A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense™, G3139) and irinotecan in patients with metastatic colorectal cancer

Purpose: To assess the feasibility and antitumor activity of oblimersen sodium, an antisense oligonucleotide directed to the Bcl-2 mRNA, combined with irinotecan in patients with advanced colorectal carcinoma, characterize the pharmacokinetic behavior of both oblimersen sodium and irinotecan, and examine Bcl-2 protein inhibition in peripheral blood mononuclear cells (PBMC). Patients and methods: Patients were treated with escalating doses of oblimersen sodium administered by continuous intravenous infusion (CIVI) days 1-8, and irinotecan administered intravenously on day 6 once every 3 weeks. Results: Twenty patients received a total of 84 courses at doses ranging from 3 to 7 mg/kg/day for oblimersen sodium and from 280 to 350 mg/m² for irinotecan. Febrile neutropenia and diarrhea limited escalation of oblimersen sodium and irinotecan to 5 mg/kg/day and 350 mg/m², respectively. Other toxicities included nausea, vomiting, fever and fatigue. Steady-state plasma concentrations were achieved within 48 h of beginning oblimersen sodium treatment and the agent was undetectable 24 h after the discontinuation of the infusion. Reduction in levels of Bcl-2 protein in PBMC was documented following treatment with oblimersen sodium. One patient experienced a partial response and 10 additional patients had stable disease lasting 2.5-10 months. Conclusions: The combination is well tolerated at the recommended phase II oblimersen sodium dose of 7 mg/kg/day CIVI days 1-8 with irinotecan 280 mg/m² intravenously on day 6 every 3 weeks.