Phase I trial of imexon in patients with advanced malignancy

Tomislav Dragovich, Michael Gordon, David Mendelson, Lucas Wong, Manuel Modiano, H. H.Sherry Chow, Betty Samulitis, Steven O'Day, Kathryn Grenier, Evan Hersh, Robert Dorr

Research output: Contribution to journalArticlepeer-review

43 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
StatePublished - May 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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