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Ref Type Journal Article
PMID (31937616)
Authors Wen PY, Cloughesy TF, Olivero AG, Morrissey KM, Wilson TR, Lu X, Mueller LU, Coimbra AF, Ellingson BM, Gerstner E, Lee EQ, Rodon J
Title 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.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 26
Issue 8
Date 2020 Apr 15
Abstract Text 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.GDC-0084 was administered orally, once daily, to evaluate safety, pharmacokinetics (PK), and activity. Fluorodeoxyglucose-PET (FDG-PET) was performed to measure metabolic responses.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.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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
GDC-0084 GDC0084|Paxalisib mTOR Inhibitor 51 PI3K Inhibitor (Pan) 38 Paxalisib (GDC-0084) is a dual pan-PI3K and mTOR inhibitor, which prevents cell proliferation and potentially inhibits tumor growth (PMID: 22619466, PMID: 32269051, PMID: 31937616).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown high grade glioma not applicable GDC-0084 Phase I Actionable In a Phase I trial, GDC-0084 treatment demonstrated expected toxicity and blood-brain barrier penetration, resulted in stable disease as best response in 40% (19/47) of patients with recurrent high-grade glioma (J Clin Oncol (PMID: 31937616; NCT01547546). 31937616