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

Andrea Wang-Gillam, Susanne M. Arnold, Ronald M. Bukowski, Mace L. Rothenberg, Wendy Cooper, Kenneth K. Wang, Eric Gauthier, A. Craig Lockhart

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Abstract

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/m 2. Pharmacokinetic studies were performed in patients at all dose levels. Result: Twentyeight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m 2. One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m 2, 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/m 2. Six patients were treated at the 18 mg/m 2 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/m 2 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/m 2 may be a tolerable dose of TTI-237.

Original languageEnglish
Pages (from-to)266-272
Number of pages7
JournalInvestigational New Drugs
Volume30
Issue number1
DOIs
StatePublished - Feb 1 2012

Keywords

  • Anti-tubulin drugs
  • Phase I study
  • TTI-237

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    Wang-Gillam, A., Arnold, S. M., Bukowski, R. M., Rothenberg, M. L., Cooper, W., Wang, K. K., Gauthier, E., & Lockhart, A. C. (2012). A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors. Investigational New Drugs, 30(1), 266-272. https://doi.org/10.1007/s10637-010-9506-3