This application describes the clinical and laboratory framework for carefully conducted phase I clinical and pharmacologic studies of new antineoplastic agents in humans at Wayne State University. It is based on our understanding of the issues involved and predicated on the efforts of our own laboratories and clinical group in the drug discovery area. Our program has focused on the identification of solid tumor selective agents utilizing a novel in vitro sensitivity assays with highly resistant solid tumor models such as pancreatic adenocarcinoma #02 and colon adenocarcinoma #38. These efforts have identified novel compounds of potential clinical significance. Included is Pyrazoloacridine (NSC 366140), a compound undergoing phase I clinical evaluation here and at Johns Hopkins. In the initial stage of evaluation of this compound, encouraging antitumor activity has been observed in patients with carcinoma of the ovary refractory to prior treatment which included Taxol and Doxorubicin. Other compounds awaiting clinical trials are: Datelliptium (NSC 311152), PD 123654, XK469, DMP840 and the Thioxanthines series. Also of interest, some of these compounds are active against several MDR positive tumors. Our studies of drug discovery include the in vivo mechanism of action studies in anticipation of their evaluation in phase I trails. By way of example, the application describes some of our preclinical studies for Pyrazoloacridine and Datelliptium. In the case of Pyrazoloacridine, design of our pharmacokinetically driven phase I clinical trial. The application describes a wide array of laboratory resources of conduct detailed standard and molecular studies of pharmacokinetics, metabolic and mechanism of action of new agents. Included are studies designed to elucidate the mechanisms of drug resistance of promising agents. Included are studies designed to elucidate the mechanisms of drug resistance of promising agents. The application blends the strengths of our preclinical group with that our clinical investigators. A process is described carefully controlled phase I studies to include: patient eligibility, philosophy on initial dose and dosage escalation, monitoring during study, pharmacokinetic toxicities, data management and quality control issues and biostatistical resources to include capabilities for the electronic transmittal of data to the granting agency. Thus, this proposal describes our understanding, expertise and specific ideas for the conduct of carefully controlled clinical and laboratory studies during the phase I evaluation of new antineoplastic chemotherapy.
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