Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervous system malignancies

Int J Radiat Oncol Biol Phys. 2009 Jun 1;74(2):433-9. doi: 10.1016/j.ijrobp.2008.08.050. Epub 2008 Dec 10.


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/m(2)/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/m(2) 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/m(2)/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/m(2)) 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Astrocytoma / drug therapy*
  • Astrocytoma / radiotherapy*
  • Boronic Acids / administration & dosage
  • Boronic Acids / adverse effects
  • Bortezomib
  • Central Nervous System Neoplasms / drug therapy*
  • Central Nervous System Neoplasms / radiotherapy*
  • Dacarbazine / administration & dosage
  • Dacarbazine / adverse effects
  • Dacarbazine / analogs & derivatives
  • Drug Administration Schedule
  • Female
  • Glioblastoma / drug therapy
  • Glioblastoma / radiotherapy
  • Humans
  • Male
  • Middle Aged
  • Pyrazines / administration & dosage
  • Pyrazines / adverse effects
  • Radiotherapy / adverse effects
  • Temozolomide
  • Treatment Outcome


  • Boronic Acids
  • Pyrazines
  • Bortezomib
  • Dacarbazine
  • Temozolomide