Phase I study with the DNA sequence-specific: Agent adozelesin

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v, infusion, (ii) characterize the toxic effects of the drug using this schedule and (III) document any anti tumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 mu g/m(2), corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies ware entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 mu g/m(2). The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined hs 180 mu g/m(2). A minor response with a 4 month duration was reported in one Previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 mu g/m(2), repeated every 4 weeks.