Phase I Trial Using Proteasome Inhibitor Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System Malignancies

Gregory J. Kubicek, Maria Werner-Wasik, Mitchell Machtay, Gayle Mallon, Thomas Myers, Michael Ramirez, David Andrews, Walter J. Curran, Adam P. Dicker

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To evaluate the toxicity and response rate of bortezomib with concurrent radiotherapy and temozolomide in the treatment of patients with central nervous system malignancies. Patients and Methods: This open-label, dose-escalation, Phase I clinical study evaluated the safety of three dose levels of intravenously administered bortezomib (0.7, 1.0, and 1.3 mg/m2/dose) on Days 1, 4, 8, and 11 of a 21-day cycle, in addition to concurrent radiotherapy and temozolomide at a daily dose of 75 mg/m2 starting on Day 1. The primary endpoint was dose-limiting toxicity, defined as any Grade 4-5 toxicity or Grade 3 toxicity directly attributable to protocol treatment, requiring hospitalization and/or radiotherapy interruption. The secondary endpoints included feasibility, non-dose-limiting toxicity, and treatment response. Results: A total of 27 patients were enrolled, 23 of whom had high-grade glioma (10 recurrent and 13 newly diagnosed). No dose-limiting toxicities were noted in any dose group, including the highest (1.3 mg/m2/dose). The most frequent toxicities were Grade 1 and 2 stomatitis, erythema, and alopecia. All 27 patients were evaluable for response. At a median follow-up of 15.0 months, 9 patients were still alive, with a median survival of 17.4 months for all patients and 15.0 months for patients with high-grade glioma. Conclusion: Bortezomib administered at its typical "systemic" dose (1.3 mg/m2) is well tolerated and safe combined with temozolomide and radiotherapy when used in the treatment of central nervous system malignancies. A Phase II study to characterize efficacy is warranted.

Original languageEnglish (US)
Pages (from-to)433-439
Number of pages7
JournalInternational Journal of Radiation Oncology Biology Physics
Volume74
Issue number2
DOIs
StatePublished - Jun 1 2009

All Science Journal Classification (ASJC) codes

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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