BACKGROUND: Activation of the mitogen-activated protein kinase pathway is 
important for growth of pediatric low-grade gliomas (LGGs). The aim of this 
study was to determine the recommended phase II dose (RP2D) and the 
dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children 
with progressive LGG.
METHODS: Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., 
using the modified continual reassessment method. Pharmacokinetic analysis was 
performed during the first course. BRAF aberrations in tumor tissue were 
determined by real-time polymerase chain reaction and fluorescence in situ 
hybridization.
RESULTS: Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 
and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated 
amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash 
(n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects 
experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, 
the median (range) area under the curve (AUC0-∞) and apparent oral clearance of 
selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 
(3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF 
abnormalities. Among the 5 (20%) of 25 subjects with sustained partial 
responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. 
Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed 
all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least 
stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%.
CONCLUSION: Selumetinib has promising antitumor activity in children with LGG. 
Rash and mucositis were the most common DLTs.