) We will conduct phase I clinical trials of new anticancer agents or combinations of anticancer agents for the purposes of characterizing drug toxicity, determining the maximum tolerated dose, evaluating the pharmacokinetics and relating the clinical endpoints to the derived pharmacokinetics parameters and/or relevant biologic endpoints. A major focus of this proposal will be to study agents that interact with novel targets such as signal traduction pathways, cell cycle regulation checkpoints, DNA repair, the metastatic process and angiogenesis alone or in combination with chemotherapy. The endpoints for the evaluation of such treatments will be clinical effect (toxicity and antineoplastic response) as well as those biochemical changes judged to be effected in the preclinical model systems.
The specific aims of these studies are to determine as efficiently as is compatible with patient safety the appropriate dose of new anticancer agents selected by the National Cancer Institute for evaluation of therapeutic activity in subsequent phase II trials; to identify clinical, pharmacokinetics or other laboratory parameters that may predict toxicity; to develop limited sampling models that may be tested prospectively in phase II trials; to evaluate in patients the effect of agents on targets identified in preclinical models; and to evaluate biologic endpoints that may be used as surrogate markers of drug effect. Studies of drug combinations will be designed based on preclinical data identifying the appropriate schedule and exposure duration of the agents in vitro. Studies of novel modulating agents will be planned to monitor and evaluate the intended modulation. Each new agent will be evaluated using a standard modified Fibonacci dose escalation scheme or the modified continual reassessment method of dose escalation in a phase I trial or using target endpoints such as blood levels in the case of nonclassical antineoplastic agents with novel targets. The studies will be designed to incorporate the appropriate pharmacokinetics analysis, drug analysis, and pharmacodynamic assessment. Pharmacokinetics/pharmacodynamic modeling of the data will be performed in those studies in which it is appropriate. By performing phase I studies in this fashion, we hope to facilitate translation of novel preclinical observations into treatments that can be assessed for efficacy in phase II and phase III trials.
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