The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer:: Results of a phase I study with pharmacokinetics

Purpose: To investigate the safety and pharmacokinetics (PK) of combined treatment with letrozole and the oral mTOR inhibitor RAD001 in patients with metastatic breast cancer stable or progressing after >= 4 months on letrozole alone. Methods: Eighteen patients received letrozole (2.5 mg/day) and RAD001 at 5 mg/day (cohort 1) or 10 mg/day (cohort 2). In the absence of DLT in cohort 1, cohort 2 was expanded to 12 patients to obtain additional safety and PK data. Results: Most common adverse events were stomatitis (50.0% of patients), fatigue (44.4%), anorexia and/or decreased appetite (44.4%), diarrhoea (38.9%), headache (33.3%) and rash (33.3%). There was 1 DLT, a grade 3 thrombocytopaenia in cohort 2. No clinically relevant PK interaction was detected. Seven patients received the combination therapy for >6 months. One patient had a complete response, and one had a 28% reduction in liver metas-tases, both in cohort 2. Conclusion: Daily therapy with RAD001 plus letrozole is promising: the results suggest antitumour activity with no PK interactions. The overall safety profile of the combination is consistent with that expected for RAD001 monotherapy. A daily dose of RAD001 10 mg is recommended for further trials. (c) 2007 Elsevier Ltd. All rights reserved.