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

项目概要/摘要 用[177Lu] DOTATATE进行肽受体放射性核素治疗（PRRT）可改善患者的生活质量和生存期。 晚期神经内分泌肿瘤患者;然而，客观肿瘤消退罕见且完全 反应非常罕见。另一方面，令人兴奋的新证据表明，PRRT与 α-发射体具有将PRRT扩展到肿瘤消退甚至完全反应的潜力。在这 研究中，我们提出使用[203 Pb] PSC-TOC（成像）/[212 Pb] PSC-TOC（α）开发一种新的治疗诊断对 发射器）用于神经内分泌肿瘤的基于图像引导的剂量测定的个性化治疗。具体目标1 根据该提案，我们将优化[203/212 Pb] PSC-TOC的放射性标记和生产，为其使用做准备 并在免疫活性小鼠中进行临床前剂量递增试验以研究药物 毒性以及毒性与器官辐射剂量的关系（使用停留时间作为替代）。的 来自α发射体的辐射剂量的精确测量是具有挑战性的 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停留时间开发器官剂量测定的替代品 使用[203 Pb] PSC-TOC的成像试验，该方法需要多天的连续成像。然后我们将 扩展剂量测定方法，以开发预测模型，确定最佳单个成像时间点 预测肾脏蓄积，类似于我们以前使用90Y-DOTATOC的工作，用于翻译 剂量测定程序应用于临床实践。最后，在具体目标3中，我们将进行1期剂量 [212 Pb] PSC-TOC在晚期患者中的个体化剂量学指导治疗的递增试验 NET已经进展或对使用β发射体的常规PRRT无效。剂量递增 范例将基于逐步增加的关键器官剂量限值（使用停留时间作为 剂量测定法）。1期临床试验的主要目的是确定最大安全性 [212 Pb] PSC-TOC治疗的肾脏剂量替代，应用于后续II期研究 与代理商的有效性试验。作为次要目的，我们将评估PRRT的客观肿瘤反应， [212Pb] PSC-TOC。 .

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. .