| Popis: |
Background Plexiform neurofibromas (PN) are a manifestation of neurofibromatosis type 1 (NF1) that may cause morbidity and impact health-related quality of life (HRQoL). Selumetinib (ARRY-142886, AZD6244) is an orally available, selective, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor approved for children with NF1 and symptomatic, inoperable PN in regions including the USA (aged ≥2 years), EU (≥3 years), and Japan (≥3 years). This open-label, single-arm, phase 1 study evaluated selumetinib in Japanese children with NF1 and symptomatic, inoperable PN. Methods Eligible patients (aged 3–18 years) received oral selumetinib (25 mg/m 2 BID) continuously in 28-day cycles in a fasted state. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, efficacy, PN-related morbidities, and HRQoL. Results Twelve patients (median age 13.3 years) were enrolled, received ≥1 selumetinib dose (data cut-off: Cycle 13 Day 1) with median follow-up of 11.5 months. All patients had baseline PN-related morbidities, most commonly disfigurement (91.7%) and pain (58.3%). Most frequently reported any-grade adverse events were dermatologic and gastrointestinal. Objective response rate was 33.3%; median duration of response was not reached. Most patients (83.3%) had target PN volume reduction versus baseline. No patients reported worsening of PN-related morbidities. Selumetinib was rapidly absorbed with moderate-to-high inter-patient variability in maximum plasma concentration (Cmax) and area under the concentration–time curve from time 0–6 hours (AUC)0–6. Conclusions Consistent with results of the phase 2 SPRINT trial, 25 mg/m 2 selumetinib BID was well tolerated with a manageable safety profile in Japanese children with NF1 and symptomatic, inoperable PN. |
