A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma

Int J Radiat Oncol Biol Phys. 2024 Nov 1;120(3):738-749. doi: 10.1016/j.ijrobp.2024.05.009. Epub 2024 May 19.

Abstract

Purpose: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM).

Methods and materials: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry.

Results: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors.

Conclusions: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Alkylating / pharmacokinetics
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / mortality
  • Brain Neoplasms* / radiotherapy
  • Brain Neoplasms* / therapy
  • Chemoradiotherapy* / methods
  • Copper* / blood
  • Copper* / therapeutic use
  • Disulfiram* / administration & dosage
  • Disulfiram* / pharmacokinetics
  • Disulfiram* / therapeutic use
  • Female
  • Glioblastoma* / drug therapy
  • Glioblastoma* / genetics
  • Glioblastoma* / mortality
  • Glioblastoma* / radiotherapy
  • Glioblastoma* / therapy
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Proto-Oncogene Proteins B-raf / genetics
  • Temozolomide* / administration & dosage
  • Temozolomide* / pharmacokinetics
  • Temozolomide* / therapeutic use

Substances

  • Disulfiram
  • Temozolomide
  • Copper
  • Isocitrate Dehydrogenase
  • Antineoplastic Agents, Alkylating
  • Proto-Oncogene Proteins B-raf