Alpha-Particle Emitter Peptide Receptor Targeted Radionuclide Therapy for Neuroendocrine Tumors

α粒子发射肽受体靶向放射性核素治疗神经内分泌肿瘤

• 批准号: 10152579
• 负责人: Yusuf Menda
• 金额: $ 60.66万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-03 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152579
• 关键词: 90Y; Alpha Particle Emitter; Alpha Particles; Amino Acids; Animals; Biological Markers; Blood; Bone Marrow; Chelating Agents; Clinical; Clinical Research; Clinical Trials; Computer software; Data; Data Analyses; Dependence; Detection; Diagnosis; Dose; Dose-Limiting; Drug toxicity; Female; Histologic; Human; Image; Immunocompetent; In complete remission; Incidence; Infusion procedures; Injury; Isotopes; Kidney; Label; Letters; Literature; Marrow; Measurement; Measures; Metastatic Neoplasm to the Liver; Methodology; Multi-Institutional Clinical Trial; Mus; Neuroendocrine Tumors; Organ; Outcome; PET/CT scan; Patient Selection; Patient-Focused Outcomes; Patients; Peptide Receptor; Peptides; Performance; Phase; Phase I Clinical Trials; Positioning Attribute; Preparation; Procedures; Production; Protocols documentation; Quality of life; Radiation Dose Unit; Radiolabeled; Radiometry; Radionuclide therapy; Radiopharmaceuticals; Randomized; Refractory; Research; Running; Safety; Serum; Study models; Systemic Therapy; Therapeutic; Therapy trial; Time; Toxic effect; Translations; Validation; Work; X-Ray Computed Tomography; base; clinical practice; cohort; dosimetry; effective therapy; efficacy trial; human imaging; human subject; image guided; imaging study; improved; improved outcome; male; mouse model; multi-site trial; peptide B; personalized medicine; phantom model; phase III trial; pre-clinical; preclinical toxicity; predictive modeling; reduce symptoms; residence; response; serial imaging; single photon emission computed tomography; standard of care; theranostics; tumor; urinary

PROJECT SUMMARY/ABSTRACT Peptide receptor radionuclide therapy (PRRT) with [177Lu]DOTATATE improves quality of life and survival in patients with advanced neuroendocrine tumors; however objective tumor regression is infrequent and complete responses are exceedingly rare. On the other hand, exciting-emerging evidence suggests that PRRT with alpha-emitters has the potential to extend PRRT to tumor regression and even complete response. In this study we propose to develop a new theranostic pair using [203Pb]PSC-TOC (imaging) / [212Pb]PSC-TOC (alpha emitter) for image-guided dosimetry based personalized therapy for neuroendocrine tumors. In Specific Aim 1 of the proposal, we will optimize the radiolabeling and production of [203/212Pb]PSC-TOC to prepare for its use in clinical trials and perform a preclinical dose escalation trial in immune-competent mice to investigate drug toxicity and the relation of toxicity with radiation dose (using residence time as a surrogate) to the organs. The accurate measurement of radiation dose from alpha-emitters is challenging due to dependence of the dose on the distribution of the radiopharmaceutical at cellular and subcellular level. In Specific Aim 2, we propose to develop a surrogate for organ dosimetry based on the residence time of the radiopharmaceutical in a human imaging trial with [203Pb]PSC-TOC, This methodology requires serial imaging over multiple days. We will then extend the dosimetry methodology to develop a predictive model to identify the best single imaging time point that predicts kidney accumulation, similar to our previous work with 90Y-DOTATOC, for translation of the dosimetry procedure into the clinical practice. Finally in Specific Aim 3 we will conduct a Phase 1 dose escalation trial of personalized dosimetry-guided therapy with [212Pb]PSC-TOC in patients with advanced stage NETs who have progressed or are refractory to conventional PRRT with beta emitters. The dose escalation paradigm will be based on escalating critical organ dose limits (using residence time as surrogate for dosimetry). The primary objective of the Phase 1 clinical trial will be the identification of the maximum safe kidney dose surrogate from treatment with [212Pb]PSC-TOC that should be used for a subsequent Phase 2 efficacy trial with the agent. As a secondary objective we will assess objective tumor response to PRRT with [212Pb]PSC-TOC. .

项目摘要/摘要 多肽受体放射性核素治疗(PRRT)联合[177Lu]DOTATE改善小鼠的生活质量和生存 晚期神经内分泌肿瘤的患者；然而，客观的肿瘤消退是罕见的和完全的 人们的回应极为罕见。另一方面，令人兴奋的新证据表明，PRRT与 阿尔法发射体有可能将PRRT扩展到肿瘤消退甚至完全缓解。在这 研究我们建议开发一种新的治疗对，使用[203Pb]PSC-TOC(成像)/[212Pb]PSC-TOC(α 发射器)，用于神经内分泌肿瘤的基于图像引导剂量学的个性化治疗。在特定目标中1 我们将优化[203/212Pb]PSC-TOC的放射性标记和生产，为其使用做准备 在临床试验中，并在免疫能力强的小鼠中进行临床前剂量递增试验，以研究药物 毒性及毒性与器官辐射剂量的关系(以停留时间为指标)。这个 准确测量阿尔法辐射源的辐射剂量具有挑战性，因为辐射剂量依赖于 放射性药物在细胞和亚细胞水平的分布。在具体目标2中，我们建议 根据放射性药物在人体内的滞留时间研制器官剂量测定的替代物 使用[203Pb]PSC-TOC进行成像试验，该方法需要多天的连续成像。到时候我们会的 扩展剂量学方法以开发预测模型以确定最佳单次成像时间点 这预测了肾脏的积累，类似于我们之前与90Y-DOTATOC的工作，用于翻译 将剂量学程序应用于临床实践。最后，在具体目标3中，我们将进行阶段1剂量 晚期患者应用[~(212)Pb]PSC-TOC个体化剂量学指导治疗的升级试验 已经取得进展或对使用贝塔发射器的传统PRRT无效的Net。剂量递增 范例将基于不断增加的临界器官剂量限制(使用停留时间替代 剂量学)。第一阶段临床试验的主要目标将是确定最大的安全性 使用[212Pb]PSC-TOC治疗的肾脏剂量替代物，应用于后续的第二阶段 使用该试剂进行疗效试验。作为次要目标，我们将评估客观的肿瘤对PRRT的反应 [212Pb]PSC-TOC。 。