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.

Brain Tumor Center Siteman Cancer Center Washington University School of Medicine St Louis Missouri; Department of Neurological Surgery Washington University School of Medicine St Louis Missouri

Brain Tumor Center Siteman Cancer Center Washington University School of Medicine St Louis Missouri; Division of Medical Oncology Department of Medicine Washington University School of Medicine St Louis Missouri

Clark H Smith Brain Tumour Centre Charbonneau Cancer Institute University of Calgary Calgary Alberta Canada

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 Pediatrics Washington University School of Medicine St Louis Missouri; Department of Neuroscience Washington University School of Medicine St Louis Missouri

Department of Radiation Oncology Washington University School of Medicine St Louis Missouri

Department of Radiation Oncology Washington University School of Medicine St Louis Missouri; Brain Tumor Center Siteman Cancer Center Washington University School of Medicine St Louis Missouri

Department of Radiation Oncology Washington University School of Medicine St Louis Missouri; Department of Computational and Quantitative Medicine Radiation Oncology Surgery Division of Biostatistics City of Hope Duarte California

Division of Medical Oncology Department of Medicine Washington University School of Medicine St Louis Missouri; Division of Medical Oncology Department of Oncology Mayo Clinic Rochester Minnesota

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

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