TY - JOUR
T1 - A phase i trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma
T2 - A Pediatric Brain Tumor Consortium (PBTC) study
AU - Banerjee, Anuradha
AU - Jakacki, Regina I.
AU - Onar-Thomas, Arzu
AU - Wu, Shengjie
AU - Nicolaides, Theodore
AU - Young Poussaint, Tina
AU - Fangusaro, Jason
AU - Phillips, Joanna
AU - Perry, Arie
AU - Turner, David
AU - Prados, Michael
AU - Packer, Roger J.
AU - Qaddoumi, Ibrahim
AU - Gururangan, Sridharan
AU - Pollack, Ian F.
AU - Goldman, Stewart
AU - Doyle, Lawrence A.
AU - Stewart, Clinton F.
AU - Boyett, James M.
AU - Kun, Larry E.
AU - Fouladi, Maryam
N1 - Publisher Copyright:
© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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/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.
AB - 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/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.
KW - low-grade glioma
KW - phase I trial
KW - selumetinib
UR - http://www.scopus.com/inward/record.url?scp=85026920103&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026920103&partnerID=8YFLogxK
U2 - 10.1093/neuonc/now282
DO - 10.1093/neuonc/now282
M3 - Article
C2 - 28339824
AN - SCOPUS:85026920103
SN - 1522-8517
VL - 19
SP - 1135
EP - 1144
JO - Neuro-oncology
JF - Neuro-oncology
IS - 8
ER -