Summary
Introduction The PI3 kinase (PI3K) pathway is a commonly dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective dual PI3K/mTOR inhibitor. Methods Patients were enrolled in a 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetics (PK) of BEZ235 when administered twice-daily as an oral sachet. For intrapatient PK comparison, patients were to receive a lead in of the total daily dose in a QD schedule for the first 8 days of the initial 28 day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred. Results Thirty-three patients received BEZ235. Initial dose levels of 200 and 400 mg BID had no DLTs. At the 600 mg BID dose level with 1200 mg QD lead in dose two DLTs of grade 3 mucositis occurred early in the first treatment cycle, the lead-in QD dosing was eliminated. Fatigue and mucositis limited dosing at 600 mg BID in subsequent patients. The 400 mg BID dose level was re-explored, with DLTs of grade 3 hyperglycemia, dehydration, fatigue, and grade 3 thrombocytopenia. Twelve patients were enrolled at an intermediate dose of 300 mg BID; a grade 3 mucositis DLT was reported in 1 patient, and this dose was declared the MTD. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. Fifteen patients experienced stable disease as their best response, including 10 (colorectal [4 patients], endometrial [3 patients], carcinoid NOS, pancreas, and melanoma) who had disease control for ≥16 weeks. Conclusions The recommended dose of BEZ235 administered BID as an oral sachet formulation is 300 mg BID. Toxicities seen have been reported for other dual PI3K/mTOR inhibitors.
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Acknowledgments
The investigators are grateful to the patients who participated in this trial as well as the very important contributions of the site personnel.
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The study was funded in part by a grant from Novartis. The authors declare that they have no conflicts of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Bendell, J.C., Kurkjian, C., Infante, J.R. et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Invest New Drugs 33, 463–471 (2015). https://doi.org/10.1007/s10637-015-0218-6
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DOI: https://doi.org/10.1007/s10637-015-0218-6