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A phase I study of oxaliplatin in combination with gemcitabine: correlation of clinical outcome with gene expression

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Abstract

Purpose

Oxaliplatin has in vitro activity similar to or higher than other platinum agents. Preclinically, gemcitabine has demonstrated synergy when combined with platinum compounds. These facts formed the rationale for determining the maximum tolerated dose (MTD) of gemcitabine in combination with oxaliplatin.

Methods

Eligible patients with advanced incurable solid tumors were given oxaliplatin 130 mg/m2 as a 2-h infusion on day 1 followed by escalating doses of gemcitabine given over 30 min on day 1 and 8 of a 21-day cycle.

Results

A total of 43 patients were enrolled, including 30 patients at the MTD in an expanded cohort. At a gemcitabine dose of 800 mg/m2, 1/6 patients had a dose limiting toxicity (DLT) (grade 3 blurred vision and memory loss). At 1,000 mg/m2, 1/6 patients had a DLT (grade 3 increase in AST). At 1,200 mg/m2, 2/3 patients had a DLT (grade 4 thrombocytopenia and grade 3 confusion). The MTD of gemcitabine with 130 mg/m2 of oxaliplatin was therefore 1,000 mg/m2. The clearances of gemcitabine and ultrafilterable platinum are within the ranges previously reported for single agents. A patient with colon cancer had a partial response, and 21 patients had a best response of stable disease. In patients with tumor biopsies treated at the MTD, decreased ribonucleotide reductase M2 expression correlated with response.

Conclusion

Treatment with gemcitabine and oxaliplatin was well tolerated with primarily hematologic toxicity at the MTD. Study of biochemical correlates of response remain of interest althought current results remain exploratory.

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Authors and Affiliations

  1. Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA

    Stephen Shibata, Warren Chow, Paul Frankel, Agnes Juhasz, Lucille Leong, Dean Lim, Kim Margolin, Robert Morgan, Edward Newman, George Somlo, Yun Yen, Timothy Synold & James Doroshow

  2. University of California at Davis, Cancer Center, Sacramento, CA, USA

    David Gandara

  3. University of Southern California Norris, Cancer Center, Los Angeles, CA, USA

    Heinz-Josef Lenz

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  1. Stephen Shibata
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  2. Warren Chow
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  3. Paul Frankel
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Correspondence to Stephen Shibata.

Additional information

This study was supported by National Cancer Institute grants U01 CA62505 and P30 CA33572.

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Shibata, S., Chow, W., Frankel, P. et al. A phase I study of oxaliplatin in combination with gemcitabine: correlation of clinical outcome with gene expression. Cancer Chemother Pharmacol 59, 549–557 (2007). https://doi.org/10.1007/s00280-006-0297-3

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