A phase I trial of c-raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer

Raf proteins play a central role in the mitogen-activated protein kinase si gnaling pathway and hence are involved in oncogenic transformation and tumo r fell proliferation, ISIS 5132 is a 20-base antisense phosphorothioate oli godeoxyribonucleotide that specifically down-regulates c-raf expression. We report here an initial study of the safety and tolerability of an i.v. inf usion of ISIS 5132 in patients with advanced cancer. A continuous i.v. infu sion 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 all owed, 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. Phar macokinetic studies were performed for 30 patients treated at doses of less than or equal to 4.0 mg/kg/day, The initial dose of ISIS 5132 was 0.5 mg/k g body weight and was successfully increased incrementally to 5.0 mg/kg bod y 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 5 132, Two patients had prolonged stabilization of their disease, and one pat ient,vith ovarian carcinoma had a significant response with a 97% reduction in CA-125 levels. ISIS 5132, an antisense oligonucleotide against c-raf, w as well tolerated at doses up to and including 4.0 mg/kg/day by 21-day cont inuous i.v. infusion and demonstrated antitumor activity at the doses teste d.