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

• 批准号: 7628623
• 负责人: NAGI B. KUMAR
• 金额: $ 70.73万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 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/7628623
• 关键词: Address; Aftercare; American Cancer Society; Angiogenesis Inhibitors; Animal Model; Apoptosis; Apoptotic; Biochemical; Biological; Biological Markers; Biopsy; Blood; Body Fluids; Bortezomib; Breast; Cancer Center; Catechin; Cell Proliferation; Cell Survival; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Colon; Complex; DNA Binding; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Diet; Diet Records; Disease; Disease Progression; Dose; Drug Formulations; Drug Kinetics; Dysplasia; Endogenous Factors; Epidemiology; Epigallocatechin Gallate; Epithelial; Epithelial Cells; Esophagus; Evaluation; Experimental Models; Frequencies; Gelatinase A; Gelatinase B; Genetic; 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; Knowledge; Laboratory Study; Lesion; 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; Nutrient; Outcome; Pathway interactions; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Phenotype; Physical activity; Physiological; Placebos; Plasma; 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; Recruitment Activity; Reporting; Risk; Safety; Sampling; 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; cell growth; chymotrypsin; clinical infrastructure; cohort; cyclin-dependent kinase inhibitor 1B; experience; high risk; improved; in vivo; indexing; innovation; lifestyle factors; lower urinary tract symptoms; men; mortality; multicatalytic endopeptidase complex; pill; prevent; pro-apoptotic protein; prostate carcinogenesis; protein expression; research clinical testing; tumor; tumor growth; tumor progression

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（由申请人提供）：流行病学和实验室研究已经确定绿茶多酚（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剂，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。我们的研究小组已经证明，EGCG和Polyphenon E可以有效和选择性地抑制完整的人类CaP细胞中的蛋白酶体凝乳胰蛋白酶样活性，从而积累IkB-o和p27蛋白，导致生长停滞。几种GTP制剂的药代动力学和安全性，特别是多酚E在600-1200毫克EGCG剂量范围内已在I期试验中得到证实。在一项初步研究中，Bettuzzi等26在60名确诊为HGPIN的男性中证明了gtp （400 mg EGCG/天）用于化学预防CaP的安全性和有效性，gtp治疗的男性中只有1例（3%）被诊断出肿瘤，而安慰剂治疗组有9例（30%）被诊断出癌症。基于我们的研究和其他人的研究结果，包括Bettuzzi等人的研究结果，一项明确的II期临床试验将在诊断为HGPIN病变的更大队列中检验EGCG在抑制CaP进展中的作用，这是合乎逻辑的下一步。拟议的II期临床试验的中心假设是，与服用安慰剂的HGPIN患者相比，接受Polyphenon E剂量为400 mg EGCG/天12个月的HGPIN患者将显著减少CaP的进展。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，抑制前列腺细胞存活，诱导细胞凋亡，从而减缓HGPIN向前列腺癌的进展。为了验证这一假设，我们的具体目标将是招募、随机分组并治疗240名（120名男性/组）被诊断患有HGPIN的男性，接受含有400 mg EGCG的Polyphenon E或安慰剂治疗一年，评估依从性、症状、毒性，评估HGPIN和前列腺癌在6个月和12个月时的发病率，以及前列腺组织活检中与治疗相关的蛋白酶体活性抑制和诱导凋亡。我们的另一个目标是探索其他潜在的机制，以开发和完善EGCG和GTP的基本分子途径模型。我们的建议是创新的，及时的，并提供了一个强有力的方法来评估一种有前途的基于营养的化学预防剂，以预防一种具有重大公共卫生意义的疾病。如果多酚E对CaP化学预防的安全性和效果得到证实，我们计划在大型III期试验中检查该药物的长期效果。