First-in-human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-kinase inhibitor, in Patients with Advanced Solid Tumor Malignancies
Mené sur 170 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale d'un composé appelé GSK458, un inhibiteur de PI3K
Purpose: GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, δ), with pre-clinical studies demonstrating broad anti-tumor activity. We performed a first-in-human phase 1 study in patients with advanced solid tumors. Experimental Design: Patients received oral GSK458 once or twice daily in a dose escalation design to define the maximally tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics (PD), pharmacokinetics (PK), and clinical activity in histologically- and molecularly-defined cohorts. Results: 170 patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (DLTs) (grade 3 diarrhea, n=4; fatigue and rash, n=1) occurred in 5 patients (n=3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). PK analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (OR) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated with PIK3CA mutations (OR rate: 5% wild-type versus 6% mutant). Conclusions: Although the MTD of GSK458 was 2.5 mg once daily, twice daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as PD markers of drug exposure. Select patients achieved durable responses however PIK3CA mutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.