Triple negative breast cancer: a phase 2, multi-center, open-label, randomized trial of gemcitabine/carboplatin (G/C), with or without BSI-201, a PARP inhibitor.

Abstract

Abstract Abstract #2120 Background: PARP is a critical enzyme of cell proliferation and DNA repair and BSI-201 has been shown to be a potent inhibitor of PARP-1 in humans. Triple negative breast cancer (TNBC) shares important features with BRCA1-related breast cancer, a validated target for PARP inhibition. Our studies demonstrate that PARP-1 gene expression is statistically significantly upregulated in TNBC compared with normal breast tissue. The primary objective of this study is to assess the Clinical Benefit Rate (CBR=CR+PR+SD > 6 months) of Gemcitabine/Carboplatin with or without BSI-201 in patients with TNBC.
 Methods: Eligible subjects are ≥ 18 years old who had received ≤ 2 prior chemotherapies for metastatic disease with histologically documented breast cancer that is ER-negative, PR-negative, and HER2-negative. Patients were randomized (1:1 ratio) to one of 2 study arms: a) arm 1: G/C alone; b) arm 2: BSI-201 + G/C. G/C was given on days 1 and 8; G = 1000 mg/m2, C at an AUC=2. In study arm 2, BSI-201 was administered I.V. twice weekly (days 1, 4, 8 and 11) at a dose of 5.6 mg/kg. Cycles were defined as being 21 days in duration. Modified RECIST criteria are used to assess tumor response every 6 weeks (every 2 cycles). Subjects who have progressive disease may crossover to receive BSI-201 and continue G/C. Archived tissue samples were retrieved for the assay of cancer related genes including PARP-1 by multiplex quantitative RT-PCR.
 Results: To date, 50 subjects have been enrolled and treated for up to 8 cycles of therapy. Overall 39 of 50 (78%) subjects experienced at least 1 adverse event. The frequency and nature of the AE's do not differ between the two treatment groups. Gene expression profiling results from the first 28 patients enrolled confirm that the cancers of patients enrolled have uniformly low hormone receptor expression, variable HER2 receptor expression and significant upregulation of PARP-1 compared with normal breast tissue.
 Conclusions: This is the first randomized study of a PARP inhibitor in cancer patients. BSI-201 is safe and well tolerated when given in combination with G/C and adverse events observed were consistent with the known safety profiles of G / C regimens. An updated evaluation of toxicity profile and PARP-1 expression analysis will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2120.