Journal
NEURO-ONCOLOGY
Volume 19, Issue 8, Pages 1135-1144Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/now282
Keywords
low-grade glioma; phase I trial; selumetinib
Categories
Funding
- National Institutes of Health [U01 CA 81457]
- American-Lebanese Syrian Associated Charities (ALSAC)
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Background. Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric lowgrade 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/m(2)/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/m(2)/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/m(2)/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 (AUC(0-infinity)) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng x h/mL) and 6.5 L x h(-1) x m(-2) (3.4 to 14.0 L x h(-1) x 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.
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