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
AU - Sparano, Joseph A.
N1 - Funding Information:
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).
Funding Information:
Patients were required to have histologically or cytologically confirmed adenocarcinoma of the breast, clinical stage IIB–IIIC, and HER2/neu non-overexpressing disease (0 or 1? by immunohistochemistry, or non-amplified by fluorescent in situ hybridization). Other requirements included: (1) age C 18 years, (2) ECOG performance status 0 or 1, (3) normal organ and marrow function (leukocytes C 3,000/µl, absolute neutrophil count C 1,500/µl, platelets 100,000/µl, serum creatinine and total bilirubin within institutional normal limits, aspartate transaminase and/or alanine transaminase B2.5-fold above the institutional upper limit of normal, and left ventricular ejection fraction within normal institutional limits). The study was reviewed, approved, and sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI study number P7868, Clinical Trials.gov identifier NCT00470301). The protocol was reviewed by the local institutional review board at each participating institution, and all the patients provided written informed consent.
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
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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
C2 - 24068539
AN - SCOPUS:84887052280
VL - 141
SP - 429
EP - 435
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
SN - 0167-6806
IS - 3
ER -