title: A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy.
abstract: Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500-1000 mg once daily, in combination with 150-200 mg/m(2) temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2-3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells.
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, 63110, USA. jhuang@radonc.wustl.edu.|Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, 63110, USA. jhuang@radonc.wustl.edu.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, 63110, USA.|Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USA.
authors.forename: Jian L
authors.initials: JL
authors.lastname: Campian
authors.affiliation: Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, 63110, USA.
authors.forename: Amit D
authors.initials: AD
authors.lastname: Gujar
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, 63110, USA.|Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, 63110, USA.|Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Tran
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, 63110, USA.|Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USA.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, 63110, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: DeWees
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, 63110, USA.|Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, 63110, USA.
authors.forename: Christina I
authors.initials: CI
authors.lastname: Tsien
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, 63110, USA.|Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, 63110, USA.
authors.forename: Albert H
authors.initials: AH
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004221:Disulfiram / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning; D004359:Drug Therapy, Combination; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000097:blood / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015173:Supratentorial Neoplasms / Q000097:blood / Q000628:therapy*; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D003606:Dacarbazine; D046988:Proteasome Endopeptidase Complex; D004221:Disulfiram; D000077204:Temozolomide
keywords: Disulfiram; Glioblastoma; Phase I clinical trial; Proteasome inhibition; Temozolomide