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

Abstract

PURPOSE:

To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide 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 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 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 metabolites.

RESULTS:

Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and 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 non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life.

CONCLUSION:

No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.

• Authors: J Nemunaitis, J T Holmlund, M Kraynak, D Richards, J Bruce, N Ognoskie, T J Kwoh, R Geary, A Dorr, D Von Hoff, S G Eckhardt
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 17 Issue 11 Pg. 3586-95 (Nov 1999) ISSN: 0732-183X [Print] United States
• PMID: 10550158 (Publication Type: Case Reports, Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Isoenzymes
• Oligodeoxyribonucleotides, Antisense
• Thionucleotides
• ISIS 3521
• PRKCA protein, human
• Protein Kinase C
• Protein Kinase C-alpha

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, blood, pharmacokinetics)
• Area Under Curve
• Combined Modality Therapy
• Dose-Response Relationship, Drug
• Electrophoresis, Capillary
• Female
• Half-Life
• Humans
• Isoenzymes (drug effects)
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism, therapy)
• Oligodeoxyribonucleotides, Antisense (administration & dosage, adverse effects, blood, pharmacokinetics)
• Protein Kinase C (drug effects)
• Protein Kinase C-alpha
• Thionucleotides (administration & dosage, adverse effects, blood, pharmacokinetics)
• Tomography, X-Ray Computed