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。对于散发性病例和遗传性综合征，如家族性腺瘤性息肉病(FAP)，基因的影响也有助于结直肠癌的病因。降低FAP患者风险的手术干预通常与使用非类固醇抗炎药(NSAIDs)的预防策略相结合。然而，这些药物都不能完全有效地阻止胃肠道腺瘤的生长，舒林酸仍然被视为许多临床环境中的标准治疗药物。舒林酸在临床前FAP模型中是有效的，包括APC驱动的息肉病。最近的临床试验(Samadier等人，JAMA 315：1266-1275,2016)使用舒林酸每日两次与厄洛替尼的联合方案治疗6个月，被证明在减轻FAP患者的十二指肠息肉负担方面有效。然而，这两种药物的联合毒性可能不允许在预防环境中进行长期治疗。本任务单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/或时间表，以减少与这些药物相关的毒性，同时维持或提高按动物等量剂量给予的治疗方案的疗效；确定与较低的结肠癌相比，这两种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；以及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.