Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours

CT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine-hyd rogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to d etermine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, phar macokinetic profile and antitumour effects at escalating dose levels. CT-25 84 HMS was given as a continuous infusion for 6 hours for 5 consecutive day s every 3 weeks. Plasma samples for pharmacokinetic studies were analysed u sing 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 increas es in plasma concentration (C-max and AUC) appeared proportional to the dos e. 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 esc alation was halted at 585 mg/m(2) because of malaise and lethargy, which wa s sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial resp onse to treatment confirmed by CT scanning. A dose level of 520 mg/m(2) dai ly x 5 days would be suitable for Phase II testing. Alternative schedules o f CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination. (C) 2000 Cancer Research Campaign.