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

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• 作者：Kenneth F. Grossmann (1)
  Howard Colman (2)
  Wallace A. Akerley (1)
  Michael Glantz (3)
  Yuko Matsuoko (2)
  Andrew P. Beelen (4)
  Margaret Yu (5)
  John F. De Groot (6)
  Robert D. Aiken (7)
  Jeffery J. Olsen (8)
  Brent A. Evans (9)
  Randy L. Jensen (10) randy.jensen@hsc.utah.edu
• 关键词：Glioblastoma multiforme &#8211 ; Verubulin &#8211 ; Carboplatin &#8211 ; Vascular disrupting agent
• 刊名：Journal of Neuro-Oncology
• 出版年：2012
• 出版时间：November 2012
• 年：2012
• 卷：110
• 期：2
• 页码：257-264
• 全文大小：425.9 KB
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• 作者单位：1. Division of Oncology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA2. Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA3. Department of Neurosurgery, Penn State College of Medicine Hershey Medical Center, Hershey, PA 17033, USA4. Department of Clinical Research, Myrexis, Inc, 305 Chipeta Way, Salt Lake City, UT 84108, USA5. Janssen Research and Development, 10990 Wilshire Blvd, Suite 1200, Los Angeles, CA 90024, USA6. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030, USA7. Department of Neuroscience, Neurosurgery, Medical Oncology, Radiation Oncology, Division of Neurological Oncology, Rush University Medical Center, Chicago, IL 60612, USA8. Translational Neuro-oncology Laboratory, Department of Neurological Surgery, The Emory Clinic, 1365-B Clifton Rd., NE, Ste. 2200, Atlanta, GA 30322, USA9. Department of Biostatistics, Myrexis, Inc, 305 Chipeta Way, Salt Lake City, UT 84108, USA10. 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
• ISSN：1573-7373

文摘

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.