This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Children with high-risk neuroblastoma have a poor long-term survival rate of approximately 30% despite intensive multimodality therapy. Novel therapies and combinations of agents are urgently required. The three agents, cyclophosphamide (CTX), bevacizumab (BV) and zoledronic acid (ZA), proposed on this study each have individual promise against neuroblastoma, have completed early pediatric testing, and are expected to be well tolerated when given in combination. Several investigators have demonstrated that the delivery of continuous low-dose, or metronomic, cytotoxic therapy targets the tumor vascular endothelium and that blocking VEGF, the principal endothelial mitogen and survival factor, can both amplify these anti-vascular effects and potentially improve drug delivery of standard-dose chemotherapy by vascular normalization. Recurrent or refractory high-risk neuroblastoma is frequently associated with metastases to cortical bone that cause pain, fractures, and limitations to quality of life. ZA can disrupt osteoclastic activity, reduce skeletal related events and has also been reported to have indirect antiangiogenic properties. This single-arm, open label trial is designed to determine the toxicities and feasibility of the combination of bolus intravenous CTX plus metronomic oral CTX and ZA, with and without the addition of BV. If such a regimen were tolerable, it might serve as a platform for future trials with additional biologically targeted agents or immunotherapies. Therefore, secondary endpoints will include: exploratory analyses of changes in circulating endothelial and progenitor cells, plasma angiogenic factors, angiogenic and inflammatory gene expression, and markers of bone resorption;providing preliminary investigation of the immunologic effects of this combination;and evaluating antitumor activity within the confines of a Phase I study.
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