Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer

Purpose: To determine the maximum-tolerated dose (MTD) and pharmacologic be havior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleoti de to protein kinase C-alpha, Patients and Methods: Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a a-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated ever y 4 weeks, plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full -length antisense oligonucleotide in addition to chain-shortened metabolite s. Results: Drug-related toxicities included mild to moderate nausea, vomiting , fever, chills, and fatigue, Hematologic toxicity was limited to thrombocy topenia (grade I, four patients; grade 2, one patient; grade 3, one patient ). There was no relationship between dose, maximum concentration of the dru g (C-max), or area under the plasma concentration versus time curve (AUC) a nd coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with n on-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a sho rt elimination half-life (18 to 92 minutes), as well as a dose-dependent de crease in clearance and dose-dependent increases in C-max, AUC, and elimina tion half-life, Conclusion: No dose limiting toxicity of ISIS 3521 was identified, and clin ical activity was observed. A short elimination half-life was identified, w hich suggests that alternate schedules with prolonged administration may be necessary for further clinical development, (C) 1999 by American Society o f Clinical Oncology.