Abstract 2055: A first-in-class hemoglobin-floxuridine conjugate for the treatment of advanced stage liver cancer
Authors: Brookes Steve , Cutler Murray J. , Seo Jin Seog , Adamson Gord , Bell David 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide; few treatment options are available, especially for advanced stage disease. Therapure has developed a novel drug delivery platform based upon the attachment of 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 to the liver to improve treatment for HCC. Systemic toxicity associated with free floxuridine restricts its use to locoregional administration (0.2-0.5 mg/kg/d) via continuous hepatic arterial infusion. Although hepatic arterial infusion of floxuridine can reduce hepatic tumor burden, toxicity from floxuridine and complications associated with direct hepatic infusion pumps can be significant. HDC technology exploits the natural pathway for hemoglobin clearance through the liver to provide selective drug targeting while preserving floxuridine activity following standard intravenous (IV) infusion. In a preclinical efficacy study of TBI 302, mice bearing human liver cancer cell line-derived orthotopic liver tumors received twice-weekly tail vein dosing of saline, 3.7 mg/kg floxuridine, or TBI 302. Following 6 weeks of treatment, 70% of the orthotopically implanted mice treated with 170.5 mg/kg TBI 302 (3.7 mg/kg floxuridine) had no measurable liver tumors, indicating suppression of tumor growth. In contrast, only 30% of mice treated with an equivalent dose of unconjugated floxuridine and 20% of mice treated with saline experienced liver tumor growth suppression. These results demonstrate the capability of the HDC platform to enhance the efficacy of cytotoxics through liver targeting. 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 (0.08, 0.19, and 0.4 mg/kg floxuridine, respectively) was well tolerated at all dose levels. Increasing doses of TBI 302 resulted in proportional increases in area under the concentration-time curve (AUC) and maximum concentration (Cmax) of total plasma floxuridine. 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 (0.4 mg/kg floxuridine). A Phase I safety study of TBI 302 as second-line therapy in HCC has been approved by the FDA. The primary objective is to determine safety and tolerability of TBI 302. 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, while potentially reducing extra-hepatic toxicity of drugs.
Citation Format: Steve Brookes, Murray J. Cutler, Jin Seog Seo, Gord Adamson, David Bell. A first-in-class hemoglobin-floxuridine conjugate for the treatment of advanced stage liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2055.