Pretherapy 124I-MIBG Dosimetry for Planning 131I-MIBG Neuroblastoma Therapy

用于规划 131I-MIBG 神经母细胞瘤治疗的治疗前 124I-MIBG 剂量测定

• 批准号: 8265566
• 负责人: Youngho Seo
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265566
• 关键词: Adult; Affect; Animal Model; Animals; Area; Behavior; Beta Particle; Cell Line; Cells; Child; Childhood; Clinical; Clinical Research; Data; Detection; Development; Dose; Drug Kinetics; Embryo; Ensure; Evaluation; Gamma Cameras; Goals; Half-Life; Hour; Human; I131 isotope; Image; Investigation; Investigational Drugs; Investigational New Drug Application; Label; Malignant - descriptor; Nerve Tissue; Neuroblastoma; Neurons; Norepinephrine; Organ; Outcome; Patients; Photons; Positron-Emission Tomography; Primary Neoplasm; Radiation; Radiation therapy; Radioisotopes; Radiometry; Radionuclide therapy; Recurrent disease; Research Project Grants; Resistance; Retrieval; Safety; Schedule; Scheme; Software Tools; Solid Neoplasm; Specificity; Staging; Testing; Therapeutic; Time; Toxic effect; Tracer; United States Food and Drug Administration; advanced disease; conventional therapy; design; dosimetry; fluorodeoxyglucose positron emission tomography; high risk; imaging modality; in vivo; metaiodobenzylguanidine; mouse model; neoplastic cell; neuroblastoma cell; noradrenaline transporter; pre-clinical; preclinical evaluation; preclinical study; radiotracer; response; single photon emission computed tomography; software development; therapy outcome; tool; treatment effect; tumor; uptake

DESCRIPTION (provided by applicant): Neuroblastoma is the most common extracranial malignant solid tumor in children. Although the conventional treatment options are often curative at early stages, advanced disease remains fatal for a large percentage of patients, particularly for those who become resistant to conventional therapy. MIBG is taken up by sympathetic neurons via a specific norepinephrine transporter (NET) and 90% of all neuroblastoma tumors are MIBG-avid. Thus, when MIBG is labeled with 131I, a radionuclide that emits therapeutic beta particles with a relatively long physical half-life (8.02 days), 131I-MIBG becomes an agent for targeted radionuclide therapy of neuroblastoma. For the treatment with131I-MIBG, individualized radiation dosimetry can be achieved by pretherapy imaging using the same tracer with a different radioiodine such as I-123. I-123 is a favored imaging agent using gamma camera and SPECT; but it has a relatively shorter half-life than that of I-131 (13.2 hours versus 8.02 days) so that following the full time course of 123I-MIBG behavior in patients over a few days is not straightforward, and technically challenging. Instead, another radioiodine, I-124 has a closer half-life (4.2 days) to that of I-131, and can be imaged by PET that is considered quantitatively more accurate than SPECT. Our goals are to use 124I-MIBG PET/CT as an individualized 131I-MIBG radiotherapy prescription tool to achieve optimal treatment of tumors and minimal radiation dose to radiosensitive organs. Since 124I-MIBG has not been used in children for this indication (although 124I-MIBG was used in a limited number of adults), carefully designed preclinical studies with end points of radiation dose estimations should proceed before its human use. Our specific aims are: Aim 1: To determine the distribution of 124I-MIBG in tumors and normal organs in vivo using animal models of neuroblastoma. Small animal PET/CT with 124I-MIBG will be performed at multiple time points over four days, and the imaging data will be analyzed to study pharmacokinetics in tumors and other organs. Aim 2: To calculate the pediatric human-equivalent effective radiation dose in the range of patient sizes from preclinical 124I-MIBG imaging data. For this aim, our goal is to estimate the normal organ doses with 124I-MIBG to ensure safety, not specifically intended for 131I-MIBG treatment prescription. We will apply for the IND, and will prepare for human imaging as a part of this aim. Aim 3: To assess the feasibility of tumor and organ dosimetry with pediatric 124I-MIBG PET/CT in selected neuroblastoma patients who are scheduled for 131I-MIBG treatment. We will develop a patient-specific dosimetry calculation tool that will be available for the dose prescription of 131I-MIBG. Estimations of radiation dose will be focused on the determination of optimal activity needed to effectively deliver therapeutic dose to tumor cells while keeping radiation dose to normal organs at an acceptable level. The outcomes of the individualized prescription of the 131I-MIBG treatment will be descriptively compared to the therapy outcomes, particularly the primary tumor size reduction.

描述(申请人提供)：神经母细胞瘤是儿童最常见的颅外恶性实体瘤。虽然常规治疗方案在早期往往是治愈的，但晚期疾病对很大比例的患者仍然是致命的，特别是对那些对传统治疗产生抵抗力的患者。MIBG通过一种特殊的去甲肾上腺素转运蛋白(Net)被交感神经元摄取，所有神经母细胞瘤中90%的肿瘤是MIBG亲和性的。因此，当131I标记MIBG时，131I-MIBG成为神经母细胞瘤的靶向放射性核素治疗的试剂。131I-MIBG是一种释放出相对较长的物理半衰期(8.02天)的治疗性β粒子的放射性核素。对于131I-MIBG治疗，可以通过在治疗前使用同一示踪剂与不同的放射性碘(如I-123)进行成像来实现个体化的辐射剂量测定。I-123是一种使用伽马相机和SPECT的受欢迎的显像剂；但它的半衰期比I-131短(13.2小时对8.02天)，因此在患者身上跟踪完整的123I-MIBG几天的行为并不简单，而且在技术上具有挑战性。相反，另一种放射性碘I-124的半衰期与I-131的半衰期更接近(4.2天)，并且可以通过被认为在定量上比SPECT更准确的PET进行成像。我们的目标是使用124I-MIBG PET/CT作为个性化的131I-MIBG放射治疗处方工具，以实现肿瘤的最佳治疗和对放射敏感器官的最小辐射剂量。由于124I-MIBG尚未用于儿童的这一适应症(尽管124I-MIBG在有限数量的成人中使用)，因此在人类使用124I-MIBG之前，应进行精心设计的临床前研究，并进行辐射剂量估计的终点。我们的具体目标是：目的1：利用神经母细胞瘤动物模型，确定~(124)I-MIBG在肿瘤和正常器官中的体内分布。小动物的124I-MIBG PET/CT将在四天内在多个时间点进行，成像数据将被分析以研究肿瘤和其他器官的药代动力学。目的：根据临床前~(124)I-MIBG显像数据，计算患者大小范围内的儿科人体等效有效辐射剂量。为此，我们的目标是估计124I-MIBG的正常器官剂量，以确保安全，而不是专门用于131I-MIBG的治疗处方。我们将申请IND，并将准备人体成像作为这一目标的一部分。目的：评价儿童~(124)I-MIBG PET/CT对拟接受~(131)I-MIBG治疗的神经母细胞瘤患者进行肿瘤和器官剂量测定的可行性。我们将开发一种患者特有的剂量学计算工具，用于131I-MIBG的剂量处方。辐射剂量的估计将侧重于确定有效地向肿瘤细胞提供治疗剂量所需的最佳活动，同时将对正常器官的辐射剂量保持在可接受的水平。131I-MIBG个体化治疗处方的结果将与治疗结果进行描述性比较，特别是原始肿瘤体积缩小。