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A Phase 1 and Pharmacokinetic Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

Phase 1
3 Years
21 Years
Open (Enrolling)
Childhood Low-grade Cerebellar Astrocytoma, Childhood Low-grade Cerebral Astrocytoma, Childhood Mixed Glioma, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Oligodendroglioma, Recurrent Childhood Visual Pathway and Hypothalamic Glioma, Recurrent Childhood Visual Pathway Glioma

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Trial Information

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.

Inclusion Criteria:

- Patients with a histologically confirmed diagnosis of low grade gliomas (World Health
Organization [WHO] Grades I and II) that is recurrent or refractory; patients with
optic pathway gliomas are eligible with clinical and/or radiographic evidence of

- Patients must have received prior therapy other than surgery and must have fully
recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or
radiotherapy prior to entering this study

- Patients must have received their last dose of known myelosuppressive anticancer
chemotherapy at least three weeks prior to study registration or at least six weeks
if nitrosourea

- Patient must have recovered from any acute toxicity potentially related to the agent
and received their last dose of the biologic agent >= 7 days prior to study
registration; for biologic agents that have a prolonged half-life, at least three
half-lives must have elapsed prior to registration

- Monoclonal antibody treatment: At least three half-lives must have elapsed prior to

- Radiation: Patients must have:

- Had their last fraction of local irradiation to primary tumor >= 12 weeks prior
to registration; investigators are reminded to review potentially eligible cases
to avoid confusion with pseudo-progression

- Had their last fraction of craniospinal irradiation (> 24 Gy) or total body
irradiation > 3 months prior to registration

- Bone Marrow Transplant: Patient must be:

- >= 6 months since allogeneic bone marrow transplant prior to registration

- >= 3 months since autologous bone marrow/stem cell prior to registration

- Corticosteroids: Patients who are receiving dexamethasone must be on a stable or
decreasing dose for at least 1 week prior to registration

- Growth factors: Off all colony forming growth factor(s) for at least 1 week prior to
registration (filgrastim, sargramostim, erythropoietin) and at least 2 weeks for
long-acting formulations

- Patients treated at 25 mg/m^2/dose BID must have body surface area (BSA) >= 0.55 m^2

- Patients with neurological deficits should have deficits that are stable for a
minimum of 1 week prior to registration

- Patients must be able to swallow capsules

- Karnofsky Performance Scale (for > 16 yrs of age) or Lansky Performance Score (for =<
16 years of age) >= 60 assessed within two weeks prior to registration

- Absolute neutrophil count >= 1,000/µL (unsupported)

- Platelets >= 100,000/µL (unsupported)

- Hemoglobin >= 8 g/dL (may be supported)

- Total bilirubin < 1.5 times upper limit of normal for age

- Aspartate aminotransferase (AST)(serum glutamic oxalo-acetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal for age

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 or a serum creatinine based on age as follows:

- =< 5 years: 0.8 mg/dL

- > 5 years but =< 10 years:1 mg/dL

- > 10 years but =< 15 years: 1.2 mg/dL

- >15 years: 1.5 mg/dL

- Sodium, potassium, calcium and magnesium within the institutional limits of normal

- Albumin >= 3 g/dL

- Female patients of childbearing potential must not be pregnant or breast-feeding;
female patients of childbearing potential must have a negative serum or urine
pregnancy test

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation, and for four weeks after dosing with
selumetinib ceases; women of child-bearing potential must have a negative pregnancy
test prior to entry; should a woman become pregnant or suspect she is pregnant while
she or her partner is participating in this study, she should inform her treating
physician immediately; please note that the selumetinib manufacturer recommends that
adequate contraception for male patients should be used for 16 weeks post-last dose
due to sperm life cycle

- Ability to understand and the willingness to sign a written informed consent document
according to institutional guidelines

Exclusion Criteria:

- Patients with any clinically significant unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction),
likely to interfere with the study procedures or results

- Patients who are receiving any other anticancer or investigational agents

- Patients with uncontrolled seizures are not eligible for the study

- Previous MEK inhibitor use such as PD-0325901; CI1040; AS73026; GDC 0973; ARRY43182;

- Prior treatment with a BRAF inhibitor

- Patients with QTc interval > 450 msecs or other factors that increase the risk of QT
prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history
of long QT interval syndrome) including heart failure that meets New York Heart
Association (NYHA) class III and IV definitions

- Required use of a concomitant medication that can prolong the QT interval

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to selumetinib

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose and recommended phase 2 dose of selumetinib determined by dose-limiting toxicities

Outcome Description:

Toxicities will be graded according to CTCAE version 4.0 of the NCI Common Terminology Criteria for Adverse Events CTCAE version 4.0.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Anuradha Banerjee

Investigator Role:

Principal Investigator

Investigator Affiliation:

Pediatric Brain Tumor Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

April 2010

Completion Date:

Related Keywords:

  • Childhood Low-grade Cerebellar Astrocytoma
  • Childhood Low-grade Cerebral Astrocytoma
  • Childhood Mixed Glioma
  • Recurrent Childhood Brain Stem Glioma
  • Recurrent Childhood Cerebellar Astrocytoma
  • Recurrent Childhood Cerebral Astrocytoma
  • Recurrent Childhood Oligodendroglioma
  • Recurrent Childhood Visual Pathway and Hypothalamic Glioma
  • Recurrent Childhood Visual Pathway Glioma
  • Astrocytoma
  • Glioma
  • Oligodendroglioma
  • Optic Nerve Glioma



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