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

Abstract

Summary 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 × 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.

Regulation of Phospholipase C-β Activity by Phosphatidic Acid: Isoform Dependence, Role of Protein Kinase C, and G Protein Subunits

“…Ischemia results in an increase in PA levels (30). Malignant transformed cells have elevated PA levels (31,32). It will be of interest to determine whether these changes in PA levels impact PLC-β 1 signaling.…”