Temozolomide and Irinotecan Hydrochloride With or Without Bevacizumab in Treating Young Patients With Recurrent or Refractory Medulloblastoma or CNS Primitive Neuroectodermal Tumors

PRIMARY OBJECTIVES:

l. To compare the overall survival (OS) of subjects receiving the combination of temozolomide
and irinotecan with that of subjects receiving temozolomide, irinotecan (irinotecan
hydrochloride), and bevacizumab for recurrent medulloblastoma (MB)/primitive neuroectodermal
tumor (PNET) of childhood.

SECONDARY OBJECTIVES:

I. To assess the response rate for each treatment arm amongst patients who are enrolled with
measurable disease.

II. To determine event-free survival (EFS) for each patient compared across regimens.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive temozolomide orally (PO) and irinotecan hydrochloride IV over 90
minutes on days 1-5.

ARM II: Patients receive temozolomide PO and irinotecan hydrochloride IV as in arm I and
bevacizumab IV over 30-90 minutes on days 1 and 15.

In both arms, treatment repeats every 28 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.

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

Inclusion Criteria:

- Medulloblastoma or PNET of childhood that has relapsed or become refractory to
standard chemotherapy; patients with pineoblastoma are eligible

- Patients must have had histologic verification of the malignancy at original diagnosis
or at the time of recurrence

- Patients must have clear residual disease, defined as tumor that is measurable in two
perpendicular diameters on magnetic resonance imaging (MRI) OR diffuse leptomeningeal
disease OR clear MRI evidence of disease that may not be measurable in two
perpendicular diameters

- All patients must have a brain MRI with and without gadolinium and a spine MRI with
gadolinium performed within 2 weeks prior to study enrollment

- Patients must have a Lansky or Karnofsky performance status score of >= 50%,
corresponding to Eastern Cooperative Oncology Group (ECOG) categories of 0, 1, or 2
(use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of
age)

- Patients must have a life expectancy of >= 8 weeks

- Patients must have experienced at least one and at most two relapses prior to study
enrollment; patients with primary refractory disease are eligible

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

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

- Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
with a biologic agent; at least 3 weeks for biologic agents with a long half
life, such as antibodies

- External beam radiation therapy (XRT): Must not have received craniospinal
radiotherapy within 24 weeks prior to study entry; the tumor designated as
"measurable" for protocol purposes must not have received radiation within 12
weeks prior to study entry); focal radiation to areas of symptomatic metastatic
disease must not be given within 14 days of study entry

- Stem cell transplant (SCT): For autologous SCT, >= 3 months must have elapsed
prior to study entry

- Study specific limitations on prior therapy:

- Patients must not have previously received bevacizumab, irinotecan,
temozolomide or other anti-vascular endothelial growth factor (VEGF)
inhibitor

- Patients must not be taking enzyme-inducing antiepileptic medicines within 1
week of study entry

- Patients must have recovered from any surgical procedure before enrolling on this
study:

- Patients with a major surgical procedure within 28 days prior to enrollment
should be excluded

- Patients with an intermediate surgical procedure within 14 days prior to
enrollment should be excluded

- For minor surgical procedures (including Broviac line or infusaport placement),
patients should not receive the first planned dose of bevacizumab until the wound
is healed and at least 7 days have elapsed

- There should be no anticipation of need for major surgical procedures during the
course of the study

- Examples of major, intermediate, or minor surgical procedures:

- Major procedures: Major craniotomy for tumor resection; organ
resection; bowel wall anastomosis; arteriovenous grafts; exploratory
laparotomy; thoracotomy

- Intermediate procedures: Ventriculoperitoneal (VP)-shunt placement;
stereotactic brain biopsy

- Minor procedures: Incision and drainage of superficial skin abscesses;
punch biopsy of skin lesions; superficial skin wound suturing; bone
marrow aspirate and/or biopsy; fine needle aspirations; Broviac line or
infusaport placement; paracentesis or thoracocentesis

- Please note: Lumbar punctures or placement of peripherally inserted central
catheter (PICC) lines are not considered minor procedures and may occur at any
time prior to or during therapy

- Hypertension must be well controlled (=< 95th percentile for age and height if patient
is =< 17 years) on stable doses of medication

- Concomitant medications restrictions:

- Growth factor(s): Must not have received within 7 days of entry onto this study

- Steroids: Patients who are receiving corticosteroids must be on a stable or
decreasing dose for at least 7 days

- Study Specific: Patients must not be currently taking nonsteroidal
anti-inflammatory drugs (NSAIDs), clopidrogel, dipyridamole or aspirin therapy >
81 mg/day

- Peripheral absolute neutrophil count (ANC) >= 1000/uL (must not have received
filgrastim [G-CSF] within the prior 7 days)

- Platelet count >= 100,000/uL (transfusion independent)

- Hemoglobin >= 8.0 gm/dL (may receive packed red blood cell [PRBC] transfusions)

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

- =< 0.4 mg/dL (for patients aged 1 month to < 6 months)

- =< 0.5 mg/dL (for patients aged 6 months to < 1 year)

- =< 0.6 mg/dL (for patients aged 1 to < 2 years)

- =< 0.8 mg/dL (for patients aged 2 to < 6 years)

- =< 1 mg/dL (for patients aged 6 to < 10 years)

- =< 1.2 mg/dL (for patients aged 10 to < 13 years)

- =< 1.4 mg/dL (for female patients aged >= 13 years)

- =< 1.5 mg/dL (for male patients aged 13 to < 16 years)

- =< 1.7 mg/dL (for male patients aged >= 16 years)

- Urine protein should be screened by dipstick analysis; if protein >= 2+ on dipstick,
then urine protein creatinine (UPC) ratio should be calculated; if UPC ratio > 0.5,
24-hour urine protein should be obtained and the level should be < 1000 mg/24 hours
for patient enrollment

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
upper limit of normal (ULN) for age

- Central nervous system function defined as

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

- Adequate coagulation defined as

- International normalized ratio (INR)/prothrombin time (PT) =< 1.5 x upper limit
of normal

Exclusion Criteria:

- Patients with a serious or non-healing wound, ulcer, or bone fracture are not eligible
for this study

- Patients must not have a history of abdominal fistula, gastrointestinal perforation or
intra-abdominal abscess within 6 months prior to study entry

- Patients must not have a known bleeding diathesis or coagulopathy

- Patients must not have had significant vascular disease (eg, aortic aneurysm requiring
surgical repair, deep venous or arterial thrombosis) within the last 6 months prior to
study entry

- Patients must not have a known thrombophilic condition (i.e. protein S, protein C or
antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation,
homocysteinemia or antiphospholipid antibody syndrome); testing is not required in
patients without thrombophilic history

- Patients must not have evidence of new CNS hemorrhage on baseline MRI obtained within
14 days prior to study enrollment

- Patients with a history of stroke, myocardial infarction, transient ischemic attack
(TIA), severe or unstable angina, peripheral vascular disease, or grade II or greater
congestive heart failure within the past 6 months are not eligible

- Patients must not have serious and inadequately controlled cardiac arrhythmia

- Female patients who are pregnant are not eligible for this study

- Female patients who are breastfeeding are not eligible for this study unless they
agree not to breastfeed

- Female patients of childbearing potential must have a negative pregnancy test

- Sexually active patients of childbearing potential must agree to use an effective
method of contraception during the study and for at least 6 months after the
completion of bevacizumab therapy

- Patients with known hypersensitivity to Chinese hamster ovary cell products or other
recombinant human antibodies