) Neuroblastoma is the most common extra-cranial solid tumor of childhood and only 40 percent of children with high-risk features at diagnosis survive despite intensive therapy. Goal. New approaches are needed to treat high-risk neuroblastoma since maximum dose intensity alone, or without hematopoietic rescue, has only modestly improved survival. Hypothesis. We hypothesize those new therapies that are not affected by resistance of tumor cells to chemotherapy, irradiation, or 13-cis retinoic acid will significantly improve treatment of these patients.
Specific Aims. (1) To establish the safety, and within the confines of phase I studies, the efficacy (a) of cytotoxic agents with new mechanisms of activity or increased tumor specificity and (b) of biologic agents which may act on resistant tumors without overlapping toxicities with cytotoxic drugs. (2) To target in vivo levels of these agents using pharmacokinetic and dosimetric studies. Research Design. Cytotoxic agents to be studied include buthionine sulfoximine (BSO) with melphalan, a synergistic combination in which BSO sensitizes tumor cells by glutathione depletion. Melphalan will be tested in both non-ablative and marrow ablative doses. A tumor targeted cytotoxic therapy to be tested is 131 I-MIBG for specific concentrated radiotherapy delivery with ablative doses of carboplatin, etoposide, and melphalan and autologous stem cell transplantation (ASCT). Fenretinide, which is cytotoxic in vitro against drug and retinoic acid resistant cell lines, and which we have shown acts by increasing tumor cell ceramide levels, will be tested in combination with tamoxifen and possibly other agents that modulate ceramide levels. A humanized antibody/GM-CSF fusion protein directed against the GD2 antigen and capable of inducing high-level neutrophil cytotoxicity against neuroblastoma cells in vitro will be evaluated. Methods. These phase I studies will be performed by a consortium of nine institutions and will include (a) patients failing front-line phase ill trials, because of poor response to induction chemotherapy; (b) patients with progressive disease; and (c) those with minimal residual disease after myeloablative therapy. These studies will provide new approaches to improving outcome in children with high-risk neuroblastoma which can be tested in larger Children's Oncology Group phase III trials.
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