280O - Pharmacokinetics and pharmacodynamics of paxalisib in newly diagnosed glioblastoma patients with unmethylated MGMT promoter status: Final phase II study results

Background

Paxalisib is being developed for the treatment of glioblastoma multiforme (GBM). Post hoc analysis of phase 1 fluorodeoxyglucose-positron emission tomography (FDG-PET) scans suggested that paxalisib crosses the blood-brain barrier with a uniform distribution throughout the brain.

Methods

The recently completed phase 2 trial (NCT03522298) enrolled patients with newly diagnosed GBM with unmethylated MGMT promoter status following surgical resection and chemotherapy (Stupp Regimen). Study outcomes comprised maximum tolerated dose (MTD), safety, preliminary efficacy, pharmacokinetics (PK) at the MTD under fed and fasted conditions and change in FDG-PET uptake in patients with measurable disease.

Results

Patients (n=30; 70.0% males, mean age 58.5 years) received between 1 and 29 treatment cycles. At the MTD (60 mg/day), paxalisib prolonged median progression free survival (8.4 months [RANO], 8.6 months [mRANO]) and improved median overall survival (15.7 months). Paxalisib was steadily absorbed (median T^max 2.5 and 4 hours postdose) and declined with a mean elimination half-life ranging from 20.2 to 29.0 hours. Mean half-life (20.2 to 29.0 hours) was similar across dose levels and under fed and fasted conditions. Systemic exposure to paxalisib appeared slightly higher for the 60 mg fed status compared to 60 mg fasted status. Comparison of fed versus fasted treatment was statistically significant for C^max at the 90% level (geometric least squares mean ratios: AUC^0-last 1.33, AUC^0-inf 1.06, and C^max 1.52). Ten patients underwent FDG-PET imaging, 8 (80%) had a decrease in FDG uptake on Day 3 and/or Day 7 in Cycle 1 and 4 (40%) had a metabolic partial response.

Conclusions

PK parameters were consistent with prior clinical experience and there was no evidence of a deviation from dose-proportionality. At the MTD FDG-PET data provide evidence that paxalisib has the ability to exert biological effect in tumour tissue, irrespective of fed or fasted status. Further evaluation is ongoing in GBM AGILE (NCT03970447).

Clinical trial identification

NCT03522298.

Editorial acknowledgement

Hazel Palmer ISMP CMPP, Scriptix Pty Ltd., Sydney, NSW, Australia.

Legal entity responsible for the study

Kazia Therapeutics Limited.

Funding

Kazia Therapeutics Limited.

Disclosure

P. Wen: Financial Interests, Personal, Advisory Role: Agios, AstraZeneca, Vascular Biogenics, VBI Vaccines, Tocagen, Bayer, Blue Earth Diagnostics, Karyopharm Therapeutics, Voyager Therapeutics, QED Therapeutics, Imvax, ElevateBio, Integral Health, Prelude Therapeutics, Novocure, Mundipharma, Black Diamond Therapeutics, Day One Biopharmaceuticals, Sapience Therapeutics, Nuvation Bio, Celularity, Novartis, Merck, Boston Pharmaceuticals, Chimerix; Financial Interests, Institutional, Funding, Research Funding: Agios, AstraZeneca, Merck, Novartis, Oncoceutics, Lilly, Beigene, Kazia Therapeutics, MediciNova, Vascular Biogenics, VBI Vaccines, Puma Biotechnology, Celgene, Bayer, Nuvation Bio, Chimerix, Karyopharm Therapeutics. J.F. de Groot: Other, Personal, Full or part-time Employment, Recipient is Immediate Family Member: ZIOPHARM Oncology; Financial Interests, Personal, Advisory Role: Genetech/Roche, AbbVie, Merck, Mundipharma Research, GenomiCare, KIYATEC, resTORbio, Janssen, Bioasis Technologies, InSightec, DelMar Pharmaceuticals, Samus Therapeutics, Magnolia Innovation, Karyopharm Therapeutics, Prelude Therapeutics, Cure Brain Cancer Foundation, Sapience Therapeutics, GlaxoSmithKline, Tocagen, Voyager Therapeutics, Novartis, Debiopharm Group, Agios, Monteris Medical; Other, Personal, Leadership Role, Recipient is Immediate Family Member: ZIOPHARM Oncology; Financial Interests, Personal, Other: VBI Vaccines; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, WuXi Biologics; Other, Personal, Ownership Interest, Recipient is Immediate Family Member: ZIOPHARM Oncology; Financial Interests, Personal, Funding, Research funding: CarThera, Haihe Pharmaceutical, Taiho Pharmaceutical. J. Battiste: Financial Interests, Personal, Other: SVN Med. S. Goldlust: Financial Interests, Personal, Full or part-time Employment: Regional Cancer Care Associates; Financial Interests, Personal, Advisory Role: NovoCure, Boston Biomedical, Sumitomo Dainippon Pharma Oncology, Cellevolve; Financial Interests, Personal, Leadership Role: Cellevolve; Financial Interests, Personal, Speaker’s Bureau: NovoCure; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: NovoCure, Caris Life Sciences, Kyowa Kirin International; Financial Interests, Personal, Stocks/Shares: COTA; Financial Interests, Personal, Other, Honoraria: Cornerstone Specialty Network, Daiichi Sankyo/AstraZeneca, Physicans' Education Resource; Financial Interests, Institutional, Funding, Research Funding: NovoCure, Celldex, Cortice Biosciences, Acerta Pharma, Bristol Myers Squibb, Tocagen, Wex Pharmaceuticals, Northwest Biotherapeutics, AbbVie, Celgene, Boston Biomedical, Cantex Pharmaceuticals, Diffusion Pharmaceuticals, Amgen, CNS Healthcare, Karyopharm Therapeutics, Novogen, Pfizer, Sanofi, Kazia Therapeutics, Imvax, Merck, Regeneron, Boehringer Ingelheim, Ono Pharmaceutical, Sumitomo Dainippon Pharma Oncology, Celularity; Financial Interests, Institutional, Funding, Research fundingResearch Funding: ImmunoCellular Therapeutics. D. Damek: Financial Interests, Institutional, Funding, Research Funding: Kazia Therapeutics, NovoCure. B. Ellingson: Financial Interests, Personal, Advisory Role: Siemens, Medicenna, MedQIA, Imaging Endpoints, Neosoma, Kazia Therapeutics, VBL Therapeutics, Global Coalition for Adaptive Research, Servier, Janssen, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Monteris Medical, Alpheus Medical; Financial Interests, Personal, Funding, Research funding: Siemens, Jansssen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Siemens. J. Garner: Financial Interests, Personal, Full or part-time Employment: Kazia Therapeutics; Financial Interests, Personal, Leadership Role: Kazia Therapeutics; Financial Interests, Personal, Stocks/Shares: Kazia Therapeutics. J. Friend: Financial Interests, Personal, Full or part-time Employment: Helsinn Therapeutics, Kazia Therapeutics; Financial Interests, Personal, Leadership Role: Helsinn Therapeutics, Kazia Therapeutics; Financial Interests, Personal, Stocks/Shares: Kazia Therapeutics. J. Simpson: Financial Interests, Personal, Full or part-time Employment: Kazia Therapeutics; Financial Interests, Personal, Leadership Role: Kazia Therapeutics; Financial Interests, Personal, Stocks/Shares: Kazia Therapeutics. A. Olivero: Financial Interests, Personal, Advisory Role: Genentech/Roche, ORIC Pharmaceuticals, Imugene, Kazia Therapeutics, Genentech; Financial Interests, Personal, Royalties, Has patents fro employment with Genentech/Roche: Genentech/Roche; Financial Interests, Personal, Stocks/Shares: Roche, Kazia Therapeutics; Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Leadership Role: Genentech; Financial Interests, Personal, Other, Research funding in the form of medical writing support, furnished by Daniel Clyde, PhD, of Health Interactions,: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Kazia Therapeutics, Genentech. T. Cloughesy: Financial Interests, Personal, Advisory Role: Roche/Genentech, Tocagen, VBL Therapeutics, Novartis, Agios, AbbVie, Pfizer, Bristol Myers Squibb, Merck, GW Pharmaceuticals, Boehringer Ingelheim, KIYATEC, VBI Vaccines, Bayer, DelMar Pharmaceuticals, QED Therapeutics, Amgen, Pascal Biosciences, Karyopharm Therapeutics, Katmai Pharmaceuticals, Global Coalition for Adaptive Research, DNAtrix, Inovio Pharmaceuticals, Sapience Therapeutics; Financial Interests, Personal, Royalties, U.S. Provisional Application No.: 62/819,322 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Filing Date: March 15, 2019 Inventor(s): David A. Nathanson et al. FH Reference No.: UCH-17760 (32246-17760) Your Reference No.: [UCLA 2019-630-1] US: UCLA; Financial Interests, Personal, Other: Global Coalition for Adaptive Research, Break Through Cancer; Financial Interests, Personal, Stocks/Shares: Notable Labs, Katmai Pharmaceuticals, Chimerix.