Abstract PR-10: Randomized placebo controlled trial of pioglitazone for oral premalignant lesions: A cross-consortium collaborative study in progress
Authors: Boyle Jay O. , Ondrey Frank G. , Brown Powel H. , Bailey Howard H. , Kim Kyung Mann , El-Naggar Adel K. , Szabo Eva M. 
Published: January 2011

Abstract
There are currently no proven safe and effective oral cancer prevention treatments. Overall, approximately 5% of oral leukoplakias progress to squamous cell carcinoma and are therefore considered an important precursor lesion for cancer prevention intervention. Nuclear receptor agonists are agents that can affect cell maturation pathways in the oral cavity and other sites. The hypothesis of this National Cancer Institute/Division of Cancer Prevention (NCI/DCP)-sponsored trial is that 6 months of 45 mg pioglitazone daily will shrink oral premalignant lesions and favorably modulate surrogate endpoint biomarkers of cancer prevention. The study agent, pioglitazone, is a PPARγ agonist shown to modulate critical cellular pathways. There is preclinical evidence suggesting the potential efficacy of PPARγ ligands in prevention of cancer. Moreover, in an earlier nonrandomized phase IIa study, response rates of over 70% were achieved in patients with oral leukoplakia after 3 months of treatment. In this current study, 100 participants with dysplastic oral premalignant lesions are being recruited and randomized to active drug or placebo for a period of 6 months. The primary endpoint is lesion size reduction or histologic improvement after 6 months of drug intervention. The secondary endpoints are the following biomarkers: PPARγ, cyclin D1, p21, TUNEL assay for apoptosis, Ki-67 for proliferation, transglutaminase, involucrin, 15-PGDH, LOH, and the change in plasma level of CRP. Plasma drug levels and cotinine levels are also measured. Accrual and evaluation is planned for 24 months. Due to the large size of this study and the relative rarity of these lesions, an international interconsortium study was designed to facilitate accrual.
The lead DCP Consortia institutions, University of Wisconsin Carbone Cancer Center (UWCCC) and University of Texas MD Anderson Cancer Center (MDACC), and their nine participating organizations, Memorial Sloan-Kettering Cancer Center, Columbia University Medical Center, Weill Medical College of Cornell University, University of Maryland, University of Minnesota, University of Iowa, University of Alabama, Roswell Park Cancer Institute, and European Institute of Oncology (EIO) in Milan, Italy, make up the 11 sites for accrual for this study.
During the process of protocol development, a streamlined centralized pathology review system was developed to improve consistency in histological diagnosis utilizing a web-based Aperio system. Additionally, to insure high-quality data an extensive Manual of Procedures (MOP) delineating all protocol activities is used by all sites. Centralized data entry utilizing Westat-developed Remote Data Capture database is used. The data analysis will include stratification by group (UWCCC vs. MDACC vs. EIO) and severe vs. mild dysplasia. Study drug and placebo are encapsulated by Fisher BioServices. The repository for banked biological specimen for future studies is held at the Analytical Instrumentation Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics (3P) lab at UWCCC. In conclusion a large oral cancer prevention inter-consortium study has been designed and implemented at 10 U.S. sites and one Italian site to evaluate the efficacy of pioglitazone treatment in oral premalignant lesions.
This talk is also presented as Poster A73.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):PR-10.