A PHASE 1 STUDY OF VELIPARIB (ABT-888) IN COMBINATION WITH CARBOPLATIN/PACLITAXEL IN JAPANESE SUBJECTS WITH NON-SMALL CELL LUNG CANCER (NSCLC)

ABSTRACT Aim: Veliparib (V; ABT-888) is a potent, orally bio-available PARP inhibitor that delays the repair of DNA damage induced by chemotherapeutic agents, triggering cell death and enhancing efficacy. The objectives of this study were to determine the recommended phase 2 dose (RPTD) of V in combination with carboplatin (C) and paclitaxel (P), to assess pharmacokinetics (PK) and to evaluate preliminary efficacy in Japanese subjects (sbj) with NSCLC. Methods: C and P were dosed at an AUC of 6 mg/mL/min and 200mg/m2 on day 3 of a 21 day cycle. Dose escalation of V began at 40 mg BID on day 1 to day 7 in dose level 1, increased to 80 mg in the next cohort, then to the maximum of 120 mg. Sbj received 6 cycles, unless predefined discontinuation criteria were met. Adverse events (AEs) were reported according to NCI-CTCAE ver. 4.03, PK parameters were analyzed, and tumor response was measured by RECIST ver.1.1. Results: A total of 12 sbj were treated, 10/2 male /female, with a median age of 66.5 years (range 44-73). All had NSCLC; 2 (16.7%) had prior surgery; none had other prior treatment. The most common treatment emergent AEs related to study treatment were leukopenia (12; 100%), neutropenia (12, 100%), anemia (10, 83.3%), thrombocytopenia (9, 75%), increased alanine aminotransferase (8, 66.7%) and increased aspartate aminotransferase (8, 66.7%). Grade 3 or 4 AEs occurring in ≥2 sbj were neutropenia (12, 100%), leukopenia (4, 33.3%), anemia (3, 25%) and hyponatremia (2, 16.7%). No DLTs were observed at any dose level during the DLT assessment period. The RPTD of V administered with C and P was determined to be 120 mg BID. V Cmax and AUC values were approximately dose proportional. Co-administration of C and P had no significant effect on V PK. The overall response rate per protocol was 54.5% (6/11 sbj, [95%CI: 23.4% – 83.3%]), 1 sbj had PD (9.1%), no sbj achieved a CR, 6 (54.5%) achieved PR and 4 (36.4%) stable disease ranging from 40 to 143 days. Conclusions: Administration of C and P had no significant effect on V PK and vice versa. In Japanese sbj, V, in combination with C and P, had a manageable safety profile up to 120 mg BID and V at 120 mg BID was determined as the RPTD. The data suggests that the addition of V to C and P may provide clinical benefit in Japanese sbj with NSCLC. Disclosure: Drs Mizugaki, Nokihara, Yamamoto, Fujiwara, Horinouchi, Kanda, Kitazono and Yagishita have no conflicts to disclose. Dr. Tamura has received grant funding and lecture fees from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Eli Lilly, Bristol-Myers, Boehringer-Ingelheim, Yakult Honsha Co., AbbVie, GlaxoSmithKline, Ono Pharmaceuticals, Kyowa Hakko Kirin Co. and Quintiles Transnational Japan. Drs Xiong, Qian, Shepherd and Giranda are employed by AbbVie and may own stock. AbbVie provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data as well as the writing, review and approval of the abstract. Acknowledgements: Medical writing support was provided by Teresa McNally and Jacqueline Nielsen, employees of AbbVie.