Neuroblastoma (NB), a childhood malignancy is metastatic at diagnosis in 60% of patients, and is lethal in most children despite aggressive conventional therapies The monoclonal antibody 3F8 binds to NB cells, leading to tumor cell killing. When combined with radioactive iodine (131I-3F8), it delivers radiation specifically to NB cells while relatively sparing surrounding normal tissues. 131I-3F8 has been used safely as targeted radiotherapy for treating patients with NB. Although it is effective for patients who have a small amount of residual disease, it is less useful for patients who have a significant amount of resistant NB. Furthermore, although 131I-3F8 is active in some patients with NB, the high doses of radioactivity administered suppress the bone marrow requiring reinfusion of stored stem cells for bone marrow rescue. Aggressive and metastatic NB express vascular endothelial growth factor (VEGF) that promotes development of new blood vessels to tumor, a process called angiogenesis. Bevacizumab, a newer monoclonal antibody binds to VEGF and shuts off angiogenesis starving tumor cells of nutrients. When tumors are treated with radiotherapy they release substances including VEGF that may increase angiogenesis and allow the tumor to escape the effects of radiotherapy. Bevacizumab, by blocking VEGF has been shown to increase tumor cell death initiated by radiotherapy. In experiments carried out in our laboratory, mice with well established NB tumors had reduction in size or eradication of tumors, and an increased survival when treated with a combination of bevacizumab and low doses of 131I-3F8. Neither bevacizumab nor low dose 131I-3F8, alone was effective. This combination was not associated with any side effects in mice. We have initiated a phase I study in which we propose to test the toxicity and anti-NB response of this novel combination in patients with resistant NB. The dose of 131I-3F8 that can be used safely in combination with bevacizumab, as well as the dose of 131I-3F8 that can be utilized without requiring reinfusion of stored stem cells will be determined. In those 131I-3F8/bevacizumab-treated patients who require stem cell reinfusion, the success of stem cells in reconstituting bone marrow will be evaluated. Changes in angiogenic factors in patients' blood will be studied, as will the effect of bevacizumab on the targeting of tumor by 131I-3F8 and on its clearance from blood. 24 patients will be treated in 4 cohorts of 6 patients each, the dose of 131I-3F8 being escalated across cohorts, while the dose of bevacizumab will remain constant. Patients may receive up to 4 cycles, each consisting of one dose of 131I-3F8 and two doses of bevacizumab if they do not experience toxicity or disease progression. Patients will be monitored for adverse events and for possible efficacy of the combination. Gamma camera scans will be performed to assess targeting of NB by 131I-3F8 and blood radioactivity levels measured to evaluate clearance of 131I-3F8. Patients will be rescued with stored stem cells if their bone marrow is severely suppressed. ? ? ?
