Bevacizumab, Irinotecan and Temozolomide for Relapsed or Refractory Neuroblastoma

Inclusion Criteria:

* Patients must have the diagnosis of NB in accordance with the International Criteria, i.e., either histopathology (confirmed by the MSKCC Department of Pathology) or BM involvement plus elevated urinary catecholamines.
* Must have a history of tumor progression or recurrence or failure to achieve complete response with standard therapy.
* Patients must have evaluable (microscopic marrow metastasis, MIBG or PET scans) or measurable (CT, MRI) disease.
* Patients of all ages are eligible.
* Prior Therapy: At least 2 weeks should have elapsed since any biologic therapy. Three weeks should have elapsed since last dose of chemotherapy.
* Minimum life expectancy of eight weeks.
* Signed informed consent indicating awareness of the investigational nature of this program.

Exclusion Criteria:

* Severe major organ toxicity. Renal, cardiac, hepatic, pulmonary, gastrointestinal and neurologic toxicity should all be grade 2 or less (per NCI CTC version 4.0 criteria). Specifically, serum creatinine should be ≤3 x upper limit of normal (ULN), serum AST and ALT ≤5 x ULN, serum bilirubin ≤ 3 x ULN, LV shortening fraction should be ≥15%.
* Patients with myelosuppression are not excluded if ANC ≥ 500/uL. Platelet count should be \> 35,000/ul and hemoglobin should be \> 8gm/dl. Patients should not have received filgrastim, platelet or red blood cell transfusions for 2 days prior to achieving the above ANC, platelet and hemoglobin levels.
* Patients with documented chronic non-healing wound, ulcer or bone fracture
* Surgical procedures.
* Patients who have undergone major surgery \<28 days prior to beginning therapy with bevacizumab are excluded.
* Patients must be least 24 hours from having after surgical procedures such as placement of central catheter.
* Patients \<7days from minor surgeries (e.g. fine needle or core biopsies) and/or the unhealed wounds from these procedures are excluded.
* Patients will be excluded if major surgery (e.g. abdominal or thoracic surgery for resection of tumor) is anticipated during the course of the study.
* Known bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
* Thrombosis: patients must not have had a deep venous or arterial thrombosis (non-central venous catheter related) within the last three months prior to study entry. Patients with cerebrovascular accident or transient ischemic attack within 6 months of therapy are excluded. Patients with history of peripheral vascular disease, myocardial infarction or unstable angina are excluded.
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study entry.
* Known CNS metastases, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement except for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include radiotherapy, chemotherapy or immunotherapy Patients with CNS metastases treated by neurosurgical resection or biopsy performed within 3 months of treatment will be excluded.
* Proteinuria: Urine protein: creatinine ratio ≥ 1.0.
* Uncontrolled (lasting \>24 hrs on antihypertensive medication) hypertension as defined by age-appropriate criteria. Hypertension is defined as average systolic blood pressure and/or diastolic blood pressure that is 95th percentile for gender, age, and height on 3 occasions93. 95th percentiles for gender, age and height are provided in Appendix A. For patients ≥18 years of age, hypertension is defined as systolic blood pressure \>150mmHg and/or diastolic blood pressure \>100mmHg.
* Prior history of hypertensive crisis or hypertensive encephalopathy
* History of hypersensitivity to any component of bevacizumab
* History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1.
* Active serious infections not controlled by antibiotics.
* Pregnant women are excluded for fear of danger to the fetus. Therefore negative pregnancy test is required for all women of child-bearing age, and appropriate contraception is used during the study period.
* Inability or unwillingness to comply with protocol requirements.