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 in: Neuro-oncology (Charlottesville, Va.) Vol. 19; no. 8; pp. 1135 - 1144
• Main Authors: Banerjee, Anuradha, Jakacki, Regina I., Onar-Thomas, Arzu, Wu, Shengjie, Nicolaides, Theodore, Young Poussaint, Tina, Fangusaro, Jason, Phillips, Joanna, Perry, Arie, Turner, David, Prados, Michael, Packer, Roger J., Qaddoumi, Ibrahim, Gururangan, Sridharan, Pollack, Ian F., Goldman, Stewart, Doyle, Lawrence A., Stewart, Clinton F., Boyett, James M., Kun, Larry E., Fouladi, Maryam
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2017
• Subjects: Adolescent; Benzimidazoles - pharmacokinetics; Benzimidazoles - therapeutic use; Brain Neoplasms - drug therapy; Child; Child, Preschool; Clinical Investigations; 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; selumetinib; phase I trial; low-grade glioma
• ISSN: 1522-8517; 1523-5866; 1523-5866
• DOI: 10.1093/neuonc/now282

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.