A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies

Abstract

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 C_max and AUC_0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus C_max and AUC_0-24 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.

Fig. 1

Consort diagram. The schematic demonstrates patient enrollment and allocation

Fig. 2

Plasma concentration-time profiles of BEZ235 and everolimus. a) Plasma concentration-time profile of BEZ235 on day 1 after 200, 400, and 800 mg/day dose. b) Plasma concentration-time profile of everolimus on day 1 and day 28 after 2.5 mg/day dose

Fig. 3

PK analysis for everolimus. a) Individual change in everolimus AUC_0-24 and CL/F from day 1 to day 28. b) Simulated concentration-time profile of everolimus at 2.5 mg/day using the reported population pharmacokinetic model (mean concentrations: black; 90% confidence interval: grey shaded area) and observed concentrations from the current study (mean: circles; 90% confidence interval: black line)