First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma
Patrick Y Wen, Timothy F Cloughesy, Alan G Olivero, Kari M Morrissey, Timothy R Wilson, Xuyang Lu, Lars U Mueller, Alexandre F Coimbra, Benjamin M Ellingson, Elizabeth Gerstner, Eudocia Q Lee, Jordi Rodon, Patrick Y Wen, Timothy F Cloughesy, Alan G Olivero, Kari M Morrissey, Timothy R Wilson, Xuyang Lu, Lars U Mueller, Alexandre F Coimbra, Benjamin M Ellingson, Elizabeth Gerstner, Eudocia Q Lee, Jordi Rodon
Abstract
Purpose: GDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. A first-in-human, phase I study was conducted in patients with recurrent high-grade glioma.
Patients and methods: GDC-0084 was administered orally, once daily, to evaluate safety, pharmacokinetics (PK), and activity. Fluorodeoxyglucose-PET (FDG-PET) was performed to measure metabolic responses.
Results: Forty-seven heavily pretreated patients enrolled in eight cohorts (2-65 mg). Dose-limiting toxicities included 1 case of grade 2 bradycardia and grade 3 myocardial ischemia (15 mg), grade 3 stomatitis (45 mg), and 2 cases of grade 3 mucosal inflammation (65 mg); the MTD was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (∼19 hours) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded preclinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥45 mg/day, a trend toward decreased median standardized uptake value in normal brain was observed, suggesting central nervous system penetration of drug. In two resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor-to-plasma ratio of >1 and >0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%) and progressive disease in 26 patients (55%); 2 patients (4%) were nonevaluable.
Conclusions: GDC-0084 demonstrated classic PI3K/mTOR-inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood-brain barrier.
Trial registration: ClinicalTrials.gov NCT01547546.
©2020 American Association for Cancer Research.
Source: PubMed