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A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors

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Summary

Purpose: This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Patients and methods: Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m2. Pharmacokinetic studies were performed in patients at all dose levels. Result: Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m2. One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m2, and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m2. Six patients were treated at the 18 mg/m2 dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t1/2) for TTI-237 was 25–29 h, and the mean area under the concentration time curve at 31.5 mg/m2 was 2,768 ng•h/mL. Conclusion: A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m2 may be a tolerable dose of TTI-237.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA

    Andrea Wang-Gillam & A. Craig Lockhart

  2. University of Kentucky, 800 Rose Street, cc445, Lexington, KY, 40536, USA

    Susanne M. Arnold

  3. Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH, 44195, USA

    Ronald M. Bukowski

  4. Pfizer, Inc, 235 East 42nd Street, New York, NY, 10017, USA

    Mace L. Rothenberg, Kenneth K. Wang & Eric Gauthier

  5. Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 37232, USA

    Wendy Cooper

  6. Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8056, St. Louis, MO, 63110, USA

    A. Craig Lockhart

Authors
  1. Andrea Wang-Gillam
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  2. Susanne M. Arnold
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  3. Ronald M. Bukowski
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  4. Mace L. Rothenberg
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  5. Wendy Cooper
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  6. Kenneth K. Wang
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  7. Eric Gauthier
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  8. A. Craig Lockhart
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Correspondence to A. Craig Lockhart.

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Wang-Gillam, A., Arnold, S.M., Bukowski, R.M. et al. A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors. Invest New Drugs 30, 266–272 (2012). https://doi.org/10.1007/s10637-010-9506-3

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  • DOI: https://doi.org/10.1007/s10637-010-9506-3

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