A Phase 1 Study Of Niraparib In Japanese Patients With Advanced Solid Tumors

Background Niraparib is an oral, potent, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) -1 and -2 inhibitor, and approved in US and Europe for the maintenance treatment of patients with recurrent ovarian cancer. Safety, tolerability and pharmacokinetics (PK) of niraparib were investigated in Japanese patients with advanced solid tumors. Methods This Phase 1 study followed a standard 3 + 3 dose escalation design with two dose levels. Niraparib was administered orally once daily (QD) continuously for 21-days in a cycle until treatment discontinuation. Intensive PK was evaluated on day 1 and day 21 during cycle 1. Results Total of 9 subjects were enrolled, 3 in cohort 1 (200 mg) and 6 in cohort 2 (300 mg). No DLT was observed in cohort 1 whereas one DLT was observed in 1 of 6 subjects in cohort 2. The observed DLT was grade 4 thrombocytopenia. According to the preliminary data, the treatment-emergent adverse events reported in more than 1 subject were vomiting and thrombocytopenia/platelet count decreased (4 subjects each), nausea and anorexia (3 subjects each), and diarrhoea, alkaline phosphatase increased, creatinine increased, leukopenia/white blood cell count decreased, neutropenia-related events (including neutrophil count decreased and febrile neutropenia) and fatigue/malaise (2 subjects each). Cmax and AUC24 of niraparib after a single and multiple dose (QD) administration were increased generally in dose-proportional manner between dose of 200 mg and 300 mg. The PK profiles were generally comparable across Western and Japanese patients. Three subjects stay on treatment at the timing of cutoff date (February 21, 2019) Conclusion Niraparib was well tolerated and MTD was considered 300 mg or higher with recommended phase 2 dose as 300 mg in Japanese patients with advanced solid tumors. No unknown safety concerns were identified. No obvious PK difference was observed between Japanese and non-Japanese patients.