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

Eleni Andreopoulou, Ivette S. Vigoda, Vicente Valero, Dawn L. Hershman, George Raptis, Linda T. Vahdat, Hyo S. Han, John J. Wright, Christine M. Pellegrino, Massimo Cristofanilli, Ricardo H. Alvarez, Karen Fehn, Susan A. Fineberg, Joseph A. Sparano

Research output: Contribution to journalArticle

10 Citations (Scopus)

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/m 2 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.

Original languageEnglish (US)
Pages (from-to)429-435
Number of pages7
JournalBreast Cancer Research and Treatment
Volume141
Issue number3
DOIs
StatePublished - Oct 2013

Fingerprint

tipifarnib
Transferases
Paclitaxel
Estrogen Receptors
Doxorubicin
Cyclophosphamide
Breast Neoplasms
Carcinoma
Breast
Confidence Intervals
Drug Therapy
Antineoplastic Agents

Keywords

  • Breast cancer
  • Farnesyl transferase inhibitor
  • Inflammatory breast cancer
  • Neoadjuvant chemotherapy
  • Ras
  • Tipifarnib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Andreopoulou, Eleni; Vigoda, Ivette S.; Valero, Vicente; Hershman, Dawn L.; Raptis, George; Vahdat, Linda T.; Han, Hyo S.; Wright, John J.; Pellegrino, Christine M.; Cristofanilli, Massimo; Alvarez, Ricardo H.; Fehn, Karen; Fineberg, Susan A.; Sparano, Joseph A.

In: Breast Cancer Research and Treatment, Vol. 141, No. 3, 10.2013, p. 429-435.

Research output: Contribution to journalArticle

Andreopoulou, Eleni ; Vigoda, Ivette S. ; Valero, Vicente ; Hershman, Dawn L. ; Raptis, George ; Vahdat, Linda T. ; Han, Hyo S. ; Wright, John J. ; Pellegrino, Christine M. ; Cristofanilli, Massimo ; Alvarez, Ricardo H. ; Fehn, Karen ; Fineberg, Susan A. ; Sparano, Joseph A. / 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. In: Breast Cancer Research and Treatment. 2013 ; Vol. 141, No. 3. pp. 429-435.
@article{0e32cc5620bf4974ac81f3ae07f65317,
title = "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",
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/m 2 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.",
keywords = "Breast cancer, Farnesyl transferase inhibitor, Inflammatory breast cancer, Neoadjuvant chemotherapy, Ras, Tipifarnib",
author = "Eleni Andreopoulou and Vigoda, {Ivette S.} and Vicente Valero and Hershman, {Dawn L.} and George Raptis and Vahdat, {Linda T.} and Han, {Hyo S.} and Wright, {John J.} and Pellegrino, {Christine M.} and Massimo Cristofanilli and Alvarez, {Ricardo H.} and Karen Fehn and Fineberg, {Susan A.} and Sparano, {Joseph A.}",
year = "2013",
month = "10",
doi = "10.1007/s10549-013-2704-x",
language = "English (US)",
volume = "141",
pages = "429--435",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "3",

}

TY - JOUR

T1 - 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

AU - Andreopoulou, Eleni

AU - Vigoda, Ivette S.

AU - Valero, Vicente

AU - Hershman, Dawn L.

AU - Raptis, George

AU - Vahdat, Linda T.

AU - Han, Hyo S.

AU - Wright, John J.

AU - Pellegrino, Christine M.

AU - Cristofanilli, Massimo

AU - Alvarez, Ricardo H.

AU - Fehn, Karen

AU - Fineberg, Susan A.

AU - Sparano, Joseph A.

PY - 2013/10

Y1 - 2013/10

N2 - 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/m 2 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.

AB - 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/m 2 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.

KW - Breast cancer

KW - Farnesyl transferase inhibitor

KW - Inflammatory breast cancer

KW - Neoadjuvant chemotherapy

KW - Ras

KW - Tipifarnib

UR - http://www.scopus.com/inward/record.url?scp=84887052280&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887052280&partnerID=8YFLogxK

U2 - 10.1007/s10549-013-2704-x

DO - 10.1007/s10549-013-2704-x

M3 - Article

VL - 141

SP - 429

EP - 435

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 3

ER -