NANT 2007-02 - A PHASE I STUDY OF BEVACIZUMAB WITH BOLUS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 患有高危神经母细胞瘤的儿童的长期生存率很低， 尽管进行了强化的多模式治疗，但仍有约30%。迫切需要新的治疗方法和药物组合。本研究中提出的三种药物，环磷酰胺（CTX），贝伐单抗（BV）和唑来膦酸（ZA），每种药物都有单独的抗神经母细胞瘤的前景，已经完成了早期的儿科试验，预计联合给药时耐受性良好。一些研究者已经证明，连续低剂量或节律性细胞毒性治疗的递送靶向肿瘤血管内皮，并且阻断VEGF，主要的血管内皮细胞， 内皮细胞有丝分裂原和存活因子都可以放大这些抗血管作用，并通过血管正常化潜在地改善标准剂量化疗的药物递送。复发性或难治性高危神经母细胞瘤常伴有皮质骨转移，导致疼痛、骨折和生活质量受限。ZA可以破坏骨细胞活性，减少骨骼相关事件， 据报道具有间接的抗血管生成特性。这项单臂、开放标签试验旨在确定静脉推注CTX+节拍口服CTX和ZA联合用药（加或不加BV）的毒性和可行性。如果这样的方案是可耐受的，它可能会作为一个平台，为未来的试验与其他生物靶向药物或免疫疗法。因此，次要终点将包括：对循环内皮细胞变化的探索性分析， 祖细胞、血浆血管生成因子、血管生成和炎症基因表达以及骨吸收标志物;提供该组合的免疫学效应的初步研究;以及在I期研究的范围内评估抗肿瘤活性。

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.