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
基本信息
- 批准号:10396517
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-03 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:90YAlpha Particle EmitterAlpha ParticlesAmino AcidsAnimalsBiological MarkersBloodBone MarrowChelating AgentsClinicalClinical ResearchClinical TrialsComputer softwareDataData AnalysesDependenceDetectionDiagnosisDoseDose-LimitingDrug toxicityFemaleHistologicHumanImageImmunocompetentIn complete remissionIncidenceInfusion proceduresInjuryIsotopesKidneyLabelLettersLiteratureMarrowMeasurementMeasuresMetastatic Neoplasm to the LiverMethodologyMulti-Institutional Clinical TrialMusNeuroendocrine TumorsOrganOutcomePET/CT scanPatient SelectionPatient-Focused OutcomesPatientsPeptide ReceptorPeptidesPerformancePhasePhase I Clinical TrialsPositioning AttributePreparationProceduresProductionProtocols documentationQuality of lifeRadiation Dose UnitRadiolabeledRadiometryRadionuclide therapyRadiopharmaceuticalsRandomizedRefractoryResearchRunningSafetySerumStudy modelsSystemic TherapyTherapeuticTherapy trialTimeToxic effectTranslationsValidationWorkX-Ray Computed Tomographybaseclinical practicecohortdosimetryeffective therapyefficacy trialhuman imaginghuman subjectimage guidedimaging studyimprovedimproved outcomemalemouse modelmulti-site trialpersonalized medicinephantom modelphase III trialpre-clinicalpreclinical toxicitypredictive modelingreduce symptomsresidenceresponseserial imagingsingle photon emission computed tomographystandard of caretheranosticstumorurinary
项目摘要
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.
.
项目概要/摘要
[177Lu]DOTATATE 肽受体放射性核素治疗 (PRRT) 可改善患者的生活质量和生存率
晚期神经内分泌肿瘤患者;然而客观的肿瘤消退是罕见且完全的
回应极为罕见。另一方面,令人兴奋的新证据表明 PRRT 与
α发射体有可能将 PRRT 扩展到肿瘤消退甚至完全缓解。在这个
研究中,我们建议使用 [203Pb]PSC-TOC(成像)/[212Pb]PSC-TOC(α
发射器)用于基于图像引导剂量测定的神经内分泌肿瘤个性化治疗。具体目标 1
根据该提案,我们将优化 [203/212Pb]PSC-TOC 的放射性标记和生产,为其使用做好准备
进行临床试验并在免疫功能正常的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(使用停留时间作为替代)的关系。这
由于剂量依赖于 α 发射体的辐射剂量,准确测量具有挑战性
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中的停留时间开发器官剂量测定的替代方法
使用 [203Pb]PSC-TOC 进行成像试验,该方法需要多天的连续成像。我们随后将
扩展剂量测定方法以开发预测模型来确定最佳的单一成像时间点
预测肾脏蓄积,类似于我们之前对 90Y-DOTATOC 的研究,用于翻译
剂量测定程序进入临床实践。最后,在具体目标 3 中,我们将进行第一阶段剂量
在晚期患者中使用 [212Pb]PSC-TOC 进行个性化剂量测定指导治疗的升级试验
对使用 β 发射器的传统 PRRT 已进展或难治的 NET。剂量递增
范式将基于不断升级的关键器官剂量限制(使用停留时间作为替代
剂量测定)。第一阶段临床试验的主要目标是确定最大安全剂量
[212Pb]PSC-TOC 治疗的肾脏剂量替代值,应用于随后的第 2 阶段
与药剂的功效试验。作为次要目标,我们将评估客观肿瘤对 PRRT 的反应
[212Pb]PSC-TOC。
。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Yusuf Menda其他文献
Yusuf Menda的其他文献
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{{ truncateString('Yusuf Menda', 18)}}的其他基金
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:
10673599 - 财政年份:2019
- 资助金额:
-- - 项目类别:
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 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Project 1: Theranostics in Neuroendocrine Tumors
项目 1:神经内分泌肿瘤的治疗诊断学
- 批准号:
10264528 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Image-guided Diagnosis and Therapy of Neuroendocrine Tumors
神经内分泌肿瘤的影像引导诊断和治疗
- 批准号:
8687491 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Image-guided Diagnosis and Therapy of Neuroendocrine Tumors
神经内分泌肿瘤的影像引导诊断和治疗
- 批准号:
8532860 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Image-guided Diagnosis and Therapy of Neuroendocrine Tumors
神经内分泌肿瘤的影像引导诊断和治疗
- 批准号:
8880867 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Image-guided Diagnosis and Therapy of Neuroendocrine Tumors
神经内分泌肿瘤的影像引导诊断和治疗
- 批准号:
8300346 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Imaging Thymidine Uptake During Treatment for Head and Neck Cancer
头颈癌治疗期间胸苷摄取的成像
- 批准号:
7329121 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Imaging Thymidine Uptake During Treatment for Head and Neck Cancer
头颈癌治疗期间胸苷摄取的成像
- 批准号:
7476342 - 财政年份:2007
- 资助金额:
-- - 项目类别:
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Alpha-Particle Emitter Peptide Receptor Targeted Radionuclide Therapy for Neuroendocrine Tumors
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