A first-in-human phase I study of BKM120, an oral pan-class I PI3K inhibitor, in patients (pts) with advanced solid tumors.

Abstract

3003 Background: The PI3K pathway is the most frequently aberrantly hyperactivated pathway in cancer. PI3K pathway inhibition is expected to have a strong impact on tumor survival and proliferation. BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor. Unlike other inhibitors, it does not inhibit the related kinases—mTOR and Vps34. Methods: This was a phase I dose-escalation study of BKM120 given PO QD to adult pts with advanced solid tumors; a Bayesian logistic regression model with overdose control guided dose escalation was used. Results: 30 pts (13 m/17 f) were treated at 6 doses: 12.5 mg (1); 25 mg (2), 50 mg (5), 80 mg (1), 100 mg (17), 150 mg (4). Median age: 53 (37–76). Most common tumor types: colorectal (13) and breast (8 pts). Median duration on trial was 8 weeks (0.4–47+). 7 DLTs occurred: 2 grade (G)4 hyperglycemia at 150 mg, G3 upper abdominal pain, 2 G3 skin rash, and G2 and G3 mood alteration at 100 mg. The MTD was 100 mg. Treatment-related AEs in >10% of pts: rash, hyperglycemia, diarrhea, nausea, anorexia, pruritus, fatigue, mood alteration, malaise, vomiting, and mucositis. Preliminary PK data showed rapid absorption, with Cmax occurring at ∼1.8 h post-dose (0.5–4 h). Total body clearance from plasma (CL/F) was low: ∼4.5 L/h. BKM120 accumulated ∼3-fold in achieving steady-state, consistent with an effective half-life of ∼40 h. Doses ≥50 mg led to steady-state drug exposure (AUC0-24.SS) ≥10,000 ng*h/mL, a target preclinically estimated to be efficacious. BKM120 showed moderate median inter-individual variability (CV%) in systemic (AUC0-24, 28%) and peak (Cmax, 40%) exposure across all cohorts. Downregulation of pS6 in skin (mostly between 50–80%) was seen in all 15 evaluable pts at 100/150 mg. At 100 mg, 8 of 10 evaluable pts showed metabolic PR by FDG-PET, 1 pt had a confirmed partial response (triple negative BrCa) per RECIST, and 5 more pts had minor responses (2 BrCa, 1 CRC, 1 angiosarcoma, 1 lung cancer). In addition, 12 pts (40%) across all doses experienced disease stabilization for ≥4 months. Conclusions: BKM120 was evaluated from 12.5–150 mg. Daily oral dosing at 100 mg (MTD) showed a favorable PK profile, consistent PD changes, and clear signs of clinical activity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Exelixis, Merck, Novartis, Roche Novartis