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

NANT 2007-02 - 贝伐珠单抗推注的 I 期研究

• 批准号: 8356742
• 负责人: SUSAN M. BLANEY
• 金额: $ 0.51万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356742
• 关键词: Angiogenesis Inhibitors; Angiogenic Factor; Blood Vessels; Bolus Infusion; Bone Resorption; Child; Childhood; Clinical Research; Combined Modality Therapy; Cyclophosphamide; Cytotoxic Chemotherapy; Dose; Drug Delivery Systems; Endothelial Cells; Event; Fracture; Funding; Future; Gene Expression; Grant; Immunologics; Immunotherapy; Individual; Inflammatory; Intravenous Bolus; Investigation; Mitogens; National Center for Research Resources; Neoplasm Metastasis; Neuroblastoma; Oral; Pain; Plasma; Principal Investigator; Property; Quality of life; Recurrence; Refractory; Regimen; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Source; Stem cells; Survival Rate; Testing; Toxic effect; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vascular Endothelium; Zoledronic Acid; arm; bevacizumab; bone; chemotherapy; cost; design; high risk; improved; novel; open label; phase 1 study; skeletal; tumor

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 患有高危神经母细胞瘤的儿童的长期生存率很低 尽管进行了强化多学科治疗，但仍有约 30% 的患者出现这种情况。迫切需要新的疗法和药物组合。本研究提出的三种药物：环磷酰胺 (CTX)、贝伐珠单抗 (BV) 和唑来膦酸 (ZA)，每种药物都具有单独的抗神经母细胞瘤前景，已完成早期儿科测试，预计联合用药时具有良好的耐受性。几位研究人员已经证明，持续低剂量或节律性细胞毒疗法可靶向肿瘤血管内皮，并阻断 VEGF（主要作用）。 内皮有丝分裂原和生存因子都可以放大这些抗血管作用，并可能通过血管正常化改善标准剂量化疗的药物输送。复发性或难治性高危神经母细胞瘤通常与皮质骨转移相关，导致疼痛、骨折和生活质量受限。 ZA 可以破坏破骨细胞活性，减少骨骼相关事件，并且还具有 据报道具有间接抗血管生成特性。这项单臂、开放标签试验旨在确定推注静脉 CTX 加节律口服 CTX 和 ZA（添加或不添加 BV）组合的毒性和可行性。如果这样的治疗方案可以耐受，它可能会作为未来试验其他生物靶向药物或免疫疗法的平台。因此，次要终点将包括： 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；对该组合的免疫学作用进行初步研究；并在第一阶段研究的范围内评估抗肿瘤活性。