454P - Phase IB dose-escalation study of BEZ235 or BKM120 in combination with paclitaxel (PTX) in patients with advanced solid tumors

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Luc Dirix
Authors L. Dirix1, M. Schuler2, J. Machiels3, D. Hess4, A. Awada5, N. Steeghs6, L. Paz-Ares7, R. von Moos8, B. Rabault9, J. Rodon10
  • 1Clinical Trials Oncology, Sint Augustinus Hospital, Antwerp/BE
  • 2Westdeutsches Tumorzentrum, Universitätsklinikum Essen, Essen/DE
  • 3Department Of Medical Oncology, Cliniques Universitaires Saint-Luc, 1200 - Bruxelles/BE
  • 4Medical Oncology, Kantonsspital St. Gallen, St. Gallen/CH
  • 5Medical Oncology, Institute Jules Bordet, 1000 - Brussels/BE
  • 6Medical Oncology, Netherlands Cancer Institute, Amsterdam/NL
  • 7Medical Oncology, University Hospital Virgen del Rocio, Seville/ES
  • 8Medizinische Onkologie Und Hämatologie, Kantonsspital Graubünden, Chur/CH
  • 9Oncology, Novartis Pharma AG, Basel/CH
  • 10Vall d'Hebron University Hospital, Barcelona/ES



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.


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.


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-naïve), and 9 SDs were observed.


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.


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 < 30,000 swiss francs of Novartis stocks.

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.