A phase I study of chronically dosed, single-agent veliparib (ABT-888) in patients (pts) with either BRCA 1/2-mutated cancer (BRCA+), platinum-refractory ovarian cancer, or basal-like breast cancer (BRCA-wt).

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3054 Background: Veliparib (ABT-888) is an oral, potent inhibitor of PARP 1/2. Preclinically, PARP inhibitors have activity in tumors with defective homologous recombination (HR), particularly those that are BRCA+. Reduced levels of BRCA expression have been observed in ovarian cancer and basal-like breast cancer, which share genotypic and phenotypic similarities with BRCA+ cancers. We postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed veliparib. Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID. Veliparib was administered orally continuously on a 28 day cycle. Results: 63 pts have been enrolled to date. Thirty-eight were BRCA+ (20 ovary, 12 breast, 2 pancreas, and one each - prostate, peritoneal, fallopian tube, endometrial); 25 BRCA-wt. (21 breast, 4 ovarian). DLTs occurred at the following dose levels: BRCA+: gr. 2 thrombocytopenia at 50 mg BID; BRCA+: gr.3 Nausea/vomiting at 400 mg BID; BRCA-wt: gr 2 seizure at 400 mg BID. The MTD has not been determined and 500 mg BID is presently enrolling. Notable toxicities have included low-grade fatigue and nausea. PK was linear and non-saturable with t ½ of 5 h. The number of cycles administered ranged from 1- 15, median 2. In BRCA+ pts, there were 2 partial responses (breast, ovarian) and 10 pts had evidence of prolonged SD ≥ 4 months. In BRCA-wt pts, there was 1 PR (breast) and 7 pts with SD≥ 4 months. Correlative studies, including assessment of PAR inhibition and BRCA methylation status, are ongoing. Conclusions: Veliparib is tolerable on a continuous oral dosing schedule with evidence of anti-tumor activity seen in BRCA+ and BRCA-wt tumors. A mandatory biopsy expansion cohort is planned at the recommended phase II dose, which will allow further insights regarding efficacy and mechanisms of resistance to PARP inhibition.