A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer
Moulder S et al. – Weekly everolimus in combination with docetaxel every 3weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs.Methods
- Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40-75mg/m2 intravenously on day 1 of a 21-day cycle) in combination with everolimus (doses ranging from 20 to 50mg orally on days 1 and 8 of a 21-day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose.
- The first 2 patients developed a dose-limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts.
- Fifteen patients were treated.
- Dose-limiting toxicity included grade 3 mucositis (n=1), prolonged grade 4 neutropenia (n=1), and grade 3 infection/febrile neutropenia (n=3).
- Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40mg/m2.
- Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel.
- Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination.