BOWMAN-BIRK INHIBITOR CONCENTRATE AND ORAL LEUKOPLAKIA: PHASE IIB TRIAL

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们工作的总体目标是确定化学预防是否可以预防人类癌症。口腔白斑（OL）是一种易于评估、临床可识别的头颈癌前体，是研究化学预防的一个很好的模型系统，也是研究者熟悉的一个模型系统。流行病学和实验数据都有力地表明蛋白酶抑制剂在提供防止癌症形成的保护作用方面具有广泛的作用。临床前毒理学研究表明，这些药物明显无副作用，安全。研究人员已经进行了fda要求的大豆衍生的Bowman-Birk抑制剂浓缩物（BBIC）作为原型剂的I期试验，并已批准进行更长期的研究。BBIC对口腔黏膜细胞（BMC）的影响将根据以下中间标记终点（IME）进行研究：1)白斑的临床和组织学状态，2)使用蛋白酶底物boc - var - pro - arg - mca和GH-Gly-Arg-MCA的蛋白水解活性（PA）水平，以及3)RNA表达水平（c- erbb）。这些研究将在两个连续的临床化学预防试验的背景下进行。具体目标：1；在OL患者中开展短期（1个月）BBIC的IIa期癌症控制化学预防试验。试验的目的是：a)确定BBIC对口腔的影响；b)测量IME对BBIC的响应；c)确定不进一步降低IME的BBIC剂量。2. 在OL患者中开展一项安慰剂对照和随机的长期IIb期癌症控制化学预防试验。使用IIa试验中确定的BBIC剂量的基本特征包括：a)确定OL对BBIC的临床和组织学反应率；b)连续测量BBIC对IME水平的影响；c)将OL的临床和组织学反应与PA水平和c- erbb表达水平的影响联系起来；d)确定BBIC对个人和群体的副作用。在IIb期试验中：主要终点：OL的反应是通过病变的临床测量来确定的，包括摄影。完全临床反应（CR）将通过口腔活检的组织学检查来证实。将比较BBIC治疗患者和安慰剂对照组的缓解率（PR、CR和PR+CR）。这种关系将通过控制已知和疑似的口腔白斑和癌症的危险因素进行评估。次要终点：近五年来积累的数据表明，许多生化和分子特性在癌变过程中被激活。在许多系统中，癌基因的表达和蛋白酶活性的增强是早期癌症形成的突出特征。本研究将分析入选患者的以下参数：1)使用定义底物的PA活性水平和2)c- erbb表达水平。这些IME将在BBIC治疗之前，期间和之后进行监测。第三终点：在治疗结束前、治疗期间和治疗结束后，测量血液和尿液中的血血碱水平。烟草和酒精使用的简要指数将根据对标准问卷的答复所产生的风险因素分析得出。这些II期IME试验的所有方面都将与申办者和NIC协调一致，通过持续的当地评估来仔细监测合规性、安全性和毒性。这些研究的结果将为大规模头颈癌的III期随机风险降低试验提供实质性的生物学和治疗基础，并为进一步探索这些无毒化合物作为人类化学预防剂提供动力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Specific Aims The overall objective of our work is to determine whether chemoprevention can prevent cancer in humans. Oral leukoplakia (OL) is an easily assessable, clinically identifiable precursor to head and neck cancer represents an excellent model system in which to study chemoprevention, and one with which the investigators are familiar. Both epidemiologic and experimental data strongly suggest a broad role for protease inhibitors in providing a protective effect against cancer formation. Preclinical toxicology studies indicate that these agents are remarkably free of side effects and safe. The investigators have conducted an FDA-required phase I trial of the soybean-derived Bowman-Birk Inhibitor Concentrate (BBIC) as the prototype agent and have been approved to do longer term studies. The effect of BBIC on buccal mucosa cells (BMC) will be investigated with respect to the following intermediate marker endpoints (IME): 1) clinical and histologic status of leukoplakia, 2) level of proteolytic activity (PA) using the protease substrates Boc-Val-Pro-Arg-MCA and GH-Gly-Arg-MCA, and 3) level of RNA expression (c-erb-B). These studies will be performed in the context of two sequential clinical chemoprevention trials. Specific Aims: 1. To conduct a short-term (one-month) phase IIa cancer control chemoprevention trial of BBIC in patients with OL. The purposes of the trial are: a) to determine the effects of BBIC on the oral cavity; b) to measure the response of IME to BBIC; and c) to determine the dose of BBIC at which the IME are not further lowered. 2. To conduct a placebo-controlled and randomized long-term phase IIb cancer control chemoprevention trial of BBIC in patients with OL. Using the dose of BBIC determined in the IIa trial the essential features include: a) to determine the clinical and histologic response rate of OL to BBIC; b) to serially measure the effect of BBIC on IME levels; c) to correlate the clinical and histologic responses of OL to the effect on PA levels and levels of c-erb-B expression; and d) to determine the individual and group side effects to BBIC. In the Phase IIb trial: Primary endpoints: Response of OL is determined by clinical measurement of the lesion, including photography. Complete clinical response (CR) will be confirmed by histologic examination of oral biopsy. Response rates (PR, CR, and PR+CR) will be compared between BBIC treated patients and placebo controls. This relationship will be assessed with control for known and suspected risk factors for leukoplakia and cancer of the oral cavity. Secondary endpoints: Data accumulated in the last five years indicate that many biochemical and molecular properties are activated during the carcinogenesis process. Expression of oncogenes and enhanced protease activity are prominent features during early cancer formation in many systems. The following parameters will be analyzed in the patients enrolled in this study: 1) the level of PA activity using defined substrates and 2) the level of c-erb-B expression. These IME will be monitored before, during, and after BBIC therapy. Tertiary endpoints: Levels of BBIC in blood and urine will be measured before, during and after completion of treatment. Summary indices of tobacco and alcohol usage will be derived from risk factor analysis generated from response to a standard questionnaire. All aspects of these phase II IME trials will be carefully monitored for compliance, safety, and toxicity by continuous local evaluation and in concert with the sponsor and the NIC. The results from these studies should provide a substantial biologic and therapeutic rationale for a large phase III randomized risk reduction trial of head and neck cancer as well as provide impetus for further exploration of these non-toxic compounds as chemopreventive agents in humans.