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.