PHASE IIB-OLTIPRAZ CHEMOPREVENTION TRAIL

描述：（申请人的描述）保护的主要机制 对抗致癌作用的一种方法是升高致癌物质中的酶， 解毒 这些2期酶的诱导似乎是一个足够的 获得化学预防的条件，并且可以在许多靶点中实现 通过施用多种天然或合成的药物中的任何一种， 化学品 虽然这种策略在实验中广泛适用， 模型，它还没有在人类的背景下进行严格的评估 致癌作用 事实上，oltipraz是第一个取得进展的药物 临床试验 使用黄曲霉毒素-白蛋白加合物的测量， 血清作为终点，最近进行了IIa期临床试验， 中国启东中国将确定奥替普拉的剂量和时间表， 在高风险人群中调节这些生物标志物的水平， 肝细胞癌 每周一次500 mg奥替普拉，持续2个月 产生了一个小的，但显着减少水平的黄曲霉毒素-白蛋白 加合物 因此，本次后续IIb期干预的目标 试验将进行随机、双盲、安慰剂对照试验 （1）确定每周给予500 mg奥替普拉 持续1年降低黄曲霉毒素-DNA加合物水平 经尿液和/或血清中黄曲霉毒素-白蛋白加合物排泄至少25%; (2)确定每周一次的较低剂量（250 mg）的奥替普拉 时间表调节黄曲霉毒素生物标志物;（3）评估药效学 通过测量2相酶活性、mRNA水平 从参与者中获得的淋巴细胞中的转录本和基因型 在整个干预过程中;和（4）确认500 mg的最大安全剂量 如IIa期试验期间定义的每周一次奥替普拉。 总的来说，这些 结果将为正在进行的开发提供几个关键的见解， 化学预防剂 首先，这项临床试验应该澄清 奥替普拉作为高优先级化学预防剂的地位， 合理估计其在高风险人群中的疗效，以及 提供关于其药效学作用的更多信息， 剂量限制性副作用 第二，这项试验将提供一个严格的 调节致癌物表达的有效性评估 解毒酶作为人类化学预防的一般策略。

DESCRIPTION: (Applicant's Description) 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, i t 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 IIa 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-albwnin adducts. Thus, the objectives of this follow-up phase IIb intervention trial are to conduct a randomized, double masked, placebo-controlled trial to: (1) 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%; (2) determine whether a lower dose (250 mg) of oltipraz on the weekly schedule modulates aflatoxin biomarkers; (3) assess the phannacodynamic action of oltipraz by measuring phase 2 enzyme activities, levels of mRNA transcripts, and genotypes in lymphocytes obtained from participants throughout the intervention; and (4) 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.