carzelesin and Neoplasms

In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed.. Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 microg/m2. A total of 140 patients were entered and a total of 285 courses were administered.. In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen.. At this dose and schedule carzelesin did not yield activity in the types of tumors studied.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Breast Neoplasms; Colorectal Neoplasms; Duocarmycins; Female; Head and Neck Neoplasms; Humans; Indoles; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Melanoma; Middle Aged; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Prodrugs; Stomach Neoplasms

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.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Dose-Response Relationship, Drug; Drug Administration Schedule; Duocarmycins; Female; Follow-Up Studies; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Neutropenia; Prodrugs; Thrombocytopenia

Carzelesin (U-80244), one of the synthetic DNA minor groove binding cyclopropylpyrroloindole analogues, was selected for clinical development because of its high potency, promising antitumor activity in murine solid tumors and leukemia, and significant therapeutic efficacy against colon and rhabdomyosarcoma xenografts. In this Phase I study, carzelesin was given daily for 5 consecutive days to (a) determine the maximum tolerable dose (MTD) and the pattern of toxicity of this schedule; (b) define the pharmacokinetic profile of the parent, as was done for the intermediate compound U-76073 and the DNA-reactive agent U-76074; and (c) document any antitumor activity observed. Carzelesin was given as a 10-min infusion with a constant-rate infusion pump. Treatment was repeated every 4 weeks or when blood counts had recovered to normal values. The starting dose of 12 microgram/m2/day was escalated by 20-30% increments until the MTD (defined as the dose leading to grade 4 hematological or grade 3 nonhematological toxicity in at least two of six patients) was reached. Pharmacokinetic studies were planned on days 1 and 5 of the first cycle in at least two patients per dose level. Plasma levels of carzelesin, U-76073, and U-76074 were determined by high-performance liquid chromatography with UV detection and a detection limit of 0.5 ng/ml. Twenty-five patients were entered in the study, and 56 cycles were evaluable for hematological toxicity. Subsequent dose levels evaluated were 24, 30, 35, and 40 microgram/m2. Both neutropenia and thrombocytopenia were dose limiting and cumulative, with a high interpatient variability. Neutropenia occurred earlier (median time to neutrophil nadir and recovery, 15 and 29 days, respectively) than thrombocytopenia (median time to platelet nadir and recovery, 25 and >/=26 days, respectively); there were delays of treatment because of persisting thrombocytopenia in all patients treated at the MTD. At the MTD, the peak plasma concentrations of carzelesin were achieved at the end of the infusion and were higher than those found cytotoxic in vitro against tumor cell lines. Carzelesin was detectable up to a maximum of 1 h after the infusion. Smaller amounts of U-76073 were detectable for a maximum of 30 min only at the MTD, whereas U-76074 was never found. An 8-month partial remission was reported in one previously untreated patient with hepatocellular carcinoma at 40 microgram/m2. The MTD was fixed at 40 microgram/m2 daily; 35 and 30 micro

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Benzofurans; Bronchial Spasm; Drug Administration Schedule; Duocarmycins; Female; Flushing; Humans; Hypersensitivity; Indoles; Male; Middle Aged; Nausea; Neoplasms; Neutropenia; Tachycardia; Thrombocytopenia; Treatment Outcome