Background: Combined VEGF, EGFR, and mTOR inhibition with bevacizumab, erlotinib, and everolimus, respectively, may provide complimentary targeting of both tumor and stromal compartments. Everolimus and erlotinib are metabolized by, and potential inhibitors of, CYP450 3A4. Potential pharmacokinetic interactions between these agents were evaluated in a phase I /pharmacokinetic study of bevacizumab, erlotinib, and everolimus (aka BEE study).
 Methods: Patients were enrolled onto this phase I/pharmacokinetic study who had confirmed malignancy which was metastatic or unresectable and for which standard curative or palliative measures did not exist or were no longer effective. Bevacizumab was administered by IV infusion (10 mg/kg) every two weeks, while everolimus (5 mg), and erlotinib (75 mg) were given as daily oral doses. Patients were enrolled onto one of two administration schedules so that within-patient pharmacokinetic comparisons could be made for both everolimus and erlotinib. Patients in treatment group A had initiation of erlotinib delayed for 1 week from initiation of erlotinib and bevacizumab (n = 9) while those in treatment group B delayed everolimus for 1 week (n = 9) on the first cycle. The systemic pharmacokinetics of everolimus, erlotinib, and its principle metabolite (OSI-420), were analyzed by LC-MS-MS methods from serial blood samples collected on days 8 and 22. Pharmacokinetic parameters of everolimus, erlotinib and OSI-420 were determined on each day and compared using standard, two stage, non-compartmental approaches. Signed rank test p-values are presented for comparing the central tendencies of day 8 to day 22 PK measures.
 Results: The oral clearance of everolimus was 14.3 ± 4.8 and 11.7 ± 4.1 L/h on days 8 and 22, respectively (p = 0.039). Similarly, systemic exposure of everolimus was significantly higher on day 22 (476 ± 161 ng*hr/mL) compared to day 8 (393 ± 156 ng*hr/mL; p = 0.020). Erlotinib oral clearance was 4.6 ± 2.3 L/h on day 8, and 4.4 ± 2.7 L/h on day 22 (p = 0.65). There was also no significant difference in systemic exposure to erlotinib or OSI-420 between days 8 and 22. Erlotinib systemic exposure was lowest among those who smoked tobacco, as was systemic exposure to OSI-420.
 Conclusions: The systemic exposure of erlotinib was not affected by everolimus. However everolimus exposure is increased when administered concomitantly with erlotinib. These data are consistent with previous reports demonstrating reduced clearance of another CYP450 3A4 substrate (midazolam) by erlotinib.

Second AACR Centennial Conference on Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA