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

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.