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Phase II Clinical Trial of Polyphenon E in Prostate Cancer

Polyphenon E治疗前列腺癌的II期临床试验

基本信息

批准号：
7689525
负责人：
NAGI B. KUMAR
金额：
$ 12.8万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7689525
关键词：
Address American Cancer Society Angiogenesis Inhibitors Animal Model Apoptosis Apoptotic Biochemical Biological Biological Markers Biopsy Blood Body Fluids Bortezomib Cancer Center Catechin Cell Proliferation Cell Survival Cells Chemoprevention Chemopreventive Agent Clinical Clinical Trials Colon Complex Count DNA Binding Data Development Diagnosis Diagnostic Neoplasm Staging Diet Diet Records Disease Disease Progression Dose Drug Formulations Drug Kinetics Dysplasia Endogenous Factors Epigallocatechin Gallate Epithelial Epithelial Cells Esophagus Evaluation Experimental Models Frequencies Gelatinase A Gelatinase B Genetic Genus Cola Goals Green tea Growth High Prevalence Human In Situ Nick-End Labeling In Vitro Incidence Individual Differences Induction of Apoptosis Inhibitory Concentration 50 Intervention Intestines Invasive Knowledge Laboratory Study Lesion Life Style Liver Living Wills Long-Term Effects Lung Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Metabolic Modeling Molecular Molecular Genetics Molecular Target Monitor Morbidity - disease rate Neoplasm Metastasis Nodule Numbers Nutrient Outcome PS341 cpd Pathway interactions Personal Satisfaction Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Phenotype Physical activity Physiological Placebos Polyphenon E Population Positioning Attribute Premalignant Preparation Prevalence Process Prostate Prostate-Specific Antigen Prostatic Intraepithelial Neoplasias Proteasome Inhibition Protein p53 Proteins Public Health Quality of life Questionnaires Randomized Randomized Clinical Trials Range Recruitment Activity Reporting Research Infrastructure Risk Safety Sampling Score Series Severe dysplasia Skin Specimen Stomach Surrogate Endpoint Symptoms Target Populations Tea Testing Tissues Toxic effect Trypsin United States Upper arm Vascular Endothelial Growth Factors Velcade angiogenesis base cancer cell cancer chemoprevention carcinogenesis cell growth chymotrypsin cohort cyclin-dependent kinase inhibitor 1B day disorder risk experience improved in vivo indexing innovation lower urinary tract symptoms men mortality multicatalytic endopeptidase complex prevent pro-apoptotic protein protein expression research clinical testing tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Epidemiological and laboratory studies have identified epigallocatechin gallate (EGCG) in green tea polyphenols (GTP), as the most potent chemopreventive agent that can induce apoptosis, suppress the formation and growth of human cancers including prostate cancer (CaP). Our group has shown that EGCG and Polyphenon E, potently and selectively inhibits the proteasomal chymotrypsin-like activities in intact human CaP cells and consequently accumulates IkB-o and p27 proteins, leading to growth arrest. The pharmacokinetics and safety of several preparations of GTP, specifically Polyphenon E at doses ranging from 600-1200 mgs EGCG have been demonstrated in phase I trials. In a preliminary study, Bettuzzi et al26, demonstrated the safety and efficacy of GTPs (400 mgs of EGCG/day) for chemoprevention of CaP in 60 men diagnosed with HGPIN, with only 1 tumor diagnosed among the GTP-treated men (3%), compared to 9 cancers in the placebo-treated arm (30%). Based on the promising results of our studies and that of others, including Bettuzzi et al's results, a definitive phase II clinical trial, powered to examine the effects of EGCG in inhibiting the progression to CaP in larger cohort diagnosed with HGPIN lesions, is a logical next step. The central hypothesis for the proposed phase II clinical trial is that men with HGPIN who receive Polyphenon E at a dose of 400 mg EGCG/day for 12 months will significantly decrease progression to CaP compared with men with HGPIN who take placebo. We hypothesize that the primary pathway by which tea catechins, specifically EGCG will induce prostate epithelial cell apoptosis, is via the proteasome inhibition pathway, resulting in inhibition of prostate cell survival and induction of apoptosis, thereby decreasing progression from HGPIN to prostate cancer. To test this hypothesis, our specific aims will be to recruit, randomize and treat 240 (120 men/arm) men diagnosed with HGPIN to receive Polyphenon E containing 400 mg of EGCG or placebo for one year and evaluate compliance, symptoms, toxicity, evaluate HGPIN and prostate cancer incidence at 6 and 12 months and treatment-related inhibition of proteasome activity and induction of apoptosis in prostate tissue biopsies. Our other aim is to explore other potential mechanisms to develop and refine models of fundamental molecular pathways for EGCG and GTP. Our proposal is innovative, timely, and provides a robust approach to evaluate a promising nutrient-based chemopreventive agent against a disease of major public health significance. If the safety and the effects of Polyphenon E for chemoprevention of CaP are demonstrated, we plan to then examine the long-term effects of this agent in a large Phase III trial.

描述(申请人提供)：流行病学和实验室研究发现，绿茶多酚(GTP)中的表没食子儿茶素没食子酸酯(EGCG)是最有效的化学预防药物，可以诱导细胞凋亡，抑制包括前列腺癌(CAP)在内的人类癌症的形成和生长。我们的团队已经证明，EGCG和多酚E可以有效和选择性地抑制完整的人帽子细胞中蛋白酶体的糜蛋白酶样活性，从而积聚IKB-0和p27蛋白，导致生长停滞。GTP的几种制剂，特别是多酚E的剂量从600-1200毫克EGCG的药代动力学和安全性已在I期试验中得到证实。在一项初步研究中，Bettuzzi等26人证明了GTPS(每天400毫克的EGCG)对60名被诊断为HGPIN的患者进行CAP化学预防的安全性和有效性，其中接受GTP治疗的患者中只有1例被诊断为肿瘤(3%)，而接受安慰剂治疗的患者中有9例被诊断为癌症(30%)。基于我们和其他研究的有希望的结果，包括Bettuzzi等人的结果，一项最终的II期临床试验是合乎逻辑的下一步，该试验旨在检查EGCG在抑制诊断为HGPIN病变的较大队列中进展到CAP的效果。拟议的第二阶段临床试验的中心假设是，与服用安慰剂的HGPIN患者相比，每天服用400毫克EGCG、持续12个月的HGPIN患者将显著减少进展为CAP的速度。我们推测茶儿茶素，特别是EGCG诱导前列腺上皮细胞凋亡的主要途径是通过蛋白酶体抑制途径，从而抑制前列腺细胞的存活和诱导细胞凋亡，从而减缓从HGPIN到前列腺癌的进展。为了验证这一假设，我们的具体目标将是招募、随机和治疗240名(120名男性/组)被诊断为HGPIN的男性，接受含有400毫克EGCG或安慰剂的Polyhenon E治疗一年，评估依从性、症状、毒性，评估HGPIN和前列腺癌在6个月和12个月的发病率，以及与治疗相关的抑制蛋白酶体活性和诱导前列腺组织活检中的细胞凋亡。我们的另一个目标是探索其他潜在的机制来开发和完善EGCG和GTP的基本分子途径模型。我们的建议是创新的，及时的，并提供了一种强有力的方法来评估一种有前景的营养型化学预防药物对一种具有重大公共卫生意义的疾病的预防作用。如果多酚E用于CAP的化学预防的安全性和效果得到证实，我们计划随后在一项大型的III期试验中检查该制剂的长期效果。