Abstract Malignancies of the lower gastrointestinal (GI) tract share similarities in their symptoms, histology, genetic composition and sites of metastasis, but differ in their incidence rates. While colorectal cancer is common with over 130,000 new cases annually in the US alone, small intestinal adenocarcinoma is relatively rare with only 2500 new cases annually. Nevertheless, the overall clinical benefit of “standard of care” therapeutics is negligible, thereby underlining the need for novel therapeutics, especially personalized approaches. Champions Oncology focuses on personalizing cancer treatment via generating Tumorgraft models from each patient's individual whole tumor. The current study describes the attempt to identify a personalized solution for two patients with metastatic colorectal and duodenal cancers. Using Champions revolutionary Tumorgraft™ technology, personalized ‘trials’ were performed in vivo. Tumor fragments, obtained from the patient's liver metastases, were implanted into immunodeficient mice in a manner that preserves the biological properties of the original tumor and supporting stroma. Once the Tumorgrafts models were established, individual therapeutics and combinations were evaluated to identify treatment regimens likely to be maximally effective in the clinic. Each drug study encompassed 16 different treatment groups, including FDA-approved, as well as investigational agents. Of the different treatment arms in the colorectal model, two demonstrated partial response with tumor growth inhibition values of 152 and 149% for irinotecan/cetuximab/sunitinib and bevacizumab/cetuximab/irinotecan, respectively. While the combination of cetuximab/irinotecan resulted in stable disease in the duodenal model as well, complete responses were observed in all mice treated with eribulin as a single agent. Mutation status analysis of the tumors revealed wild type KRAS. Additional molecular characterization is ongoing to determine other potential signatures of response. The results from the Tumorgraft study were recommended to the patients and their medical oncologists and new lines of treatment were commenced subsequently. The results from these Tumorgraft studies, the molecular profile of the tumors, and correlation with clinical outcome will be presented. Results demonstrate the application of Personalized Tumorgraft models to personalized oncology and their impact on the future of cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1329. doi:1538-7445.AM2012-1329