Resminostat for maintenance treatment in patients with advanced-stage mycosis fungoides or Sézary syndrome: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

We aimed to evaluate the efficacy and safety of a histone deacetylase inhibitor, resminostat, as maintenance therapy in patients with advanced-stage mycosis fungoides or Sézary syndrome, in whom disease control had been previously met.

我们的目标是评估组蛋白去乙酰化酶抑制剂resminostat作为维持治疗在之前已实现疾病控制的晚期型真菌样皮肤T细胞淋巴瘤或Sézary综合征患者中的疗效和安全性。

Methods

We conducted a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial (RESMAIN) at 55 medical centres in Austria, Belgium, France, Germany, Greece, Italy, the Netherlands, Poland, Spain, Switzerland, the UK, and Japan.

我们在奥地利、比利时、法国、德国、希腊、意大利、荷兰、波兰、西班牙、瑞士、英国和日本的55个医疗中心进行了一项多中心、双盲、随机、安慰剂对照的2期临床试验（RESMAIN）。

Adult patients (aged ≥18 years) with histologically confirmed, stage IIB-IVB mycosis fungoides or Sézary syndrome; an Eastern Cooperative Oncology Group performance status score of 0-2; and disease control after at least one previous systemic therapy or total skin electron beam were eligible for inclusion.

年龄≥18岁的成年患者，经组织学证实为IIB-IVB期的皮肤真菌病或Sézary综合征；东部肿瘤协作组（Eastern Cooperative Oncology Group）表现状态评分为0-2；并且在至少一次之前的全身治疗或全身电子束照射后疾病得到控制，符合纳入标准。

Patients were randomly assigned to receive either oral resminostat (600 mg) or matching oral placebo once daily for 5 days, followed by a treatment-free period of 9 days, within a 14-day treatment cycle.

患者被随机分配接受口服雷米诺司他（600毫克）或匹配的口服安慰剂，每天一次，持续5天，随后是9天的无治疗期，构成14天的治疗周期。

Randomisation was stratified by disease stage (IIB-IVA1 vs IVA2-IVB) and remission status following previous therapy (complete or partial response vs stable disease) by use of a dynamic block allocation process (block size 100 patients).

随机分组根据疾病分期（IIB-IVA1与IVA2-IVB）和之前治疗后的缓解状态（完全或部分缓解与疾病稳定）进行分层，并使用动态分块分配过程（分块大小为100名患者）。

Participants, investigators, site staff, and study personnel involved in outcome assessment and data analysis were masked to group assignment.

参与者、研究人员、现场工作人员以及参与结果评估和数据分析的研究人员对分组分配情况不知情。

Patients with disease progression during masked treatment were unmasked; patients on placebo were offered open-label resminostat.

在盲法治疗期间疾病进展的患者被解盲；安慰剂组的患者被提供开放标签的resminostat治疗。

Treatment was continued until disease progression or unacceptable toxicity.

治疗持续进行直至疾病进展或出现无法接受的毒性反应。

The primary endpoint was progression-free survival, defined as the time from randomisation to disease progression or death from any cause (whichever occurred first), analysed by intention to treat.

主要终点是无进展生存期，定义为从随机分组到疾病进展或因任何原因死亡（以先发生者为准）的时间，按意向治疗分析。

This trial is registered with ClincalTrials.gov (NCT02953301) and has been completed.

该试验已在ClincalTrials.gov上注册（NCT02953301），并已完成。

Results

Between Jan 9, 2017, and May 11, 2022, 234 patients were screened for eligibility, of whom 201 (86%) patients were randomly assigned: 100 (50%) to resminostat and 101 (50%) to placebo. 123 (61%) participants were men and 78 (39%) were women, with a median age of 64 years (range 30-87).

在2017年1月9日至2022年5月11日期间，共有234名患者接受了资格筛查，其中201名（86%）患者被随机分配：100名（50%）接受resminostat治疗，101名（50%）接受安慰剂治疗。参与者中123名（61%）为男性，78名（39%）为女性，中位年龄为64岁（范围30-87岁）。

Most participants (173 [86%]) were White, 19 (9%) were Asian (mainly Japanese), two (1%) were Black, and seven (3%) were either another race or ethnicity, or did not disclose these data.

大多数参与者（173 [86%]）为白人，19人（9%）为亚洲人（主要是日本人），两人（1%）为黑人，七人（3%）为其他种族或民族，或未披露这些数据。

Median progression-free survivalwas 8·3 months (95% CI 4·2-15·7) in the resminostat group and 4·2 months (2·8-6·4) in the placebo group (HR 0·62 [95% CI 0·42-0·92]; p=0·015).

雷米诺司他组的中位无进展生存期为8.3个月（95%置信区间4.2-15.7），安慰剂组为4.2个月（2.8-6.4）（HR 0.62 [95%置信区间0.42-0.92]；p=0.015）。

Median follow-up time for progression-free survivalwas 11·2 months (95% CI 5·6-19·6) in the resminostat group and 17·0 months (13·9-30·5) in the placebo group.

Resminostat组的无进展生存期中位随访时间为11.2个月（95%置信区间5.6-19.6），而安慰剂组为17.0个月（13.9-30.5）。

Adverse events were reported in 96 (96%) patients receiving resminostat and in 81 (80%) patients receiving placebo.

96名（96%）接受Resminostat治疗的患者和81名（80%）接受安慰剂治疗的患者报告了不良事件。

Serious adverse events occurred in 19 (19%) patients in the resminostat group, 11 (11%) of which were considered related to treatment, and in 12 (12%) in the placebo group, of which one (1%) was considered to be treatment-related.

在使用resminostat的患者中，有19名（19%）发生了严重不良事件，其中11名（11%）被认为是与治疗相关的；而在使用安慰剂的患者中，有12名（12%）发生了严重不良事件，其中1名（1%）被认为是与治疗相关的。

Adverse events of grade 3 or above occurred in 38 (38%) patients in the resminostat group and in 15 (15%) patients in the placebo group.

在使用resminostat的患者中，有38名（38%）发生了3级或以上的不良事件；而在使用安慰剂的患者中，有15名（15%）发生了3级或以上的不良事件。

The most common treatment-related adverse events were nausea (68 [68%] in the resminostat group vs six [6%] in the placebo group), diarrhoea (44 [44%] vs nine [9%]), vomiting (32 [32%] vs one [1%]), and fatigue (29 [29%] vs 14 [14%]).

最常见的治疗相关不良事件是恶心（在resminostat组有68例[68%]，在安慰剂组有六例[6%]），腹泻（44例[44%]对比九例[9%]），呕吐（32例[32%]对比一例[1%]），以及疲劳（29例[29%]对比14例[14%]）。

There were no treatment-related deaths.

没有治疗相关的死亡事件。

interpretation

These findings support the beneficial effect of resminostat maintenance therapy in patients with advanced CTCL.

这些发现支持了在晚期CTCL患者中使用resminostat维持治疗的有益效果。

The overall safety profile of resminostat was acceptable, with gastrointestinal side-effects occurring most frequently.

Resminostat的整体安全性是可以接受的，其中胃肠道副作用发生最为频繁。

Anti-emetic prophylaxis should be considered in the future to manage side-effects and to improve tolerability and adherence to maintenance therapy.

未来应考虑使用抗呕吐预防治疗来管理副作用，并提高对维持治疗的耐受性和依从性。

funding

4SC AG.

4SC AG公司。