Phase I First-In-Human Study Of The Pi3 Kinase Inhibitor Gsk2126458 (Gsk458) In Patients With Advanced Solid Tumors (Study P3k112826).

3018 Background: Phosphatidylinositol 3-kinase (PI3K) is critical to cancer cell growth, survival, and metabolism. GSK458 is an oral, potent inhibitor of PI3K (α, β, γ, δ), mTORC1, and mTORC2. Preclinically, GSK458 has demonstrated broad anti-tumor activity against solid tumors and hematologic malignancies in vitro and in vivo. Cell lines with common activating mutations of PIK3CA are particularly sensitive to GSK458. Methods: Adult patients (pts) with relapsed or refractory advanced solid tumors received GSK458 by mouth daily until disease progression or toxicity. Dose escalation used a modified accelerated titration scheme. Expansion cohorts further evaluated pharmacodynamics (PD), pharmacokinetics and clinical activity in specific target populations. Results: Preliminary data reveal that 78 pts (51% female) with mean age of 57 (25-85) yrs received ≥1 dose of GSK458. Doses ranged from 0.1 to 3 mg. Maximum tolerated dose was 2.5 mg daily. AUC and Cmax increased with dose. Across doses: median Tmax was 2 hrs and mean t½ 10 hrs. Grade 3 diarrhea was dose-limiting in 2 pts at 3 mg and 1 pt at 1.5 mg. The incidence of grade 3 diarrhea was 7% (1/14) at 1.5 mg and 44% (4/9) at 3 mg. Grade 1 or 2 rash was reported in 22% (2/9) of patients at 3 mg. The most commonly (≥10%) reported drug-related adverse events were: fatigue (15%; G3/4 1%), nausea (15%; G3/4 1%), and diarrhea (12%; G3/4 6%). The change from baseline for fasting glucose values 1 and 2h post-dose after a single dose of GSK458 and at steady state increased with respect to dose and exposure, suggesting an on-target effect. Analysis of pre- and post-dose biopsy tissue for pAKT is ongoing. Partial response was observed in two pts, one with RCC at 0.4 mg (11+ mo), and one with bladder cancer at 2 mg (1+ mo). Conclusions: The MTD of GSK458 when administered daily is 2.5 mg. Dose-limiting toxicity is diarrhea. PD effects suggest on-target inhibition of PI3K. Two patients have experienced PR.