Sunitinib Malate in Treating Younger Patients With Recurrent, Refractory, or Progressive Malignant Glioma or Ependymoma

PRIMARY OBJECTIVES:

I. To estimate the objective response rate (partial response [PR] or complete response [CR]
≥ 8 weeks) to sunitinib in 2 strata (recurrent/progressive/refractory high-grade glioma vs
ependymoma) of recurrent or progressive brain tumors in pediatric and young adult patients.

SECONDARY OBJECTIVES:

I. To explore and report descriptively the safety and tolerability of sunitinib in pediatric
and young adult brain tumor patients who have not received prior anthracycline or
radiotherapy involving the heart.

II. To describe the pharmacokinetic profile of pediatric and young adult patients taking
sunitinib malate.

III. To describe the cumulative toxicities of sunitinib when administered over multiple
courses to pediatric and young adult patients.

IV. To estimate progression-free survival (PFS) distributions for these cohorts of patients.

V. To evaluate changes in phosphorylation of PDGFR-α and -β, MEK/ERK, S6 kinase, and AKT in
peripheral blood mononuclear cells and explore possible associations between these changes
and outcome measures.

VI. To evaluate plasma levels of soluble isoforms of VEGFR-1 and -2 prior to initiation of
therapy and at points during therapy as an exploration of possible biomarkers of clinical
response.

VII. To evaluate and report descriptively the expression and ratio of VEGF isoforms in tumor
tissue, as available.

VIII. To evaluate and report descriptively the genotype, expression, and possible
amplification of KIT and PDGFR-α and -β in tumor tissue, as available.

OUTLINE: This is a multicenter study.

Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Treatment
repeats every 42 days for up to 18 courses in the absence of disease progression or
unacceptable toxicity.

Patients may undergo blood sample collection at baseline and during courses 1 and 2 for
pharmacokinetic and pharmacodynamic studies. Tissue samples from diagnosis and surgical
resection may be also collected.

After completion of study treatment, patients are followed up for up to 5 years.

Inclusion Criteria:

- Patients must be diagnosed with ependymoma or high-grade glioma (World Health
Organization [WHO] grade III/IV):

- Stratum A: recurrent/progressive/refractory malignant glioma (i.e., anaplastic
astrocytoma, glioblastoma multiforme [including giant cell and gliosarcoma
types], anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or anaplastic
ganglioglioma) within the brain with or without spinal cord disease

- Stratum B: recurrent/progressive/refractory ependymoma (including ependymoma
variants) within the brain with or without spinal cord disease

- Patients with diffuse intrinsic pontine glioma are not eligible

- A histological diagnosis from either the initial presentation or at the time of
recurrence is required

- Patients must have radiographically documented measurable disease in the brain,
defined as at least one lesion that can be accurately measured in at least 2 planes

- To document the degree of residual tumor, the following must be obtained:

- All patients must have a brain MRI with and without gadolinium and a spine
magnetic resonance imaging (MRI), if clinically indicated,with and without
gadolinium, performed within 2 weeks prior to study enrollment

- Patients with evidence of new central nervous system (CNS) hemorrhage of more
than punctate size and/or more than 3 foci of punctate hemorrhage on baseline
MRI obtained within 14 days prior to study enrollment are not eligible

- Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2 (use
Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age)

- Neurological deficits in patients must have been relatively stable for a minimum
of 1 week prior to study enrollment; patients who are unable to walk because of
paralysis, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score

- Peripheral absolute neutrophil count (ANC) ≥ 1,000/μL

- Platelet count ≥ 75,000/μL (transfusion independent, defined as not receiving
platelet transfusions within the 7-day period prior to enrollment)

- Hemoglobin ≥ 8.0 g/dL (may receive red blood cell [RBC] transfusions)

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min OR
serum creatinine based on age/gender as follows:

- 0.4 mg/dL (1 month to < 6 months of age)

- 0.5 mg/dL (6 months to < 1 year of age)

- 0.6 mg/dL (1 to < 2 years of age)

- 0.8 mg/dL (2 to < 6 years of age)

- 1.0 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT/AST) and serum glutamic pyruvic
transaminase (SGPT/ALT) ≤ 2.5 times ULN

- Shortening fraction of ≥ 27% by echocardiogram OR ejection fraction of ≥ 50% by
radionuclide angiogram

- Corrected QT interval < 450 msec (males) or < 470 msec (females)

- Prothrombin time (PT) / international normalized ratio (INR) ≤ 1.5 times ULN

- Partial thromboplastin time (PTT) ≤ 1.5 times ULN

- Patients must not have a history of cardiac disease including, but not limited to:

- Uncontrolled hypertension within 12 months prior to enrollment; uncontrolled
hypertension is defined as follows:

- Patients aged ≤ 17 years: greater than 95th percentile systolic and
diastolic blood pressure based on age and height which is not controlled by
one anti-hypertensive medication

- Patients aged > 17 years: systolic blood pressure ≥ 140 mm Hg and/or
diastolic blood pressure ≥ 90 mm Hg which is not controlled by one
anti-hypertensive medication

- Ongoing cardiac dysrhythmias ≥ grade 2 or atrial fibrillation of any grade

- Unstable angina, symptomatic congestive heart failure, or myocardial infarction

- Patients with a seizure disorder may be enrolled if on non-enzyme-inducing
anticonvulsants and well controlled

- Commonly used non-enzyme-inducing anticonvulsants include: gabapentin,
lamotrigine, levetiracetam, tiagabine, topiramate, valproic acid, and zonisamide

- Patients must not have had a cerebrovascular accident or transient is chemic attack
within 12 months prior to enrollment

- Patients must not have had a pulmonary embolism or other significant thromboembolic
event within 12 months prior to enrollment

- Patients must not have had grade ≥ 3 hemorrhage within 4 weeks prior to enrollment

- Patients must not have had any of the following diagnoses within 6 months prior to
enrollment: peptic ulcer disease, inflammatory bowel disease, or diverticulitis

- Patients with a diagnosis of abdomen fistula, gastrointestinal (GI) perforation, or
intra-abdominal abscess within 6 months prior to enrollment are not eligible

- Patients who have an uncontrolled infection are not eligible

- Patients with hypothyroidism that has not been well-controlled by medications for at
least 2 weeks prior to study entry are not eligible

- Patients who have a personal history of genetic and/or congenital cardiac
abnormalities are not eligible

- Patients who have a history of allergic reactions to compounds of similar chemical or
biological composition to sunitinib are not eligible

- Patients who have any other condition that could result in an inability to swallow
capsules/sprinkles or absorb oral sunitinib administered through a gastric tube are
not eligible

- Patients with body surface area < 0.55 m^2 or > 2.18 m^2 are not eligible

- Female patients who are pregnant are not eligible

- Lactating females are not eligible unless they have agreed not to breastfeed their
infants

- Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained within the past 4 weeks

- Sexually active patients of reproductive potential are not eligible unless they have
agreed to use an effective contraceptive method for the duration of their study
participation

- No concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), clopidogrel,
warfarin, heparin, low molecular weight heparin, dipyridamole, or aspirin therapy >
81 mg/day

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy (RT) prior to entering this study

- Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto
this study (6 weeks if prior nitrosourea)

- At least 7 days since the completion of therapy with a biologic agent; for agents
that have known adverse events occurring beyond 7 days after administration, this
period must be extended beyond the time during which adverse events are known to
occur

- At least 3 half-lives must have elapsed since prior therapy that included a
monoclonal antibody

- At least 24 weeks must have elapsed if prior full-field RT

- ≥ 2 weeks must have elapsed if prior local palliative RT (small port) or
limited-field RT

- ≥ 3 months must have elapsed since prior stem cell transplant (SCT) or rescue
with total-body irradiation (TBI)

- No evidence of active graft-vs-host disease

- Patients who are receiving dexamethasone must be on a stable or decreasing dose for
at least 7 days prior to enrollment

- Patients must not have received potent cytochrome P450-3A4 (CY3A4) inhibitors and/or
inducers within 7 days prior to study enrollment and potent inducers within 12 days
prior to study enrollment and during study

- At least 7 days must have elapsed since the completion of therapy with a
hematopoietic growth factor

- Patients who have previously received sunitinib or who have received other VEGF-,
PDGFR-, or KIT-targeted therapy are not eligible

- Patients who received bevacizumab as part of their prior therapy may enroll on
study

- Patients must not have received more than 2 prior chemotherapy and/or RT regimens;
for example, 1 initial treatment course of chemotherapy and/or RT (counts as 1
treatment course) and at relapse may have received 1 treatment course of chemotherapy
and/or RT (counts as 1 treatment course)

- Patients who received prior therapy with known risk for cardiovascular complications
(e.g., anthracycline therapy or prior RT that included the heart and/or craniospinal
radiation) are not eligible

- Patients receiving ongoing treatment with therapeutic doses (i.e., therapeutic INR
levels) of coumarin derivatives or oral anti-vitamin K agents are not eligible

- Patients receiving antiretroviral therapy for human immunodeficiency virus (HIV)
disease are not eligible

- Patients who are started on protocol therapy on a phase II study prior to study
enrollment are considered ineligible

- No other concurrent chemotherapy, investigational agents, or immunomodulating agents

- No concurrent RT