Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

PRIMARY OBJECTIVES:

I. Estimate the rates of objective response observed prior to disease progression during the
first four courses of treatment with bevacizumab and irinotecan hydrochloride in pediatric
patients with recurrent, progressive, or refractory malignant glioma (Stratum A [closed to
accrual as of 4/21/2009]) or recurrent/progressive/refractory intrinsic brain stem glioma
(Stratum B [closed to accrual as of 4/21/2009]).

II. Estimate the rates of objective response observed prior to disease progression during the
first four courses of treatment with bevacizumab and irinotecan hydrochloride in patients
with recurrent or progressive medulloblastoma (Stratum C [closed to accrual as of
10/27/2009]) or recurrent or progressive ependymoma (Stratum D [closed to accrual as of
7/29/2010]).

III. Estimate the sustained disease stabilization rate associated with bevacizumab and
irinotecan in patients with recurrent or progressive low grade glioma (Stratum E [closed to
accrual as of 7/29/2010]).

SECONDARY OBJECTIVES:

I. Estimate the rate of treatment-related toxicity of this regimen in these patients.

II. Estimate the cumulative incidence of sustained objective responses as a function of this
regimen in these patients.

III. Estimate the distributions of survival and event-free survival of these patients.

IV. Correlate functional changes in tumor with progression-free survival and response using
MR perfusion/diffusion imaging and fludeoxyglucose F 18 positron emission tomography.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor type
(high-grade glioma [closed to accrual as of 4/21/2009] vs intrinsic brain stem tumor [closed
to accrual as of 4/21/2009] vs medulloblastoma [closed to accrual as of 10/27/2010] vs
ependymoma [closed to accrual as of 7/29/2010] vs low grade glioma [closed to accrual as of
7/29/2010]).

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan
hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab
and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats
every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable
toxicity.

Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and
fludeoxyglucose F 18 positron emission tomography at baseline and periodically during
treatment.

After completion of study treatment, patients are followed for 30 days and then every 3
months for up to 2 years.

Inclusion Criteria:

- Histologically confirmed high-grade glioma (WHO grade III or IV) at any site within
the brain, including the following:

- Anaplastic astrocytoma

- Glioblastoma multiforme (including giant cell and gliosarcoma subtypes)

- Anaplastic oligodendroglioma

- Anaplastic ganglioglioma

- Anaplastic oligoastrocytoma

- Diffuse brain stem glioma

- Histologic confirmation not required

- Histologically confirmed medulloblastoma

- Histologically confirmed ependymoma

- Primary spinal cord malignant glioma with measurable metastatic disease within
the brain

- Histologic confirmation required

- Neuraxis dissemination allowed provided there is bidimensionally measurable
disease within the brain and spinal cord

- Low grade glioma at any site within the brain with or without spinal cord disease

- Recurrent, progressive, or refractory disease (must have received prior
chemoradiotherapy)

- No more than 2 prior chemotherapy regimens following relapse

- Bidimensionally measurable disease, defined as ≥ 1 lesion that can be accurately
measured in ≥ 2 planes

- If there is spinal cord disease as well, response assessment will be based only upon
the measurable tumor in the brain

- No diffuse gliomatosis cerebri with < 1 discrete, measurable lesion

- No evidence of new symptomatic CNS hemorrhage (> grade 2) within the past 2 weeks

- No central non-cerebellar PNET's (e.g., cerebral PNET or pineoblastoma)

- No spinal cord tumors only

- Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤
16 years of age)

- Absolute neutrophil count ≥ 1,500/mm³ (unsupported)

- Platelet count ≥ 100,000/mm³ (unsupported)

- Hemoglobin > 8 g/dL (support allowed)

- Creatinine normal

- BUN < 25 mg/dL

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST ≤ 3 times ULN

- Neurological deficits must be stable for ≥ 1 week prior to study entry

- No active renal, cardiac (congestive cardiac failure, myocarditis), or pulmonary
disease

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 6 months after
completion of study treatment

- No clinically significant unrelated systemic illness that would preclude study
treatment, including any of the following:

- Serious infections

- Significant cardiac, pulmonary, hepatic, or other organ dysfunction

- No uncontrolled systemic hypertension, defined as systolic blood pressure (BP)
and/or diastolic BP > 95th percentile for age

- No stroke, myocardial infarction, or unstable angina within the past 6 months

- No clinically significant peripheral vascular disease

- No significant traumatic injury within the past 6 weeks

- No evidence of bleeding diathesis, coagulopathy, or PT INR > 1.5

- Urine protein/creatinine ratio ≤ 1.0

- No abdominal fistula or gastrointestinal perforation within the past 6 months

- No serious nonhealing wound, ulcer, or bone fracture

- At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for
nitrosoureas)

- At least 7 days since prior investigational or biologic agents (3 weeks if patient
experienced ≥ grade 2 myelosuppression or if agent has a prolonged half-life)

- More than 7 days since prior minor surgery

- More than 12 weeks since prior craniospinal or focal irradiation to primary tumor or
other sites

- At least 4 weeks since prior major surgery and recovered

- At least 3 months since prior autologous bone marrow or stem cell transplantation

- At least 2 weeks since prior colony-forming growth factors (i.e., filgrastim [G-CSF],
sargramostim [GM-CSF], epoetin alfa)

- No prior bevacizumab or irinotecan hydrochloride

- No anticipated surgery during treatment

- No concurrent prophylactic G-CSF, GM-CSF, or epoetin alfa

- Concurrent dexamethasone allowed provided the dose is stable or decreasing over the
past week

- No other concurrent anticancer or investigational drugs

- No concurrent medications that may interfere with study (e.g., immunosuppressive
agents other than corticosteroids)

- No concurrent therapeutic anticoagulation

- No concurrent nonsteroidal anti-inflammatory drugs, clopidogrel bisulfate,
dipyridamole, or acetylsalicylic acid (aspirin) > 81 mg/day