Breast Cancer Research and Treatment

, Volume 110, Issue 2, pp 327–335 | Cite as

A phase II, randomized, blinded study of the farnesyltransferase inhibitor tipifarnib combined with letrozole in the treatment of advanced breast cancer after antiestrogen therapy

  • Stephen R. D. Johnston
  • Vladimir F. Semiglazov
  • George M. Manikhas
  • Dominique Spaeth
  • Gilles Romieu
  • David J. Dodwell
  • Andrew M. Wardley
  • Patrick Neven
  • Annick Bessems
  • Youn C. Park
  • Peter M. De Porre
  • Juan J. Perez Ruixo
  • Angela J. Howes
Clinical Trial
First Online:
Received:
Accepted:

Abstract

Background

This study assessed the clinical efficacy of the farnesyltransferase inhibitor, tipifarnib, combined with letrozole in patients with advanced breast cancer and disease progression following antiestrogen therapy.

Patients and methods

Postmenopausal women with estrogen-receptor-positive advanced breast cancer that had progressed after tamoxifen were given 2.5 mg letrozole once daily and were randomly assigned (2:1) to tipifarnib 300 mg (TL) or placebo (L) twice daily for 21 consecutive days in 28-day cycles. The primary endpoint was objective response rate.

Results

Of 120 patients treated with TL (n = 80) or L (n = 40), 113 were evaluable for response. Objective response rate was 30% (95% CI; 20–41%) for TL and 38% (95% CI; 23–55%) for L. There was no significant difference in response duration, time to disease progression or survival. Clinical benefit rates were 49% (TL) and 62% (L). Tipifarnib was generally well tolerated; a higher incidence of drug-related asymptomatic grade 3/4 neutropenia was observed for TL (18%) than for L (0%). Tipifarnib population pharmacokinetics were similar to previous studies, with no significant difference in trough letrozole concentrations between the TL and L groups.

Conclusions

Adding tipifarnib to letrozole did not improve objective response rate in this population of patients with advanced breast cancer.

Keywords

Farnesyltransferase inhibitor Tipifarnib Breast cancer Letrozole 

Abbreviations

AE

Adverse event

CBR

Clinical benefit rates

CI

Confidence interval

CR

Complete response

ECOG

Eastern Cooperative Oncology Group

ER

Estrogen receptor

FTI

Farnesyltransferase inhibitor

L

Letrozole

NCI

National Cancer Institute

ORR

Objective response rate

PR

Partial response

PgR

Progesterone-receptor

RECIST

Response Evaluation Criteria in Solid Tumors

T

Tipifarnib

mTOR

Mammalian target of Rapamycin

TTF

Time to disease free survival

TTP

Time to disease progression

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Notes

Acknowledgements

We would like to thank the patients who took part in this study. This study R115777-INT-22, was sponsored by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and was registered with ClinicalTrials.gov (NCT00050141). We would also like to thank Namit Ghildyal, Ph.D. for his writing contributions.

References

  1. 1.
    Clark GJ, Der CJ (1995) Aberrant function of the Ras signal transduction pathway in human breast cancer. Breast Cancer Res Treat 35:133–144PubMedCrossRefGoogle Scholar
  2. 2.
    Clark GJ, Kinch MS, Gilmer TM et al (1996) Overexpression of the Ras-related TC21/R-Ras2 protein may contribute to the development of human breast cancers. Oncogene 12:169–176PubMedGoogle Scholar
  3. 3.
    Norgaard P, Law B, Joseph H et al (1999) Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis. Clin Cancer Res 5:35–42PubMedGoogle Scholar
  4. 4.
    End DW, Smets G, Todd AV et al (2001) Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61:131–137PubMedGoogle Scholar
  5. 5.
    Kelland LR, Smith V, Valenti M et al (2001) Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer. Clin Cancer Res 7:3544–3550PubMedGoogle Scholar
  6. 6.
    Johnston SR, Hickish T, Ellis P et al (2003) Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J Clin Oncol 21:2492–2499PubMedCrossRefGoogle Scholar
  7. 7.
    Nicholson RI, McClelland RA, Robertson JF, Gee JM (1999) Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer. Endocr Relat Cancer 6:373–387PubMedCrossRefGoogle Scholar
  8. 8.
    Simoncini T, Hafezi-Moghadam A, Brazil DP et al (2000) Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407:538–541PubMedCrossRefGoogle Scholar
  9. 9.
    Levin ER (2003) Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol 17:309–317PubMedCrossRefGoogle Scholar
  10. 10.
    Shou J, Massarweh S, Osborne CK et al (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96:926–935PubMedCrossRefGoogle Scholar
  11. 11.
    Johnston SR (2005) Combinations of endocrine and biological agents: present status of therapeutic and presurgical investigations. Clin Cancer Res 11:889s–899sPubMedGoogle Scholar
  12. 12.
    Gee JM, Harper ME, Hutcheson IR et al (2003) The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 144:5105–5117PubMedCrossRefGoogle Scholar
  13. 13.
    Martin LA, Head J, Pancholi S et al (2007) The farnesyl transferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in-vitro and in-vivo. Mol Cancer Ther (in press)Google Scholar
  14. 14.
    Ellis CA, Vos MD, Wickline M et al (2003) Tamoxifen and the farnesyl transferase inhibitor FTI-277 synergize to inhibit growth in estrogen receptor-positive breast tumor cell lines. Breast Cancer Res Treat 78:59–67PubMedCrossRefGoogle Scholar
  15. 15.
    Doisneau-Sixou SF, Cestac P, Faye JC et al (2003) Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI-277 on inhibition of MCF-7 breast cancer cell-cycle progression. Int J Cancer 106:789–798PubMedCrossRefGoogle Scholar
  16. 16.
    Long BJ, Liu G, Marrinan CH et al (2004) Combining the farnesyl transferase inhibitor (FTI) Lonafarnib (SCH66336) with antiestrogens and aromatase inhibitors results in enhanced growth inhibition of hormone-dependent human breast cancer cells and tumor xenografts. Proc Am Assoc Cancer Res 45:A3868Google Scholar
  17. 17.
    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 92:205–216PubMedCrossRefGoogle Scholar
  18. 18.
    Crul M, de Klerk GJ, Swart M et al (2002) Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 20:2726–2735PubMedCrossRefGoogle Scholar
  19. 19.
    Perez-Ruixo JJ, Piotrovskij V, Zhang S et al (2006) Population pharmacokinetics of tipifarnib in healthy subjects and adult cancer patients. Br J Clin Pharmacol 62:81–96PubMedCrossRefGoogle Scholar
  20. 20.
    Dombernowsky P, Smith I, Falkson G et al (1998) Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16:453–461PubMedGoogle Scholar
  21. 21.
    Prendergast GC, Davide JP, deSolms SJ et al (1994) Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Mol Cell Biol 14:4193–4202PubMedGoogle Scholar
  22. 22.
    Miquel K, Pradines A, Sun J et al (1997) GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res 57:1846–1850PubMedGoogle Scholar
  23. 23.
    Sepp-Lorenzino L, Rosen N (1998) A farnesyl-protein transferase inhibitor induces p21 expression and G1 block in p53 wild type tumor cells. J Biol Chem 273:20243–20251PubMedCrossRefGoogle Scholar
  24. 24.
    Du W, Liu A, Prendergast GC (1999) Activation of the PI3′K-AKT pathway masks the proapoptotic effects of farnesyltransferase inhibitors. Cancer Res 59:4208–4212PubMedGoogle Scholar
  25. 25.
    Gutierrez MC, Detre S, Johnston S et al (2005) Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23:2469–2476PubMedCrossRefGoogle Scholar
  26. 26.
    Lipton A, Leitzel K, Ali SM et al (2005) Serum HER-2/neu conversion to positive at the time of disease progression in patients with breast carcinoma on hormone therapy. Cancer 104:257–263PubMedCrossRefGoogle Scholar
  27. 27.
    Chan S, Scheulen ME, Johnston S et al (2005) Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23:5314–5322PubMedCrossRefGoogle Scholar
  28. 28.
    Boulay A, Rudloff J, Ye J et al (2005) Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 11:5319–5328PubMedCrossRefGoogle Scholar
  29. 29.
    deGraffenried LA, Friedrichs WE, Russell DH et al (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 10:8059–8067PubMedCrossRefGoogle Scholar
  30. 30.
    Baslega J, Roche H, Fumoleau P et al (2005) Treatment of postmenopausal women with locally advanced or metastatic breast cancer with letrozole alone or in combinations with temsirolimus; a randomized 3-arm, phase 2 study. 28th annual San Antonio breast cancer symposium 94S:Abstract no. 1068Google Scholar
  31. 31.
    Kaufman B (2006) Trastuzumab plus anastrozole prolongs progression-free survival in postmenopausal women with HER2 positive, hormone-dependent metastatic breast cancer (MBC). European Society for Medical Oncology (ESMO) Congress 2006:Abstract no. LBA2Google Scholar
  32. 32.
    Moulder SL, Sparano JA, Kazi A et al (2005) The farnesyltransferase inhibitor (FTI) tipifarnib inhibits FPTase in vivo and enhances the efficacy of neoadjuvant dose-dense doxorubicin-cyclophosphamide (AC) in patients with locally advanced breast cancer 28th annual San Antonio breast cancer symposium 94S:Abstract no. 5061Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Stephen R. D. Johnston
    • 1
  • Vladimir F. Semiglazov
    • 2
  • George M. Manikhas
    • 3
  • Dominique Spaeth
    • 4
  • Gilles Romieu
    • 5
  • David J. Dodwell
    • 6
  • Andrew M. Wardley
    • 7
  • Patrick Neven
    • 8
  • Annick Bessems
    • 9
  • Youn C. Park
    • 9
  • Peter M. De Porre
    • 9
  • Juan J. Perez Ruixo
    • 9
  • Angela J. Howes
    • 9
  1. 1.Department of Medicine – Breast UnitRoyal Marsden NHS Foundation TrustLondonUK
  2. 2.N.N. Petrov Research Institute of OncologySt. PetersburgRussia
  3. 3.City Oncology DispensarySt. PetersburgRussia
  4. 4.Centre Alexis VautrinNancyFrance
  5. 5.Centre Val d’AurelleMontpellierFrance
  6. 6.Yorkshire Centre for Clinical OncologyLeedsUK
  7. 7.Christie HospitalManchesterUK
  8. 8.Dienst Gyneacologische OncologieLeuvenBelgium
  9. 9.Johnson & Johnson Pharmaceutical Research & Development, L.L.C.New BrunswickUSA

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