HG-128: BO25041 - A PHASE II OPEN-LABEL, RANDOMIZED, MULTI CENTRE COMPARATIVE STUDY OF BEVACIZUMAB BASED THERAPY IN PAEDIATRIC PATIENTS WITH NEWLY DIAGNOSED SUPRATENTORIAL, INFRATENTORIAL CEREBELLAR, OR PEDUNCULAR HIGH GRADE GLIOMA

The prognosis for paediatric patients with newly diagnosed HGG remains poor; there is an unmet clinical need for new therapies. Bevacizumab is an anti-VEGF-A monoclonal antibody, which has been shown to improve PFS of newly diagnosed glioblastoma in adults and has been approved for use in adult patients with recurrent glioblastoma. The randomized phase II HERBY trial (BO25041; NCT01390948) evaluated the efficacy and safety of bevacizumab in addition to standard of care (RT/TMZ) in paediatric and adolescent patients with newly diagnosed HGG. Study patients were aged ≥3 and <18 years (median 10.5 years). Patients with gliomatosis cerebri, multifocal or metastatic high-grade gliomas were not included in the trial. Randomization was stratified on age, extent of resection, and tumor grade. Online central pathology review was requested to confirm the diagnosis before study entry. Online central radiology review was performed in case pseudoprogression was suspected before treatment discontinuation. Histone status was determined by Sanger sequencing. Hundred and twenty one patients were enrolled from October 2011 to February 2015 in 70 centers distributed in Europe, Australia ans Canada. Fifty percent of patients had a total/near total resection. The two arms did not show a difference in event-free survival (EFS), the primary efficacy endpoint (HR: 1.44 (95% CI: 0.90, 2.30), p-value: 0.13 (log-rank test)) after central review. Similar results were shown when considering the local investigator's evaluations. One year-EFS rate was 38% (95% CI: 26, 51) in the experimental arm vs 48% (95% CI: 35, 61) in the standard arm. The two arms did not show a difference in overall survival (OS), the secondary efficacy endpoint (HR: 1.23 (95% CI: 0.72, 2.09), p-value: 0.46 (log-rank test)). No new safety signals was identified. The incidence of Grade 3-5 AEs was comparable between the two treatment arms (42% vs. 38% in the experimental and standard arms, respectively). Proteinuria was observed in 13.3% of patients in the Bevacizumab arm (compared to 8.1% reported in the whole previous experience with bevacizumab). Twelve patients (20%) had to discontinue bevacizumab because of toxicity. More patients had to discontinue any component of the treatment due to toxicity in the experimental arm compared to the standard arm (22% vs 5%, respectively). In conclusion, these results do not support the use of bevacizumab in the routine management of pediatric HGG as an adjunct to the standard radiochemotherapy with temozolomide.