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: 8617253
• 负责人: Youngho Seo
• 金额: $ 40.99万
• 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/8617253
• 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; X-Ray Computed Tomography; 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（由申请人提供）：神经母细胞瘤是儿童中最常见的颅外恶性实体瘤。尽管常规治疗选择通常在早期治疗，但对于大部分患者，尤其是那些对常规治疗有抵抗力的患者，晚期疾病仍然是致命的。 MIBG通过特定的去甲肾上腺素转运蛋白（NET）被交感神经元吸收，所有神经母细胞瘤肿瘤中有90％均为MIBG-AVID。因此，当MIBG用131i标记时，一种放射性核素发射具有相对较长物理半衰期（8.02天）的治疗性β颗粒时，131i-MiBG成为靶向放射性核酰胺核疗法神经母细胞瘤的药物。对于用131i-MIBG进行治疗，可以通过使用具有不同放射性碘（例如I-123）的相同示踪剂进行预亲疗法成像来实现个性化的辐射剂量测定法。 I-123是使用伽马相机和SPECT的偏爱成像剂。但是，它的半衰期比I-131的半衰期较短（13.2小时对8.02天），因此，在几天内，患者的全日制课程在123i-MIBG行为的全日制过程中并不简单，而且在技术上具有挑战性。取而代之的是，I-124的另一个放射性碘与I-131的半衰期更接近半衰期（4.2天），并且可以被PET成像，而PET比SPECT被认为更准确。我们的目标是将124I-MIBG PET/CT用作个性化的131i-MIBG放射疗法处方工具，以实现对肿瘤的最佳治疗方法，并对放射敏感器官进行最小的辐射剂量。由于124i-mibg尚未用于儿童以进行这种迹象（尽管有限数量的成年人使用了124i-MIBG），因此应在其人类使用之前进行精心设计的具有辐射剂量估计终点的临床前研究。我们的具体目的是：目标1：使用神经母细胞瘤的动物模型确定肿瘤和正常器官中124i-MIBG的分布。在四天内将在多个时间点进行124i-MIBG的小动物PET/CT，并将分析成像数据以研究肿瘤和其他器官中的药代动力学。目标2：计算临床前124i-MIBG成像数据的患者量范围内的小儿人等效辐射剂量。为此，我们的目标是用124i-MIBG估算正常器官剂量以确保安全性，而不是专门用于131i-MIBG治疗处方。我们将申请IND，并为人类成像做准备，作为此目标的一部分。 AIM 3：评估针对计划进行131I-MIBG治疗的选定神经母细胞瘤患者的肿瘤和器官剂量法的可行性。我们将开发一种特定于患者的剂量计算工具，该工具将用于131i-MIBG的剂量处方。辐射剂量的估计将集中在确定有效地将治疗剂量输送到肿瘤细胞的同时，同时将辐射剂量保持在可接受的水平上的最佳活性上。将131i-MIBG治疗的个性化处方的结果与治疗结果相比，尤其是原发性肿瘤大小的减少将是描述性的。