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

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

Anuradha Banerjee  1 , Regina I Jakacki  1 , Arzu Onar-Thomas  1 , Shengjie Wu  1 , Theodore Nicolaides  1 , Tina Young Poussaint  1 , Jason Fangusaro  1 , Joanna Phillips  1 , Arie Perry  1 , David Turner  1 , Michael Prados  1 , Roger J Packer  1 , Ibrahim Qaddoumi  1 , Sridharan Gururangan  1 , Ian F Pollack  1 , Stewart Goldman  1 , Lawrence A Doyle  1 , Clinton F Stewart  1 , James M Boyett  1 , Larry E Kun  1 , Maryam Fouladi  1
Affiliations
Clinical Trial

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

Anuradha Banerjee et al. Neuro Oncol. .

Abstract

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.

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Figures

Fig. 1
Fig. 1
(A) DLT, dose de-escalation and time on-treatment summary. (B) Response and progression-free survival summary.
Fig. 2
Fig. 2
(A) Percent change in FLAIR volume from baseline by central review. (B) Percent change in contrast-enhancing tumor volume from baseline by central review.
See this image and copyright information in PMC

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