The Investigational New Drug application to the FDA for oral administration of CAI to patients with refractory solid tumors was approved in January 1992 and the Phase I clinical trial began accrual in March 1992. The protocol is run through and in collaboration with the Medicine Branch, DCT, NCI. Eligible patients receive a test dose of CAI in PEG-400 solution followed by blood sampling for pharmacokinetic analysis over one week. The following week, every other day administration of CAI begins with frequent blood sampling to measure plasma levels. Since initiation, 15 patients have received CAI on protocol. In all cases, CAI blood levels have been readily measured in the plasma of patients and in the pleural fluid of one patient. The plateau blood levels ranged from 2 micromoles to over 10 micromoles over the three dose escalation levels. Calculated pharmacokinetics suggest a long half life at all administered doses with increasing AUC also seen with increasing dose. Toxicity has been minimal. Mild nausea with rare vomiting and mild mood changes appear to be drug-related and may be related to peak dose. One episode of peripheral neuropathy and one episode of neutropenia have been observed; both appear to be related to the total drug exposure. Gelcap formulation is now available and test doses with pharmacokinetics will evaluate the bioavailability, toxicity, and efficacy of this new formulation. Three patients have had progression of disease during the first 28 day period of CAI administration. The remaining patients have had more than 25% increase in disease, measurable stability, or reductions of up to 22% in their disease. Further dose escalation is ongoing and Phase II trials are planned.
