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

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.

Clinical sequencing identifies potential actionable alterations in a high rate of urachal and primary bladder adenocarcinomas

“…As BRCA positivity was not an inclusion criterion in the study, the BRCA status of patients with UrC is unknown. 13 When considering copy number alterations, MYC amplification was detected at the highest frequency (5/33, 15%) in our UrC cohort, which was lower than that reported in a previous study (6/17, 35%). In addition, we found EGFR amplification in 6% (2/33) of our UrC patients, which was lower than the frequency of 20% reported by Lee et al 19 Furthermore, we found recurrent copy number gains in members of the FGF/FGFR signalling pathway (in four UrC and six PBAC patients).…”

“…However, for UrC and PBAC, only a few published series are available relating to targeted therapies. [10][11][12][13][14] From the perspective of treatment personalization, it is essential to understand the molecular mechanisms as well as the genetic alterations driving tumour development and conferring responses to specific therapies. In the past few years, the mutational pattern of UrC has been intensively investigated, although the number of examined cases and genes remains limited.…”

“…However, for UrC and PBAC, only a few published series are available relating to targeted therapies. 10 , 11 , 12 , 13 , 14 …”

Clinical sequencing identifies potential actionable alterations in a high rate of urachal and primary bladder adenocarcinomas

“…The only report on the use of a PARP inhibitor for the treatment of an UrC patient came from a Japanese phase I dose escalation study of niraparib and described progression during therapy. As BRCA positivity was not an inclusion criterion in the study, the BRCA status of the UrC patient is unknown (13).…”

“…With the lack of clinically proven systemic therapies, targeted treatments based on genomic pro ling and a biological rationale represent a promising personalized strategy for rare cancers. However, for UrC and PBAC, only a few published series are available relating to targeted therapies (10)(11)(12)(13)(14).…”