PHASE-I PHARMACOKINETIC STUDY OF DUP-937, A NEW ANTHRAPYRAZOLE

DUP-937 is a new anthrapyrazole intercalator that inhibits DNA synthesis. A phase I trial was conducted in which DUP-937 was given in an intravenous bolus weekly for 3 weeks. Cycles were repeated every 5 weeks. Twenty men and 13 women with median ECOG performance status of 1 completed 74 cycles. The starting dose was 0.55 mg/m(2)/week and doses were escalated to 16 mg/m(2)/week. Non-hematological toxicity was generally mild or moderate and consisted mainly of gastro-intestinal effects, fatigue, alopecia and local reactions. Grade 3 neutropenia was first documented at 7.36 mg/m(2) and became more common at higher dose levels. Three of four patients had greater than or equal to grade 3 neutropenia at the 16 mg/m(2) dose level. Thrombocytopenia was minimal. The dose-limiting toxicity was neutropenia and the maximum tolerated dose was 16 mg/m(2) weekly for 3 weeks. Mean area under the curve (AUC) values increased with dose. Linear pharmacokinetics were observed as total body clearance (CL(tb)), half-life (t(1/2)) and volume of distribution (Vss) did not change with increasing doses. One partial remission in a patient with prostate carcinoma was documented.