Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment

Abstract

Purpose/Objective: To assess the safety and efficacy of upfront treatment using bortezomib in combination with standard radiation therapy (RT) and temozolomide, followed by adjuvant bortezomib and temozolomide for up to 24 cycles in patients with newly-diagnosed glioblastoma multiforme (GBM). Patients and Methods: Twenty-four newly-diagnosed GBM patients were enrolled. Patients received standard external beam regional RT with concurrent temozolomide commencing 3–6 weeks after surgery, followed by adjuvant temozolomide and bortezomib for up to 24 cycles or until tumor progression. During RT, bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, 11, 29, 32, 36, and 39. Post RT, bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, and 11 every 4 weeks. Results: No unexpected adverse events occurred from the addition of bortezomib. Efficacy analysis showed median progression free survival (PFS) of 6.2 months (95% CI, 3.7–8.8) with promising PFS rates at 18 months and beyond compared to historical norms (25.0% at 18 and 24 months, 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI, 6.7–31.4) with improved OS rates at 12 months and beyond (87.5% at 12, 50.0% at 24, 34.1% at 36 throughout 60 months) compared to historical norms. Median PFS was 24.7 months (95% CI 8.5–41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9–6.2) in 13 unmethylated patients. The estimated median OS was 61 months in the methylated (the upper bound of 95% CI could not be reached) and 16.4 months (95% CI 11.8–21.0) in the unmethylated patients. Conclusion: Addition of bortezomib to current standard radio-chemotherapy in newly-diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients.

Radiomics in Glioblastoma: Current Status and Challenges Facing Clinical Implementation

“…Even in this setting, the survival is still limited at a median of 20.9 months (4). Given these poor outcomes, there is hope that up-and-coming therapies will show benefit in the randomized setting (5, 6). It will be essential to ascertain which patients can benefit from these therapies, highlighting the need for efficacious tools to offer personalized medicine.…”

Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival

“…15,16 Several clinical studies investigated BTZ as an add-on therapy to low doses of TMZ 17 combined with radiotherapy, 18 bevacizumab, 17 Tamoxifen 19 or HDAC inhibitors, 20 or as monotherapy 21 and all deemed it safe and tolerated. 19,21,22 A recent phase II study reported some survival benefit 23 after prolonged treatment.…”

Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study

“…This is consistent with previous trials using concurrent schedules 22 with intensive and prolonged treatment, as well as with various drug combinations. [33][34][35][36][37][38][39] Our patients scored relatively high on the quality of life EQ-5D-5L questionnaire that was previously validated for the Norwegian population. 40 The ability to perform usual daily activity, ataxia, and changes in strength were the strongest predictors of KPS and this finding is corroborated by a previous study of Norwegian patients after surgery.…”

“…BTZ, bortezomib; IFNγ, interferon γ; IL, interleukin; TMZ, temozolomide; TNF-α, tumor necrosis factor α schedule with monotherapy BTZ, metronomic doses of TMZ, or were conducted in newly diagnosed patients. [33][34][35][36][37] In this phase IB study, we successfully dose escalated TMZ to the target 200 mg/m 2 dose for combination with 1.3 mg/m 2 BTZ and no grade 3 or 4 toxicities were registered in our study. This is consistent with previous trials using concurrent schedules 22 with intensive and prolonged treatment, as well as with various drug combinations.…”