Veliparib (V) is a potent, orally bio-available PARP inhibitor that inhibits DNA damage repair. Up to 50% high-grade serous ovarian cancer (HGSOC) is considered to have deficiencies in homologous recombination and thus be particularly sensitive to PARP inhibition. V has single-agent activity in HGSOC, as well as in BRCA-mutated breast, pancreatic or prostate cancers. The objectives of this study were to determine the recommended phase 3 dose (RPTD) of V monotherapy, to assess pharmacokinetics (PK) and to evaluate preliminary efficacy in Japanese subjects with HGSOC or other BRCA mutated cancers.
Tolerability was assessed in 2 dose cohorts (200 mg and 400 mg BID) on Days 1 - 28 of a 28 day cycle), and an expansion cohort (400 mg BID). Subjects continued to receive V until PD or predefined discontinuation criteria were met. Adverse events (AEs) were reported according to CTCAE Ver. 4.03. PK parameters were analyzed. Tumor response was measured by RECIST 1.1 and tumor markers including CA-125.
A total of 16 subjects treated were all female, with a median age of 59 yrs (range 43 - 83). All but 1 subject with BRCA-mutated breast cancer were with HGSOC. All had prior surgeries and chemotherapies (range 1 - 7). The most common treatment emergent AEs were nausea and vomiting (15/16, 94% each), decreased appetite (10/16, 63%), and abdominal pain, diarrhea and malaise (5/16, 31% each). Grade 3 AEs occurring in 2 or more subjects were anemia, nausea and vomiting (2/16, 13% each). One subject developed DLTs (nausea, vomiting, decreased appetite and fatigue, all Grade 3) at 400 mg BID. The RPTD was determined to be 400 mg BID. Nausea and vomiting were observed at higher incidence than Western and were the major cause of dose modification or discontinuation. PK parameters were dose proportional and comparable to Western. The objective response rate was 14% (2/14 subjects, [95%CI: 1.8% – 42.8%]) with no CR, 2 PR (14%), 8 SD (57%), and 3 PD (21%). Additional CA-125 responder was reported with the longest study duration of 340 days.
V 400 mg BID (RPTD for Western) was considered to be tolerable for Japanese; however, anti-emetic therapy may be needed. Manageable safety profile and no ethnic difference of PK warrant participation of Japan in multinational Phase 3 study.
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K. Matsumoto: Institution has received grants from Ono Pharmaceutical, MSD, and AbbVie. K. Tamura: Institution has received grants from Ono Pharmaceutical, MSD, AstraZeneca, Daiichi-Sankyo, Eisai, Pfizer and AbbVie. C. Shimizu: Institution has received grants from Chugai Pharmaceutical, Eli Lilly, and Pfizer. M. Yunokawa: Has received payment for lectures/speakers from AstraZeneca. H. Xiong, T. Kiriyama, T. Leahy, S. Shepherd: Employed by AbbVie and may own stock. H. Hashiba: Employed by AbbVie. K. Fujiwara: Lectures/speakers: Kyowa Hakko Kirin, Taiho Phar., Yakult Honsha, Nippon Kayaku and Asahi Kasei Medical. Advisory boards (AB): GSK, Chugai Phar. Institution grants (IG): Zeria Phar., Sanofi, Kaken Phar., and AbbVie. AB/IG: AstraZeneca, Pfizer, and Eisai. All other authors have declared no conflicts of interest.