Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervous system malignancies.
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.
Kubicek
Gregory J
GJ
Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.
Werner-Wasik
Maria
M
Machtay
Mitchell
M
Mallon
Gayle
G
Myers
Thomas
T
Ramirez
Michael
M
Andrews
David
D
Curran
Walter J
WJ
Dicker
Adam P
AP
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
D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003606:Dacarbazine; D000077204:Temozolomide