A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study

Neuro Oncol. 2017 Aug 1;19(8):1135-1144. doi: 10.1093/neuonc/now282.


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.

Keywords: low-grade glioma; phase I trial; selumetinib.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / therapeutic use*
  • Brain Neoplasms / drug therapy*
  • Child
  • Child, Preschool
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Female
  • Glioma / drug therapy*
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / drug therapy
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*


  • AZD 6244
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinases