A Phase I Study of CED of Liposomal-Irinotecan using imaging in High Grade Glioma

使用成像技术对高级别胶质瘤进行脂质体伊立替康 CED 的 I 期研究

• 批准号: 8699561
• 负责人: Nicholas A Butowski
• 金额: $ 32.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699561
• 关键词: Antineoplastic Agents; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Canis familiaris; Cannulas; Clinical; Clinical Trials; Computer software; Contrast Media; Convection; Data; Development; Drug Formulations; Encapsulated; Ensure; Gadolinium; Glioma; Goals; Grant; Human; Image; Injection of therapeutic agent; Intracranial Neoplasms; Lead; Liposomes; Liquid substance; Magnetic Resonance Imaging; Mind; Modality; Modeling; Monitor; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Pre-Clinical Model; Primates; Procedures; Protocols documentation; Publishing; Rattus; Recurrence; Safety; System; Therapeutic; Time; Tissues; Toxic effect; Water; Work; arm; base; chemotherapeutic agent; chemotherapy; design; drug distribution; gadolinium oxide; gadoteridol; human study; improved; industry partner; irinotecan; nanoliposome; novel; novel strategies; phase 1 study; pre-clinical; pressure; public health relevance; tumor

DESCRIPTION (provided by applicant): Chemotherapy for high grade glioma (HGG) is limited by the poor activity of available agents and the compromised delivery of chemotherapy across the blood brain barrier. With these limitations in mind, the proposed phase I clinical trial utilizs two delivery modalities which may improve the efficacy of chemotherapeutic agents: liposomal irinotecan and MR imaged real-time convection enhanced delivery (CED). Several anticancer drugs have been encapsulated in liposomes, and have demonstrated therapeutic benefits over their unencapsulated counterparts. Thus, an appropriately designed liposome formulation of irinotecan may reduce the toxicity to healthy tissue while maintaining and increasing its anti-tumor potency. A major advance in the use of CED is the development of real-time MR imaged CED, which utilizes MRI to visualize the CED in real-time with the aid of co-convected contrast agents. CED improves chemotherapeutic delivery to brain tumors by utilizing bulk flow, or fluid convection, established as a result of a pressure gradient. Additionally, CED both obviates the challenges of crossing the BBB while minimizing systemic toxicity. The use of real-time MR imaging allows us to monitor CED into the brain and to take corrective action for technical complexities; this represents an important improvement over recent CED clinical trials which lacked effective imaging monitoring. Consequently, armed with our published preclinical work, with the support of an industry partner, and ultimately via this grant, we propose the first in human phase I study of CED of liposomal-irinotecan using real-time imaging with gadolinium in patients with recurrent HGG. We'll also examine the imaging data from this trial in an effort to optimize the MR image-guided intracranial injection procedure in HGG patients by correlating the observed distribution of gadolinium to pre-treatment modeling of the drug distribution utilizing predictive imaging software.

描述(由申请人提供)：高级别胶质瘤(HGG)的化疗受到可用药物活性差和化疗跨越血脑屏障的影响。考虑到这些限制，拟议的I期临床试验使用了两种可能提高化疗药物疗效的给药方式：脂质体伊立替康和磁共振成像实时对流增强给药(CED)。几种抗癌药物已被包裹在脂质体中，并显示出比未包裹的同类药物更好的治疗效果。因此，设计适当的伊立替康脂质体制剂可以减少对健康组织的毒性，同时保持和增加其抗肿瘤效力。CED应用的一个主要进展是开发了实时MR成像CED，它利用MRI在共附子造影剂的帮助下实时显示CED。CED通过利用压力梯度建立的大量流动或液体对流来改善对脑肿瘤的化疗输送。此外，CED既避免了跨越血脑屏障的挑战，又将全身毒性降至最低。实时磁共振成像的使用使我们能够监测进入大脑的CED，并针对技术复杂性采取纠正措施；这与最近缺乏有效成像监测的CED临床试验相比是一项重要的改进。因此，在我们已发表的临床前工作的基础上，在一家行业合作伙伴的支持下，并最终通过这笔赠款，我们提出了第一项人类I期脂质体-伊立替康CED研究，在复发的HGG患者中使用Gd实时成像。我们还将检查这项试验的成像数据，通过将观察到的Gd分布与使用预测成像软件对药物分布进行治疗前建模相关联，努力优化HGG患者的MR图像引导的颅内注射程序。