Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome

Author:

Raza Azra1,Galili Naomi1,Smith Scott2,Godwin John3,Lancet Jeffrey4,Melchert Magda4,Jones Marsha5,Keck James G.5,Meng Lisa5,Brown Gail L.5,List Alan4

Affiliation:

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

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference31 articles.

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2. Chronic myelodysplastic syndrome: Short survival with or without evolution to acute leukaemia.;Weisdorf;Br J Haematol,1983

3. Myelodysplastic syndromes: natural history and features of prognostic importance.;Mufti,1986

4. Classification of the myelodysplastic syndromes.;Bennett,1986

5. International scoring system for evaluating prognosis in myelodysplastic syndromes.;Greenberg;Blood,1997

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