This Funding Opportunity Announcement (FOA) supports the development of new exploratory research in cancer diagnosis, treatment, imaging, symptom/toxicity, and prevention clinical trials; correlative studies associated with clinical trials; novel cancer therapeutic, symptom/toxicity, and preventive agent development, radiotherapy development activities, and mechanism-driven combinations; and innovative preclinical studies--including the use of new clinically-relevant models and imaging technologies--which could lead to first-in-human clinical trials. The R21 mechanism is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of cancer research (pre-clinical or clinical).