A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer

Cancer, 04/24/2012

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.

Results

  • 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.

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