IGF::OT::IGF DETERMINATION OF DOSING REGIMENS OF ERLOTINIB IN COMBINATION WITH SULINDAC FOR PREVENTION OF COLORECTAL CANCER WHILE REDUCING AGENT TOXICITY POP 06/01/2017 - 05/31/2019

IGF::OT::IGF 确定厄洛替尼联合舒林酸预防结直肠癌同时降低药物毒性的给药方案 POP 06/01/2017 - 05/31/2019

• 批准号: 9566448
• 负责人: POWEL BROWN
• 金额: $ 77.5万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2019-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9566448
• 关键词: Adenomatous Polyposis Coli; Age; Animals; Clinical; Clinical Trials; Colonic Neoplasms; Colorectal Cancer; Coupled; Diet; Dose; Duodenum; Erlotinib; Ethnic Origin; Etiology; Gastrointestinal tract structure; Gender; Genetic; Geographic Locations; Growth; Individual; Inherited; Intestines; Long-Term Effects; Modeling; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Polyps; Prevention; Prevention strategy; Reducing Agents; Regimen; Resistance development; Risk; Schedule; Sulindac; Syndrome; Toxic effect; Treatment Efficacy; Treatment Protocols; adenoma; colorectal cancer prevention; improved; lifestyle factors; mortality; pharmacodynamic biomarker; polyposis; pre-clinical; predictive marker; standard of care; tumor

Mortality rates for colorectal cancer (CRC) vary according to geographic region, gender, age, ethnicity, and diet/lifestyle factors. Genetic influences also contribute to the etiology of CRC, for both sporadic cases and hereditary syndromes, such as familial adenomatous polyposis (FAP). Risk‐reducing surgical intervention in FAP patients often is coupled to prevention strategies using NSAIDs (nonsteroidal anti-inflammatory drugs). However, none of these agents is completely effective against adenoma growth in the GI tract, and Sulindac continues to be viewed as the standard of care in many clinical settings. Sulindac is effective in preclinical FAP models, including the Apc‐driven polyposis. Recent clinical trials (Samadder et al., JAMA 315:1266-1275, 2016) using a combination regimen of Sulindac administered twice/day with daily erlotinib for 6 months was shown to be effective in reducing the duodenal polyp burden in patients with FAP. However, the toxicity of the two drugs in combination may not allow long term treatment in a prevention setting. The purpose of this Task Order is to determine the optimal dosing and/or scheduling of erlotinib and Sulindac, individually and in combination, which reduce the toxicities associated with these drugs while maintaining or improving efficacy of the treatment regimens administered at animal equivalent dose levels; to determine the effects of the agents on tumor parameters in small intestinal compared to lower colonic tumors; to assess the effects of long term agent exposure on the potential to develop resistance; and assess pharmacodynamic markers predictive of agent efficacy.

结直肠癌 (CRC) 的死亡率因地理区域、性别、年龄、种族和饮食/生活方式因素而异。遗传影响也影响结直肠癌的病因，无论是散发病例还是遗传综合征，例如家族性腺瘤性息肉病 (FAP)。对 FAP 患者进行降低风险的手术干预通常与使用 NSAID（非甾体抗炎药）的预防策略相结合。然而，这些药物都不能完全有效地抑制胃肠道腺瘤的生长，而舒林酸仍然被视为许多临床环境中的标准治疗方法。舒林酸在临床前 FAP 模型中有效，包括 Apc 驱动的息肉病。最近的临床试验（Samadder 等人，JAMA 315：1266-1275，2016）显示，每天两次使用舒林酸与每日厄洛替尼联合用药，持续 6 个月，可有效减少 FAP 患者的十二指肠息肉负担。然而，两种药物组合的毒性可能不允许在预防环境中进行长期治疗。本任务令的目的是确定厄洛替尼和舒林酸单独或联合使用的最佳剂量和/或时间安排，以减少与这些药物相关的毒性，同时维持或提高动物等效剂量水平下治疗方案的疗效；确定药物对小肠肿瘤参数与下结肠肿瘤参数的影响；评估长期接触药剂对产生耐药性的可能性的影响；并评估预测药物功效的药效学标志物。