- Phase II-a
The Oltipraz Chemoprevention Trial (Dr. Thomas Kensler, Principal Investigator) was a phase II randomized clinical trial designed to evaluate weekly and daily administrations of oltipraz for reducing urinary and/or serum aflatoxin biomarkers compared to placebo. The study's goals were to define a dose and schedule of oltipraz for reducing levels of validated aflatoxin biomarkers, and to characterize dose-limiting toxicities. In 1995, 234 adults from Qidong, Jiangsu Province, People's Republic of China were enrolled and subsequently followed in a Phase II Chemoprevention Trial. Healthy eligible individuals,
including those infected with hepatitis B virus, were randomized to receive either 125 mg oltipraz daily, 500 mg oltipraz weekly, or placebo. Blood and urine specimens were collected to monitor toxicities and evaluate biomarkers over the 8 week intervention and subsequent 8 week follow-up periods. Among the unique aspects of this trial were the synchronous follow- up schedule, daily observance of the administration of all medications, timely international data transference, and the use of biomarkers as outcomes. The methodologic aspects of the clinical trial have been published under the leadership of Dr. Jacobson. [LP Jacobson, et al. Cancer Epidemiol Biomarkers Prev 1997;6:257-265].
- Phase II-b
A major mechanism for protection against carcinogenesis is the elevation of enzymes involved in carcinogen detoxication. Induction of these phase 2 enzymes appears to be a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of natural or synthetic chemicals. While this strategy is broadly applicable in experimental models, it has not yet been rigorously evaluated in the context of human carcinogenesis. Indeed, oltipraz is the first of these agents to progress into clinical trials. Using measurements of aflatoxin-albumin adducts in serum as endpoints, a Phase II-a clinical trial was recently conducted in Qidong, P. R. China to identify a dose and schedule of oltipraz that could modulate levels of these biomarkers in a population at high risk for hepatocellular carcinoma. A weekly schedule of 500 mg oltipraz for 2 months produced a small but significant reduction in levels of aflatoxin-albumin adducts. Thus, the objectives of this follow-up Phase II-b intervention trial are to conduct a randomized, double masked, placebo-controlled trial to :
- Determine whether the administration of 500 mg of oltipraz weekly for 1 year persistently decreases the levels of aflatoxin-DNA adducts excreted in urine and/or aflatoxin-albumin adducts in serum by at least 25%;
- Determine whether a lower dose (250 mg) of oltipraz on the weekly schedule modulates aflatoxin biomarkers;
- Assess the pharmacodynamic action of oltipraz by measuring phase 2 enzyme activities, levels of mRNA transcripts, and genotypes in lymphocytes obtained from participants throughout the intervention;
- Confirm the maximum safe dose of 500 mg oltipraz weekly as defined during the Phase IIA trial. Collectively, these results will provide several pivotal insights for the ongoing development of chemopreventive agents.
First, this clinical trial should clarify the status of oltipraz as a high priority chemopreventive agent by providing a reasonable estimate of its efficacy in a high-risk population, as well as providing further information regarding its pharmacodynamic action and dose-limiting side effects. Second, this trial will provide a rigorous assessment of the usefulness of modulating expression of carcinogen detoxication enzymes as a general strategy for chemoprevention in humans.
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