Bevacizumab, Irinotecan and Temozolomide for Relapsed or Refractory Neuroblastoma
Condition: Neuroblastoma
MeSH terms: Neuroblastoma
Intervention: Bevacizumab, Irinotecan and Temozolomide
Intervention description: Patients will initially receive bevacizumab IV at 15mg/kg/dose (this is defined as Day 1 Three days later (starting day 4), they will receive concurrently, IV irinotecan at 50mg/m2/day x 5 days plus PO temozolomide 150mg/m2/day x 5 days. A second dose of bevacizumab will be administered 14 days after the first one(day 15). The treatment schedule may require minor adjustment as clinically indicated (e.g., due to PDH closure for holidays).
Intervention MeSH terms: Bevacizumab; Irinotecan; Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 34.0
Sex: All
Healthy volunteers: No
Keywords: Bevacizumab; Irinotecan; Temozolomide; 10-015

Summary:

      The purpose of this study is to find how good and how safe the combination of irinotecan,
      temozolomide and bevacizumab is for patients with resistant or recurrent neuroblastoma. These
      drugs have each been given separately to patients, but they have never been given all
      together. Irinotecan and temozolomide are two drugs that have been used together to treat
      neuroblastoma in many people. These drugs are considered chemotherapy. Bevacizumab is another
      drug used to treat cancer. It is made by a company called Genentech. Bevacizumab is an
      antibody. Antibodies are proteins that are found in the blood and can attach themselves to
      bacteria and viruses. Bevacizumab attaches itself to a special protein in the bloodstream.
      This protein helps tumors grow new blood vessels. Blood vessels carry nutrients to feed the
      tumor. Bevacizumab is thought to block this growth of new blood vessels and starve tumors. It
      has been used for the treatment of many cancers in adults. It is approved by the FDA for the
      treatment of adults with colon cancer and other cancers but not for people with
      neuroblastoma. There is only a small amount of information known on using this drug in
      children. It has been used with irinotecan before to treat cancer but not in children with
      neuroblastoma.
    

Eligibility criteria:

        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.