1. The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study
- Author
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Kan Yonemori, Akihiko Shimomura, Ryota Shibaki, Takafumi Koyama, Shigehisa Kitano, Ashish Suri, Yoichi Kase, Noboru Yamamoto, Shunsuke Kondo, Kenji Tamura, Shuuji Sumino, Satoru Iwasa, Jun Sato, and Toshio Shimizu
- Subjects
Adult ,Male ,Oncology ,PARP Inhibitor ,Cancer Research ,medicine.medical_specialty ,Indazoles ,pharmacokinetics, PARP ,neoplasms ,Cmax ,Poly(ADP-ribose) Polymerase Inhibitors ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Piperidines ,Pharmacokinetics ,Internal medicine ,medicine ,AcademicSubjects/MED00300 ,Humans ,Radiology, Nuclear Medicine and imaging ,030212 general & internal medicine ,Adverse effect ,Aged ,business.industry ,clinical trial ,General Medicine ,Drug holiday ,phase I ,Middle Aged ,medicine.disease ,Clinical trial ,Tolerability ,030220 oncology & carcinogenesis ,Cohort ,Original Article ,Female ,niraparib ,business ,Progressive disease - Abstract
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 Cmax and AUC0–24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax 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., This study investigated the safety of niraparib in Japanese patients with metastatic or locally advanced solid tumours. One patient receiving 300 mg/day developed a dose-limiting toxicity (platelet count decreased)
- Published
- 2021