Background: Paxalisib, a potent oral selective brain-penetrant small molecule PI3K/mTOR inhibitor, has shown activity in nonclinical brain cancer models and promising phase 1 data in progressive / recurrent high-grade gliomas (NCT01547546). This multicenter phase 2 progressive design trial (NCT03522298) aimed to establish the maximum tolerated dose (MTD) for once-daily (QD) dosing, and to evaluate safety, tolerability, pharmacokinetics (PK), and clinical activity of paxalisib in patients with newly diagnosed glioblastoma and unmethylated MGMT promotor status. Methods: Eligible patients were males or females, aged ≥18 years, who had undergone surgical resection and chemoradiotherapy (Stupp Regimen), and were considered to be progression free before starting adjuvant paxalisib. Stage 1 used a standard 3+3 dose-escalation design to determine the MTD in this population. Stage 2 was a two-arm, open-label, expansion cohort with patients randomized 1:1 to receive paxalisib at the MTD under fed or fasted conditions. In both stages, treatment comprised daily paxalisib administered in 28-day cycles, continuously until disease progression or unacceptable toxicity. Efficacy analyses are based on investigator review and from date of diagnosis. Results: Patients (n = 30; 70.0% males, 83.3% white, mean age 58.5 years) had a mean time since diagnosis of 3.75 months. The majority (n = 29) received between 1 and 6 treatment cycles and one received 29 cycles. In Stage 1 (n = 9), an MTD of 60mg was established on the dose-limiting toxicities of hyperglycemia (n = 1) and stomatitis (n = 1) at 75mg. Paxalisib at 60mg was well-tolerated and adverse events were consistent with other PI3K inhibitor medicines. At the MTD (60mg), the PK profile was linear and dose-proportional with no differences in T_max and elimination half-life under fed and fasted conditions. For the overall ITT population, the median progression free survival was 8.4 months (RANO) and 8.6 months (mRANO) and the median overall survival was 15.7 months. In a mITT (n = 22 patients treated with 60mg daily and ≥1 post-baseline assessment), the median PFS was 9.6 months (mRANO). Conclusions: The primary study endpoints were met; PK and safety were consistent with prior clinical experience. The MTD showed encouraging clinical activity, prolonging PFS and improving OS. Further efficacy confirmation of paxalisib 60 mg QD in newly diagnosed glioblastoma in a pivotal trial is ongoing (GBM AGILE, NCT03970447). Clinical trial information: NCT03522298.