A Phase 2 Study of Dabrafenib (NSC# 763760) with Trametinib (NSC# 763093) after Local Irradiation in Newly-Diagnosed BRAFV600 -Mutant High-Grade Glioma (HGG) (IND# 145355)

A Phase 2 Study of Dabrafenib (NSC# 763760) with Trametinib (NSC# 763093) after Local Irradiation in Newly-Diagnosed BRAFV600 -Mutant High-Grade Glioma (HGG) (IND# 145355) Pediatric high-grade gliomas (HGGs) are a heterogeneous group of brain tumors that continue to have a poor overall survival. In recent years, there have been considerable advances in defining subsets of pediatric HGG by genotyping and expression profiling. Approximately 10% of tumors will have evidence of BRAFV600 mutations that constitutively activate the mitogen-activated protein kinase (MAPK) pathway. Combination therapy with MAPK pathway inhibitors, dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor), have demonstrated clinical success in adult patients with BRAFV600 mutant malignancies. This study will investigate if a combination of these two MAPK pathway inhibitors (dabrafenib and trametinib) will improve event-free survival (EFS) in children with newly-diagnosed BRAFV600-mutant HGG. Patients will undergo a maximal safe surgical resection and tumor tissue will be sent for rapid central screening coordinated by the Biopathology Center, including histopathologic review and molecular sequencing to confirm the presence of a BRAFV600 mutation. Eligible patients who consent to this trial will receive standardized local irradiation (target dose of 54?59.4 Gy) followed by maintenance cycles of dabrafenib and trametinib. Patients will receive up to 24 cycles of maintenance therapy in the absence of disease progression or unacceptable toxicity.