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

M M Mita, L Ochoa, E K Rowinsky, J Kuhn, G Schwartz, L A Hammond, A Patnaik, I-T Yeh, E Izbicka, K Berg, A W Tolcher

Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA.

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2006 Feb

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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 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. 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. 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.

Citation

M M Mita, L Ochoa, E K Rowinsky, J Kuhn, G Schwartz, L A Hammond, A Patnaik, I-T Yeh, E Izbicka, K Berg, A W Tolcher. A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2006 Feb;17(2):313-21