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Vorinostat as a radiosensitizer for brain metastasis: a phase I clinical trial

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Abstract

Perform a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) in patients with brain metastasis. A multi-institutional phase I clinical trial enrolled patients with a histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 to 400 mg daily using a 3+3 trial design. Seventeen patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n = 1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 and 300 mg dose levels. In the 400 mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Both events were most likely related to disease progression rather than treatment; nonetheless, we conservatively classified the death as a dose limiting toxicity. We found Vorinostat administered with concurrent WBRT to be well tolerated to a dose of 300 mg once daily. This is the recommended dose for phase II study.

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Acknowledgments

Merck & Co., Inc. supplied the Vorinostat in the preclinical and clinical studies and provided funding for both studies. Merck & Co., Inc. helped finance the clinical trial, the company also supplied the active drug, vorinostat.

Conflict of interest

Wenyin Shi: consultation for Varian, and Elekta. Hak Choy: advisory board for EMD and Bayer. Research grant from Celegene.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Wenyin Shi, Yaacov Richard Lawrence, Maria Werner-Wasik, Voichita Bar-Ad & Adam P. Dicker

  2. Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    David W. Andrews, James J. Evans, Kevin D. Judy, Christopher J. Farrell & Yaron Moshel

  3. Department of Surgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Adam C. Berger

  4. Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Hak Choy

  5. Department of Radiation Oncology, Sheba Medical Center, Tel HaShomer, Israel

    Yaacov Richard Lawrence

Authors
  1. Wenyin Shi
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  2. Yaacov Richard Lawrence
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  3. Hak Choy
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  4. Maria Werner-Wasik
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  5. David W. Andrews
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  6. James J. Evans
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  7. Kevin D. Judy
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  8. Christopher J. Farrell
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  9. Yaron Moshel
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  10. Adam C. Berger
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  11. Voichita Bar-Ad
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  12. Adam P. Dicker
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Corresponding author

Correspondence to Wenyin Shi.

Additional information

Wenyin Shi and Yaacov Richard Lawrence contributed equally to this project.

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Shi, W., Lawrence, Y.R., Choy, H. et al. Vorinostat as a radiosensitizer for brain metastasis: a phase I clinical trial. J Neurooncol 118, 313–319 (2014). https://doi.org/10.1007/s11060-014-1433-2

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  • DOI: https://doi.org/10.1007/s11060-014-1433-2

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