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

Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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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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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.

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Authors

Corresponding author

Correspondence to Stephen R. D. Johnston.

Appendix

Appendix

In addition to the authors, the following investigators (listed in alphabetical order) participated in the R115777-INT-22 study: Belgium—M. Berlière (Brussels); France—M. Campone (St. Herblain), P. Chollet (Clermont-Ferrand), P. Kerbrat (Rennes), L. Mauriac (Bordeaux); The Netherlands—H. P. Sleeboom (Den Haag); Russia—M. Y. Biakhov (Moscow), D. B. Korman (Moscow), A. N. Makhson (Moscow), S. A. Tjulandin (Moscow); United Kingdom—P. A. Ellis (London), J. K. Joffe (Huddersfield), M. W. Verrill (Newcastle-upon-Tyne); United States—M. J. Ellis (St. Louis, MO), P. Khosla (Chicago, IL), P.K. Marcom (Durham, NC), R. L. Ruxer (Fort Worth, TX), P. Silverman (Cleveland, OH), S Vukelja (Tyler, TX).

Author contributions

 

Conception and design: Stephen Johnston, Youn Park, Peter De Porre, Juan Jose Perez Ruixo, Angela Howes.

 

Administrative support: Annick. Bessems, Angela Howes.

 

Provision of study materials or patients: Stephen Johnston, Vladimir Semiglazov, George Manikhas, Dominique Spaeth, Gilles. Romieu, David Dodwell, Andrew Wardley, Patrick Neven.

 

Collection and assembly of data: Annick. Bessems, Youn Park, Juan Jose Perez Ruixo, Angela Howes.

 

Data analysis and interpretation: Stephen Johnston, Youn Park, Peter De Porre, Juan Jose Perez Ruixo, Angela Howes.

 

Manuscript writing: Stephen Johnston, Youn Park, Peter De Porre, Angela Howes.

 

Final approval of manuscript: Stephen Johnston, Vladimir Semiglazov, George Manikhas, Dominique Spaeth, Gilles. Romieu, David Dodwell, Andrew Wardley, Patrick Neven.

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Johnston, S.R.D., Semiglazov, V.F., Manikhas, G.M. et al. A phase II, randomized, blinded study of the farnesyltransferase inhibitor tipifarnib combined with letrozole in the treatment of advanced breast cancer after antiestrogen therapy. Breast Cancer Res Treat 110, 327–335 (2008). https://doi.org/10.1007/s10549-007-9726-1

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  • DOI: https://doi.org/10.1007/s10549-007-9726-1

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