Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome
Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome
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DOI：
10.1182/blood-2009-01-176032
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发表时间：
2009-06-25
期刊：
影响因子：
20.3
通讯作者：
List, Alan
中科院分区：
文献类型：
--
作者：
Raza, Azra;Galili, Naomi;List, Alan
在一项多剂量递增研究中进行了ezatiostat（一种谷胱甘肽S-转移酶P1-1抑制剂）治疗骨髓增生异常综合征的I期试验。患者在21天周期的第1 - 7天接受10个剂量水平（200、400、1000、1400、2000、2400、3000、4000、5000和6000 mg）的ezatiostat片剂分次给药，最多8个周期。评价ezatiostat的安全性和药代动力学。入组了45例低至中等国际预后评分系统风险骨髓增生异常综合征患者。未观察到剂量限制性毒性。最常见的1级或2级治疗相关不良事件分别为非血液学：恶心（56%，9%）、腹泻（36%，7%）、呕吐（24%，7%）、腹痛（9%，0%）、便秘（4%，9%）、厌食（3%，7%）和消化不良（3%，7%）。主要活性代谢产物TLK 236的浓度与ezatiostat剂量成比例增加。根据国际工作组标准，在200 - 6000 mg/天剂量水平下观察到17例血液学改善（HI）反应，在4000 - 6000 mg/天剂量水平下观察到11例HI反应。HI反应发生在所有谱系中，包括3个双系和1个完全细胞遗传学反应。红细胞和血小板输注数量减少，在某些情况下实现了输血独立性。ezatiostat片剂的延长剂量方案正在研究中。本研究在http://www.clinicaltrials.gov上注册为NCT 00280631。（血。2009; 113：6533-6540）
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. (Blood. 2009; 113: 6533-6540)