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Annals of Oncology Advance Access originally published online on December 1, 2005
Annals of Oncology 2006 17(2):313-321; doi:10.1093/annonc/mdj067
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© 2005 European Society for Medical Oncology

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

M. M. Mita1, L. Ochoa1, E. K. Rowinsky1, J. Kuhn2, G. Schwartz3, L. A. Hammond1, A. Patnaik1, I.-T. Yeh4, E. Izbicka1, K. Berg1 and A. W. Tolcher1,*

1 Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX; 2 Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX; 3 Brooke Army Medical Center, San Antonio, TX; 4 Department of Pathology, University of Texas Health Science Medical Center, San Antonio, TX, USA

* Correspondence to: Dr A. W. Tolcher, Institute for Drug Development, Cancer Therapy and Research Center, 7979 Wurzbach Road, Suite Z414, San Antonio, TX 78229, USA. Tel: +1-210-616-5914; Fax: +1-210-692-7502; E-mail: atolcher{at}idd.org

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.

Key words: antisense oligonucleotide, Bcl-2, irinotecan, oblimersen, phase I pharmacokinetics


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