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药物穿过血脑屏障的递送受损的限制。考虑到这些局限性，拟议的I期临床试验利用两种可能提高化疗药物疗效的给药方式：伊立替康脂质体和MR成像实时对流增强给药（CED）。几种抗癌药物已被封装在脂质体中，并已证明其治疗益处超过其未封装的对应物。因此，适当设计的伊立替康脂质体制剂可降低对健康组织的毒性，同时维持和增加其抗肿瘤效力。CED使用的一个主要进展是开发了实时MR成像CED，其利用MRI在共对流造影剂的帮助下实时可视化CED。CED通过利用由于压力梯度而建立的整体流动或流体对流来改善对脑肿瘤的化疗递送。此外，CED既避免了穿过BBB的挑战，又最大限度地减少了全身毒性。使用实时MR成像使我们能够监测CED进入大脑，并针对技术复杂性采取纠正措施;这代表了对缺乏有效成像监测的最近CED临床试验的重要改进。因此，凭借我们已发表的临床前工作，在行业合作伙伴的支持下，并最终通过该资助，我们提出了第一项在复发性HGG患者中使用钆实时成像的脂质体-伊立替康CED的人体I期研究。我们还将检查本试验的成像数据，通过将观察到的钆分布与使用预测成像软件的药物分布的治疗前建模相关联，优化HGG患者的MR图像引导颅内注射程序。