PROTEIN KINASE ANTAGONISTS: PRECLINICAL AND CLINICAL

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This project area is studying in initial Phase I clinical trials two protein kinase antagonists, flavopiridol and UCN-01. In addition, indirect means of modifying protein kinase signalling pathways through alkylphospholipids including Perifosine was undertaken during the project period listed. A phase I trial of UCN-01 administered as a 72 hr continuous infusion for the first course, followed by half the dose every four weeks was completed, and preliminary results presented(ASCO, 1999) Forty-seven patients were treated on the intial trial. Dose limiting toxicities included pulmonary, hyperglycemia, and lactic acidosis. The MTD is 42.5 mg/M2/d x 3. Additional toxicities included fatigue, hypotension, and myalgias. Initial studies revealed a marked difference in the human pharmacology of UCN-01, in comparison to pre- clinial studies in mice, rats, and dogs. Specifically, humans have high affinity binding to plasma alpha acidic glycoprotein, and therefore have very long half times (T1/2 > 1000 hr) of the drug and tolerate much higher concentrations of drug. Future plans are to consider future Phase Is of more brief infusion duration and in combination with standard chemotherapy agents. A Phase I trial utilizing intermittent bolus dosing of flavopiridol, based on preclinical studies of efficiacy in hematopoietic neoplasms has been undertaken. The initial MTD when administered on a qd x 5 schedule was 37 mg/M2/d. Concentrations at peak in excess of 2 uM are being achieved.Successive decreases in the period of dosing are being undertaken, with completion of qd x 3 and once weekly schedules anticipated during FY2000. Initial dose levels of perifosine, administered as a loading dose and a continued daily oral dosing appear well tolerated. A Phase II protocol of intermittent IV bolus dosing of flavopiridol in patients with squamous carcinoma of the head and neck will be developed also in FY2000. - cell signaling, chemotherapeutics, pharmacokinetics, pharmacology, protein kinase, - Human Subjects & Human Tissues, Fluids, Cells, etc.