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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.

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Submitted January 16, 2009
Accepted April 13, 2009

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

Azra Raza*, Naomi Galili, Scott Smith, John Godwin, Jeffrey Lancet, Magda Melchert, Marsha Jones, James G. Keck, Lisa Meng, Gail L. Brown, and Alan List

University of Massachusetts Medical Center, Worcester, MA, United States
Loyola University Chicago, Cardinal Bernardin Cancer Center, Maywood, IL, United States
SIU Simmons Cooper Cancer Institute, Springfield, IL, United States
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
Telik, Inc., Palo Alto, CA, United States

* Corresponding author; email: araza{at}aptiumoncology.com.

Phase 1 testing of ezatiostat, a glutathione-S transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome (MDS) 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 1-7 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 INT-2 IPSS risk MDS were enrolled. No dose-limiting toxicities were observed. The most common Grade 1 or 2, respectively, treatment-related adverse events were non-hematologic: 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 metabolite, TLK236, increased proportionate to ezatiostat dosage. Seventeen hematologic improvement (HI) responses by IWG criteria at dose levels of 200-6000 mg/day with 11 HI responses at doses of 4000-6000 mg/day. HI responses occurred in all lineages including 3 bilineage and 1 complete cytogenetic response. Decreased number of RBC and platelet transfusions and in some cases transfusion independence was attained. Extended dose schedules of ezatiostat tablets are under investigation. This study was registered: www.clinicaltrials.gov NCT00280631.


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