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

点击翻译按钮获取中文摘要

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.