To evaluate the toxicity and response rate of bortezomib with concurrent radiotherapy and temozolomide in the treatment of patients with CNS malignancies.
Patients and Methods
This open-label, dose-escalation, phase 1 clinical study evaluated the safety of 3 dose levels of intravenously administered bortezomib (0.7, 1.0, 1.3 mg/m2/dose) on days 1, 4, 8, 11 of a 21-day cycle, in addition to concurrent radiation therapy and temozolomide at a daily dose of 75 mg/m2 starting on day 1. The primary endpoint was dose-limiting toxicity (DLT), defined as any Grade 4–5 toxicity or Grade 3 toxicity(ies) directly attributable to protocol treatment, requiring hospitalization and/or radiation interruption. Secondary endpoints included feasibility, non-dose-limiting toxicity, and response.
Twenty-seven patients were enrolled, 23 of whom had a high grade glioma (ten recurrent and 13 newly diagnosed). There were no dose-limiting toxicities (DLTs) noted in any dose groups, including the highest dose level group (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; median survival was 17.4 months for all patients and 15.0 months for patients with high-grade gliomas.
Bortezomib administered at its typical “systemic” dose (1.3 mg/m2) is well tolerated and safe in combination with temozolomide and radiation when used in the treatment of CNS malignancies. A phase II study to characterize efficacy is warranted.
Keywords: proteasome inhibitors, bortezomib, CNS malignancy, GBM, radiation