Background: GDC-0084 is a potent, oral, selective, brain-penetrant small molecule inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) kinase. A first-in-human, phase 1 dose escalation study was conducted in patients with high-grade glioma. Methods: GDC-0084 was administered orally, once daily on a continuous dosing schedule to evaluate the safety and pharmacokinetic (PK) characteristics. Plasma samples for PK analysis were collected on Day 1 and Day 8 or Day 15 of Cycle 1. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed at baseline and on-treatment. Results: 47 pts enrolled in eight successive dose escalation cohorts (2-65 mg). Dose-limiting toxicities (DLTs) reported were one case of Gr 2 bradycardia and Gr 3 myocardial ischemia (15 mg), Gr 3 stomatitis (45 mg) and two cases of Gr 3 mucosal inflammation (65 mg); the MTD was 45 mg. The most frequent adverse events (AE) attributed to GDC-0084 were fatigue, hyperglycemia, nausea, hypertriglyceridemia, rash, hypophosphatemia, decreased appetite, diarrhea, and stomatitis. PK data showed linear and dose proportional increases in exposure, with a half-life supportive of once daily dosing (t_1/2 ~19 hr). At a dose of 45 mg steady-state concentrations were consistent with antitumor activity observed in xenograft models. On FDG-PET, 5 of 27 (18.5%) evaluable patients show a metabolic PR. Additionally, at doses of ≥45 mg QD, a trend towards decreased median SUV in normal brain was observed, suggesting CNS penetration of the study drug. In two available exploratory specimens, GDC-0084 was detected at similar levels in brain tumor and brain tissue, with a brain tissue/tumor to plasma ratio of >1 and >0.5 for total and free drug, respectively. Of the evaluable patients, 26 patients (55.3%) had a best overall response of progressive disease, 19 patients (40.4%) had stable disease. Conclusions: The safety profile demonstrated classic Pi3K/mTOR-inhibitor related AEs. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crosses the blood brain barrier, with a uniform distribution throughout the brain. Clinical trial information: NCT01547546