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Blood, 25 June 2009, Vol. 113, No. 26, pp. 6533-6540. Prepublished online as a Blood First Edition Paper on April 27, 2009; DOI 10.1182/blood-2009-01-176032. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-01-176032v1 113/26/6533    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Raza, A. Articles by List, A. PubMed PubMed Citation Articles by Raza, A. Articles by List, A. Related Collections Free Research Articles Myeloid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome Azra Raza1, Naomi Galili1, Scott Smith2, John Godwin3, Jeffrey Lancet4, Magda Melchert4, Marsha Jones5, James G. Keck5, Lisa Meng5, Gail L. Brown5, and Alan List4 1 University of Massachusetts Medical Center, Worcester; 2 Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL; 3 Simmons Cooper Cancer Institute, Southern Illinois University, Springfield; 4 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and 5 Telik, Palo Alto, CA Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles. The safety and pharmacokinetics of ezatiostat were evaluated. Forty-five patients with low to intermediate-2 International Prognostic Scoring System risk myelodysplastic syndrome were enrolled. No dose-limiting toxicities were observed. The most common grade 1 or 2, respectively, treatment-related adverse events were nonhematologic: nausea (56%, 9%), diarrhea (36%, 7%), vomiting (24%, 7%), abdominal pain (9%, 0%), constipation (4%, 9%), anorexia (3%, 7%), and dyspepsia (3%, 7%). Concentration of the primary active metabolite, TLK236, increased proportionate to ezatiostat dosage. Seventeen hematologic improvement (HI) responses by International Working Group criteria were observed at dose levels of 200 to 6000 mg/day with 11 HI responses at doses of 4000 to 6000 mg/day. HI responses occurred in all lineages including 3 bilineage and 1 complete cytogenetic response. Decreased number of red blood cell and platelet transfusions and in some cases transfusion independence were attained. Extended dose schedules of ezatiostat tablets are under investigation. This study was registered at http://www.clinicaltrials.gov as NCT00280631 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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