ct-2584 and Arrhythmias--Cardiac

CT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3, 7-dimethylxanthine-hydrogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to determine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, pharmacokinetic profile and antitumour effects at escalating dose levels. CT-2584 HMS was given as a continuous infusion for 6 hours for 5 consecutive days every 3 weeks. Plasma samples for pharmacokinetic studies were analysed using a validated high-performance liquid chromatographic assay. Mean C(max)and AUC values for each dose group were similar on days 1 and 5 and increases in plasma concentration (C(max)and AUC) appeared proportional to the dose. CT-2584 HMS had a mean elimination half-life of 7.3 hours. Values of V(d)and clearance were independent of dose and duration of treatment. Dose escalation was halted at 585 mg/m(2)because of malaise and lethargy, which was sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial response to treatment confirmed by CT scanning. A dose level of 520 mg/m(2)daily x 5 days would be suitable for Phase II testing. Alternative schedules of CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Fatigue; Female; Hematuria; Humans; Hypersensitivity; Hypotension; Infusions, Intravenous; Male; Middle Aged; Myocardial Ischemia; Nausea; Neoplasms; Phosphatidic Acids; Proteinuria; Treatment Outcome; Vomiting; Xanthines