Jordi Rodon1, Alejandro Pérez-Fidalgo2, Ian E Krop3, Howard Burris4, Angel Guerrero-Zotano5, Carolyn D Britten6, Carlos Becerra7, Jan Schellens8, Donald A Richards7, Martin Schuler9, Maysa Abu-Khalaf10, Faye M Johnson11, Malcolm Ranson12, Jeff Edenfield13, Antonio P Silva14, Wolfgang Hackl14, Cornelia Quadt14, David Demanse14, Vincent Duval14, Jose Baselga15. 1. Medical Oncology Department, Vall d'Hebrón University Hospital, Barcelona, Spain. jrodon@vhio.net. 2. INCLIVA Biomedical Research Institute, Valencia, Spain. 3. Dana-Farber Cancer Institute, Boston, MA, USA. 4. Sarah Cannon Research Institute, Nashville, TN, USA. 5. Instituto Valenciano de Oncología, Valencia, Spain. 6. Medical University of South Carolina, Charleston, SC, USA. 7. Texas Oncology, Dallas, TX, USA. 8. The Netherlands Cancer Institute, Amsterdam, The Netherlands. 9. West German Cancer Center, University Hospital Essen, Essen, Germany. 10. Thomas Jefferson University, Philadelphia, PA, USA. 11. MD Anderson Cancer Center, Houston, TX, USA. 12. Manchester University, Manchester, UK. 13. Greenville Memorial Hospital, Greenville, SC, USA. 14. Novartis Pharma AG, Basel, Switzerland. 15. Memorial Sloan Kettering Cancer Center, New York, USA.
Abstract
PURPOSE: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2. METHODS: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed. RESULTS: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%). CONCLUSIONS: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.
PURPOSE: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2. METHODS: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed. RESULTS: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%). CONCLUSIONS: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.
Entities:
Keywords:
BEZ235; Breast cancer; Inhibitor; PI3K; mTORC1/2
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