We propose to conduct Phase I clinical and pharmacologic investigations of new anticancer drugs. To this end, we will; define the acute toxicities of new anticancer agents in patients with advanced cancer; establish the acute toxicities and pharmacokinetics of anticancer agents administered in combination with agents to modulate toxicity or antitumor effect; and, provide information on the pharmacokinetic characteristics and the pharmacodynamics of selected antitumor agents. The resulting data will determine treatment regimens suitable for evaluation of antitumor activity in Phase II trials. Through population kinetic studies and directed studies in patients with impaired end organ function we will establish appropriate Phase Ii doses for the widest possible application in the entire population. The agents to be studied under this program will include new anticancer agents originating either from the NCI's Drug Screening Program, or from pharmaceutical industry sources presented for collaborative development with NCI. Existing anticancer drugs will be examined, both in high dose regiments in combination with colony stimulating factors, and in standard dose regimens with agents targeted to the drug resistant phenotype. Where methods development is feasible, all Phase I studies will have a pharmacokinetic component. Further, we will perform rigorous biochemical and pharmacodynamic studies of combination regimens directed to drug resistance mechanisms. Our particular interest in gene expression as it relates to response and toxicity of anticancer drugs will be directed toward maximizing the probability of response in Phase I and subsequent trials.