This application describes the clinical and laboratory framework for conducting Phase I studies of new anticancer agents at Wayne State University. It is based on our understanding of the issues involved and, in part, predicated on the efforts of our Phase I program and the associated pharmacology laboratories in translational research and clinical development. Our program has focused on the early clinical development of solid tumor selective agents, incorporating into the trial design guidance provided by in vitro and in vivo efficacy and toxicology assays human drug metabolism, and preclinical pharmacokinetic (PK) studies. In addition to NCI/CTEP sponsored drugs (i.e. bryostatin, KRN5500,flavopiradol), our own efforts have contributed additional compounds for NCI-supported Phase I trials, including pyrazoloacridine (PZA; NSC 366140), acetyldinaline (CI-994)and WIN33377 (a thioxanthenone). Other compounds (i.e. XK469, second generation thioxanthenones) are awaiting Phase I clinical trial support. By way of example, this application describes development of PZA, CI994 and WIN33377, from initial preclinical identification through clinical investigation. In the case of PZA, our preclinical PK studies supported a successful PK-guided dose-escalation phase I trial and our in vitro assessment of human myelotoxicity confirmed that the targeted plasma AUC would be tolerated. With CI994, our translational studies helped define the clinical schedule and dose that resulted in maximal drug exposure. This application proposes to incorporate our laboratory expertise in pharmacokinetics, CYP 450 drug metabolism and hematotoxicology into efficient and rapid Phase I clinical trial designs. A process is described in detail with all the considerations necessary for the appropriate conduct of carefully controlled phase I studies to include: patient eligibility and rapid accrual of women and minority patients, philosophy of initial dose and dosage escalation, pharmacokinetic, pharmacodynamic and drug metabolism studies, the attaining of the maximally tolerated dose, reporting of adverse drug reactions, data management and quality control, biostatistical resources to include capabilities for the electronic transmittal of data and an evaluation of the impact of pharmacologic studies on the efficiency of the Phase I trial design. Thus, this proposal describes our understanding, expertise and specific ideas for the conduct of carefully controlled clinical and pharmacologic studies for the Phase I evaluation of new anticancer agents in a population that includes substantial numbers of women and minorities.
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