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Phase I study of a novel pro-apoptotic drug R-etodolac in patients with B-cell chronic lymphocytic leukemia

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Summary

R-etodolac is a novel pro-apoptotic agent with potential antitumor activity against B-cell chronic lymphocytic leukemia (B-CLL). This phase I clinical trial was conducted to determine the tolerability, safety, and maximum tolerated dose (MTD) of R-etodolac, administered orally twice a day (BID), in patients with B-CLL. Secondary objectives included evaluating clinical response, pharmacodynamic activity (reduction of lymphocytes), and pharmacokinetic (PK) profile. Forty-three patients were enrolled in the study. The most frequently reported adverse events were diarrhea, rash, pruritus, and headache. Increases in alanine aminotransferase (ALT) were also observed. Adverse events were generally mild and self-limiting, although in an apparent dose–response relationship, grade 2 and 3 gastrointestinal toxicities and grade 3 skin toxicities were reported with the highest dose regimens (1,800 and 2,400 mg BID). Hematologic toxicity was rare. The MTD was determined to be 1,200 mg BID. PK results indicated that oral absorption of R-etodolac was rapid (time to maximum concentration ranged from 2 to 4 h), and the half-life ranged from 5 to 7 h. The increase in maximum concentration, however, was not proportional to the increase in dose. R-etodolac significantly reduced absolute lymphocyte count (ALC) in B-CLL patients in a dose-dependent manner up to 1,800 mg BID and caused partial responses in 2 patients. Further study of R-etodolac as a possible new maintenance therapy or as a part of combination therapy of B-CLL appears warranted.

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Acknowledgements

We thank Jennifer Wright Oliver, MD, for assistance with data interpretation and editorial guidance. We thank Margret Platz, Achim Rothe, and Sven Trelle for indispensable help in patient management and data collection. We also acknowledge the literature research and editorial contributions of Bridget O’Keeffe, Ph.D., and Mona Lee, Ph.D., of Helix Medical Communications LLC in the development of this manuscript. Dr. Österborg received research support from Salmedix, Inc.

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Authors and Affiliations

  1. University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany

    Markus Jensen & Andreas Engert

  2. Medizinische Poliklinik der Universität, Würzburg, Germany

    Florian Weissinger

  3. Onkologische Gemeinschaftspraxis, Bethanien Krankenhaus, Frankfurt, Germany

    Wolfgang Knauf

  4. Karolinska University Hospital Huddinge, Stockholm, Sweden

    Eva Kimby

  5. University Hospital of Wales, Cardiff, Wales, UK

    Christopher Poynton

  6. Midwest Cancer Research Group, Inc., Skokie, IL, USA

    Ira Anton Oliff

  7. University of Giessen, Giessen, Germany

    Mathias J. Rummel

  8. Karolinska University Hospital Solna, Stockholm, Sweden

    Anders Österborg

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  1. Markus Jensen
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  2. Andreas Engert
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  3. Florian Weissinger
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  9. Anders Österborg
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Correspondence to Markus Jensen.

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Jensen, M., Engert, A., Weissinger, F. et al. Phase I study of a novel pro-apoptotic drug R-etodolac in patients with B-cell chronic lymphocytic leukemia. Invest New Drugs 26, 139–149 (2008). https://doi.org/10.1007/s10637-007-9106-z

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  • DOI: https://doi.org/10.1007/s10637-007-9106-z

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