An adaptive randomized phase II trial to determine pathologic complete response with the addition of carboplatin with and without ABT-888 to standard chemotherapy in the neoadjuvant treatment of triple-negative breast cancer.

Abstract

TPS1135 Background: Inhibition of poly (ADP-ribose) polymerase (Parp) is a potential targeted therapy for triple-negative breast cancer (TNBC). Clinical trials of Parp inhibitors in metastatic TNBC have shown conflicting results. Issues regarding the use of Parp inhibitors in TNBC include choosing a selective Parp inhibitor and selecting an appropriate chemotherapy backbone. The current trial addresses these questions by combining a validated Parp inhbitor, ABT-888, with carboplatin and paclitaxel. Platinum agents have shown synergy with Parp inhibitors in preclinical models and efficacy in clinical trials. The combination of paclitaxel and carboplatin with Parp inhibitors has shown efficacy in phase I trials. Methods: This is a phase II, two-arm neoadjuvant trial of women with TNBC. Eighty patients will be enrolled. Randomization will follow a 1:1 allocation initially, then will follow a Bayesian adaptive allocation in which each prior response will be evaluated and patients assigned preferentially to the better responding arm. The primary endpoint is pathologic complete response (pCR). Secondary endpoints include correlation of pCR with biomarkers, imaging, and circulating tumor cells (CTCs). Treatment: Arm 1: Paclitaxel 80 mg/m2 + carboplatin AUC=2 (12 weekly cycles) + filgrastim followed by doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 (4 cycles every 3 weeks) + pegfilgrastim. Arm 2: ABT-888 (150mg PO bid) + paclitaxel 80 mg/ m2 + carboplatin AUC=2 (12 weekly cycles) + (filgrastim) followed by doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 (4 cycles every 3 weeks) + (pegfilgrastim). Eligibility: Women ≥ 18 years old with clinical stage IIB or stage IIIA, IIIB, or IIIC untreated TNBC (ER <1% , PR <1% , Her-2/neu 0, 1+ on IHC or 2+ and FISH ratio < 1.8) are eligible. Correlative Studies: Correlation of pCR with tissue expression of CK5, EGFR, ERCC1, Ki-67, Parp1, and longitudinal enumeration of CTCs will be done. Exploratory tissue biomarkers with prognostic and predictive value will be correlated with pCR. Enrollment: The trial will begin accrual in February 2013.