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|Ref Type||Journal Article|
|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|
|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.|
|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|