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We hypothesize that new insights into how cancers progress and respond to treatment will come from clinical trials that i) extensively characterize the molecular features of a patient’s cancer; ii) use results to predict drug susceptibilities; iii) treat in accordance with these predictions; and iv) learn from individual patient outcomes to iterate and improve over time. To investigate the feasibility of this type of clinical study, we launched the "Intensive Trial of OMics in Cancer" (ITOMIC) for patients with metastatic triple negative breast cancer (TNBC) (Clinicaltrials.gov ID: NCT01957514). Eligible patients have metastatic TNBC, are platinum-naive, and are scheduled to receive Cisplatin. Biopsies are performed under carefully controlled conditions prior to Cisplatin – starting all subjects on a common treatment path, and uncoupling the time needed for specimen analysis from immediate therapy. Biopsies are repeated upon completion of Cisplatin and following subsequent therapies. A subset of specimens is chosen for whole Exome Sequencing, deep sequencing of a panel of cancer associated genes, and RNA-sequencing. De-identified results are placed on a web-based server for analysis and discussed at a meeting of the ITOMIC tumor board. A report describing results and potential therapies is provided to the subject’s oncologist. Treatment decisions are left to the discretion of the oncologist. If a decision is taken to pursue treatments identified in our report we offer assistance in accessing those treatments. Ten patients have been screened and seven have enrolled. Subjects range in age from 40 to 77 years and all but one has received extensive prior treatment for metastatic TNBC. All seven underwent an initial set of biopsies, targeting between two and five metastatic sites. For most metastatic sites, multiple core needle passes are performed. All subjects tolerated the biopsies well without significant adverse events, and all started treatment with Cisplatin. Three subjects completed Cisplatin and underwent a second round of biopsies. Potential targets for therapy were identified in 5 of the first 6 subjects, and three subjects have received four predicted therapies: 1) a patient with somatic loss of BRCA1 and two linked FGFR2 activating mutations, who was treated first with Veliparib through a single-patient IND and then switched to Ponatinib which produced a partial response; 2) a patient with a novel missense ROS1 mutation treated with crizotinib; and 3) a patient with CYP3A4 copy gain treated with cyclophosphamide. Conclusion: Our early experience indicates that this approach is feasible and may increase the efficiency of learning from patients with advanced cancer. Citation Format: C Anthony Blau, Colin Pritchard, Michael O Dorschner, Sibel Blau, Brigham Mecham, Elisabeth Mahen, VK Gadi, Wayne Monsky, Kimberly Burton, Arturo Ramirez, Jackie Stilwell, Eric Kladjian, Carol Collins, Jeannine S McCune, William S Noble, Julie Gralow, Frank Senecal, Linda Dhaene, Nicole Kuderer, Jennifer Specht, Chaozhong Song, Carla Grandori, Nathan Price, Mary Goldman, Aime Radenbaugh, David Haussler, Jingchun Zhu. Assessing the safety and feasibility of efficient hypothesis testing in patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-08-01.