title: Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervous system malignancies.
abstract: OBJECTIVE
  To evaluate the toxicity and response rate of bortezomib with concurrent radiotherapy and temozolomide in the treatment of patients with central nervous system malignancies.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kubicek
authors.forename: Maria
authors.initials: M
authors.lastname: Werner-Wasik
authors.forename: Mitchell
authors.initials: M
authors.lastname: Machtay
authors.forename: Gayle
authors.initials: G
authors.lastname: Mallon
authors.forename: Thomas
authors.initials: T
authors.lastname: Myers
authors.forename: Michael
authors.initials: M
authors.lastname: Ramirez
authors.forename: David
authors.initials: D
authors.lastname: Andrews
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001254:Astrocytoma / Q000188:drug therapy* / Q000532:radiotherapy*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D011878:Radiotherapy / Q000009:adverse effects; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003606:Dacarbazine; D000077204:Temozolomide