Endovascular ChemoFilter to Reduce Doxorubicin Toxicity during Intra-Arterial Chemotherapy

血管内化学过滤器可减少动脉化疗期间阿霉素的毒性

• 批准号: 10840035
• 负责人: Steven William Hetts
• 金额: $ 100万
• 依托单位: FILTRO MEDICAL INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10840035
• 关键词: Endovascular; ChemoFilter; Reduce; Doxorubicin; Toxicity

PROJECT SUMMARY Dosing of chemotherapeutics is limited by systemic toxic side effects. We are developing a new class of image- guided temporarily deployable, endovascular catheter-based medical devices that selectively remove specific drugs from the blood stream to reduce systemic toxicities. The proposed ChemoFilters incorporate specialized materials that bind target drugs in situ through a variety of mechanisms. During intraarterial chemotherapy (IAC) infusion to a target organ (e.g., a solid organ containing a tumor), excess drug not trapped in the target organ passes through to the veins draining the organ and then is circulated to the rest of the body, causing toxicities in distant locations. By temporarily deploying a ChemoFilter in the vein(s) draining the organ undergoing IAC, we seek to bind excess drug before it can escape to cause systemic toxicity. The ChemoFilter would then be removed in the interventional radiology suite shortly after the IAC procedure, thus removing excess drug from the patient. Although paired intraaterial infusion and venous filtration can theoretically be used for any drug that has its site of therapeutic action in one location and its site of dose-limiting toxicity in another location, the most compelling application for this technology is increasing efficacy and safety of locoregional cancer chemotherapy. Primary and metastatic liver tumors are among the top three causes of cancer death worldwide. Image-guided transarterial chemoembolization (TACE), a form of IAC, cost-effectively increases survival in this population. Doxorubicin (Dox) is a low-cost, highly effective, chemotherapeutic agent frequently used in IAC. Dox use is limited by systemic toxicities, most importantly irreversible cardiac failure. Dox follows a therapeutic linear dose-response model, in which increasing dose linearly increases tumor cell kill, providing motivation for higher-dose Dox therapy. Our initial project has yielded ChemoFilters that can reduce Dox deposition in the heart by 46% in animal models. We seek to build upon that success by designing, building, and testing new devices that can be more easily navigated to the hepatic veins in human patients. Prototype ChemoFilters will be modeled, built, validated in vitro for efficacy, and tested in vivo in a large animal model for navigability in Phase I by experienced teams from Filtro, Inc and UCSF. In phase II, the optimized devices from phase I will then be tested for efficacy and safety in a large animal model and a first-in-man safety and efficacy study in patients with unresectable liver cancer will be planned and initiated. Achievement of these aims will create new minimally invasive medical devices that should markedly increase the efficacy of image-guided locoregional intraarterial chemotherapy by lowering systemic drug concentrations and reducing systemic toxicities for the usual dose of Dox as part of TACE. Completion of this study will poise the ChemoFilter technology for a pivotal clinical trial that would assess Dox dose escalation in any given IAC/TACE procedure to achieve better local tumor control in fewer IAC/TACE sessions.

项目摘要 化疗药物的剂量受到全身毒性副作用的限制。我们正在发展一种新的形象- 本发明涉及一种基于引导的可暂时展开的血管内导管的医疗装置， 血液循环，以减少全身毒性。所提出的ChemoFilters结合了结合靶点的专用材料， 药物通过多种机制在原位。在向靶器官（例如，固体 含有肿瘤的器官），未被捕获在靶器官中的过量药物通过至排出该器官的静脉， 然后循环到身体的其他部位，在远处引起毒性。通过在中临时部署ChemoFilter 静脉引流进行IAC的器官，我们寻求在过量药物逃逸引起全身毒性之前结合过量药物。的 然后在IAC手术后不久在介入放射室中取出ChemoFilter，从而取出 从患者体内取出过量药物。虽然成对的动脉内输注和静脉过滤理论上可以用于任何药物 在一个位置具有治疗作用，在另一个位置具有剂量限制毒性， 该技术的应用增加了局部癌症化疗的有效性和安全性。 原发性和转移性肝肿瘤是全球癌症死亡的三大原因之一。图像引导 经动脉化疗栓塞（TACE），一种形式的IAC，成本有效地增加生存在这个群体。阿霉素 (Dox)是一种廉价、高效、常用于IAC的化疗药物。Dox的使用受到全身毒性的限制， 最重要的是不可逆的心力衰竭。Dox遵循治疗线性剂量反应模型，其中增加剂量 线性增加肿瘤细胞杀伤，为更高剂量的Dox治疗提供动力。我们最初的项目产生了ChemoFilters 在动物模型中可以减少46%的Dox沉积。我们寻求通过设计， 构建和测试新的设备，可以更容易地导航到人类患者的肝静脉。 将对原型ChemoFilters进行建模、构建、体外有效性验证，并在大型动物模型中进行体内试验 由来自Filtro，Inc和UCSF的经验丰富的团队在第一阶段进行导航。在第二阶段，第一阶段的优化设备 然后将在大型动物模型中测试疗效和安全性，并在患有以下疾病的患者中进行首次人体安全性和疗效研究 将计划并启动不可切除的肝癌。这些目标的实现将创造新的微创医疗 器械应通过降低 全身药物浓度和降低作为TACE一部分的常用剂量的Dox的全身毒性。完成本 这项研究将使ChemoFilter技术在一项关键的临床试验中发挥平衡作用，该试验将评估在任何给定的 IAC/TACE手术，以更少的IAC/TACE疗程实现更好的局部肿瘤控制。