Disulfiram在多项临床前研究中已经展示出广泛的抗肿瘤作用，其中之一的推荐适应症是治疗恶性胶质母细胞瘤。本研究是一个多中心、开放标签、随机的2/3期临床试验，并采用平行组设计，旨在评估在复发性恶性胶质母细胞瘤患者中，加用Disulfiram和铜作为碱化剂化疗的附加治疗的疗效和安全性。研究在瑞典的7个研究中心和挪威的2个研究中心招募了患者，时间从2017年1月至2020年11月。符合条件的患者年龄需大于18岁，第一次复发的恶性胶质母细胞瘤，并符合碱化剂化疗的治疗指征。患者随访至死亡或最多24个月。最终随访日期为2021年1月15日，数据分析从2022年2月至9月进行。本研究采用1:1随机分组，其中一组接受标准治疗（SOC）的碱化剂化疗，另一组除了接受SOC碱化剂化疗外还加用Disulfiram（每日400mg）和铜（每日2.5mg）。本研究的主要终点是6个月存活率，次要终点包括总生存期、无进展生存期、不良事件和患者报告的生活质量。88名患者随机接受SOC（n = 45）或SOC加Disulfiram和铜（n = 43）治疗，其中63人（72%）为男性，平均年龄（SD）为55.4（11.5）岁。研究组（SOC vs SOC加Disulfiram和铜）在6个月存活率方面没有显著差异（62% [26/42] vs 44% [19/43]; P = .10）。SOC组的中位总生存期为8.2个月（95% CI，5.4-10.2个月），SOC加Disulfiram和铜组的中位总生存期为5.5个月（95% CI，3.9-9.3个月），中位无进展生存期分别为2.6个月（95% CI，2.4-4.6个月）和2.3个月（95% CI，1.7-2.6个月）。与SOC组相比，SOC加Disulfiram和铜组的患者中更多出现了3级或更高级别的不良事件（34% [14/41] vs 11% [5/44]; P = .02）和严重不良事件（41% [17/41] vs 16% [7/44]; P = .02），其中10名患者（24%）因不良反应而终止Disulfiram治疗。本随机临床试验发现，在复发性恶性胶质母细胞瘤患者中，与仅化疗相比，加用Disulfiram和铜附加治疗导致显著增加毒副作用，但在生存期方面没有显著差异。这些结果表明，对于复发性恶性胶质母细胞瘤患者来说，Disulfiram和铜没有任何益处。ClinicalTrials.gov号：NCT02678975；EUDRACT号：2016-000167-16。

Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.Among the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16.