A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer
| Autor: | C C, Cunningham, J T, Holmlund, J H, Schiller, R S, Geary, T J, Kwoh, A, Dorr, J, Nemunaitis |
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| Rok vydání: | 2000 |
| Předmět: |
Adult
Male Dose-Response Relationship Drug Fever Vomiting Alanine Transaminase Antineoplastic Agents Nausea Middle Aged Thionucleotides Hematologic Diseases Anorexia Oligodeoxyribonucleotides Antisense Proto-Oncogene Proteins c-raf Treatment Outcome Area Under Curve Neoplasms Humans Female Aspartate Aminotransferases Enzyme Inhibitors Infusions Intravenous Aged |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 6(5) |
| ISSN: | 1078-0432 |
| Popis: | Raf proteins play a central role in the mitogen-activated protein kinase signaling pathway and hence are involved in oncogenic transformation and tumor cell proliferation. ISIS 5132 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically down-regulates c-raf expression. We report here an initial study of the safety and tolerability of an i.v. infusion of ISIS 5132 in patients with advanced cancer. A continuous i.v. infusion of ISIS 5132 was administered for 21 days every 4 weeks to 34 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 5132 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 5.0 mg/kg body weight was reached. Toxicity was scored by common toxicity criteria, and tumor response was monitored. Pharmacokinetic studies were performed for 30 patients treated at doses ofor =4.0 mg/kg/day. The initial dose of ISIS 5132 was 0.5 mg/kg body weight and was successfully increased incrementally to 5.0 mg/kg body weight. Toxicities through the 4.0 mg/kg dose level were not dose limiting. Side effects were minimal and could not be specifically related to ISIS 5132. Two patients had prolonged stabilization of their disease, and one patient with ovarian carcinoma had a significant response with a 97% reduction in CA-125 levels. ISIS 5132, an antisense oligonucleotide against c-raf, was well tolerated at doses up to and including 4.0 mg/kg/day by 21-day continuous i.v. infusion and demonstrated antitumor activity at the doses tested. |
| Databáze: | OpenAIRE |
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