NCI Experimental Therapeutics-Clinical Trials Network with Phase 1 Emphasis

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DESCRIPTION (provided by applicant): We will conduct Phase I clinical trials of new anticancer agents or combinations of anticancer agents to characterize drug toxicity, determine the maximum tolerated dose, evaluate the pharmacokinetics, perform pharmacogenetic analysis, and relating clinical endpoints to pharmacokinetics, pharmacogenetics, and/or biologic endpoints. A major focus of this proposal is the study agents that interact with novel targets such as signal transduction pathways, cell cycle checkpoint components, DNA repair pathways and apoptosis regulators, either alone or in combination with standard chemotherapy. The endpoints for the evaluation of such treatments will be clinical effect (toxicity and antineoplasti response) as well as alterations in biochemical pathways affected in preclinical model systems. The specific aims of these studies are: to determine as efficiently as compatible with patient safety the appropriate dose of new anticancer agents selected by the National Cancer Institute using novel trial designs including accelerated titration, Bayesian design, and other advanced design schemes; to identify clinical, pharmacokinetic, or other laboratory parameters that may predict toxicity; to determine whether functional polymorphisms of drug metabolizing or other enzymes associated with drug response alter pharmacokinetics, toxicity and/or activity of agents being studied; to obtain mechanistic proof-of-principle data for new agents directed at novel molecular cancer targets when appropriate; to evaluate translational endpoints in clinical trials o investigational agents such as, levels of expression and/or activity of molecular targets and/or downstream effectors pertinent to a given agent or pathway modulated by the agent under study; to identify potential biomarkers (with particular emphasis where possible on genomics and imaging) that may serve as predictors of outcome in later phase trials; to translate novel discoveries from R0l, SPORE, or other peer reviewed mechanisms into clinical trials that leverage the scientific community expertise with a team science approach. Studies will be designed to incorporate the appropriate pharmacokinetic and pharmacogenetic analysis, drug analysis, and biological analysis of drug effects on the intended target or pathway. RELEVANCE: The Mayo Clinic Cancer Center and University of Maryland Greenebaum Cancer Center provides an exceptional environment to perform early phase trials in a diverse population. The team environment and expertise of the 2 centers that will be brought to focus on phase 1 trials will facilitate translation of novel preclinical discoveries into treatments that ca be assessed for efficacy in Phase II and Phase III trials.