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A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer
Article first published online: 17 OCT 2011
Copyright © 2011 American Cancer Society
Volume 118, Issue 9, pages 2378–2384, 1 May 2012
How to Cite
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. and Tran, H. T. (2012), A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer. Cancer, 118: 2378–2384. doi: 10.1002/cncr.26571
- Issue published online: 20 APR 2012
- Article first published online: 17 OCT 2011
- Manuscript Accepted: 15 AUG 2011
- Manuscript Revised: 1 AUG 2011
- Manuscript Received: 2 MAY 2011
- phase 1;
- metastatic breast cancer
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.
Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40-75 mg/m2 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.
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/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.
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. Cancer 2012. © 2011 American Cancer Society.