with the PI3K inhibitor class with the most common events were rash, oral mucositis, and fatigue. PK at the MTD was broadly consistent with the data published for the phase 1 study. For eight response-evaluable patients in Part I 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. Conclusions: A higher MTD of 60mg was identified in newly diagnosed GBM with unmethylated MGMT promotor status than the 45mg MTD previously identified in recurrent high-grade glioma. An encouraging PFS signal is described in this poor-prognosis, unmethylated MGMT patient population. Clinical trial information: NCT03522298.

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Abstract Details

Meeting

2020 ASCO Virtual Scientific Program

Session Type

Poster Session

Session Title

Central Nervous System Tumors

Track

Central Nervous System Tumors

Sub Track

Central Nervous System Tumors

Clinical Trial Registration Number

NCT03522298

Citation

J Clin Oncol 38: 2020 (suppl; abstr 2550)

DOI

10.1200/JCO.2020.38.15_suppl.2550

Abstract #

2550

Poster Bd #

41

Abstract Disclosures

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