This project represents the clinical arm of the program project and it intends to validate in humans the predictive in-vitro solid tumor selectivity assay of Corbett. Promising compounds derived from Project #2 and Core #3 selected because of potential efficacy against cancers of the breast, lung and colon will be studied clinically through initial Phase I clinical and pharmacologic studies and, thereafter, Phase II efficacy trials in patients with advanced cancers of the breast, lung and colon, respectively. Thus, correlations will be established between preclinical in-vitro and in-vivo observations with those derived from studies in humans. A number of promising solid tumor selective agents are being studied or are to be studied in the clinic shortly. Included is Pyrazoloacridine (NSC 366140), a compound now undergoing NCI sponsored Phase II trials against several tumor types at multiple centers throughout the U.S., including Phase II trials in colon, lung and breast cancer here at Wayne State University. In the initial stages of evaluation of this compound, encouraging antitumor activity has been observed in patients with carcinomas of the ovary refractory to prior treatment which included Taxol and Cisplatin. Other compounds in early clinical trials are PD 123654, CI-994 and WIN 33377. XK469, cryptophycin 8 and Nanopysosulpan await clinical investigation. Phase I studies of new agents will include careful pharmacokinetic, metabolic and mechanism of action studies as proposed in Project #3 of this grant application. A process is described in detail with all the necessary considerations for the appropriate conduct of Phase I and Phase II studies to include: patient eligibility, philosophy on initial dose and dose escalation, monitoring during study, pharmacokinetic studies, data management and quality control issues and biostatistical resources such as capabilities for the electronic transmittal of data to the granting agency. The information to be derived from these studies will contribute to our understanding of predicting solid tumor activity in humans by a novel in-vitro discovery of new chemotherapy.
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