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Phase I–II study of the farnesyl transferase inhibitor tipifarnib plus sequential weekly paclitaxel and doxorubicin–cyclophosphamide in HER2/neu-negative inflammatory carcinoma and non-inflammatory estrogen receptor-positive breast carcinoma

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Abstract

Tipifarnib (T) is a farnesyl transferase inhibitor (FTI) that enhances the antineoplastic effects of cytotoxic therapy in vitro, has activity in metastatic breast cancer, and enhances the pathologic complete response (pCR) rate to neoadjuvant doxorubicin–cyclophosphamide (AC) chemotherapy. We, therefore, performed a phase I–II trial of T plus neoadjuvant sequential weekly paclitaxel and 2-week AC chemotherapy in locally advanced breast cancer. Eligible patients with HER2-negative clinical stage IIB–IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m2) followed by AC (60/600 mg/m2 every 2 weeks and filgrastim), plus T (100 or 200 mg PO on days 1–3 of each P dose, and 200 mg PO on days 2–7 of each AC cycle). The trial was powered to detect an improvement in breast pCR rate from 15 to 35 % (α = 0.10, β = 0.10) in two strata, including ER and/or PR-positive, non-inflammatory (stratum A) and inflammatory carcinoma (stratum B). Of the 60 patients accrued, there were no dose-limiting toxicities among the first six patients treated at the first T dose level (100 mg BID; N = 3) or second T dose level (200 mg BID; N = 3) plus paclitaxel. Breast pCR occurred in 6/33 patients (18 %, 95 % confidence intervals (CI) 7–36 %) and 1/22 patients (4 %, 95 % CI 0–8 %) in stratum B. Combination of the FTI T with weekly paclitaxel–AC is unlikely to be associated with a breast pCR rate of 35 % or higher in patients with locally advanced HER2/neu-negative inflammatory or non-inflammatory ER- and/or PR-positive breast carcinoma.

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Acknowledgments

Supported by United States Department of Health and Human Service contract N01-CM-62204 (P. I. Joseph A. Sparano, MD) and Grant RO1CA98473 (P. I. Said Sebti, PhD, co-PI: Joseph A. Sparano, MD).

Conflict of interest

The authors have no financial disclosures with the exception of Dr. Sparano, who serves as a paid consultant to Johnson & Johnson.

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Authors and Affiliations

  1. Department of Oncology, Montefiore Medical Center-Weiler Division/ Albert Einstein College of Medicine, 2 South, 1825 Eastchester Road, Bronx, 10461, NY, USA

    Eleni Andreopoulou, Ivette S. Vigoda, Christine M. Pellegrino, Karen Fehn, Susan Fineberg & Joseph A. Sparano

  2. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Vicente Valero & Ricardo H. Alvarez

  3. Columbia University College of Physicians and Surgeons, New York, NY, USA

    Dawn L. Hershman

  4. North Shore-LIJ Cancer Institute, Manhasset, NY, USA

    George Raptis

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

    Linda T. Vahdat

  6. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Hyo S. Han

  7. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    John J. Wright

  8. Thomas Jefferson University, Philadelphia, PA, USA

    Massimo Cristofanilli

Authors
  1. Eleni Andreopoulou
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  2. Ivette S. Vigoda
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  3. Vicente Valero
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  4. Dawn L. Hershman
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  7. Hyo S. Han
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  9. Christine M. Pellegrino
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  11. Ricardo H. Alvarez
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  12. Karen Fehn
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  13. Susan Fineberg
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  14. Joseph A. Sparano
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Corresponding author

Correspondence to Joseph A. Sparano.

Additional information

This study was conducted on behalf of New York Cancer Consortium and collaborating institutions.

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Andreopoulou, E., Vigoda, I.S., Valero, V. et al. Phase I–II study of the farnesyl transferase inhibitor tipifarnib plus sequential weekly paclitaxel and doxorubicin–cyclophosphamide in HER2/neu-negative inflammatory carcinoma and non-inflammatory estrogen receptor-positive breast carcinoma. Breast Cancer Res Treat 141, 429–435 (2013). https://doi.org/10.1007/s10549-013-2704-x

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  • DOI: https://doi.org/10.1007/s10549-013-2704-x

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