Phase i and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas

Michelle A. Rudek, Pamela New, Tom Mikkelsen, Surasak Phuphanich, Jane B. Alavi, Louis B. Nabors, Steven Piantadosi, Joy D. Fisher, Stuart A. Grossman

Research output: Contribution to journalArticle

Abstract

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m 2/day and escalated by 25 mg/m 2/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m 2/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m 2/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.

Original languageEnglish (US)
Pages (from-to)375-381
Number of pages7
JournalJournal of neuro-oncology
Volume105
Issue number2
DOIs
StatePublished - Nov 1 2011

Keywords

  • Anticonvulsants
  • COL-3
  • Gliomas
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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    Rudek, M. A., New, P., Mikkelsen, T., Phuphanich, S., Alavi, J. B., Nabors, L. B., Piantadosi, S., Fisher, J. D., & Grossman, S. A. (2011). Phase i and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas. Journal of neuro-oncology, 105(2), 375-381. https://doi.org/10.1007/s11060-011-0602-9