IGF::OT::IGF A RANDOMIZED, DOUBLE-BLIND, PHASE I DOSE-ESCALATION STUDY OF THE NOVEL RETINOID 9CUAB30

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

Retinoids represent a promising class of chemoprevention agents. Notably, effects of retinoids demonstrate a significant dose-response relationship, which include evidence of therapeutic efficacy at higher doses. To date, translating the observed in vitro and in vivo effects into clinical chemoprevention has been limited by the acute and chronic toxicities. Examples of observed toxicities that have limited the application of various retinoids include: skin toxicity, angular chelitis, headache, hyperlipidemia, vision changes and elevations in hepatic transaminases. 9cUAB30 was developed at the University of Alabama as an RXR-selective retinoid. It has been shown to have chemopreventive activity in both ER+ and ER- mammary gland tumor models. The National Cancer Institute, Division of Cancer Prevention (NCI, DCP) has completed pre-IND development through the Rapid Access to Preventive Intervention Development (RAPID) program. A 28-day toxicity study in rats that tested 9cUAB30 at doses of 3, 15, and 100 mg/kg-bw/day has been completed.. Drug-related mortalities and clinical signs of toxicity were not seen. Liver weights were dose-dependently increased in both male and females, and significant increases in serum AST and alkaline phosphatase were noted in females at 100 mg/kg-bw/day, along with significant decreases in serum albumin. Histopathologic observations at the highest dose showed hepatic vacuolation consistent with glycogen deposition. 9cUAB30 influenced the coagulation system, especially the extrinsic pathway of coagulation (PT) homeostasis. A single dose (5mg, 10mg and 20mg) study of 9cUAB30 in normal volunteers demonstrated that 9cUAB30 is orally available with a Tmax after approximately 3 hours. Both Cmax and AUC increase in a dose proportion manner, with an average half-life of approximately 5 hours. The percent excreted unchanged in urine over 24 hours is 4.85% for the 5mg dose, 2.46% for the 10mg dose and 17% for the 20mg dose, suggesting extensive hepatic metabolism and adequate exposure with daily dosing. DCP initiated a double-blind, placebo-controlled single and multi-dose study of 9cUAB30 in healthy volunteers. Over the course of two different protocols, the agent was tested in cohorts of 10 participants (8 9cUAB30:2 placebo), starting at 20 mg/day with planned dose escalation to 40 mg, 80 mg, 160 mg and potentially higher if minimal toxicity and linear pharmacokinetics were observed. Early evaluation of observed toxicity did not reveal any severe or consistent toxicity concerns. Reports of nausea or headache were rare and did not persist despite continuation of study drug. Skin changes or fatigue were reported rarely. Serum lipid abnormalities were noted, but were rarely elevated consistently from baseline. Continued dose-escalation is required to determine a recommended phase II dose.