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

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
progression

- 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
registration

- 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;
GSK110212

- 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