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

基本信息

批准号：
10588065
负责人：
Steven William Hetts
金额：
$ 19.97万
依托单位：
FILTRO MEDICAL INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10588065
关键词：
Achievement Animal Model Binding Blood Cancer Etiology Catheters Cessation of life Chemoembolization Chemotherapy-Oncologic Procedure Clinical Trials Deposition Devices Disease Distant Dose Dose-Limiting Doxorubicin Drug Targeting Drug toxicity Filtration Heart Heart failure Hematologic Agents Human In Situ In Vitro Infusion procedures Interventional radiology Liver neoplasms Location Malignant Neoplasms Malignant neoplasm of liver Medical Device Metastatic Neoplasm to the Liver Modeling Motivation Organ Patients Pharmaceutical Preparations Phase Population Procedures Rest Safety Site Solid Stream Technology Testing Therapeutic Toxic effect Unresectable Veins Venous base cancer therapy cell killing chemotherapeutic agent chemotherapy cost design efficacy study efficacy testing experience fighting first-in-human hepatic vein image guided improved in vivo minimally invasive neoplastic cell prototype response safety study side effect success systemic toxicity tumor

项目摘要

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.

项目概要化疗药物的剂量受到全身毒副作用的限制。我们正在开发一类新的图像 - 引导临时可部署、基于血管内导管的医疗设备，可选择性地从血管内去除特定药物血流以减少全身毒性。拟议的化学过滤器包含结合目标的特殊材料药物通过多种机制原位发挥。在动脉化疗 (IAC) 期间输注至靶器官（例如，固体含有肿瘤的器官），未滞留在目标器官中的过量药物会通过静脉排出器官，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 在进行 IAC 的器官引流静脉中，我们寻求在过量药物逸出导致全身毒性之前将其结合。这在 IAC 手术后不久，ChemoFilter 将在介入放射学套件中被移除，从而移除患者体内过量的药物。尽管配对的动脉内输注和静脉滤过理论上可以用于任何药物其治疗作用位点位于一个位置，而其剂量限制性毒性位点位于另一位置，这是最引人注目的该技术的应用正在提高局部癌症化疗的有效性和安全性。原发性和转移性肝脏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术 (TACE) 是 IAC 的一种形式，可以经济有效地提高该人群的生存率。阿霉素 (Dox) 是一种低成本、高效的化疗药物，常用于 IAC。 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力，为更高剂量的 Dox 治疗提供动力。我们最初的项目已经产生了 ChemoFilters 在动物模型中，可以将心脏中的 Dox 沉积减少 46%。我们力求通过设计、构建和测试可以更轻松地导航到人类患者肝静脉的新设备。原型化学过滤器将在体外进行建模、构建、有效性验证，并在大型动物模型中进行体内测试由 Filtro, Inc 和 UCSF 经验丰富的团队负责第一阶段的导航。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有效性和安全性，并在患有以下疾病的患者中进行首次人体安全性和有效性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设备应通过降低作为 TACE 的一部分，Dox 的常用剂量可提高全身药物浓度并降低全身毒性。完成此研究将为 ChemoFilter 技术做好关键临床试验的准备，该试验将评估任何给定情况下的 Dox 剂量递增 IAC/TACE 程序可在更少的 IAC/TACE 疗程中实现更好的局部肿瘤控制。