A first-in-human phase 1 study to evaluate the brain-penetrant PI3K/mTOR inhibitor GDC-0084 in patients with progressive or recurrent high-grade glioma.

2012Background: 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, hypertriglyceri...