Pharmacokinetics and Safety of Selumetinib Granule Formulation in Children With Symptomatic, Inoperable Neurofibromatosis Type 1-Related Plexiform Neurofibromas (SPRINKLE; phase I/II).
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PURPOSE: Neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN) can substantially affect quality of life. The capsule and granule formulations of selumetinib (ARRY-142886, AZD6244) are approved for pediatric patients with symptomatic, inoperable NF1-PN (age ≥1 to 3 years, region dependent). SPRINKLE (ClinicalTrials.gov identifier: NCT05309668) assessed pharmacokinetics (PK), safety, and palatability of the selumetinib granule formulation in children (age ≥1 to <7 years) with symptomatic, inoperable NF1-PN. METHODS: Participants enrolled into Global Cohort (GC)1 (≥4 to <7 years), GC2 (≥1 to <4 years), or the Japan Cohort (JC; ≥1 to <7 years) received selumetinib 25 mg/m2 (dose equivalent) twice a day in 28-day cycles. Primary objectives assessed single-dose selumetinib PK exposure (area under concentration-time curve from time 0-12 hours [AUC0-12]) in GCs and selumetinib safety. Secondary objectives assessed selumetinib and N-desmethyl selumetinib metabolite PK (single/multiple dose), and palatability. At first data cutoff (April 8, 2024), all participants had completed ≥3 cycles. RESULTS: There were 36 participants (GC1: n = 15, GC2: n = 17, JC: n = 4). Geometric mean (95% CI) selumetinib AUC0-12 (single dose) in GC1 (n = 13) and GC2 (n = 15) was 1,902 (1,647 to 2,197) and 1,699 (1,436 to 2,009) h × ng/mL, respectively. Primary PK end point was met: 95% CIs of AUC0-12 (single dose) were within the acceptance range on the basis of the capsule formulation exposure. Median duration of exposure was approximately 11 months (range, 2.7-25.3). 97.2% of participants had ≥1 treatment-related adverse event; most were grade 1 or 2 and none led to discontinuation or dose reduction. Most participants reported swallowing the medication without problems. CONCLUSION: Selumetinib granule formulation (25 mg/m2 dose equivalent, twice a day) had comparable exposure to selumetinib capsule formulation, and was palatable with a manageable safety profile. Selumetinib granule formulation is potentially suitable for young children with NF1-PN who cannot swallow capsules.