A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma

J Neurooncol. 2019 May;142(3):537-544. doi: 10.1007/s11060-019-03125-y. Epub 2019 Feb 15.


Purpose: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ.

Methods: This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety.

Results: From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1-12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase).

Conclusions: Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.

Trial registration: ClinicalTrials.gov NCT03034135.

Keywords: Clinical trial; Copper; Disulfiram; Recurrent glioblastoma; Temozolomide.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Acetaldehyde Dehydrogenase Inhibitors / administration & dosage
  • Adult
  • Aged
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Copper / administration & dosage
  • Disulfiram / administration & dosage
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Humans
  • Male
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Survival Rate
  • Temozolomide / administration & dosage
  • Trace Elements / therapeutic use


  • Acetaldehyde Dehydrogenase Inhibitors
  • Antineoplastic Agents, Alkylating
  • Trace Elements
  • Copper
  • Disulfiram
  • Temozolomide

Associated data

  • ClinicalTrials.gov/NCT03034135