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

Stacy Moulder*, Gregory Gladish, Joe Ensor, Ana Maria Gonzalez-Angulo, Massimo Cristofanilli, James L. Murray, Daniel Booser, Sharon H. Giordano, Abeena Brewster, Julia Moore, Edgardo Rivera, Gabriel N. Hortobagyi, Hai T. Tran

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

BACKGROUND: Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction. METHODS: Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40-75 mg/m 2 intravenously on day 1 of a 21-day cycle) in combination with everolimus (doses ranging from 20 to 50 mg 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 40 mg/m 2. 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. CONCLUSIONS: Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs.

Original languageEnglish (US)
Pages (from-to)2378-2384
Number of pages7
JournalCancer
Volume118
Issue number9
DOIs
StatePublished - May 1 2012

Keywords

  • docetaxel
  • everolimus
  • metastatic breast cancer
  • phase 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Moulder, S., Gladish, G., Ensor, J., Gonzalez-Angulo, A. M., Cristofanilli, M., Murray, J. L., Booser, D., Giordano, S. H., Brewster, A., Moore, J., Rivera, E., Hortobagyi, G. N., & Tran, H. T. (2012). A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer. Cancer, 118(9), 2378-2384. https://doi.org/10.1002/cncr.26571