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

  1. Stacy Moulder MD, MSCI1,2,†,*,
  2. Gregory Gladish MD3,
  3. Joe Ensor PhD4,
  4. Ana Maria Gonzalez-Angulo MD1,
  5. Massimo Cristofanilli MD1,
  6. James L. Murray MD1,
  7. Daniel Booser MD1,
  8. Sharon H. Giordano MD1,
  9. Abeena Brewster MD1,
  10. Julia Moore RN1,
  11. Edgardo Rivera MD1,
  12. Gabriel N. Hortobagyi MD1,
  13. Hai T. Tran PharmD5

Article first published online: 17 OCT 2011

DOI: 10.1002/cncr.26571

Issue

Cancer

Cancer

Volume 118, Issue 9, pages 2378–2384, 1 May 2012

Additional Information

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

Author Information

  1. 1

    Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas

  2. 2

    Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas

  3. 3

    Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas

  4. 4

    Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas

  5. 5

    Department of Thoracic Head and Neck Medical Oncology and Pharmacy Research, The University of Texas MD Anderson Cancer Center, Houston, Texas

  1. †

    Fax: (713) 794-4385

*Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301438, Houston, TX 77030

  1. †

    Fax: (713) 794-4385

Publication History

  1. Issue published online: 20 APR 2012
  2. Article first published online: 17 OCT 2011
  3. Manuscript Accepted: 15 AUG 2011
  4. Manuscript Revised: 1 AUG 2011
  5. Manuscript Received: 2 MAY 2011

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Keywords:

  • phase 1;
  • everolimus;
  • docetaxel;
  • metastatic breast cancer

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/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.

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/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.

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. Cancer 2012. © 2011 American Cancer Society.

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