Abstract A166: A Phase I pharmacokinetic/pharmacodynamic (PK/PD) study of the sachet formulation of the oral dual PI3K-mTOR inhibitor BEZ235 given twice daily (BID) in patients (pts) with advanced solid tumors.

Abstract

Abstract Background: The PI3 kinase pathway is the most dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective PI3K inhibitor that also binds to the catalytic site of mTOR, inhibiting mTORC1/2. Methods: Pts were enrolled in a 3+3 dose escalation design to determine the maximum tolerated dose, toxicities, PK, and PD of BEZ235 when administered BID as an oral sachet formulation. For intrapatient PK comparison, pts received the total dose in a QD schedule for the first 8 days of the initial 28 day cycle. The QD lead-in was later eliminated. PK and PD assessments (PET scans, skin biopsies, and blood-based biomarkers) were collected and disease assessments were conducted every 2 cycles. Results: 33 pts (median age 62, range 20-86 yrs; 17 male/16 female) received BEZ235 at the doses described below in the table. Two DLTs of gr 3 mucositis occurred early in the treatment cycle at 600 mg BID, so the lead-in QD dosing was eliminated. However, DLTs of fatigue and mucositis limited dosing at 600 mg BID in subsequent pts. The 400 mg BID dose level was re-explored, but dosing was again limited by DLTs and chronic low grade toxicities. Twelve pts were enrolled at an intermediate dose of 300 mg BID with no QD lead-in, and DLT (gr 3 mucositis) was reported in a single patient. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. PET scan evaluations demonstrate anti-PI3K activity via decreased SUV uptake at various doses, including the lowest dose. 15 pts experienced stable disease as their best response. Conclusions: The recommended dose of BEZ235 administered twice daily as an oral sachet formulation is 300 mg BID. The toxicity profile for BID dosing is similar to that reported for other PI3K and mTOR inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A166. Citation Format: Johanna C. Bendell, Carla Kurkjian, Jeffrey R. Infante, Todd Bauer, Howard A. Burris, David R. Spigel, Denise A. Yardley, F Anthony Greco, Kent C. Shih, Dana S. Thompson, Suzanne F. Jones. A Phase I pharmacokinetic/pharmacodynamic (PK/PD) study of the sachet formulation of the oral dual PI3K-mTOR inhibitor BEZ235 given twice daily (BID) in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A166.