CLINICAL THERAPY TRIALS

神经母细胞瘤是一种起源于胚胎神经嵴的肿瘤，是最常见的颅外实体瘤 在儿童期，只有不到40%的具有高危特征的儿童在接受强化治疗后仍能存活。 假设：新的肿瘤靶向治疗与标准化疗无交叉耐药， 已在临床前研究中得到验证，将在难治性肿瘤患者中诱导应答， 改善结果。具体目的：1）确定[131]L-MIBG（靶向于 去甲肾上腺素转运蛋白）与造血干细胞支持联合化疗时，新 生物制剂和/或具有针对耐药神经母细胞瘤的组合临床前活性的放射增敏剂; 2)定义靶向与肿瘤途径和/或与肿瘤相关的关键分子的药物的合理组合， 肿瘤-微环境相互作用，可与标准细胞毒性剂组合， 对神经母细胞瘤的疗效，在MTD水平进行药代动力学和药效学验证; 3)开发生物标志物和半定量成像技术，提供额外的神经母细胞瘤特异性 终点，以评价对治疗的反应。 方法和相互作用：我们将重点关注具有特定原理的联合治疗， 神经母细胞瘤，利用I期数据的单一药物测试对更广泛的实体瘤， 结合项目1-3和临床前试验核心D的实验室数据。代理商的例子 测试包括MIBG与放射增敏剂和化疗，抗IL 6与节拍 环磷酰胺和zometa（项目1），免疫疗法（项目2），PIS激酶抑制剂（项目3）。 NANT（神经母细胞瘤治疗新方法）是我们的15个机构的联盟，将进行 在行政研究支持、组织病理学、临床前研究、 测试，生物统计学，以及NANT运营中心。NANT在非常密切的合作下工作 与儿童肿瘤学小组（COG）、CTEP和FDA以及行业赞助商合作，目标是 将我们第一阶段试验中最有前途的药物带入第二阶段，然后进入国家第三阶段。 审判

Neuroblastoma, a tumor arising from embryonic neural crest, is the most common extra-cranial solid tumor of childhood, and less than 40% of children with high-risk features survive despite intensive treatment. Hypothesis: New tumor-targeted therapies that are non-cross resistant with standard chemotherapy and have been validated in pre-clinical studies will induce responses in patients with refractory tumors and improve outcome. Specific Aims: 1) To establish the tolerability and efficacy of [131]l-MIBG (targeting the norepinephrine transporter) with hematopoietic stem cell support when combined with chemotherapy, novel biologies, and/or radiosensitizers with combinatorial pre-clinical activity against resistant neuroblastoma; 2) Define rational combinations of agents that target key molecules relevant to tumor pathways and/or to tumor-microenvironment interactions that may be combined with standard cytotoxic agents to maximize efficacy against neuroblastoma, with pharmacokinetic and pharmacodynamic validation at the MTD; 3) Develop biomarker and semi-quantitative imaging technologies that provide additional neuroblastomaspecific endpoints to evaluate response to therapies. Methods and Interactions: We will focus on combination therapy that has specific rationale for neuroblastoma, utilizing Phase I data for single agents tested against a broader spectrum of solid tumors in combination with laboratory data from Projects 1-3 and Pre-Clinical Testing Core D. Examples of agents to be tested include MlBG with radiosensitizers and chemotherapy, anti-IL6 with metronomic cyclophosphamide and zometa (Project 1), immunotherapy (Project 2), PIS kinase inhibitors (Project 3). NANT (New Approaches to Neuroblastoma Therapy), is our consortium of 15 institutions that will conduct the clinical trials with the support of the cores for administrative research support, histopathology, pre-clinical testing, biostatistics, as well as the NANT Operations Center. The NANT works in very close cooperation with the Children's Oncology Group (COG), CTEP and the FDA, and industry sponsors with the goal of bringing the most promising agents from our Phase I trials forward into Phase II and then national Phase III trials.