Topoisomerase I/II inhibitor intoplicine administered as a 24 h infusion: phase I and pharmacologic study

Intoplicine, an antitumor drug which interacts with both topoisomerase enzy mes I and II, has demonstrated a broad spectrum of activity in preclinical studies. This indicates further clinical evaluation. In the present phase I study, with the primary objective to determine the maximum tolerated dose, intoplicine was administered by a 24 h continuous infusion every 21 days t o 32 patients with solid malignant tumors. The patients received 12-640 mg/ m(2) by a central venous catheter. Liver toxicity was dose limiting. One pa tient died in a hepatic coma after the first course (dose 640 mg/m(2)), whi ch was associated with intoplicine treatment. Other side effects were spora dic and mild. Myelotoxicity was virtually absent. Twenty-two patients had s table disease for four to six courses of treatment. The plasma concentratio n-time curves were compatible with standard linear pharmacokinetic models, with a protracted terminal half-life (mean 115 h). Although one sudden deat h occurred probably due to intoplicine toxicity, we nevertheless feel that research with intoplicine should continue, mainly because of its preclinica l activity and its unique mechanism of action. The recommended dose for pha se II studies with intoplicine administered as a 24 h infusion is 384 mg/m( 2). Liver toxicity, also seen in studies employing other dosages and infusi on durations, should be investigated extensively in further clinical studie s. [(C) 1999 Lippincott Williams & Wilkins.]