A phase I-II study of tipifarnib plus weekly paclitaxel (P) followed by dose-dense doxorubicin/cyclophosphamide (AC) in stage IIb-IIIc breast cancer (BC).

Abstract

1118 Background: Tipifarnib (T) is an orally bioavailable farnesyl transferase inhibitor (FTI) that has activity in metastatic BC (J Clin Oncol 2003; 21:2492-9). We previously showed that adding T (200 mg PO BID days 2-7) to preoperative AC was associated with a higher pathologic complete response (pCR) than expected compared with historical data (Clin Cancer Res. 2009;15;2942-8), and preclinical data suggest that FTIs enhance the antineoplastic effects of P (Cancer Res 2005; 65:3883-93). Methods: Eligible pts with HER2-negative clinical stage IIB-IIIC BC received 12 weekly doses of P (80 mg/m2) followed by AC (60/600 mg/m2 every 2 weeks and pegfilgrastim), plus T 100 mg or 200 mg on days 1-3 of each P dose in cohorts of 3-6 pts in the phase I (and T 200 mg PO BID on days 2-7 each AC cycle in both the phase I and II). Simon two-stage design used for the phase II in two strata generally resistant to neoadjuvant chemotherapy. The trial was powered to detect an improvement in breast pathologic complete response (pCR) from 15% to 35% in each stratum (alpha 0.10, beta 0.10), which required breast pCR in at least 4/19 eligible pts in stage I to proceed to stage II, and at least 8/33 pts in stage I and II to be considered promising. Results: Sixty patients accrued in both the phase I and II. Two patients were non evaluable. There were no DLTs in the first 6 evaluable patients treated at dose level 1 and 2.The recommended phase II dose of T identified in the phase I trial was 200 mg BID.All protocol therapy was completed in 43/55 pts (78%) in the phase II, and one pt died of pneumonitis during therapy of uncertain cause. The prespecified efficacy endpoint was not met for either stratum. Conclusions: The addition of the FTI tipifarnib to neoadjuvant sequential weekly paclitaxel followed by dose-dense AC did not result in a higher breast pCR rate compared with historical data. Clinical trial information: NCT00049114. [Table: see text]