Exisulind for Chemoprevention of Lung Cancer

Exisulind 用于肺癌的化学预防

• 批准号: 7125588
• 负责人: GEROLD BEPLER
• 金额: $ 101.19万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125588
• 关键词: antineoplastics; apoptosis; biomarker; biopsy; bronchoscopy; cancer prevention; cancer risk; cell proliferation; chemoprevention; clinical research; clinical trials; computed axial tomography; cooperative study; cytokine; drug screening /evaluation; histopathology; human subject; lung neoplasms; nonsmall cell lung cancer; patient oriented research; respiratory airflow disorder; smoking; sputum

DESCRIPTION (provided by applicant) Lung cancer is the leading cause of cancer death in the United States. Cure rates from primary treatment are low (approximately 15%). There is an urgent need to develop compounds, which can prevent the disease in individuals with a history of cigarette smoking and other factors associated with increased lung cancer risk. A number of compounds have been tested but trials to date have not resulted in a decrease of lung cancer incidence. In fact, two large-scale chemoprevention trials that evaluated beta-carotene in active and former smokers, resulted in an increase of incidence and mortality from lung cancer. Recently, the focus of lung cancer chemoprevention has shifted towards investigations using inhibitors of inflammatory response pathways and inhibitors of growth factor signaling pathways. A novel class of agents has been developed that induce apoptosis. Exisulind (Aptosyn) is the first agent in this class, and it has shown promise in chemoprevention of colorectal carcinoma by reducing the number of size of adenomatous polyps in humans. In animal studies, this agent has resulted in a reduction of carcinogen-induced lung cancer. To test the clinical utility of this agent in lung cancer prevention, we propose to perform a double-blind, placebo-controlled, randomized, clinical efficacy trial in former smokers. Participants will be stratified by lung cancer risk based on airway obstruction, prior history of completely resected stage I non-small cell lung cancer, and the histopathology of bronchial biopsies. They will be randomized 2:1 to drug vs. placebo. A surrogate marker of lung cancer, the proliferation marker Ki-67, will be used as the primary endpoint. Other markers previously and currently investigated by us and others (MCM2, hnRNP, apoptosis, cytokine response profiles, (epi) genetic alterations, morphology) will be explored as surrogate trial endpoints. Exisulind will be given orally at a dose of 500 mg daily for 6 months. With 93 evaluable participants randomized to exisulind, the study will have 80% power to detect a 50% or greater decrease in the mean Ki-67 labelling index as a result of treatment. Since we anticipate a 25% attrition rate, we are planning to enroll a total of 186 subjects over 4 years. Given the number of eligible subjects at our institution that already participate in early detection trials, we are confident that the goal of this proposed study can be achieved during the 5-years of funding. The data generated by these investigations will be important for future decisions on large-scale chemoprevention trials using disease incidence and mortality as endpoints.

描述（由申请人提供） 肺癌是美国癌症死亡的主要原因。初级治疗的治愈率很低（约 15%）。迫切需要开发一种化合物，可以预防有吸烟史和其他与肺癌风险增加相关的因素的个体患这种疾病。已经测试了多种化合物，但迄今为止的试验尚未导致肺癌发病率降低。事实上，两项评估活跃吸烟者和戒烟者中β-胡萝卜素的大规模化学预防试验导致肺癌发病率和死亡率增加。最近，肺癌化学预防的焦点已转向使用炎症反应途径抑制剂和生长因子信号途径抑制剂的研究。已经开发出一类诱导细胞凋亡的新型试剂。 Exisulind (Aptosyn) 是此类药物中的第一个药物，它通过减少人类腺瘤性息肉的数量，在结直肠癌的化学预防方面显示出了前景。在动物研究中，这种药物可以减少致癌物诱发的肺癌。为了测试该药物在肺癌预防中的临床效用，我们建议对前吸烟者进行双盲、安慰剂对照、随机临床疗效试验。将根据气道阻塞、完全切除的 I 期非小细胞肺癌既往病史以及支气管活检的组织病理学对参与者进行肺癌风险分层。他们将以 2:1 的比例随机分配到药物组和安慰剂组。肺癌的替代标志物增殖标志物 Ki-67 将用作主要终点。我们和其他人之前和目前研究的其他标志物（MCM2、hnRNP、细胞凋亡、细胞因子反应谱、(epi) 遗传改变、形态学）将作为替代试验终点进行探索。 Exisulind 将以每天 500 mg 的剂量口服，持续 6 个月。 93 名可评估的参与者被随机分配至 exisulind，该研究将有 80% 的功效检测到治疗后平均 Ki-67 标记指数下降 50% 或更多。由于我们预计流失率为 25%，因此我们计划在 4 年内总共招收 186 名受试者。考虑到我们机构已经参与早期检测试验的合格受试者数量，我们相信这项拟议研究的目标可以在 5 年的资助期间实现。这些调查产生的数据对于未来以发病率和死亡率为终点的大规模化学预防试验的决策非常重要。