454P - Phase IB Dose-Escalation Study of BEZ235 or BKM120 in Combination with Paclitaxel (PTX) in Patients With Advanced Solid Tumors

Abstract

ABSTRACT Background The pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235 have demonstrated preclinical and clinical antitumor activity as single agents and in combination with other drugs. Here, we report interim results of BKM120 or BEZ235 + PTX in pts with advanced solid tumors. Methods In the first 2 arms of this 4-arm Phase Ib dose-escalation study, pts with metastatic or locally advanced solid tumors received once-daily oral BKM120 or BEZ235 + wkly IV PTX. Dose-escalation was guided by a Bayesian logistic regression model with overdose control. The primary objective was to determine the MTD of BKM120 or BEZ235 + PTX. Results 33 pts were treated with BKM120 (mg/d) + PTX (mg/m2) at 6 dosing levels: 40/70 (1 pt); 40/80 (5 pts); 60/80 (3 pts); 80/80 (4 pts); 100/80 (16 pts); and 120/80 (4 pts). DLTs were observed in 4 pts (1/16 at 100/80 and 3/4 at 120/80), including asthenia, hyperglycemia, and depression. The MTD of BKM120/PTX was declared as 100/80. Most common G3/4-suspected study treatment-related AEs (>5%) were neutropenia, hyperglycemia, and anemia. For the BEZ235 arm, 29 pts were treated with BEZ235 (mg/d) + PTX (mg/m2) at 4 dosing levels: 400/70 (2 pts); 400/80 (3 pts); 600/80 (4 pts); and 800/80 (20 pts). DLTs were observed in 4 pts (3/20 at 800/80 and 1/4 at 600/80), including GI events, peripheral neuropathy, and febrile neutropenia. The MTD of BEZ235/PTX was declared as 800/80. Most common G3/4-suspected study treatment-related AEs (>10%) were fatigue, diarrhea, and anemia. As of Feb 29, 29 pts were evaluable for response in each arm. In the BKM120/PTX arm, 1 CR (penile carcinoma [Ca]), 4 PRs (breast and ovarian Ca pts, each with multiple lines of prior therapy [12 and 3] and progression on prior PTX; cervical and vulvar Ca), and 11 SDs were observed. In the BEZ235/PTX arm, 1 PR (large-cell Ca of the lung, taxane-naive), and 9 SDs were observed. Conclusion BKM120 or BEZ235 + PTX were generally well tolerated and showed preliminary signs of efficacy. The MTDs of both BKM120/PTX and BEZ235/PTX were reached. For BKM120, the MTD in combination with PTX was the same as the single-agent MTD. Arms 3 and 4 will determine the MTD of BEZ235 or BKM120 + PTX and trastuzumab in pts with advanced HER2+ breast Ca. Disclosure M. Schuler: Martin Schuler is an advisor for Novartis, and receives research funding from Novartis. J. Machiels: Jean-Pascal Machiels is on an advisory board for Boehringer, and receives a research grant from Sanofi. D. Hess: Dagmar Hess owns N. Steeghs: Neeltje Steeghs receives research funding from Novartis. L. Paz-Ares: Luis Paz-Ares has been an advisor for Lilly, Bayer, Roche and Pfizer. He has also received honoraria from all of the above. R. von Moos: Roger von Moos is a participant of advisory boards for Amgen, Novartis, Roche, BMS, and MSD, and receives unrestricted research grants and speaker honoraria from Amgen and Roche. B. Rabault: Bertrand Rabault is a employee of Novartis Pharma AG and owns stock in novartis pharma. All other authors have declared no conflicts of interest.