Phase I trial of imexon in patients with advanced malignancy

Tomislav Dragovich, Michael Gordon, David Mendelson, Lucas Wong, Manuel Modiano, Hsiao-Hui Chow, Betty Samulitis, Steven O'Day, Kathryn Grenier, Evan M Hersh, Robert T Dorr

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Purpose: Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. Patients and Methods: Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. Results: There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m 2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve-dependent decrease in cystine levels 8 hours after dosing at ≥ 750 mg/m2/d. Conclusion: The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.

Original languageEnglish (US)
Pages (from-to)1779-1784
Number of pages6
JournalJournal of Clinical Oncology
Volume25
Issue number13
DOIs
Publication statusPublished - May 1 2007

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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