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. 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. 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 Tmax 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 Cmax at the 90% level (geometric least squares mean ratios: AUC0-last 1.33, AUC0-inf 1.06, and Cmax 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. 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).
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