Endovascular ChemoFilter to Reduce Doxorubicin Toxicity during Intra-Arterial Chemotherapy

PROJECT SUMMARYDosing 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.PROJECT NARRATIVE We propose a paradigm shift in cancer therapy: ChemoFilter, an endovascular catheter-based medical device that will be inserted under image guidance into the veins of the body to directly filter specific chemotherapy drugs out of the blood stream after these drugs have had their effect on a tumor but before they have caused systemic toxic effects. ChemoFilter would help patients fight cancer by minimizing drug toxicity, allowing for high-dose therapy to better treat their disease and improve survival. Patients suffering from primary and oligometastatic liver cancers are the first targets for this device.