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

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通过血脑屏障递送受损的限制。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递送方式：伊立替康脂质体和MR成像实时对流增强递送（CED）。几种抗癌药物已经被包封在脂质体中，并且已经证明比未包封的药物更有治疗效果。因此，适当设计的伊立替康脂质体制剂可以降低对健康组织的毒性，同时保持和增加其抗肿瘤效力。实时磁共振成像技术的发展是实时磁共振成像技术的一个主要进步，该技术利用磁共振成像技术在共对流造影剂的帮助下实时显示CED。CED通过利用由压力梯度形成的大流量或流体对流，改善了化疗对脑肿瘤的输送。此外，CED既避免了穿越血脑屏障的挑战，又将全身毒性降至最低。使用实时核磁共振成像使我们能够监测CED进入大脑，并对技术复杂性采取纠正措施；这代表了最近缺乏有效成像监测的CED临床试验的重要改进。因此，在我们已发表的临床前研究成果的支持下，在行业合作伙伴的支持下，最终通过这笔拨款，我们提出了第一个在复发性HGG患者中使用钆实时成像的脂质体伊立替康的CED的人类I期研究。我们还将检查该试验的成像数据，通过使用预测成像软件将观察到的钆分布与治疗前药物分布建模相关联，以优化HGG患者的MR图像引导颅内注射程序。

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.