A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma
Language English Country United States Media print-electronic
Document type Journal Article, Clinical Trial, Phase I, Clinical Trial, Phase II
PubMed
38768767
DOI
10.1016/j.ijrobp.2024.05.009
PII: S0360-3016(24)00660-6
Knihovny.cz E-resources
- MeSH
- Antineoplastic Agents, Alkylating therapeutic use pharmacokinetics MeSH
- Chemoradiotherapy * methods MeSH
- Disulfiram * therapeutic use pharmacokinetics administration & dosage MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Glioblastoma * radiotherapy genetics mortality therapy drug therapy MeSH
- Isocitrate Dehydrogenase genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Copper * blood therapeutic use MeSH
- Brain Neoplasms * radiotherapy mortality genetics therapy MeSH
- Proto-Oncogene Proteins B-raf genetics MeSH
- Aged MeSH
- Temozolomide * therapeutic use pharmacokinetics administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase I MeSH
- Clinical Trial, Phase II MeSH
- Names of Substances
- Antineoplastic Agents, Alkylating MeSH
- Disulfiram * MeSH
- Isocitrate Dehydrogenase MeSH
- Copper * MeSH
- Proto-Oncogene Proteins B-raf MeSH
- Temozolomide * MeSH
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.
Department of Neurological Surgery Washington University School of Medicine St Louis Missouri
Department of Pathology and Immunology Washington University School of Medicine St Louis Missouri
Department of Radiation Oncology Washington University School of Medicine St Louis Missouri
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