Skip to main content

Advertisement

SpringerLink
Log in

Phase II trial of a novel capecitabine dosing schedule in combination with lapatinib for the treatment of patients with HER2-positive metastatic breast cancer

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

Abstract

Our group applied mathematical modeling to capecitabine dosing and predicted 7 days of treatment followed by 7 days of rest (7–7) would improve efficacy and minimize toxicity. The conventional schedule of capecitabine limits full dosing in combination with other agents due to toxicity. Lapatinib inhibits the tyrosine kinase of HER2 and has activity when added to conventionally scheduled capecitabine for the treatment of patients with trastuzumab-refractory, HER2-positive, metastatic breast cancer (MBC). We performed this study to evaluate the activity and tolerability of capecitabine 7–7 with lapatinib in patients with trastuzumab-refractory MBC. Eligible patients had measurable, HER2-positive, MBC that progressed following exposure to trastuzumab. Treatment consisted of capecitabine 2,000 mg orally twice daily, 7–7 and lapatinib 1,250 mg orally daily. The primary endpoint was response rate. Secondary endpoints included toxicity, progression-free survival, and stable disease ≥6 months. Twenty-three patients were treated on study. More than 60% had prior chemotherapy for MBC and all had prior trastuzumab. After a median of 23 weeks (range 2–96+), five patients had partial responses (23; 95 CI, 7–44%) and six (27; 95 CI, 10–48%) had stable disease ≥6 months. Median progression-free survival was 9.4 months. The most common treatment-related toxicities ≥ grade (gr) 2 were hand-foot syndrome (gr 2 43%; gr 3 4% gr 4 0%), diarrhea (gr 2 26%; gr 3/4 0%), elevated liver chemistries (gr 2 17%; gr 3/4 0%), and anemia (gr 2 13%; gr 3 4%; gr 4 4%). No grade ≥3 nausea, vomiting, or diarrhea events occurred. This study demonstrated feasibility and after meeting biostatistical requirements for continued accrual was terminated in anticipation of slow enrollment. Capecitabine 7–7 with lapatinib was well tolerated with minimal gastrointestinal toxicity. Antitumor activity was observed in patients with trastuzumab-refractory MBC.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Slamon D et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    Article  PubMed  CAS  Google Scholar 

  2. Vogel CL et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726

    Article  PubMed  CAS  Google Scholar 

  3. Seidman AD 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 9,840. J Clin Oncol 26(10):1642–1649

    Article  PubMed  CAS  Google Scholar 

  4. Cobleigh M et al (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER 2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648

    PubMed  CAS  Google Scholar 

  5. Slamon DJ et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792

    Article  PubMed  CAS  Google Scholar 

  6. Seidman AD et al (2001) Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19(10):2587–2595

    PubMed  CAS  Google Scholar 

  7. Gomez HL et al (2008) Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 26(18):2999–3005

    Article  PubMed  CAS  Google Scholar 

  8. Burstein HJ et al (2008) A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann Oncol 19(6):1068–1074

    Article  PubMed  CAS  Google Scholar 

  9. Blackwell KL et al (2009) Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann Oncol 20(6):1026–1031

    Article  PubMed  CAS  Google Scholar 

  10. Geyer CE et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743

    Article  PubMed  CAS  Google Scholar 

  11. Oshaughnessy JA et al (2001) Randomized, open-label, phase II trial of oral capecitabine (Xeloda) versus a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12(9):1247–1254

    Article  PubMed  CAS  Google Scholar 

  12. Miller KD et al (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23(4):792–799

    Article  PubMed  CAS  Google Scholar 

  13. Mackean M et al (1998) Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 16(9):2977–2985

    PubMed  CAS  Google Scholar 

  14. Leonard R et al (2006) Detailed analysis of a randomized phase III trial: can the tolerability of capecitabine plus docetaxel be improved without compromising its survival advantage? Ann Oncol 17(9):1379–1385

    Article  PubMed  CAS  Google Scholar 

  15. Stockler M et al (2007) A randomized trial of capecitabine (C) given intermittently (IC) rather than continuously (CC) compared to classical CMF as first-line chemotherapy for advanced breast cancer (ABC). J Clin Oncol 25(18_suppl):1031 (Meeting Abstracts)

    Google Scholar 

  16. Soto C et al (2006) Capecitabine (X) and taxanes in patients (pts) with anthracycline-pretreated metastatic breast cancer (MBC): sequential versus combined therapy results from a MOSG randomized phase III trial. J Clin Oncol (Meeting Abstracts) 24(18_suppl):570

    Google Scholar 

  17. Blum JL et al (2006) Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 24(27):4384–4390

    Article  PubMed  CAS  Google Scholar 

  18. Norton L et al (1976) Predicting the course of gompertzian growth. Nature 264:542–545

    Article  PubMed  CAS  Google Scholar 

  19. Traina T et al (2010) Optimizing chemotherapy dose and schedule by norton-simon mathematical modeling. Breast Dis 31(1):7–18

    Google Scholar 

  20. Traina T et al (2006) In vivo activity of a novel regimen of capecitabine in a breast cancer xenograft model breast cancer research and treatment. Breast Cancer Res Treat 100(Suppl. 1):279–280

    Google Scholar 

  21. Traina TA et al (2008) Phase I study of a novel capecitabine schedule based on the norton-simon mathematical model in patients with metastatic breast cancer. J Clin Oncol 26(11):1797–1802

    Article  PubMed  CAS  Google Scholar 

  22. Robert NJ et al (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2–negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29(10):1252–1260

    Article  PubMed  CAS  Google Scholar 

  23. Brufsky A et al (2009) RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer. Cancer Res 69:42 (MeetingAbstracts)

    Article  Google Scholar 

  24. Gajria D et al (2011) Phase 2 trial of a novel capecitabine dosing schedule in combination with bevacizumab for patients with metastatic breast cancer. Cancer (epublication)

  25. Blum JL et al (1999) Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17(2):485–493

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Conflict of interest

Clifford Hudis, MD—consulting fees from Genentech. Tiffany Traina, MD—consulting fees from Genentech

Author information

Authors and Affiliations

  1. Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA

    Devika Gajria, Joseph Gonzalez, Maria Theodoulou, Pamela Drullinsky, Gabriella D’Andrea, Diana Lake, Larry Norton, Clifford A. Hudis & Tiffany A. Traina

  2. Radiology, Memorial Sloan-Kettering Cancer Center, 55 East 14th St, New York, NY, 10003, USA

    Kimberly Feigin

  3. Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 307 East 63rd St, New York, NY, 10065, USA

    Sujata Patil

  4. Cardiology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Carol Chen

  5. Weill Medical College of Cornell University, New York, NY, USA

    Tiffany A. Traina

Authors
  1. Devika Gajria
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kimberly Feigin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sujata Patil
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carol Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Theodoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pamela Drullinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gabriella D’Andrea
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Diana Lake
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Larry Norton
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Clifford A. Hudis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tiffany A. Traina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tiffany A. Traina.

Additional information

Supported in part by GlaxoSmithKline.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gajria, D., Gonzalez, J., Feigin, K. et al. Phase II trial of a novel capecitabine dosing schedule in combination with lapatinib for the treatment of patients with HER2-positive metastatic breast cancer. Breast Cancer Res Treat 131, 111–116 (2012). https://doi.org/10.1007/s10549-011-1749-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1749-y

Keywords

Search

Navigation