Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial.
Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial.
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DOI：
10.1016/s1470-2045(11)70265-0
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发表时间：
2011-12
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通讯作者：
Martell RE
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作者：
Younes A;Oki Y;Bociek RG;Kuruvilla J;Fanale M;Neelapu S;Copeland A;Buglio D;Galal A;Besterman J;Li Z;Drouin M;Patterson T;Ward MR;Paulus JK;Ji Y;Medeiros LJ;Martell RE
复发性霍奇金淋巴瘤患者的预后，特别是干细胞移植后复发的患者，仍然很差，针对这一相对年轻的患者群体开发新药代表了未满足的医疗需求。在这项研究中，我们检查了mocetinostat（一种口服同种型选择性组蛋白脱乙酰酶抑制剂）在复发性经典霍奇金淋巴瘤患者中的安全性和有效性。年龄≥ 18岁的复发性或难治性经典霍奇金淋巴瘤患者接受mocetinostat治疗，口服剂量每周三次，28天为一个周期。评价了两个剂量队列（85 mg和110 mg）。患者接受治疗直至疾病进展或出现抑制性毒性。主要目的是评估mocetinostat诱导的疾病控制率，定义为通过意向治疗分析的CR、PR或SD（至少6个周期）。该试验已完成，并在ClinicalTrials.gov注册，编号NCT 00358982。最初，23例患者入组110 mg队列。随后，另外28例患者接受了85 mg的减量治疗，以改善治疗耐受性。基于意向治疗分析，110 mg和85 mg组的总体疾病控制率分别为34.8%和25%。完成至少2个周期治疗的42例患者中有34例（81%）的肿瘤测量值下降。47%（24/51）的患者因疾病进展而停止治疗，85 mg队列中为57%（16/28），110 mg队列中为34%。24%（12/51）的患者因不良事件停药，85 mg队列中为32%（9/28），110 mg队列中为13%（3/23）。最常见的治疗相关的3级和4级不良事件包括中性粒细胞减少，在4例患者中观察到。（17.4%）例患者在110 mg组和3例（10.7%）85 mg组患者;疲乏（110 mg组5例（21.7%）vs 85 mg组3例（10.7%））;肺炎（110 mg组4例（17.4%）vs 85 mg组2例（7.1%））。4例患者（均在110 mg队列中）在研究期间死亡，其中2例被认为可能与治疗相关。Mocetinostat 85 mg每周三次在复发性经典霍奇金淋巴瘤患者中具有有希望的单药临床活性，毒性可控。MethylGene Inc.，加拿大蒙特利尔; Celgene Corporation，Summit，新泽西; Tufts Medical Center，Boston，MA
The prognosis of patients with relapsed Hodgkin lymphoma, especially those who relapsed after stem cell transplant, remains poor, and the development of new agents for this relatively young patient population represents an unmet medical need. In this study, we examined the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin lymphoma Patients with relapsed or refractory classical Hodgkin lymphoma aged 18 years or older were treated with mocetinostat administered as an oral dose three-times weekly, in 28-day cycles. Two dose cohorts were evaluated (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary objective was to estimate the disease control rate induced by mocetinostat, defined as CR, PR or SD (for at least 6 cycles) analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982 A total of 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, 28 additional patients were treated with a reduced dose of 85 mg to improve treatment tolerance. Based on intent to treat analysis, the overall disease control rate was 34.8% and 25% for the 110 mg and 85 mg groups, respectively. Thirty-four out of 42 (81%) patients who completed at least 2 cycles of therapy had a decrease in their tumor measurements. Forty-seven percent (24/51) discontinued therapy due to disease progression, 57% (16/28) in the 85 mg cohort and 34% in the 110 mg cohort. Twenty-four percent (12/51) discontinued due to adverse events, 32% (9/28) in the 85 mg cohort and 13% (3/23) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events included neutropenia, which was observed in 4 (17.4%) patients in the 110 mg group and in 3 (10.7%) patients in the 85 mg group; fatigue (in 5 (21.7%) of the 110 mg group vs 3 (10.7%) of the 85 mg group); and pneumonia (4 (17.4%) of the 110 mg group vs 2 (7.1% of the 85 mg group). Four patients, all in the 110 mg cohort, died during study, of whom two were considered possibly related to treatment. Mocetinostat 85 mg three-times weekly has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin lymphoma. MethylGene Inc., Montreal, Canada; Celgene Corporation, Summit, New Jersey; Tufts Medical Center, Boston, MA