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

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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.

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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.

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    Authors and Affiliations

    1. Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, 63110, USA

      Jiayi Huang, David D. Tran, Todd A. DeWees & Christina I. Tsien

    2. Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, 63110, USA

      Jiayi Huang, Jian L. Campian, David D. Tran, A. Craig Lockhart, Christina I. Tsien & Albert H. Kim

    3. Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USA

      Jian L. Campian, David D. Tran & A. Craig Lockhart

    4. Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, 63110, USA

      Amit D. Gujar & Albert H. Kim

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    1. Jiayi Huang
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    Jian L. Campian and Amit D. Gujar contributed equally to this work.

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    Huang, J., Campian, J.L., Gujar, A.D. et al. A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy. J Neurooncol 128, 259–266 (2016). https://doi.org/10.1007/s11060-016-2104-2

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