Enabling high dose regional chemotherapy while minimizing systemic toxicity

DESCRIPTION (provided by applicant): Enabling high dose regional chemotherapy with minimal systemic toxicity Abstract: The primary objective of this proposed study is to develop a filtration system that maximizes the removal (gt90%) of chemotherapeutic agents, such as doxorubicin, from blood while minimizing adverse effects of filtration on blood chemistry and hematological parameters. Vascular Vision Pharmaceuticals Co. (VVP) and Delcath Systems are at the forefront of cancer treatment. Delcath's proprietary technology for localized drug delivery, Percutaneous Hepatic Perfusion (PHP ), allows the delivery of significantly higher doses of anti-cancer drug directly to the cancer site as compared to systemic delivery without exposure of the entire body to potent levels of drug. Initial results from clinical studies in liver cancer patients have confirmed that delivery of higher levels of anti-cancer drug directly to the tumor site with minimal exposure of other regions of the body enhances tumor shrinkage and improves quality of life as compared to systemic cancer therapies. PHPTM is currently under testing in Phase II clinical trials for a variety of cancers of the liver. The proposed research program relates to the application of PHPTM to localized cancer therapy and targeted drug delivery. Current Delcath filters consist of activated carbon coated with polymethacrylate to insulate the blood from direct contact with the filter material. These filters exhibit low first-pass extraction capability, resulting in suboptimal removal of chemotherapeutic agent, and shedding of carbon debris, resulting in activation of the clotting cascade and damage to the blood. Thus, there is an urgent need for filters with better efficiency and biocompatibility. The specific aims of this Phase I STTR proposal are as follows: Specific Aim 1: Determine the type of filter material required for the efficient removal of doxorubicin from blood. This will be accomplished by a) preparing carbon beads with three different coatings (cellulose with heparin, PMMA and PMMA with heparin) to enhance the biocompatibility of the carbon filters during blood perfusion, and then b) testing the efficiency and capacity of coated carbon in a batch mode filter to remove doxorubicin from bovine blood. Specific Aim 2: Determine the blood biocompatibility of the different coated filters by a) measuring changes in blood coagulation parameters and b) measuring changes in platelet activation state. Specific Aim 3: Carry out a perfusion study using optimized filters. This will be accomplished as follows: a) prepare large-scale optimized coated carbon filters based on the results of Aims 1 and 2; and b) test the efficiency of the optimized filter to remove doxorubicin from bovine blood. PUBLIC HEALTH RELEVANCE: The primary objective of this proposed study is to develop a novel Polymethyl methacrylate coated activated carbon filter with different compositions including cellulose and heparin for the maximum removal chemotherapy such as doxorubicin and others from blood while minimizing filter impact on blood chemistry. Initial clinical results from studies treating hepatic cancer patients confirm that delivering more chemotherapy drug to the tumor site, and less to the other regions of the body, enhances tumor shrinkage with improved quality of life over systemic cancer therapies.