PHASE-I AND PHARMACOKINETIC STUDY OF GI147211, A WATER-SOLUBLE CAMPTOTHECIN ANALOG, ADMINISTERED FOR 5 CONSECUTIVE DAYS EVERY 3 WEEKS

GI147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin ana logue that inhibits the nuclear enzyme topoisomerase I, In this Phase I and pharmacological study, 24 patients with advanced solid malignanc ies received a total of 72 courses of GI147211 as a 30-min infusion da ily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m(2)/ day, Severe neutropenia precluded dose escalation above 1.5 mg/m(2)/da y in minimally pretreated patients, and both severe neutropenia and th rombocytopenia were dose limiting in heavily pretreated patients at do ses above 1.0 mg/m(2)/day, These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparab le prior therapy, Nonhematological toxicities, including nausea, vomit ing, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, w ith renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI1 47211 and effects on neutrophils; however, patients who developed dose -limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug, The hydrolysis kinetics of GI147 211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in e rythrocytes, perhaps accounting for the observed lactone:total area un der the concentration-time curve ratio of 0.27, These results indicate that GI147211 exhibits predictable toxicities and that further studie s are warranted to determine the distinct role of this compound among currently available camptothecin analogues.