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

Abstract

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-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 of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 μg m −2 . According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 μg m −2 , the haematological toxicity (particularly thrombocytopenia) 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 μg m −2 . From the dose level 170 μg 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 μg m −2 . The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml −1 ) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values. © 1999 Cancer Research Campaign

Use of KW-2189, a DNA Minor Groove-Binding Agent, in Patients with Hepatocellular Carcinoma: A North Central Cancer Treatment Group (NCCTG) Phase II Clinical Trial

“…Subsequently analogs of CC-1065, including adozelesin, bizelesin, and carzelesin, were developed and have been evaluated in phase I-II clinical trials. [17][18][19][20][21][22][23][24][25] Hematologic toxicity, particularly neutropenia and thrombocytopenia, was dose limiting in the phase I trials. [18,19,21,22,24,25] The onset of hematologic toxicity tends to be delayed and prolonged.…”

DNA: Still A Target Worth Aiming At?

“…[57] Prolonged recovery of neutrophil and platelet counts resulted in treatment delays. When given as a single IV bolus at doses of 130 μg/m 2 or above, this pattern of bone marrow suppression was observed in 26% of courses of chemotherapy.…”

“…Three patients with renal carcinoma have had prolonged disease stabilization (15, 9 and 6 months). No responses [57] IV bolus, 1 day q4w 51 53 (21-71)/1 (0-2) 24-300 μg/m 2 (9) Neutropenia; thrombocytopenia 9 SD 300 μg/m 2 150 μg/m 2 Bizelesin Pitot et al [60] IV bolus, 1 day q4w 15 66 ( have been observed to date. Toxicity has consisted of transient neutropenia with no neutropenic fever.…”