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A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with
Trisha M Wise-Draper1, Ganesh Moorthy2, Mohamad A Salkeni1,3
1Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
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.
Insights
The combination of BEZ235 (dactolisib) and everolimus showed limited efficacy and tolerance in advanced tumors. BEZ235 exposure increased with dose, but drug interactions and gastrointestinal toxicity were noted.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Preclinical models showed synergy between everolimus and BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor.
- This combination targets advanced tumors.
Purpose of the Study:
- To assess the clinical feasibility, safety, and pharmacokinetics of combining everolimus and BEZ235.
- Investigate dose-escalation in patients with advanced malignancies.
Main Methods:
- Phase Ib dose-escalation trial with 19 patients.
- BEZ235 (200-800 mg daily) and everolimus (2.5 mg daily) in 28-day cycles.
- Safety (CTCAE v4.0), response (RECIST 1.1), and pharmacokinetics were evaluated.
Main Results:
- Common toxicities included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes.
- No confirmed tumor responses were observed.
- BEZ235 showed dose-proportional Cmax and AUC0-24 with high variability; everolimus showed increased Cmax, AUC0-24, and decreased clearance.
Conclusions:
- The combination of BEZ235 and everolimus exhibited limited efficacy and tolerance.
- BEZ235's low oral bioavailability and gastrointestinal toxicity were observed.
- Potential drug-drug interactions between BEZ235 and everolimus warrant further investigation.