OT3-01-05: PARP Inhibition after Preoperative Chemotherapy in Patients with Triple-Negative Breast Cancer (TNBC) or Known BRCA 1/2 Mutations: Hoosier Oncology Group BRE09-146.

Abstract

Abstract Background Based on recently reported I-SPY trial, TNBC patients who had residual disease category II or III had 2-year disease free survival (DFS) of only ∼40% (J Clin Oncol 2009;27:18s). Currently, no standard systemic therapy exists for this high-risk group. It represents a real opportunity to explore the potential impact of novel therapies. Recent laboratory and early clinical studies (Nature 2005;434:913) identified a unique sensitivity to DNA-damaging chemotherapy and PARP inhibition. We initiated a randomized phase II trial of DNA-damaging chemotherapy (cisplatin) or PARP-inhibition + cisplatin in TNBC patients with substantial residual invasive disease after standard anthracycline and/or taxane containing neoadjuvant chemotherapy. Methods: To ensure a high-risk population, patients must have residual disease category 0–2 based on the Miller-Payne classification system, residual cancer burden classification II or III, residual lymph node involvement, or at least 2 cm of residual invasive disease in the breast. After completion of standard radiation therapy (when indicated), patients are randomized 1:1 to cisplatin (75 mg/M2 IV Day 1 every 3 weeks x 4 cycles) alone or in combination with PARP inhibition (PF-01367338 — 24 mg IV D1, 2, 3 of each 3 week cycle with a single dose escalation to 30 mg in the absence of significant toxicity in cycle 1 followed by maintenance PARP inhibition weekly x 24 weeks). The primary objective is 2-year DFS. To detect an improvement in 2-year DFS from 40% with cisplatin alone to 63.2% in the cisplatin + PF-01367338 arm (corresponding to HR=0.5), with 80% power using a one-side log-rank test with 0.10 level of significance, 102 patients are required in the primary analysis. Secondary objectives include safety, 1-year DFS, overall survival, and biomarkers of tumor recurrence, resistance to chemotherapy and/or PARP inhibition. Two dose escalation safety cohorts (N=13) were completed without dose limiting toxicity; the randomized portion began enrolment in 11/2010 has enrolled 20 patients as of 05/2011. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-05.