Phase I trial of GTI-2040, oxaliplatin, and capecitabine in the treatment of advanced metastatic solid tumors: A California Cancer Consortium Study

Stephen I. Shibata, James H. Doroshow, Paul Frankel, Timothy W. Synold, Yun Yen, David R. Gandara, Heinz Josef Lenz, Warren A. Chow, Lucille A. Leong, Dean Lim, Kim A. Margolin, Robert J. Morgan, George Somlo, Edward M. Newman

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10 引文 斯高帕斯(Scopus)

摘要

Background: GTI-2040 is a 20-mer antisense oligonucleotide targeting the mRNA of ribonucleotide reductase M2. It was combined with oxaliplatin and capecitabine in a phase I trial in patients with advance solid tumors based on previous studies demonstrating potentiation of chemotherapy with ribonucleotide reductase inhibitors. Methods: Patients at least 18 years of age with advanced incurable solid tumors and normal organ function as well as a Karnofsky performance status of ≥60% were eligible. One prior chemotherapy regimen for advanced disease or relapse within 12 months of adjuvant chemotherapy was required. Patients could have received prior fluoropyrimidines, including capecitabine, but not oxaliplatin. Treatment cycles were 21 days. In each cycle, GTI-2040 was given as a continuous intravenous infusion over 14 days, oxaliplatin as a 2-h intravenous infusion on day 1, and capecitabine orally twice a day for 14 days. In cycle 1 only, oxaliplatin and capecitabine were started on day 2 to allow ribonucleotide reductase mRNA levels to be measured with and without oxaliplatin and capecitabine. Doses were escalated in cohorts of three patients using a standard 3 + 3 design until the maximum tolerated dose was established, defined as no more than one first-cycle dose-limiting toxicity among six patients treated at a given dose level. Results: The maximum tolerated dose was estimated to be the combination of GTI-2040 3 mg/kg per day for 14 days, capecitabine 600 mg/m2 twice daily for 14 days, and oxaliplatin 100 mg/m2 every 21 days. Dose-limiting toxicities were hematologic. GTI-2040 pharmacokinetics, obtained at steady-state on days 7 and 14, showed the high inter-patient variability previously reported. Two of six patients had stable disease at the maximum tolerated dose and one patient, with heavily pre-treated non-small cell lung cancer, had a partial response at a higher dose level. In samples from a limited number of patients, there was no clear decrease in ribonucleotide reductase expression in peripheral blood mononuclear cells during treatment. Conclusion: A combination of GTI-2040, capecitabine and oxaliplatin is feasible in patients with advanced solid tumors.

原文英語
頁(從 - 到)1149-1155
頁數7
期刊Cancer Chemotherapy and Pharmacology
64
發行號6
DOIs
出版狀態已發佈 - 11月 2009
對外發佈

ASJC Scopus subject areas

  • 腫瘤科
  • 毒理學
  • 藥理
  • 癌症研究
  • 藥學(醫學)

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