Selumetinib Granules Match Capsule Pharmacokinetics in Pediatric NF1-PN Study

The SPRINKLE phase 1/2 clinical trial (NCT05309668) evaluated a novel granule formulation of selumetinib (Koselugo), a potent MEK1/2 inhibitor, for pediatric patients with neurofibromatosis type 1-related plexiform neurofibromas (NF1-PN) who are unable to swallow capsules. The study successfully met its primary end points, demonstrating that the granule formulation (at a 25 mg/m² twice-daily dose) provides drug exposure comparable with the established capsule formulation in the pivotal SPRINT (NCT01362803) study.^1–3

Comparability was established if the 95% confidence intervals (CIs) of the granule formulation's geometric mean area under the curve (AUC₀₋₁₂) fell within a predefined acceptance range (60%-140%) of the SPRINT study's value (2,009 h·ng/mL).

Selumetinib was rapidly absorbed from the granule formulation, with the median time to maximum concentration observed at approximately 2 hours after dosing. The median duration of exposure was approximately 11 months (329.5 days), with a range of 2.7 to 25.3 months (83 to 771 days).

The exposure of the active metabolite, N-desmethyl selumetinib, was also within the acceptance range based on SPRINT study data, representing approximately 7%-8% of the parent selumetinib exposure.

No clear correlation was found between key exposure parameters and age. While exposure generally increased with increasing body surface area at steady state, the exposure ranges were widely overlapping across groups.

Safety and Tolerability

Key findings also indicate a manageable safety profile consistent with previous selumetinib studies and the known safety profile of the capsule formulation, with most adverse events (AEs) being mild to moderate (grade 1 or 2) and none leading to treatment discontinuation or dose reduction. All 36 patients reported at least 1 treatment-emergent AE, and 35 patients (97.2%) had a treatment-related AE. The most common AEs of any cause were pyrexia and dry skin (17 patients each; 47.2%). The most common treatment-related AE was paronychia (n = 16; 44.4%).

Most AEs were mild (grade 1) or moderate (grade 2). Four patients (11.1%) experienced a grade 3 AE (2 of which were treatment-related: paronychia and increased blood creatine phosphokinase). No grade 4 or grade 5 AEs were reported. Two patients (5.6%) experienced serious AEs (pyrexia, gastroenteritis, and upper respiratory tract infection), none of which were deemed related to selumetinib.

No patients discontinued treatment or required a dose reduction due to AEs. Eleven patients (30.6%) had a temporary dose interruption due to an AE, but these were typically of short duration and did not substantially affect overall dose intensity.

These results establish the selumetinib granule formulation as a suitable and viable treatment for pediatric patients aged 1 year and older with symptomatic, inoperable NF1-PN, leading to its approval by the FDA on September 10, 2025. In November 2025, the FDA approved selumetinib for adult patients with NF1-PN.

Based on these findings, the selumetinib granule formulation provides a critical new treatment option for pediatric patients aged 1 year and older with symptomatic, inoperable NF1-PN, expanding access to this targeted therapy for the youngest and most vulnerable patients.

Palatability

Furthermore, parent-reported assessments confirmed high palatability when mixed with soft food, with most children swallowing the medication without issue and acceptance improving over time. Palatability generally improved between cycle 1 and cycle 7; reports of resistance to swallowing decreased from 16.1% to 4.3%, incidents of spitting out medication decreased from 3.2% to 0.0%, and there were no reports of medication being vomited.

The medication was successfully taken in 90.5% of expected administrations (811 out of 896). In cases where the medication was taken, patients could swallow it without problems 82.4% of the time (668 out of 811).

“Initial results of parent-reported palatability assessments demonstrated high acceptance of swallowing selumetinib granules when added to a soft food vehicle,” noted Driever et al, authors of the study. “The proportion of responses suggesting swallowing resistance and other swallowing problems was lower in [cycle] 7 than in [cycle] 1, showing that palatability may improve over time, and demonstrating that administration of a granule formulation could circumvent potential issues with swallowing capsules that may be present in young children. Therefore, parents should not necessarily be deterred if their child struggles with taking the granule formulation at first.”

Study Rationale and Overview

Selumetinib is a highly selective oral inhibitor of MEK1/2, which blocks key signaling pathways to prevent PN growth and reduce tumor volume. A capsule formulation of selumetinib was previously approved for pediatric patients (age ≥2 or ≥3 years, depending on the region) based on the SPRINT study, which demonstrated durable tumor shrinkage and a manageable safety profile.

However, a critical unmet need exists for young children and those with NF1-related swallowing difficulties, as the capsules cannot be chewed, dissolved, or opened. To address this, a granule formulation was developed, designed to be mixed with soft food. The SPRINKLE trial was initiated to assess the PK, safety, and palatability of this new formulation in children aged ≥1 to <7 years.

The SPRINKLE study is a phase 1/2 trial whose primary end point was to assess the PK and safety of the selumetinib granule formulation. Secondary end points included further PK assessment of selumetinib and its active metabolite, N-desmethyl selumetinib, and an evaluation of palatability. The results presented are from the first data cutoff (April 8, 2024), after all participants had completed at least 3 28-day treatment cycles.

Study Design and Patient Characteristics

The trial had a total enrollment of 36 patients with symptomatic, inoperable NF1-PN, placed into 3 cohorts. All patients received a selumetinib granule formulation dose equivalent to 25 mg/m², administered twice daily.

• Global cohort 1: 15 patients, aged ≥4 to <7 years.
• Global cohort 2: 17 patients, aged ≥1 to <4 years.
• Japan cohort: 4 patients, aged ≥1 to <7 years.

The total study population had a median age of 3.9 years, with 61.1% being male and 61.1% being White. The most common AEs associated with the target PNs at baseline were disfigurement (72.2%), pain (44.4%), and airway issues (25.0%).

REFERENCES

1.Driever P, Kordes U, Brecht I, et al. Pharmacokinetics and safety of selumetinib granule formulation in children with symptomatic, inoperable neurofibromatosis typ 1-related plexiform neurofibromas (SPRINKLE; phase I/II). J Clin Oncol. Published January 27, 2026. Accessed January 29, 2026.doi: 10.1200/JCO-25-01447.

2.Pharmacokinetics, safety and efficacy of the selumetinib granule formulation in children aged ≥1 to <7 years with NF1-related symptomatic, inoperable PN (SPRINKLE). ClinicalTrials.gov. Updated December 18, 2025. Accessed January 29, 2026. https://clinicaltrials.gov/study/NCT05309668

3.AZD6244 hydrogen sulfate for children with nervous system tumors. ClinicalTrials.gov. Updated January 16, 2026. Accessed January 29, 2026. https://clinicaltrials.gov/study/NCT01362803