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Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme

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An Erratum to this article was published on 23 March 2013

Abstract

Verubulin (MPC-6827) is a microtubule-destabilizing agent that achieves high concentrations in the brain. Verubulin disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of verubulin administered in combination with carboplatin in patients with relapsed glioblastoma multiforme (GBM). Three pre-selected doses of verubulin were tested: 2.1, 2.7, and 3.3 mg/m2 in a standard “3+3” design. Verubulin was given every second week of a 6-week cycle in the 2.1 mg/m2 cohort or weekly for 3 weeks of a 4-week cycle in subsequent cohorts. Carboplatin was administered intravenously at an area under the curve (AUC) dosage 4 every 2 weeks for the 2.1 mg/m2 cohort or on day 1 of each 4-week cycle in subsequent cohorts. Nineteen patients with GBM in first or second relapse were enrolled. Four patients (21 %) experienced a grade 3 or greater verubulin- or carboplatin-related adverse event, including hypesthesia, cerebral ischemia, anemia, and thrombocytopenia. The mean plasma half life of verubulin was 3.2 h (SD = 0.82). Two patients achieved at least a partial response by Macdonald criteria. One of these patients remains progression free and off treatment more than 24 months beyond his initiation of verubulin. Five patients had stable disease. Median progression-free survival (PFS) across all patients was 8 weeks, and the 6-month PFS rate was 21 %. The combination of verubulin at the previously determined single-agent maximum tolerated dose of 3.3 mg/m2 with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no cerebral hemorrhage was observed.

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Acknowledgments

We thank Kristin Kraus, MS, for editorial assistance in preparing this paper. This project was funded by Myrexis Inc. (formerly Myriad Pharmaceuticals).

Conflict of interest

The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Division of Oncology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT, 84112, USA

    Kenneth F. Grossmann & Wallace A. Akerley

  2. Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT, 84112, USA

    Howard Colman & Yuko Matsuoko

  3. Department of Neurosurgery, Penn State College of Medicine Hershey Medical Center, Hershey, PA, 17033, USA

    Michael Glantz

  4. Department of Clinical Research, Myrexis, Inc, 305 Chipeta Way, Salt Lake City, UT, 84108, USA

    Andrew P. Beelen

  5. Janssen Research and Development, 10990 Wilshire Blvd, Suite 1200, Los Angeles, CA, 90024, USA

    Margaret Yu

  6. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX, 77030, USA

    John F. De Groot

  7. Department of Neuroscience, Neurosurgery, Medical Oncology, Radiation Oncology, Division of Neurological Oncology, Rush University Medical Center, Chicago, IL, 60612, USA

    Robert D. Aiken

  8. Translational Neuro-oncology Laboratory, Department of Neurological Surgery, The Emory Clinic, 1365-B Clifton Rd., NE, Ste. 2200, Atlanta, GA, 30322, USA

    Jeffery J. Olsen

  9. Department of Biostatistics, Myrexis, Inc, 305 Chipeta Way, Salt Lake City, UT, 84108, USA

    Brent A. Evans

  10. Departments of Neurosurgery, Radiation Oncology, Oncological Sciences, Huntsman Cancer Institute, Clinical Neuroscience Center, University of Utah, 175 North Medical Drive, Salt Lake City, UT, 84132, USA

    Randy L. Jensen

Authors
  1. Kenneth F. Grossmann
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  2. Howard Colman
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  3. Wallace A. Akerley
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  4. Michael Glantz
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  5. Yuko Matsuoko
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  6. Andrew P. Beelen
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  7. Margaret Yu
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  8. John F. De Groot
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  9. Robert D. Aiken
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  10. Jeffery J. Olsen
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  11. Brent A. Evans
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  12. Randy L. Jensen
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Corresponding author

Correspondence to Randy L. Jensen.

Additional information

Kenneth F. Grossmann and Howard Colman contributed equally to this study.

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Grossmann, K.F., Colman, H., Akerley, W.A. et al. Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme. J Neurooncol 110, 257–264 (2012). https://doi.org/10.1007/s11060-012-0964-7

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  • DOI: https://doi.org/10.1007/s11060-012-0964-7

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