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

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)