Abstract

Abstract BACKGROUND GDC-0084 is an oral, highly selective and potent inhibitor of class I PI3K and moderate inhibitor of mTOR, with an established adult maximum tolerated dose (MTD) of 60 mg/day and evidence of brain tumor penetration in adult recurrent glioblastoma. METHODS We used a rolling-6 design to evaluate the safety and pharmacokinetic (PK) properties and establish the pediatric MTD of once-daily GDC-0084 administered after focal RT in children with newly diagnosed DIPG and histone H3 K27M-mutant DMG. Non-compartmental plasma PK analyses were performed using samples collected on cycle 1 days 1–3 after single-dose and day 28 at steady-state. RESULTS Twenty-five patients have been enrolled, 16 of whom were treated at study dosage levels of 27 mg/m2 (n=11) and 35 mg/m2 (n=5). Two dose limiting toxicities (DLTs) observed at 35 mg/m2 were grade 3 mucositis and grade 3 rash. Grade 3 hyperglycemia was the only DLT at 27 mg/m2. The most frequent grade 3 or 4 adverse events attributed to GDC-0084 were rash (5 patients), neutropenia (4), and hyperglycemia (2). After single-dose, GDC-0084 exposures (AUC0-48h) at 27 and 35 mg/m2 were 3399±1301 and 4462±2868 hr·ng/mL, respectively. Mean GDC-0084 half-life was 20.6±9.1 hr, comparable to that observed in adults. CONCLUSIONS The dosage of 27 mg/m2 has been established as the pediatric MTD of GDC-0084, which is approximately equivalent to 80% of the adult MTD. At 27 mg/m2, GDC-0084 is well tolerated in children where the spectrum of toxicities is similar to those observed in adults and consistent with this class of agents.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call