N2007-02: Bevacizumab, Cyclophosphamide, and Zoledronic Acid in Patients With Recurrent or Refractory High-Risk Neuroblastoma

Status: Recruiting
Phase: Phase 1
Diagnosis: Pediatric Neuroblastoma
NCT ID: NCT00885326 (View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 09-078


RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Zoledronic acid may stop the growth of tumor cells in bone. Giving bevacizumab together with cyclophosphamide and zoledronic acid may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects of giving bevacizumab together with cyclophosphamide and zoledronic acid in treating patients with recurrent or refractory high-risk neuroblastoma.


Conducting Institutions:
Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:
Suzanne Shusterman, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

Eligibility Criteria

DISEASE CHARACTERISTICS: - Diagnosis of high-risk neuroblastoma, verified by 1 of the following: - Histology - Demonstration of tumor cells in the bone marrow with increased urinary catecholamines - Meets one of the following criteria: - Recurrent or progressive disease - Refractory disease (i.e less than partial response). No Biopsy required - Persistent disease after achieving at least a partial response to front-line therapy.Patients in this category are REQUIRED to have a biopsy. - Measurable disease, as defined by having at least ONE of the following: - Measurable tumor on MRI or CT scan, defined as at least one lesion ≥ 20 mm in at least one dimension by conventional techniques OR ≥ 10 mm by spiral CT scan. - MIBG scan with positive uptake at a minimum of one site. - For patients with persistent disease , a biopsy of the MIBG positive site demonstrating viable neuroblastoma is required. - If the lesion was irradiated, biopsy must have been done ≥ 4 weeks after completion of radiotherapy - Bone marrow with tumor cells seen on routine morphology (not by neuron-specific enolase [NSE] staining alone) of bilateral aspirate and/or biopsy on one bone marrow sample PATIENT CHARACTERISTICS: - Karnofsky or Lansky performance status (PS) 50-100% (patients who are unable to walk because of paralysis or tumor pain, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing PS) - Life expectancy ≥ 4 months - ANC ≥ 750/mm^3 - Platelet count ≥ 50,000/mm^3 (transfusion independent, defined as no platelet transfusion for 1 week) - Hemoglobin ≥ 8 g/dL (transfusion allowed) - PT and aPTT < 1.2 times upper limit of normal for age - Glomerular filtration rate or creatinine clearance ≥ 70 mL/min OR maximum serum creatinine based on age as follows: - 0.8 mg/dL (for patients ≤ 5 years of age) - 1.0 mg/dL (for patients 6 to 10 years of age) - 1.2 mg/dL (for patients 11 to 15 years of age) - 1.5 mg/dL (for patients > 15 years of age) - Hematuria ≤ 1+ by urinalysis - No more than trace protein by urinalysis OR ≤ 500 mg protein by 24-hour urine collection - Total bilirubin ≤ 1.5 times normal for age - ALT and AST < 5 times normal for age - Ionized serum calcium ≥ 1.0 mmol/L (calcium supplements allowed provided serum calcium is stable) - Ejection fraction > 55% by either ECHO or radionuclide MUGA scan OR shortening fraction ≥ 27% by ECHO - Not pregnant or nursing - Fertile patients must use effective contraception - Able to comply with the safety monitoring requirements of the study - No arterial thrombosis (including transient ischemic attack or cerebrovascular accident) within the past 6 months - No deep venous thrombosis (including pulmonary embolism) within the past 3 months - No history of bleeding diathesis , hemoptysis, myocardial infarction, severe or unstable angina, or peripheral vascular disease - No NYHA class II-IV congestive heart failure - Hypertension allowed provided it is well controlled on stable doses of medication for ≥ 2 weeks prior to study enrollment - No history of hypertensive crisis - No history of abdominal fistula, chronic ulcer, or non-healing wound - No documented significant trauma within the past 28 days - No uncontrolled infection - No acute active dental issues requiring intervention - No known hypersensitivity to bevacizumab - No other ongoing serious medical issues unless approved by the study chair prior to study enrollment PRIOR CONCURRENT THERAPY: - Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, radiotherapy, or surgery - At least 3 months since prior autologous or allogeneic stem cell transplant - No requirement for immunosuppressants AND no active signs of graft-vs-host disease - At least 6 weeks since prior therapeutic doses of MIBG - At least 28 days since prior major surgical procedure (e.g., laparotomy or tumor resection) - At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and/or biological therapy - At least 2 weeks since prior radiotherapy (6 weeks for large-field radiotherapy [i.e., total-body irradiation, craniospinal therapy, whole abdominal or total lung radiotherapy, or radiotherapy to > 50% of marrow space]) - At least 7 days since prior hematologic growth factors . - More than 7 days since prior minor surgical procedures (e.g., core or small incisional biopsies ; Mediport catheter placement; or intratumoral needle biopsy for diagnostic purposes) - No other concurrent anticancer agents - No concurrent full-dose anticoagulants - Concurrent low-dose aspirin (≤ 325 mg/day) allowed for patients at a higher risk for arterial thromboembolic disease - Concurrent corticosteroids allowed provided the patient has been a stable dose for ≥ 2 weeks or is on a tapering schedule
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