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.

Published

Journal Article

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.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.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%.Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

Full Text

Cited Authors

  • Banerjee, A; Jakacki, RI; Onar-Thomas, A; Wu, S; Nicolaides, T; Young Poussaint, T; Fangusaro, J; Phillips, J; Perry, A; Turner, D; Prados, M; Packer, RJ; Qaddoumi, I; Gururangan, S; Pollack, IF; Goldman, S; Doyle, LA; Stewart, CF; Boyett, JM; Kun, LE; Fouladi, M

Published Date

  • August 2017

Published In

Volume / Issue

  • 19 / 8

Start / End Page

  • 1135 - 1144

PubMed ID

  • 28339824

Pubmed Central ID

  • 28339824

Electronic International Standard Serial Number (EISSN)

  • 1523-5866

International Standard Serial Number (ISSN)

  • 1523-5866

Digital Object Identifier (DOI)

  • 10.1093/neuonc/now282

Language

  • eng