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Cited by 34Glioma Diagnosis and TreatmentPARP inhibition in cancer therapyRadiation Therapy and Dosimetry

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

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Huang, Jiayi, Campian, Jian L., DeWees, Todd A., Skrott, Zdenek, Mistrik, Martin, Johanns, Tanner M., Ansstas, George, Butt, Omar +11 more·2024·International Journal of Radiation Oncology*Biology*Physics
DOI 10.1016/j.ijrobp.2024.05.009PMC PMC13123272
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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.

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Authors
Huang, J., Campian, J. L., DeWees, T. A., Skrott, Z., Mistrik, M., Johanns, T. M., Ansstas, G., Butt, O., Leuthardt, E., Dunn, G. P., Zipfel, G. J., Osbun, J. W., Abraham, C., Badiyan, S., Schwetye, K., Cairncross, J. G., Rubin, J. B., Kim, A. H., & Chheda, M. G.
Affiliations
  • Washington University in St. Louis (US)
  • Mayo Clinic (US)
  • City Of Hope National Medical Center (US)
  • University of Calgary (CA)
Corresponding author
Huang, Jiayi
ORCID
Venue
International Journal of Radiation Oncology*Biology*Physics
Publisher
Elsevier BV
Published
2024-11
Volume
120
Issue
3
Pages
738-749
ISSN
0360-3016 (ISSN-L)
DOI
10.1016/j.ijrobp.2024.05.009
PMC
PMC13123272
OpenAlex
W4397049743
Cited by
34
References
41
Citations by year
2026: 18 · 2025: 14 · 2024: 2
FWCI
9.57
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Radiation Oncology*Biology*Physics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (#P30 CA091842)
  • UNC Department of Radiation Oncology
  • Washington University in St Louis School of Medicine
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
Keywords
disulfiram, copper, glioblastoma, temozolomide, radiotherapy, adjuvant chemotherapy, maximum tolerated dose, dose-limiting toxicity, BRAF mutation, IDH mutation, NF1 mutation, pharmacokinetics, tumor drug concentration, overall survival, progression-free survival
MeSH terms
Temozolomide, Progression-Free Survival, Adult, Aged, Brain Neoplasms, Copper, Disulfiram, Female, Glioblastoma, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Antineoplastic Agents, Alkylating, Proto-Oncogene Proteins B-raf, Chemoradiotherapy

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