Optimizing 131I-mIBG Therapy for Children with Advanced Neuroblastoma

放射治疗在许多成人和儿童癌症的治疗中起着至关重要的作用。提高放射治疗的疗效和安全性是当务之急。提高放射治疗阈值的两种潜在策略是使用靶向放射性核素和使用放射增敏剂。作为评估这两种策略的模型，我们将重点关注晚期神经母细胞瘤儿童的靶向放射性核素131I- mIBG。尽管多模式强化治疗，晚期神经母细胞瘤儿童的预后仍然很差。为了提高这些患者的治愈率，需要新的靶向治疗方法。靶向放射性核素131I-mIBG是晚期神经母细胞瘤患者最活跃的药物之一，因此是进一步临床开发的优先事项。R01奖的申请包括两个互补的目标，旨在评估治疗性放射性核素的辐射致敏性。在目的1中，我们将评估使用全身放射增敏剂与131I-mIBG治疗的策略。我们将进行一项前瞻性多中心三组II期选择设计临床试验，以确定与最高总体客观反应率相关的131I-mIBG治疗方案。复发或难治性神经母细胞瘤患者将在研究开始时随机接受三个131I-mIBG治疗组之一：(1)单药131I-mIBG， (2) 131I-mIBG联合长春新碱和伊立替康，或(3)131I-mIBG联合伏立他。该试验将在nci赞助的神经母细胞瘤治疗新方法（NANT）研究联盟中进行。主要终点是一个疗程后的总体客观肿瘤反应。共有105名患者将接受治疗，每个治疗组随机分配35名患者。在试验结束时，最积极的方案将被纳入未来的研究中，用于新的

DESCRIPTION: Radiation therapy plays a critical role in the treatment of many adult and pediatric cancers. Improving the efficacy and safety of radiation therapy is a high priority. Two potential strategies to improve the therapeutic threshold for radiation are the use of targeted radionuclides and the use of radiation sensitizers. As a model for evaluating both of these strategies, we will focus on the targeted radionuclide, 131I- mIBG, for children with advanced neuroblastoma. Children with advanced neuroblastoma continue to have poor outcomes despite intensive multimodality therapy. To improve cure rates for these patients, novel targeted therapies are required. The targeted radionuclide 131I-mIBG is one of the most active agents for patients with advanced neuroblastoma and is therefore a high priority for further clinical development. This application for an R01 award includes two complementary aims designed to evaluate radiation sensitization in the context of a therapeutic radionuclide. In Aim 1, we will evaluate the strategy of using a systemic radiation sensitizer together with 131I-mIBG therapy. We will conduct a prospective multicenter three- arm phase II selection design clinical trial to identify the 131I-mIBG treatment regimen associated with the highest overall objective response rate. Patients with relapsed or refractory neuroblastoma will be randomized at study entry to one of three 131I-mIBG treatment arms: (1) single agent 131I-mIBG, (2) 131I-mIBG plus vincristine and irinotecan, or (3) 131I-mIBG plus vorinostat. The trial will be conducted within the NCI-sponsored New Approaches to Neuroblastoma Therapy (NANT) research consortium. The primary endpoint is overall objective tumor response after one course of therapy. A total of 105 patients will be treated, with 35 patients/randomized to each treatment arm. At the conclusion of the trial, the most active regimen will be incorporated into future studies for patients with newly diagnosed high-risk neuroblastoma. In Aim 2, we will evaluate a panel of markers of organ toxicity, DNA damage, and cellular response to DNA damage in patients treated on the clinical trial in Aim 1. Patients will provide blood samples at baseline and approximately 72 hours after 131I-mIBG infusion. We will use these samples to quantify serum amylase, plasma Flt3 ligand, lymphocyte ¿H2AX foci, and mRNA transcript for a panel of genes involved in response to DNA damage. We will evaluate the effect of 131I-mIBG with and without radiation sensitizers on these markers as a tool to understand the mechanism of radiation sensitization. While our emphasis is on 131I-mIBG therapy for neuroblastoma, our findings will have important implications for other applications. For example, 131I-mIBG is also used in the treatment of adults with pheochromocytoma. More generally, our work will inform other research focused on the use of radiation sensitizers and on development of novel biomarkers in patients receiving other forms of radiotherapy.