Skip to main content

Advertisement

Springer Nature Link
Log in

A phase II trial of trastuzumab plus weekly ixabepilone and carboplatin in patients with HER2-positive metastatic breast cancer: an Eastern Cooperative Oncology Group Trial

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The epothilone B analogue, ixabepilone, binds to β-tubulin, is effective for taxane-refractory metastatic breast cancer (MBC), and may be given every 3 weeks or weekly. We evaluated the efficacy of weekly ixabepilone (I) plus trastuzumab (T) and carboplatin (C) as first line therapy in HER2 + MBC. Patients with HER2+ (3+ by IHC or FISH amplified) MBC received I (15 mg/m2 IV) and C (area under the curve, AUC = 2 IV) on days 1, 8, and 15 of a 28-day cycle for a maximum of 6 cycles, plus weekly T (4 mg/kg loading dose then 2 mg/kg IV) during chemotherapy then every 3 weeks (6 mg/kg IV) until disease progression. The primary objective was to determine whether the combination was associated with a response rate (RR) of at least 75%. Fifty-nine patients were treated, and 39 had HER2 overexpression confirmed in a central lab (cHER2+). For all treated patients, objective response occurred in 26 patients (44%; 95% CI 31–58%), median time to progression was 8.2 months (95% CI 6.3–9.9), and median overall survival was 34.7 months (95% CI 25.7 to [not reached]). Results were comparable for cHer2+ cancers. Grade 3–4 adverse events included neutropenia (49%), thrombocytopenia (14%), fatigue (12%), nausea (7%), diarrhea (7%), and neuropathy (7%). One patient died from treatment complications during cycle 1. Weekly ixabepilone and carboplatin plus trastuzumab have an acceptable toxicity profile, but are not likely to be associated with an RR of 75% in HER2+ MBC. Efficacy appears comparable to paclitaxel, carboplatin, and trastuzumab.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  CAS  PubMed  Google Scholar 

  2. Burris H III, Yardley D, Jones S et al (2004) Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer. J Clin Oncol 22:1621–1629

    Article  CAS  PubMed  Google Scholar 

  3. Ruiz M, Salvador J, Bayo J et al (2008) Phase-II study of weekly schedule of trastuzumab, paclitaxel, and carboplatin followed by a week off every 28 days for HER2+ metastatic breast cancer. Cancer Chemother Pharmacol 62:1085–1090

    Article  CAS  PubMed  Google Scholar 

  4. Pegram MD, Pienkowski T, Northfelt DW et al (2004) Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 96:759–769

    Article  CAS  PubMed  Google Scholar 

  5. Perez EA, Suman VJ, Rowland KM et al (2005) Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer 6:425–432

    Article  CAS  PubMed  Google Scholar 

  6. Robert N, Leyland-Jones B, Asmar L et al (2006) Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24:2786–2792

    Article  CAS  PubMed  Google Scholar 

  7. Sparano JA, Wang M, Martino S et al (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671

    Article  CAS  PubMed  Google Scholar 

  8. Seidman AD, Berry D, Cirrincione C et al (2008) Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642–1649

    Article  CAS  PubMed  Google Scholar 

  9. Gori S, Mosconi AM, Basurtol C et al (2002) Weekly paclitaxel in metastatic breast cancer patients: a phase II study. Tumori 88:470–473

    PubMed  Google Scholar 

  10. Green MC, Buzdar AU, Smith T et al (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983–5992

    Article  CAS  PubMed  Google Scholar 

  11. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R (2001) Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 19:4216–4223

    CAS  PubMed  Google Scholar 

  12. Nettles JH, Li H, Cornett B, Krahn JM, Snyder JP, Downing KH (2004) The binding mode of epothilone A on alpha, beta-tubulin by electron crystallography. Science 305:866–869

    Article  CAS  PubMed  Google Scholar 

  13. Lee FY, Borzilleri R, Fairchild CR et al (2001) BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429–1437

    CAS  PubMed  Google Scholar 

  14. Perez EA, Lerzo G, Pivot X et al (2007) Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 25:3407–3414

    Article  CAS  PubMed  Google Scholar 

  15. Thomas E, Tabernero J, Fornier M et al (2007) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 25:3399–3406

    Article  CAS  PubMed  Google Scholar 

  16. Low JA, Wedam SB, Lee JJ et al (2005) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 23:2726–2734

    Article  CAS  PubMed  Google Scholar 

  17. Roche H, Yelle L, Cognetti F et al (2007) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol 25:3415–3420

    Article  CAS  PubMed  Google Scholar 

  18. Denduluri N, Low JA, Lee JJ et al (2007) Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol 25:3421–3427

    Article  CAS  PubMed  Google Scholar 

  19. Awada A, Piccart MJ, Jones SF et al (2009) Phase I dose escalation study of weekly ixabepilone, an epothilone analog, in patients with advanced solid tumors who have failed standard therapy. Cancer Chemother Pharmacol 63:417–425

    Article  CAS  PubMed  Google Scholar 

  20. Plummer R, Woll P, Fyfe D et al (2008) A phase I and pharmacokinetic study of ixabepilone in combination with carboplatin in patients with advanced solid malignancies. Clin Cancer Res 14:8288–8294

    Article  CAS  PubMed  Google Scholar 

  21. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  CAS  PubMed  Google Scholar 

  22. Kaplan EL, Meier P (1958) Nonparametric estimator from incomplete observations. J Am Stat Assoc 53:457–481

    Google Scholar 

  23. Rugo HS, Campone M, Amadori A et al (2009) Randomized phase II study of weekly versus every-3-week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC). J Clin Oncol 27:15s (suppl; abstr 1029)

    Article  Google Scholar 

  24. Sparano JA (2000) Taxanes for breast cancer: an evidence-based review of randomized phase II and phase III trials. Clin Breast Cancer 1:32–40 discussion 1–2

    Article  CAS  PubMed  Google Scholar 

  25. Rivera E, Mejia JA, Arun BK et al (2008) Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer 112:1455–1461

    Article  CAS  PubMed  Google Scholar 

  26. Fromes Y, Gounon P, Veitia R, Bissery MC, Fellous A (1996) Influence of microtubule-associated proteins on the differential effects of paclitaxel and docetaxel. J Protein Chem 15:377–388

    Article  CAS  PubMed  Google Scholar 

  27. Gueritte-Voegelein F, Guenard D, Lavelle F, Le Goff MT, Mangatal L, Potier P (1991) Relationships between the structure of taxol analogues and their antimitotic activity. J Med Chem 34:992–998

    Article  CAS  PubMed  Google Scholar 

  28. Verweij J, Clavel M, Chevalier B (1994) Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind. Ann Oncol 5:495–505

    CAS  PubMed  Google Scholar 

  29. Pegram MF, Forbes J, Pienkowski T et al (2007) BCIRG 007: first overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC). J Clin Oncol 2007; ASCO annual meeting proceedings, vol 25

Download references

Acknowledgment

This study was supported in part by grants from the Department of Health and Human Services and the National Institutes of Health (CA23318 to the ECOG statistical center, CA66636 to the ECOG data management center, CA21115 to the ECOG coordinating center, CA25224 to NCCTG).

Author information

Authors and Affiliations

  1. Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, Unit 1354, P.O. Box 301438, Houston, TX, 77030, USA

    Stacy Moulder

  2. Dana Farber Cancer Institute, Boston , MA, USA

    Hailun Li & Molin Wang

  3. Northwestern University, Evanston, IL, USA

    William J. Gradishar, Michael Pins & Ximing Yang

  4. Mayo Clinic, Jacksonville, FL, USA

    Edith A. Perez

  5. Montefiore Medical Center, Bronx, NY, USA

    Joseph A. Sparano

  6. Indiana University Medical Center, Indianapolis, IN, USA

    George W. Sledge

Authors
  1. Stacy Moulder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hailun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Molin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William J. Gradishar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edith A. Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joseph A. Sparano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Pins
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ximing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. George W. Sledge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stacy Moulder.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moulder, S., Li, H., Wang, M. et al. A phase II trial of trastuzumab plus weekly ixabepilone and carboplatin in patients with HER2-positive metastatic breast cancer: an Eastern Cooperative Oncology Group Trial. Breast Cancer Res Treat 119, 663–671 (2010). https://doi.org/10.1007/s10549-009-0658-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0658-9

Keywords

Search

Navigation