TY - JOUR
T1 - A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies
AU - Wise-Draper, Trisha M.
AU - Moorthy, Ganesh
AU - Salkeni, Mohamad A.
AU - Karim, Nagla Abdel
AU - Thomas, Hala Elnakat
AU - Mercer, Carol A.
AU - Beg, M. Shalaan
AU - O’Gara, Sue
AU - Olowokure, Olugbenga
AU - Fathallah, Hassana
AU - Kozma, Sara C.
AU - Thomas, George
AU - Rixe, Olivier
AU - Desai, Pankaj
AU - Morris, John C.
N1 - Publisher Copyright:
© 2017, The Author(s).
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Background: The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model. Objective: To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed. Patients and Methods: BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed. Results: Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr. Conclusions: The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug–drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104[Figure not available: see fulltext.].
AB - Background: The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model. Objective: To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed. Patients and Methods: BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed. Results: Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr. Conclusions: The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug–drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104[Figure not available: see fulltext.].
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U2 - 10.1007/s11523-017-0482-9
DO - 10.1007/s11523-017-0482-9
M3 - Article
C2 - 28357727
AN - SCOPUS:85016431230
SN - 1776-2596
VL - 12
SP - 323
EP - 332
JO - Targeted Oncology
JF - Targeted Oncology
IS - 3
ER -