This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dragovich, T. Articles by Dorr, R. Search for Related Content PubMed PubMed Citation Articles by Dragovich, T. Articles by Dorr, R. Social Bookmarking                            What's this?

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

From the College of Medicine, Arizona Cancer Center, University of Arizona; Arizona Clinical Research Center; AmpliMed Corp, Tucson; Premiere Oncology, Scottsdale, AZ; Scott & White Clinic, Temple, TX; and The Angeles Clinic and Research Institute, Santa Monica, CA

Address reprint requests to Robert Dorr, PhD, RPh, Arizona Cancer Center, University of Arizona, 1515 N Campbell Ave, Tucson, AZ 85724; e-mail: bdorr{at}azcc.arizona.edu

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/m²/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.

Supported by Grant No. CA-17094 (R.D.) from the National Institutes of Health, National Cancer Center, Bethesda, MD; a Rapid Access to Intervention Development grant from the National Cancer Center; and a grant from the AmpliMed Corporation, Tucson, AZ.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?