Image-guided dosimetry-based alpha particle therapy for neuroblastoma.
基于图像引导剂量测定的阿尔法粒子治疗神经母细胞瘤。
基本信息
- 批准号:10480167
- 负责人:
- 金额:$ 99.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-04 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdultAlpha ParticlesBeta ParticleBiodistributionBostonCessation of lifeChemistryChildClinicClinicalClinical TrialsCommunicationDataDoctor of PhilosophyDocumentationDoseDose-LimitingEvaluationExerciseFDA approvedFormulationGenetic EngineeringHumanImageImmunocompetentIn complete remissionInflammatoryIowaKidneyLabelLegal patentLuciferasesMYCN geneMalignant Childhood NeoplasmMalignant NeoplasmsMarrowModelingMonitorMusNeoplasm MetastasisNeuroblastomaNeuroendocrine TumorsOutcomePamphletsPatientsPediatric HospitalsPeptide ReceptorPeptidesPharmacology and ToxicologyPhasePreparationProcessProductionPrognosisPropertyProtocols documentationPublished CommentRadionuclide therapyRadiopharmaceuticalsRegimenResearch PersonnelResistanceRiskRodent ModelSCID MiceSSTR2 geneSafetySecureSeriesSmall Business Innovation Research GrantTechnology TransferTemperatureTherapeuticTherapy trialTimeToxic effectTrainingTreatment ProtocolsUnited StatesUniversitiesbasechildhood cancer mortalityclinical research sitedosimetryefficacy evaluationfallsimage guidedimage guided radiation therapyimage guided therapyimprovedinflammatory markerinnovationmeetingsmouse modelnext generationnovel therapeuticsparticle therapypeptide structurephase I trialphase III trialresearch and developmentresponsesingle photon emission computed tomographysomatostatin receptor 2standard of caretargeted treatmenttherapy outcometumortumor growth
项目摘要
SIGNIFICANCE: Neuroblastoma is the most common pediatric cancer, accounting for 15% of cancer deaths,
with a 5-yr survival of <40% due to resistant metastases. Neuroblastoma tumors almost universally express the
somatostatin receptor 2 (SSTR2) and high expression has been shown clinically using peptides targeting SSTR2
(PMID10706954). FDA approved SSTR2-targeted beta(β-)-emitting 177Lu-labeled Lutathera™ has been shown to
be safe and feasible (PMID21680680), but tumor response to SSTR2-targeted β--therapy has been poor. On the
other hand, Viewpoint’s next-generation SSTR2-targeted [212Pb]VMT-α-NET alpha(α)-particle therapy (α-PRRT)
produced complete responses (CRs) in 70% of mice bearing SSTR2+ tumors. Data show that the significantly
improved PK properties of VMT-α-NET compared to competing SSTR2 targeted radiopharmaceuticals leads to
significantly improved tumor to normal accumulation and lower risk of toxicities (particularly in dose limiting kidneys). In
the revised application, the team introduces an innovative immune-competent genetically engineered metastatic
mouse model (GEMM) of neuroblastoma (new Co-Investigator Wang PhD at Nationwide Children’s Hospital) that
genetically mimics neuroblastoma in humans and develops spontaneously in mice. Thus, we will identify effective
regimens and assess potential toxicities (e.g., kidney) and inflammatory markers in preparation for FDA submissions.
The revised project is significant because predicate data demonstrate that Viewpoint’s [212Pb]VMT-α-NET α-PRRT has the potential to provide for complete/durable tumor responses (and be well tolerated) for neuroblastoma
patients. The project is further significant because the GEMM rodent model and CMC plan included is aligned
with FDA guidance for micro-dosed radiopharmaceutical therapeutics and our communications with the FDA for
Fast Track designation. Therefore, there is a critical need to advance Viewpoint’s α-PRRT to clinical trials for
neuroblastoma patients for whom other therapies (including SSTR2 β-particle therapy) fall short.
PREDICATE MILESTONES: $13M Series A; 70% CRs in mice; 203Pb/212Pb secured; Communications with FDA
to secure two INDs and complete a pre-IND meeting with support from the FDA for α-particle therapy for adult
trials. FDA communications are ongoing. We will achieve our objectives by completing these Specific Aims.
AIM 1. Determine the dosing regimens of [203Pb]VMT-α-NET image-guided [212Pb]VMT-α-NET therapy that
maximize complete responses and minimize toxicity in mouse models of metastatic neuroblastoma.
AIM 2. Optimize [212Pb]VMT-α-NET production and complete technology transfer for CMC and IND
submission to the US FDA to initiate a Phase 1 imaging-guided therapy trial in neuroblastoma patients.
IMPACT: With completion of these Aims, we expect to have developed a detailed understanding of the
therapeutic regimens that maximize tumor responses (minimizing toxicity) in metastatic models of neuroblastoma
in mice that align with FDA guidance for a Fast Track application. We further expect to complete formulation and
CMC documentation for the submission of an IND for Phase 1 trials of Viewpoint’s TAT for neuroblastoma.
意义:神经母细胞瘤是最常见的儿童癌症,占癌症死亡的15%,
由于耐药转移,5年存活率为40%。神经母细胞瘤几乎普遍表达
针对生长抑素受体2(SSTR2)的多肽已在临床上被证明是高表达的
(PMID10706954)。FDA批准的SSTR2靶向测试版(β-)-发射177Lu标记的Lutathera™已被证明
是安全和可行的(PMID21680680),但肿瘤对SSTR2靶向β治疗的反应一直很差。论
另一方面,观察点的下一代SSTR2靶向[212Pb]VMT-α-Net Alpha(α)-粒子疗法(α-PrRT)
在70%的SSTR2+肿瘤小鼠中产生了完全应答(CRS)。数据显示,显著的
与竞争对手的α靶向放射性药物相比,VMT-SSTR2-Net的PK特性改善导致
显著改善肿瘤向正常蓄积的状态,降低毒性风险(特别是在剂量限制的肾脏)。在……里面
在修改后的应用程序中,该团队引入了一种创新的免疫能力基因工程转移瘤
神经母细胞瘤小鼠模型(全国儿童医院新合作者王博导)
在基因上模仿人类的神经母细胞瘤,并在小鼠身上自发发展。因此,我们将确定有效的
并评估潜在的毒性(例如肾脏)和炎症标志物,为FDA提交的文件做准备。
修订后的项目意义重大,因为谓词数据表明,观点公司的[212Pb]VMT-α-Netα-PrRT有可能为神经母细胞瘤提供完整/持久的肿瘤反应(并具有良好的耐受性
病人。该项目的意义更加重大,因为GEMM啮齿动物模型和CMC计划是一致的
根据FDA对微剂量放射性药物治疗的指导,以及我们与FDA的沟通
快速通道指定。因此,迫切需要将视点的α-PrRT推进到临床试验中
神经母细胞瘤患者,其他疗法(包括SSTR2β-颗粒疗法)效果不佳。
预测里程碑:1300万美元A系列;70%的小鼠CRS;203Pb/212Pb安全;与FDA沟通
在食品和药物管理局的支持下,确保两个IND并完成IND前的会议,用于成人的α颗粒疗法
审判。FDA的沟通正在进行中。我们将通过完成这些具体目标来实现我们的目标。
目的1.确定[~(203)Pb]VMT-α-Net影像引导[~(201)Pb]VMT-α-Net治疗的给药方案。
在转移性神经母细胞瘤小鼠模型中最大限度地提高完全反应并最大限度地减少毒性。
目标2.优化[212Pb]VMT-α-Net生产,完成CMC和Ind的技术转让
提交给美国食品和药物管理局,以启动神经母细胞瘤患者的影像引导治疗第一阶段试验。
影响:随着这些目标的完成,我们预计将对
神经母细胞瘤转移模型中最大化肿瘤反应(最小化毒性)的治疗方案
在符合FDA快速通道应用指南的小鼠身上。我们还预计将完成制定和
CMC文件,为视点的TAT治疗神经母细胞瘤的1期试验提交IND。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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ALAN Brent PACKARD其他文献
ALAN Brent PACKARD的其他文献
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{{ truncateString('ALAN Brent PACKARD', 18)}}的其他基金
Image-guided dosimetry-based alpha particle therapy for neuroblastoma.
基于图像引导剂量测定的阿尔法粒子治疗神经母细胞瘤。
- 批准号:
10677002 - 财政年份:2022
- 资助金额:
$ 99.02万 - 项目类别:
2014 Metals in Medicine Gordon Research Conference
2014 年戈登医学金属研究会议
- 批准号:
8710800 - 财政年份:2014
- 资助金额:
$ 99.02万 - 项目类别:
A Novel F-18 PET Myocardial Perfusion Radiopharmaceutical based on Rhodamine Dyes
基于罗丹明染料的新型 F-18 PET 心肌灌注放射性药物
- 批准号:
8086347 - 财政年份:2011
- 资助金额:
$ 99.02万 - 项目类别:
A Novel F-18 PET Myocardial Perfusion Radiopharmaceutical based on Rhodamine Dyes
基于罗丹明染料的新型 F-18 PET 心肌灌注放射性药物
- 批准号:
8447345 - 财政年份:2011
- 资助金额:
$ 99.02万 - 项目类别:
A Novel F-18 PET Myocardial Perfusion Radiopharmaceutical based on Rhodamine Dyes
基于罗丹明染料的新型 F-18 PET 心肌灌注放射性药物
- 批准号:
8247718 - 财政年份:2011
- 资助金额:
$ 99.02万 - 项目类别:
A Novel F-18 PET Myocardial Perfusion Radiopharmaceutical based on Rhodamine Dyes
基于罗丹明染料的新型 F-18 PET 心肌灌注放射性药物
- 批准号:
9983130 - 财政年份:2011
- 资助金额:
$ 99.02万 - 项目类别:
A Novel F-18 PET Myocardial Perfusion Radiopharmaceutical based on Rhodamine Dyes
基于罗丹明染料的新型 F-18 PET 心肌灌注放射性药物
- 批准号:
8611961 - 财政年份:2011
- 资助金额:
$ 99.02万 - 项目类别:
A Novel F-18 PET Myocardial Perfusion Radiopharmaceutical based on Rhodamine Dyes
基于罗丹明染料的新型 F-18 PET 心肌灌注放射性药物
- 批准号:
9384402 - 财政年份:2011
- 资助金额:
$ 99.02万 - 项目类别:
Functional Imaging of Multidrug Resistance with PET
PET 多重耐药性功能成像
- 批准号:
6868155 - 财政年份:2004
- 资助金额:
$ 99.02万 - 项目类别:
Functional Imaging of Multidrug Resistance with PET
PET 多重耐药性功能成像
- 批准号:
6727183 - 财政年份:2004
- 资助金额:
$ 99.02万 - 项目类别:
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