Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

Abstract

ImportanceDisulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.ObjectiveTo evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.Design, Setting, and ParticipantsThis 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.InterventionsPatients 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).Main Outcomes and MeasuresThe 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.ResultsAmong 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.Conclusions and RelevanceThis 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.Trial RegistrationClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16

Copper homeostasis and cuproptosis in tumor pathogenesis and therapeutic strategies

“…Unfortunately, few clinical trials of DSF have achieved the expected results owing to the inefficient delivery of DSF and Cu 2+ to tumor sites and small sample sizes. For example, a phase II/III clinical trial found that among patients with recurrent glioblastoma, DSF combined with temozolomide led to significantly increased toxic effects but no significant difference in survival, compared with chemotherapy alone, suggesting that DSF and copper did not benefit patients with recurrent glioblastoma ( Werlenius et al, 2023 ). Taken together, these findings suggest that altering the intracellular copper concentration could be a promising therapeutic strategy for a subset of tumors.…”

Antitumor Activity and Mechanistic Insights of a Mitochondria-Targeting Cu(I) Complex

“…Copper-ionophores have been clinically tested as anticancer agents, such as clioquinol 14 and disulfiram. 15 By chelating extracellularly and releasing Cu(II) under the reductive intracellular environment, 16,17 copper-ionophores exhibit a complex anticancer mechanism, including generating reactive oxygen species (ROS) and inducing cellular oxidative stress, 18 inhibiting proteasomal activity, 19 enhancing the clearance of Xlinked inhibitor of apoptosis protein (XIAP). 20 Elesclomol (ES), developed by Synta Pharmaceuticals, has achieved the furthest advance in clinical trials among these copper-ionophores.…”

Cuproptosis: unveiling a new frontier in cancer biology and therapeutics

“…This study registered with ClinicaTrials.gov (NCT03034135) across multiple institutions demonstrated that DSF/Cu treatment exhibits minimal efficacy in treating IDH-wild type glioblastoma patients without selection and seemingly fails to enhance sensitivity to temozolomide significantly [ 248 ]. Another clinical trial (NCT02678975) also indicated that combining disulfiram and copper with standard chemotherapy for the treatment of recurrent glioblastoma did not lead to an increase in patient survival rates [ 249 ]. Moreover, a daily treatment with a 400 mg dose of disulfiram was associated with a higher incidence of adverse effects.…”

“…Moreover, a daily treatment with a 400 mg dose of disulfiram was associated with a higher incidence of adverse effects. Consequently, the study concluded that this combination therapy does not confer an advantage for patients with recurrent glioblastoma [ 249 ].…”