PHASE-I STUDY OF ADOZELESIN ADMINISTERED BY 24-HOUR CONTINUOUS INTRAVENOUS-INFUSION

Background: Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations. Purpose: We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase II testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed. Methods: Adozelesin was given as a 24-hour continuous intravenous infusion. Treatments were initially scheduled every 3 weeks, but the prolonged myelosuppression observed necessitated a final dosing interval of every 6 weeks. The starting dose of 30 mug/M2 was escalated using a modified Fibonacci scheme until dose-limiting toxicity was encountered. Results: Twenty-nine patients were entered in the study. Successive dose levels used were 30, 60, 100, 150, 120, and 100 mug/M2. Prolonged thrombocytopenia and granulocytopenia were dose limiting. No antitumor responses were observed. Conclusion: We recommend that the phase II dose of adozelesin given as a continuous 24-hour intravenous infusion be 100 mug/M2, repeated every 6 weeks. Other potentially less myelosuppressive schedules could be pursued.