Phase II trial of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme

Abstract

2000 Background: Bevacizumab (BV) is a humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF). Based on the promising activity of BV in the treatment of recurrent glioblastoma, we are conducting a phase II trial to determine whether up-front treatment of newly diagnosed GBM with BV may be more advantageous than withholding BV until recurrence. In this trial, we evaluate the safety and efficacy of BV combined with standard of care radiation (RT) and temozolomide (TMZ) and radiation (RT) for newly-diagnosed GBM. Methods: This is a phase II trial with a 10-patient pilot and 60-patient expansion phases. Newly-diagnosed GBM patients with no prior treatments are eligible. Primary outcome measure is overall survival; the secondary outcome measure is TTP and 12-month survival. Therapy began between 3–5 weeks of surgery with BV (10 mg/kg every 2 weeks), TMZ (75 mg/m2 daily), and external beam RT (30 x 200 Gy) on the same day. After completion of radiation, patients are then placed on a maintenance phase of BV (10mg/kg every 2 weeks) and TMZ (150–200 mg/m2 5 out of every 28 days) until progression or 24 months in which patients are then maintained on BV only. Results: 70 of 70 projected GBM patients have been enrolled between August 2006 and November 2008 at UCLA and Kaiser Permanente (KP) (Northern and Southern California). All patients had resections to ensure that frozen tissue (>200mg) was collected. The median age was 57.4 years (range 31–75). MGMT methylation analysis has been performed on 52/70 patients with ∼40% showing methylation. Severe adverse events to date have included ischemic stroke, pulmonary embolus, wound breakdown, GI bleeding/perforation, and renal dysfunction. Isolated cases of retinal detachment and optic neuropathy have also been observed. As of now, 35/70 patients are off study (26 due to progression and 9 due to SAE). Preliminary TTP by Kaplan-Meier analysis is promising compared to that of a UCLA/KP control group of patients that received the conventional RT/TMZ regimen. Conclusions: Addition of BV to the standard regimen of TMZ and RT for newly-diagnosed GBM is well-tolerated and shows promising efficacy. More detailed analysis of safety and efficacy will presented. [Table: see text]

Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

“…No intracerebral hemorrhage or treatment-related deaths occurred during the study. Several ongoing clinical trials have also recently reported interim data on the use of bevacizumab with radiotherapy and either temozolomide or irinotecan in patients with previously untreated glioblastoma [ 80 - 86 ]. In two of the trials with longer follow-up, the addition of bevacizumab with or without irinotecan to standard radiotherapy and temozolomide was shown to provide significant benefit in PFS relative to historic controls [ 80 , 82 ].…”

“…Several ongoing clinical trials have also recently reported interim data on the use of bevacizumab with radiotherapy and either temozolomide or irinotecan in patients with previously untreated glioblastoma [ 80 - 86 ]. In two of the trials with longer follow-up, the addition of bevacizumab with or without irinotecan to standard radiotherapy and temozolomide was shown to provide significant benefit in PFS relative to historic controls [ 80 , 82 ]. In one trial having a minimum follow-up of 18 months, the regimen incorporating bevacizumab and irinotecan was associated with a median PFS that was approximately double that seen with standard therapy in patients with newly diagnosed glioblastoma (14 vs 6.9 months, respectively) [ 82 ].…”

“…In one trial having a minimum follow-up of 18 months, the regimen incorporating bevacizumab and irinotecan was associated with a median PFS that was approximately double that seen with standard therapy in patients with newly diagnosed glioblastoma (14 vs 6.9 months, respectively) [ 82 ]. In both trials, the incorporation of bevacizumab into standard frontline regimens was considered to be tolerable [ 80 , 82 ]. Large phase III studies evaluating bevacizumab-containing regimens in patients with newly diagnosed glioblastoma have recently begun enrolling patients, including a global-based study (AVAglio [NCT00943826]) [ 87 ] and a US-based study (RTOG-0825 [NCT00884741], which is sponsored by the Radiation Therapy Oncology Group).…”

Grand rounds at the National Institutes of Health: HDAC inhibitors as radiation modifiers, from bench to clinic

“…Bevacizumab, in combination with other therapies, is also under investigation as front line therapy for GBM. A Phase II trial combining bevacizumab with standard of care radiation and temozolomide has thus far demonstrated encouraging clinical responses [ 18 ]. Moreover, Phase III randomized clinical trials are currently underway to assess the efficacy of bevacizumab with current standard of care front line therapy for GBM (NCT00884741 and NCT00943826) [ 19 ].…”

Critical appraisal of temozolomide formulations in the treatment of primary brain tumors: patient considerations

“…Recently a phase II trial of bevacizumab (10 mg/kg every 2 weeks) in combination with TMZ (75 mg/m 2 /day) and RT in 70 patients with newly diagnosed GBM has been presented. 52 After completion of RT patients are then placed on a maintenance phase of bevacizumab (10 mg/kg every 2 weeks) and TMZ (150–200 mg/m 2 /day 5 days out of every 28) until progression or 24 months. There were grade 3–4 hematological and nonhematological toxicity ( Table 2 ).…”