Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-seque nce-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min IV infusion to 51 patients with advanced solid tumours . Patients received a median of two courses (range 1-5) at one or nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 mu g m(-2). According to NCI-CTC criteria, nonhaematological toxicities (grade 1/2) included feve r, nausea and vomiting, mucositis and anorexia, none of which was clearly d ose related. The dose-limiting toxicity was haematological and consisted ma inly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 mu g m(-2), the haematological toxicity (particularly thrombocyto penia) was delayed in onset, prolonged and cumulative in some patients. in several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 mu g m(-2). From the dose level 170 mu g m-2, the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 mu g m(-2). The pharm acokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have bee n established in 31 patients during the first course of treatment using a H PLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantita tion (1 ng ml(-1)) for short periods of time and only at the higher dose le vels. There was no relationship between neutropenia and the AUC of the prod rug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in A NC values.