A PHASE-I AND PHARMACOKINETIC STUDY OF A NEW CAMPTOTHECIN DERIVATIVE,9-AMINOCAMPTOTHECIN

Camptothecins are the only available antitumor agents which target the nuclear enzyme topoisomerase I. 9-Amino-camptothecin (9-AC) is a wate r-insoluble derivative of camptothecin which has demonstrated impressi ve antitumor activity in preclinical models, While two other water-sol uble derivatives, CPT-11 and topotecan, have successfully completed Ph ase I and Phase II testing, biochemical and tissue culture studies sug gest that camptothecin analogues differ in characteristics which may b e important in determining antitumor activity. We performed a Phase I trial of 9-AC to determine the pharmacokinetics, dose-limiting toxicit y, and maximum tolerated dose of this agent when administered as a 72- h continuous i.v. infusion. Thirty-one patients with resistant solid c ancers received 5-60 mu g/m(2)/h 9-AC for 72 h, repeated at 3-week int ervals. The drug was administered in a vehicle containing dimethylacet amide, polyethylene glycol, and phosphoric acid, Blood samples were co llected and the lactone (closed ring) form of 9-AC was quantitated. Th e maximum tolerated dose of 9-AC was determined to be 45 mu g/m(2)/h. Dose-limiting toxicity consisted of neutropenia. Thrombocytopenia was also prominent. There were no significant nonhematological toxicities. Minimal responses were seen in patients with gastric, colon, and non- small cell lung cancer. Although significant interpatient variation in plasma 9-AC lactone levels was observed, pooled data were fit to a tw o-compartment model, with a terminal half-life of 36 h. Analyses of to poisomerase protein levels in peripheral blood cells indicated decreas es in topoisomerase I accompanied by increases in topoisomerase II in two of three patients. 9-AC is an active antitumor agent and may be ad ministered safely as a 72-h infusion in patients with cancer. Although Phase II trials with a 72-h infusion of 9-AC are warranted, alternate schedules should be evaluated given the dramatic preclinical activity seen with more prolonged administrations.