A first-in-class therapy for the treatment of advanced stage liver cancer.

e14061 Background: Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide. Current standard of care provides only a modest improvement in overall survival and is associated with poor quality of life. Therapure has developed a novel drug delivery platform based upon the attachment of therapeutic drugs to hemoglobin (Hb) as a means of targeting the liver. TBI 302 is a hemoglobin-drug conjugate (HDC) designed to deliver the anticancer drug floxuridine (FUdR) to the liver to improve the effectiveness of treatment for HCC. Systemic toxicity associated with free FUdR restricts its use to locoregional administration (0.2-0.5 mg/kg/d) via continuous hepatic arterial infusion (HAI). Although HAI of FUdR can reduce tumor burden, toxicity from HAI FUdR and complications associated with direct hepatic infusion pumps can be significant. HDC technology uses Hb as an innovative drug carrier that exploits the natural pathway for hemoglobin clearance predominantly through the liver to provide selective drug targeting while preserving FUdR activity following intravenous (IV) infusion. Methods: To establish a safe starting dose for a first-in-human Phase 1 trial, a GLP-compliant repeat dose preclinical safety study of TBI 302 in cynomolgus monkeys was conducted. TBI 302 administered by 1-hour IV infusion once per week for 8 weeks at doses of 2, 5, and 10.5 mg/kg. Results: Increasing doses of TBI 302 resulted in proportional area under the concentration-time curve (AUC) and maximum concentration (Cmax) of total plasma FUdR. No clinical signs or biochemical toxicity was associated with IV infusion of TBI 302. The no-observed-adverse effect level (NOAEL) of TBI 302 was determined to be the highest dose level of 10.5 mg/kg. TBI 302 is estimated to have a half-life of 5 hours in humans. Conclusions: A Phase I safety study of TBI 302 as second line therapy in HCC has been approved by the US FDA. The primary objective is to determine safety and tolerability of TBI 302. The secondary objectives are to determine TBI 302 pharmacokinetics and effects on tumor burden. Therapure's HDC platform represents a new class of therapy that offers liver-specific targeting for a wide range of hepatic diseases, while potentially reducing drug toxicity.