Optimizing 131I-mIBG Therapy for Children with Advanced Neuroblastoma

优化晚期神经母细胞瘤儿童的 131I-mIBG 治疗

• 批准号: 9250108
• 负责人: Steven DuBois
• 金额: $ 36.34万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-04 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250108
• 关键词: Adult; Amylases; Area; Automobile Driving; Award; Blood; Blood specimen; Bone Marrow; CDKN1A gene; Camptothecin; Cells; Child; Clinical; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; DNA Damage; Development; Exposure to; FLT3 ligand; FLT3LG gene; Funding; Future; Gene Expression; Genes; Goals; HDAC4 gene; Hour; Infusion procedures; Interdisciplinary Study; Link; Lymphocyte; MDM2 gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Messenger RNA; Modality; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Neuroblastoma; Newly Diagnosed; Normal tissue morphology; Organ; Outcome; Patient Agents; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Pheochromocytoma; Plasma; Play; Radiation; Radiation Injuries; Radiation exposure; Radiation therapy; Radiation-Sensitizing Agents; Radiobiology; Radioisotopes; Radiopharmaceuticals; Randomized; Refractory; Regimen; Relapse; Research; Resources; Role; Safety; Salivary Glands; Sampling; Series; Serum; Surrogate Markers; Testing; Therapeutic; Therapeutic Studies; Therapy Clinical Trials; Topoisomerase; Toxic effect; Transcript; Treatment Protocols; Vincristine; Vorinostat; Work; advanced disease; anticancer research; arm; biomarker development; biomarker panel; cancer cell; cancer therapy; clinical development; clinical effect; design; high risk; improved; improved outcome; inhibitor/antagonist; insight; irinotecan; metaiodobenzylguanidine; neoplastic cell; new therapeutic target; noradrenaline transporter; novel marker; novel strategies; objective response rate; peripheral blood; prospective; public health relevance; radiation effect; radiation risk; response; small molecule; tool; tumor

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.

描述：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。提高放射治疗的有效性和安全性是当务之急。提高放射治疗阈值的两种可能战略是使用靶向放射性核素和使用辐射敏感剂。作为评估这两种策略的模型，我们将重点关注针对晚期神经母细胞瘤儿童的靶向放射性核素131I-MIBG。患有晚期神经母细胞瘤的儿童尽管进行了密集的多种治疗，但预后仍然很差。为了提高这些患者的治愈率，需要新的靶向治疗。靶向放射性核素131I-MIBG是治疗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高度优先事项。该R01奖项的申请包括两个互补的目标，旨在评估在治疗性放射性核素的背景下的辐射增敏。在目标1中，我们将评估全身放射增敏剂与131I-MIBG联合治疗的策略。我们将进行一项前瞻性的多中心三臂II期选择设计临床试验，以确定总体客观有效率最高的131I-MIBG治疗方案。复发或难治性神经母细胞瘤的患者将在研究开始时被随机分配到三个131I-MIBG治疗组中的一个：(1)单剂131I-MIBG，(2)131I-MIBG加长春新碱和伊立替康，或(3)131I-MIBG加涡流调节剂。这项试验将在NCI赞助的神经母细胞瘤治疗新方法(NANT)研究联盟内进行。主要终点是一个疗程后的总体客观肿瘤反应。总共105名患者将接受治疗，35名患者/随机分配到每个治疗组。在试验结束时，最有效的方案将被纳入未来对新生患者的研究 诊断为高危神经母细胞瘤。在目标2中，我们将评估在目标1的临床试验中接受治疗的患者的器官毒性、DNA损伤和细胞对DNA损伤的反应的一组标记物。患者将在基线和131I-MIBG输注后大约72小时提供血样。我们将使用这些样本来量化血清淀粉酶、血浆Flt3配体、淋巴细胞�H_2AX焦点和一组与DNA损伤相关的基因的转录。我们将评估131I-MIBG在有无辐射增敏剂的情况下对这些标志物的影响，以此作为了解辐射增敏机制的工具。虽然我们的重点是131I-MIBG治疗神经母细胞瘤，但我们的发现将对其他应用具有重要意义。例如，131I-MIBG也用于成人嗜铬细胞瘤的治疗。更广泛地说，我们的工作将为其他专注于辐射增敏剂的使用和接受其他形式放射治疗的患者开发新的生物标记物的研究提供参考。