The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study

BACKGROUND: Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status. METHODS: This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response. RESULTS: There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean C(max) and AUC(0–24) of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median t(max) was 3–4 h. Two patients, both in cohort 2, had a partial response to treatment. CONCLUSIONS: Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours.