OT3-01-17: Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Low-Dose Metronomic Cyclophosphamide Alone or in Combination with Veliparib (ABT-888) in Chemotherapy-Resistant ER and/or PR-Positive, HER2/neu-Negative Metastatic Breast Cancer: New York Cancer Consortium Trial P8853.
Authors: Andreopoulou E , Chen AP , Zujewski JA , Kalinsky K , Vahdat L , Raptis G , Hershman D , Novic Y , Muggia F , Sparano J 
Published: June 2012

Abstract
Background: Veliparib is an orally available, small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). PARP is an essential nuclear enzyme that plays a role in recognition of DNA damage and facilitation of DNA repair. PARP inhibitors potentiate the cytotoxicity of DNA-damaging agents, including cyclophosphamide (C). The rationale for the proposed trial is as follows: (1) low-dose, continuous metronomic C (50 mp PO daily) has activity in refractory metastatic breast cancer (MBC), (2) PARP is induced by DNA damaging agents, (3) PARP expression is comparable in ER-positive and ER-negative disease, (4) some ER-positive breast cancers exhibit defective homologous recombination pathway repair genes (eg, RAD51 and XRCC3), (5) the PARP inhibitor iniparib appears to be more effective when used in chemotherapy resistant disease. Taken together, these findings suggest that veliparib-C combination may be more effective than metronomic C alone in chemotherapy resistant MBC. Trial design: A randomized Phase II trial design 1:1. S. Blocked randomization will be performed at all participating sites. Patients are randomized to oral C (50mg PO daily) plus either veliparib (60mg PO daily) or matching placebo.
Eligibility criteria:(1) ER- and or PR-positive, HER2−negative MBC, (2) ECOG PS 0–1, (3) at least 2 prior chemotherapy regimens for MBC, including a taxane and capecitabine. 4) at least 1 line of endocrine therapy for metastatic disease (includes relapse while receiving endocrine therapy).
Specific aims: Primary: To determine if the addition of veliparib to metronomic dose C improves median progression free survival (PFS) compared with C alone in patients with ER and/or PR-positive, Her2-negative MBC who progressed on at least two lines of prior chemotherapy and one line of prior endocrine therapy.
Secondary: 1)To determine if the addition veliparib to C chemotherapy improves a) response rate b) clinical benefit rate (defined as objective response plus stable disease for at least 24 weeks from day +1) 2) Survival in patients treated with C alone and C plus veliparib. 3) Adverse event profile in patients treated with C alone and C plus veliparib.
Translational: Exploratory analyses will evaluate whether the macroH2A1.1 and PARP1 expression status in archival paraffin, or veliparib-induced PAR downregulation in peripheral blood mononuclear cells, is predictive of benefit from veliparib.
Statistical methods: The primary endpoint is PFS, and the trial is powered to detect an increase in median PFS from 3 to 6 months (alpha=0.10, beta=0.10), which will require enrollment of 62 eligible patients over 12 months.
Enrollment: The study is active and open to enrollment.
Clinical trials.gov NCT01351909
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-17.