A Phase 1 and Pharmacokinetic Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma
I. To estimate the maximum tolerated dose (MTD) or recommend a Phase II dose of AZD6244
(selumetinib) in children with recurrent or refractory low-grade glioma.
II. To describe the toxicity profile and define the dose limiting toxicity of AZD6244 in
children with recurrent or refractory low-grade glioma.
III. To study the safety of the maximum tolerated dose (MTD) or recommended a Phase II dose
(RP2D) of AZD6244 as determined based on safety data from children >= 12 years of age in
children < 12 years of age. If the MTD/RP2D of the older children is too toxic for the
younger children, we will de-escalate to one dose level below and study the safety of that
dose in the younger age cohort.
IV. To characterize the inter- and intra-patient variability in AZD6244 pharmacokinetics
administered on this schedule in patients < 12 years of age at the MTD/RP2D.
I. To characterize the inter- and intra-patient variability in AZD6244 pharmacokinetics
administered on this schedule and to assess the influence of patient specific covariates
(including concomitant drug therapy) on AZD6244 pharmacokinetics.
II. To evaluate the feasibility of collecting pre-trial tumor samples and the feasibility of
using in situ hybridization assay to identify BRAF aberrations in available tumor specimens.
III. To determine if pre-trial tumor samples show the biochemical signature that indicates
activation of the MAPK pathway.
IV. To describe magnetic resonance imaging (MRI) characteristics of the tumors before and
after treatment and to explore the diffusion changes in the tumors before and after
treatment to determine if there is an early diffusion indicator of response.
V. Within the constraints of a Phase I trial, to document antitumor activity of treatment
with AZD6244, as measured by objective responses and progression-free survival (PFS).
VI. To explore the pharmacogenetic polymorphisms in AZD6244 metabolizing enzymes and
transporters and relate these polymorphisms to AZD6244 pharmacokinetics.
OUTLINE: This is a dose-escalation study.
Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28. Courses repeat
every 28 days for up to 26 courses in the absence of disease progression or unacceptable
After completion of study treatment, patients are followed up for 30 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose and recommended phase 2 dose of selumetinib determined by dose-limiting toxicities
Toxicities will be graded according to CTCAE version 4.0 of the NCI Common Terminology Criteria for Adverse Events CTCAE version 4.0.
Pediatric Brain Tumor Consortium
United States: Food and Drug Administration
|Baylor College of Medicine||Houston, Texas 77030|
|Memorial Sloan Kettering Cancer Center||New York, New York 10021|
|Children's Hospital Los Angeles||Los Angeles, California 90027-0700|
|Children's National Medical Center||Washington, District of Columbia 20010-2970|
|St. Jude Children's Research Hospital||Memphis, Tennessee 38105-2794|
|Cincinnati Children's Hospital Medical Center||Cincinnati, Ohio 45229-3039|
|Children's Hospital of Pittsburgh of UPMC||Pittsburgh, Pennsylvania 15213|
|Duke University Medical Center||Durham, North Carolina 27710|
|Childrens Memorial Hospital||Chicago, Illinois 60614|
|University of California San Francisco Medical Center-Mount Zion||San Francisco, California 94115|
|National Cancer Institute||Bethesda, Maryland 20892-1922|
|Lucile Packard Children's Hospital Stanford University||Palo Alto, California 94304|
|Pediatric Brain Tumor Consortium||Memphis, Tennessee 38105|