A phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma

BACKGROUND. Abnormal expression of Ras proteins frequently is found with on . cogenic transformation making ras a promising therapeutic target. ISIS 25 03 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that sp ecifically downregulates H-ras expression and inhibits tumor cell growth in preclinical studies. Here, the authors report an initial clinical study of the safety and tolerability of an intravenous infusion of ISIS 2503 in pat ients with advanced cancer. METHODS. A continuous intravenous infusion of ISIS 2503 was administered fo r 14 days every 3 weeks to 23 patients with a variety of solid tumors refra ctory to standard therapy. The dose of ISIS 2503 was increased in sequentia l cohorts of patients, as toxicity allowed, until a final dose of 10.0 mg/k g/day of body weight was reached. Toxicity was scored by the National Cance r Institute's Common Toxicity Criteria, and tumor response was monitored af ter every two treatment cycles. Pharmacokinetic studies were performed in s ome of the patients up to, and including, the final dose of 10 mg/kg/day/da y of body weight. Levels of H-ras mRNA expression also were determined in t he circulating lymphocytes of some patients by quantitative reverse transcr iptase-polymerase chain reaction. RESULTS. A total of 23 patients received 63 cycles of ISIS 2503 at escalati ng doses to 10.0 mg/kg/day without dose-limiting toxicity and only minimal side effects. Four patients had stabilization of their disease for 6-10 cyc les. No consistent decreases in H-ras mRNA levels were observed in peripher al blood lymphocytes. CONCLUSIONS. ISIS 2503, an antisense oligonucleotide against H-ras, was wel l tolerated as a single agent at doses up to 10.0 mg/kg/day by 14-day conti nuous intravenous infusion. Several patients had stabilization of disease, suggesting that ISIS 2503 had some tumor growth inhibitory effects and futu re trials of ISIS 2503 in combination with chemotherapy should be considere d. (C) 2001 American Cancer Society.