Temozolomide With Irinotecan Versus Temozolomide, Irinotecan Plus Bevacizumab (NSC# 704865, BB-IND# 7921) for Recurrent/Refractory Medulloblastoma/CNS PNET of Childhood, A COG Randomized Phase II Screening Trial

Inclusion Criteria:

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

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

- Patients must have measurable residual disease, defined as tumor that is measurable
in two perpendicular diameters on MRI

- Diffuse leptomeningeal disease is not considered measurable

- 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 not have evidence of new CNS hemorrhage on baseline MRI

- Patients must have a Lansky or Karnofsky performance status score of ≥ 50%,
corresponding to ECOG categories of 0, 1, or 2 (Karnofsky for patients > 16 years of
age and Lansky for patients ≤ 16 years ofage)

- Patients must have a life expectancy of ≥ 8 weeks

- Peripheral absolute neutrophil count (ANC) ≥ 1000/μL (must not have received
G-CSFwithin the prior 7 days)

- Platelet count ≥ 100,000/μL (transfusion independent)

- Hemoglobin ≥ 8.0 g/dL (may receive PRBC transfusions)

- Creatinine clearance or radioisotope 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 < 1,000 mg/24 hours for patient enrollment

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

- SGPT (ALT) ≤ 3 x ULN for age

- INR/PT ≤ 1.5 x ULN

- 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

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

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

- 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 (e.g., 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 IIIdeficiency, Factor V Leiden, Factor II G20210A mutation,
homocysteinemia, or antiphospholipidantibody syndrome)

- Testing is not required in patients without thrombophilic history

- 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

- No patients with known hypersensitivity to Chinese hamster ovary cell products or
other recombinant human antibodies

- No concurrent radiotherapy

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

- No 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 abiologic agent; at least 3
weeks for biologic agents with a long half life, such as antibodies

- 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

- For autologous stem cell transplant, ≥ 3 months must have elapsed prior to study
entry

- Patients must not have previously received bevacizumab, irinotecan, temozolomide, or
other anti-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

- No growth factors within 7 days of entry onto this study

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

- Patients must not be currently taking NSAIDs, clopidogrel, dipyridamole,or aspirin
therapy > 81 mg/day

- No other cancer chemotherapy or immunomodulating agents are permitted (the use of
alternative or complementary therapies is discouraged)