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.
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%.


CONCLUSIONS
Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Anuradha
A
Banerjee
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Regina I
RI
Jakacki
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Arzu
A
Onar-Thomas
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Shengjie
S
Wu
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Theodore
T
Nicolaides
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Tina
T
Young Poussaint
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Jason
J
Fangusaro
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Joanna
J
Phillips
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Arie
A
Perry
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
David
D
Turner
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Michael
M
Prados
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Roger J
RJ
Packer
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Ibrahim
I
Qaddoumi
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Sridharan
S
Gururangan
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Ian F
IF
Pollack
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Stewart
S
Goldman
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Lawrence A
LA
Doyle
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Clinton F
CF
Stewart
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
James M
JM
Boyett
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Larry E
LE
Kun
University of California San Francisco, San Francisco, California; Boston Children's Hospital, Boston, Massachusetts; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; St Jude Children's Research Hospital, Memphis, Tennessee; Lurie Children's Hospital, Chicago, Illinois; Children's National Medical Center, Washington, DC; Duke University Medical Center, Durham, North Carolina; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Maryam
M
Fouladi
D000293:Adolescent; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*
C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases
low-grade glioma; phase I trial; selumetinib