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

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。遗传影响也有助于CRC的病因学，对于散发病例和遗传综合征，如家族性腺瘤性息肉病（FAP）。降低FAP患者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，这些药物中没有一种对胃肠道腺瘤生长完全有效，舒林酸继续被视为许多临床环境中的标准治疗。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）使用舒林酸每天两次与厄洛替尼每日给药的组合方案持续6个月，显示出有效降低FAP患者的十二指肠息肉负担。然而，这两种药物联合使用的毒性可能不允许在预防环境中进行长期治疗。本任务指令的目的是确定厄洛替尼和舒林酸单独和联合给药的最佳剂量和/或时间表，以降低这些药物相关的毒性，同时维持或改善以动物等效剂量水平给药的治疗方案的疗效;确定与下结肠肿瘤相比，药物对小肠肿瘤参数的影响;评估长期药物暴露对产生耐药性的可能性的影响;并评估预测药物疗效的药效学标志物。

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.