Phase I trial of veliparib, (ABT-888), a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with doxorubicin and cyclophosphamide in breast cancer and other solid tumors.

Abstract

3041 Background: Veliparib is a potent, oral inhibitor of PARP-1 and PARP-2. We previously reported phase I results of veliparib and cyclophosphamide (C). Evaluation of veliparib and C with doxorubicin (A) was conducted given activity of anthracyclines in breast cancer treatment. Main objectives were to determine maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib with AC and PAR levels in peripheral blood mononuclear cells (PBMCs). Methods: Veliparib doses ranged from 50 to 150 mg every 12 h on days 1 - 4 with fixed dosing of AC (60/600 mg/m2) on day 3 every 21 days. Prior A ≤ 300 mg/m2 was permitted. Further A was omitted after a cumulative dose of 420 mg/m2. PKs of veliparib and PAR levels were collected. Results: 18 pts (17F:1M; median age 53 yrs) treated with veliparib (mg) every 12 h at 50 (n= 3), 100 (n= 9), and 150 (n= 6) on days 1 - 4 every 21 days. Tumor types were breast (14; 5 BRCA mutation carriers), ovarian (1), and other (3). Mean cycles were 5 (2-18). Two instances of gr 3 febrile neutropenia were considered dose-limiting at the 150 mg veliparib dose level. MTD of veliparib was 100 mg every 12 h with AC. Drug-related toxicities included fatigue and myelosuppression. PK analysis suggests dose-linearity of veliparib Cmax and AUC with no significant effect of AC on Tmax (1.7 h; SD 0.7) or t1/2 (4.7 h; SD 0.5) of veliparib. In presence of AC on day 3, a 15% decrease in apparent clearance (Cl/F) (90%CI 8-22%) of veliparib relative to Cl/F of veliparib alone on day 1 (21.9 L/h; SD 5.0) was observed. Within-subject variability of veliparib Cmax and Cl/F were 34% and 28%, respectively. PARP in PBMCs was inhibited >50% in 14 pts and >90% in 4 pts. PRs were observed in 3/5 BRCA mutation carriers (2 pts too early to evaluate) with triple-negative breast tumors; 8 breast cancer pts had stable disease > 12 weeks. Conclusions: MTD of veliparib is 100 mg every 12 h with AC every 21 days. Veliparib inhibits PARP in PBMCs at all dose levels. Objective antitumor activity was seen in BRCA mutation carriers. Enrollment continues in the breast cancer dose expansion cohort. This work is supported by NCI U01-CA132194 (NJ) and NCI U01-CA099168 (PA).