The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of patients (pts) with advanced solid tumors.

Abstract

3097 Background: The PI3 kinase (PI3K) pathway is the most deregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is an oral highly specific and selective inhibitor of the PI3K and TORC1/2. The MTD (1200 mg) and toxicity profile of BEZ235 once daily dosing has been established. This study was designed to evaluate twice daily dosing of BEZ235 and its effect on treatment tolerability, PK, PD, and preliminary efficacy. Methods: Pts with advanced disease were enrolled in a 3+3 dose escalation schedule starting at 200 mg PO BID in 28 day cycles. For intrapatient PK comparison the first week pts received the total dose in a QD schedule. DLT assessment was in Cycle 1. Efficacy evaluations were every 2 cycles, and PK and PD were assessed. Results: 12 pts were enrolled at the following dose levels: 200 mg (n=3), 400 mg (n=3), 600 mg (n=3), and 600 mg (BID only, no QD lead-in) (n=3). No G4 AEs were reported. G3 related AEs were mucositis (n=2), AST/ALT elevation (n=2), anorexia (n=1) and diarrhea (n=1). The most common related G1/2 adverse events (AEs) were anorexia (n=6), diarrhea (n=3), fatigue (n=2), and headache (n=2). DLTs of G3 mucositis were observed in 2 patients at the 600 mg BID dose level with 1 week 1200 mg QD lead-in, which were attributed to the QD lead-in dosing during the first week. 3 pts then enrolled at 600 mg BID without lead in and had no further DLT. PK shows consistent increase in PK parameters with dose level. Of 10 evaluable, 3 pts had stable disease (13+ to 21+ weeks, 2 colorectal, 1 endometrial). Of 9 evaluable, 4 pts at various dose levels had decreased PET SUV uptake by greater than 25%. Conclusions: BEZ235 is tolerable at a dose of 600 mg BID, with less toxicity than has been seen with equivalent QD dosing. Preliminary signs of clinical and PD activity are noted.