P3-16-05: A Phase II Trial Expansion Cohort of the PARP Inhibitor Veliparib (ABT888) and Temozolomide in BRCA1/2 Associated Metastatic Breast Cancer.
Authors: Isakoff SJ , Overmoyer B , Tung NM , Gelman RS , Habin K , Qian J , Giranda V , Shepherd S , Garber JE , Ellisen LW , Winer EP , Goss PE 
Published: June 2012

Abstract
Background: Veliparib (ABT-888) is a novel oral inhibitor of Poly (ADP-Ribose) Polymerase (PARP) 1 and 2. Veliparib and temozolomide (TMZ) are synergistic in breast cancer xenograft models. We recently conducted a phase II study of TMZ and veliparib in 41 patients (pts) with metastatic breast cancer (MBC). Activity was observed only in pts with known BRCA1 or BRCA2 deleterious mutations, with a response rate (RR) of 50% (4/8) and clinical benefit rate (CBR) of 62.5%. In order to further evaluate the activity and safety of TMZ and veliparib, we enrolled an expansion cohort of 20 additional patients with BRCA1 or 2 mutations.
Methods: We previously conducted a single arm phase II trial of veliparib and TMZ in 41 MBC pts. Eligibility included measurable disease, ≥1 prior MBC therapy and PS ≤ 2. Available archived tumor samples were collected. In this expansion cohort, first line therapy for MBC and prior PARP inihibitor therapy were allowed, and eligible patients were required to have a known deleterious BRCA1 or BRCA2 mutation identified from prior clinical testing. The dose of veliparib in the original cohort was reduced from 40 mg PO BID to 30 mg PO BID. In the expansion cohort all patients received veliparib (30 mg PO BID days 1–7) and TMZ (150mg/m2 PO QD days 1–5) on a 28 day cycle. RECIST response was evaluated every 2 cycles. The primary endpoint was overall response rate. Secondary endpoints included PFS, OS, safety and toxicity.
Results: Between June 24, 2010 and Sept 29, 2010, 20 eligible pts (median age 42) were enrolled. Baseline characteristics included: median PS=0 (range 0–2); 9 BRCA1 carriers, 9 BRCA2 carriers, and 2 unknown. 17 pts (85%) received prior adjuvant chemotherapy. 9 patients received a prior platinum chemotherapy. The most common grade 3/4 toxicities included thrombocytopenia and neutropenia. Best response for the 20 patients evaluable at the time of abstract submission includes 3 PR (15%), 6 SD (30%), 11 PD, and a clinical benefit rate of 45%. Combined with the initial cohort of 8 known carriers from the original 41 patients, the total RR is 25% (7/28) and clinical benefit rate of 50% (7 PR, 7 SD). The RR was 40% (6/15) in pts without prior platinum treatment, and 9% (1/11) in pts with prior platinum treatment. The median PFS for the 20 BRCA carriers was 85 days, and among patients with prior platinum treatment compared to no prior platinum, the median PFS was 70 and 179 days, respectively. Three pts remain on study, 1 with a CR for &gt;20 mo.
Discussion: We previously demonstrated that veliparib and TMZ is an active combination in BRCA1/2 associated MBC. In this larger expansion cohort of 20 additional patients, the combination continued to show activity, although the response rate was not as robust as previously observed. Differences between the original cohort and the expansion cohort may account for some variation in response, such as prior platinum or PARP inhibitors therapy, number of lines of prior therapy, and the dose of veliparib used (40mg vs 30 mg). These results support further evaluation of this regimen in the BRCA1/2 carrier population, and provide the opportunity to evaluate potential factors that may predict response or resistance to this regimen.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-05.