This proposal is in response to the RFA CA-02-011 entitled "Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis" to be conducted at the NCI-designated University of Colorado Comprehensive Cancer Center. Drug development in oncology is rapidly changing. As laboratory investigations continue to elucidate mechanisms that contribute to the malignant phenotype, targets for anticancer therapy emerge. In the past, the major focus was on agents that interfered directly with the cellular replication machinery, whereas the current focus is on agents that target aberrant biological pathways. Nonetheless, regardless of the specific target, phase I trials in oncology are critical to the successful clinical development of novel agents. The overall objective of this proposal is to conduct early dose-ranging studies of investigational anticancer agents with an emphasis on biological correlates, pharmacological studies, analysis in the geriatric population, and novel combination regimens. The specific aims of this proposal are to : 1) determine the acute and chronic toxicity profiles, tolerability, and optimal dose of new agents in cancer patients including the geriatric population, 2) utilize biological markers and functional imaging to derive efficacious doses and schedules of targeted agents, 3) determine the pharmacological profile and pharmacodynamic relationships of novel agents using standard and physiologically-based methods, and 4) develop and analyze rational combination strategies of agents with standard chemotherapy, radiotherapy, and other targeted agents using the endpoints described above.