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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 i.v. 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 microg 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 microg 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 microg m(-2). From the dose level 170 microg 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 microg 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.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Awada A,Punt CJ,Piccart MJ,Van Tellingen O,Van Manen L,Kerger J,Groot Y,Wanders J,Verweij J,Wagener DJ

doi

10.1038/sj.bjc.6690232

subject

Has Abstract

pub_date

1999-03-01 00:00:00

pages

1454-61

issue

9-10

eissn

0007-0920

issn

1532-1827

journal_volume

pub_type

临床试验,杂志文章

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