Journal of Neuro-Oncology

, Volume 130, Issue 1, pp 193–201 | Cite as

Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma

  • D. Jay McCracken
  • Emma C. Celano
  • Alfredo D. Voloschin
  • William L. Read
  • Jeffrey J. Olson
Clinical Study


The average survival time for patients with recurrent glioblastoma is between 5 and 9 months. Phase I and II trials have shown a modest survival benefit with combination temozolomide and other chemotherapeutics. We conducted a phase I trial of dose-escalating temozolomide with bevacizumab and the proteasome inhibitor bortezomib for patients with recurrent disease. Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m2. Fixed doses of bortezomib and bevacizumab were given at standard intervals. Patients were monitored for dose-limiting toxicities (DLT) to determine the maximum-tolerated dose (MTD) of temozolomide with this regimen. No DLT were seen in the first two groups (25 and 50 mg/m2 temozolomide). One patient in the 75 mg/m2 group experienced a grade 4 elevation of ALT and three more patients were accrued for a total of six patients at that dose level. No other DLT occurred, thus making 75 mg/m2 the MTD. Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m2 in combination with bevacizumab and bortezomib for recurrent glioblastoma. Only one patient experienced a severe (Grade 4) elevation of ALT. This study will provide the framework for further studies to elicit effectiveness and better determine a safety profile for this drug combination.


Brain/central nervous system cancers Phase I-III trials brain/central nervous system cancers Magnetic resonance imaging (MRI) Adjuvant chemotherapy Combination chemotherapy Glioblastoma 



D.J.M. wrote the manuscript and analyzed the data, E.C.C. performed all chart reviews, collected data, assisted in manuscript creation, A.D.V. and W.L.R. were co-investigators for the clinical trial, J.J.O. served as the Primary Investigator for the clinical trial and oversaw all aspects related to its implementation.


Funding for trial provided through Genetech, Takeda, and Merck.

Compliance with ethical standards

Conflicts of interest

None of the authors have any conflicts-of-interest to report with respect to this manuscript.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • D. Jay McCracken
    • 1
  • Emma C. Celano
    • 2
  • Alfredo D. Voloschin
    • 3
  • William L. Read
    • 3
  • Jeffrey J. Olson
    • 1
  1. 1.Department of NeurosurgeryEmory University School of MedicineAtlantaUSA
  2. 2.Emory University School of MedicineAtlantaUSA
  3. 3.Department of Hematology and Medical OncologyEmory University School of MedicineAtlantaUSA

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