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Journal of Neuro-Oncology

, Volume 128, Issue 2, pp 259–266 | Cite as

A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy

  • Jiayi Huang
  • Jian L. Campian
  • Amit D. Gujar
  • David D. Tran
  • A. Craig Lockhart
  • Todd A. DeWees
  • Christina I. Tsien
  • Albert H. Kim
Clinical Study

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/m2 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.

Keywords

Glioblastoma Disulfiram Temozolomide Proteasome inhibition Phase I clinical trial 

Notes

Acknowledgments

The authors would like to thank Dr. Eric Lightcap for his helpful discussions on proteasome activity assay. We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO., for the use of the Clinical Trials Office, which provided protocol development, regulatory, data management, and study coordination services. We would like to specifically acknowledge Stephanie Myles, Bethany Rensink, Sarah Marchetti, and Maria Miller of the Siteman Cancer Center for their work on this trial. The Siteman Cancer Center is supported in part by a NCI Cancer Center Support Grant #P30 CA091842. We would also like to acknowledge our courageous patients and their families for their inspiration.

Funding

Institutional fund from the Department of Radiation Oncology, Washington University School of Medicine.

Compliance with ethical standards

Conflict of Interest

We have no conflict of interests to disclose for this work.

Supplementary material

11060_2016_2104_MOESM1_ESM.doc (39 kb)
Supplementary material 1 (DOC 39 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jiayi Huang
    • 1
    • 2
  • Jian L. Campian
    • 2
    • 3
  • Amit D. Gujar
    • 4
  • David D. Tran
    • 1
    • 2
    • 3
  • A. Craig Lockhart
    • 2
    • 3
  • Todd A. DeWees
    • 1
  • Christina I. Tsien
    • 1
    • 2
  • Albert H. Kim
    • 2
    • 4
  1. 1.Department of Radiation OncologyWashington University School of MedicineSt LouisUSA
  2. 2.Siteman Cancer CenterWashington University School of MedicineSt LouisUSA
  3. 3.Division of Oncology, Department of MedicineWashington University School of MedicineSt LouisUSA
  4. 4.Department of NeurosurgeryWashington University School of MedicineSt LouisUSA

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