""""""""This project area is studying in initial Phase I clinical trials two protein kinase antagonists, flavopiridol and UCN-01. During the project period listed, the UCN-01 Phase I as a 72 hr continuous infusion administered over an initial 72 hrs, followed by half the dose every four weeks was completed, and preliminary results presented(10th NCI-EORTC sympsoum, Amsterdam) Forty-four 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 I's 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. Concentrations at peak in excess of 2 uM are being achieved. A Phase I protocol of intermittent loading followed by maintenance schedules of perifosine, a potential modualtor of PKC signalling, has been designed.""""""""
