Cancer-related death is the second most common cause of death in the US, and the most promising strategy to reduce cancer-related deaths and cancer incidence is through cancer prevention. Previous clinical trials have demonstrated the feasibility of preventing cancer using vaccines or cancer preventive drugs. However, the use of these agents is limited due to their side effects. Clearly, safer and more effective cancer prevention interventions that are acceptable to healthy individuals are urgently needed. Thus, the overarching goal of this application is to bring a team of basic, translational, and clinical researchers together to identify novel strategies to prevent cancer, test them in cancer prevention clinical trials, and ultimately bring safe, efficacious, and acceptable preventive therapies to general use in individuals at highrisk of this disease. To achieve this goal, we formed an international consortium (the iCANPREVENT consortium) comprised of cancer prevention experts, clinical trialists, molecular biologists, translational researchers, pathologists, statisticians, and bio-informatics experts, to develop and conduct early phase cancer prevention trials. Our clinical research team has vast experience in conducting both early and late phase clinical trials, and has conducted 18 Phase I and II cancer prevention clinical trials through our previous chemoprevention clinical trial consortia. Here, we propose two aims to test the hypothesis that we can conduct trials of drug and vaccine therapies and demonstrate that these preventive therapies will safely modulate critical tumor promoting pathways. Results from these early phase clinical trials will support the advancement of these interventions to Phase III testing, and ultimately support the FDA-approval of these interventions for cancer prevention. We will 1) conduct 5 to 10 early phase clinical trials testing the safety and activity of a series of promising cancer prevention drugs, vaccines, and immune modulating interventions in individuals at high-risk of cancer, and 2) develop and implement novel methods to enhance recruitment and retention of patients in prevention trials using social media, electronic news-blasts, and mobile messaging. To demonstrate our ability to develop novel cancer prevention trials, we provide two sample trials: a Phase I trial of a novel DNA-based vaccine encoding novel frameshift antigens that develop in individuals with Lynch Syndrome, and a Phase II trial testing the ability of the mTOR inhibitor everolimus to alter breast tissue biomarkers in individuals with prior triple-negative breast cancer. The results of these early phase trials will advance cancer prevention drug development, and will ultimately help reduce cancer incidence and mortality through prevention.