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.
|
Authors | Azra Raza, Naomi Galili, Scott Smith, John Godwin, Jeffrey Lancet, Magda Melchert, Marsha Jones, James G Keck, Lisa Meng, Gail L Brown, Alan List |
Journal | Blood
(Blood)
Vol. 113
Issue 26
Pg. 6533-40
(Jun 25 2009)
ISSN: 1528-0020 [Electronic] United States |
PMID | 19398716
(Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Prodrugs
- TLK-236
- Tablets
- gamma-Glu-S-BzCys-PhGly diethyl ester
- Glutathione
|
Topics |
- Abdominal Pain
(chemically induced)
- Aged
- Aged, 80 and over
- Biotransformation
- Dose-Response Relationship, Drug
- Female
- Fever
(chemically induced)
- Food-Drug Interactions
- Gastrointestinal Diseases
(chemically induced)
- Glutathione
(administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
- Humans
- Male
- Maximum Tolerated Dose
- Middle Aged
- Myelodysplastic Syndromes
(drug therapy)
- Neutropenia
(chemically induced)
- Prodrugs
(administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
- Tablets
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|