A Phase 2 Study of Dabrafenib with Trametinib after Local Irradiation in Newly-Diagnosed BRAFV600-Mutant High-Grade Glioma (HGG).

Inclusion Criteria: - PRE-ENROLLMENT ELIGIBILITY SCREENING: Patients must be =< 25 years of age at the time of enrollment on APEC14B1 Part A CNS/HGG pre-enrollment eligibility screening. - Note: This required age range applies to the pre-enrollment eligibility screening for all HGG patients. Individual treatment protocols may have different age criteria. - PRE-ENROLLMENT ELIGIBILITY SCREENING: Patient is suspected of having localized newly-diagnosed HGG, excluding metastatic disease. - PRE-ENROLLMENT ELIGIBILITY SCREENING: Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A. - PRE-ENROLLMENT ELIGIBILITY SCREENING: The specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 as soon as possible (ASAP), preferably within 5 calendar days of the procedure. - Please note: See the APEC14B1 Manual of Procedures for a full list of detailed instructions for submitting required materials and for shipping details. - Patients must be >= 3 years and =< 25 years of age at the time of enrollment. - Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1 - Newly diagnosed high-grade glioma with BRAF^V600-mutation - Results for H3 K27M by immunohistochemistry (IHC) or sequencing - Histologically confirmed high-grade glioma (World Health Organization [WHO] grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS). - Patients must have had histologic verification of a high-grade glioma diagnosis. CSF cytology by lumbar puncture must be done if clinically indicated and determined to be safe prior to study enrollment. If cytology proves positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible. - A pre- and post-operative brain MRI with and without contrast and a baseline spine MRI with contrast must be obtained prior to enrollment. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is positive, the patient would be considered to have metastatic disease and would be ineligible. - Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. - Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment). - Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment). - Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment). - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) or - A serum creatinine based on age/gender as follows (within 7 days prior to enrollment): - Age 3 to < 6 years (Male 0.8 mg/dL, Female 0.8 mg/dL) - Age 6 to < 10 years (Male 1 mg/dL, Female 1 mg/dL) - Age 10 to < 13 years (Male 1.2 mg/dL, Female 1.2 mg/dL) - Age 13 to < 16 years (Male 1.5 mg/dL, Female 1.4 mg/dL) - Age >= 16 years (Male 1.7 mg/dL, Female 1.4 mg/dL) - Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and - Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L. - Patients with a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study. - All patients and/or their parents or legal guardians must sign a written informed consent - Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery. Exclusion Criteria: - Patients with intrinsic brainstem or primary spinal cord tumors will be excluded. - Patients with metastatic disease (defined as neuraxis dissemination either by imaging or by cytology) will be excluded. - Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the treatment of HGG other than surgical intervention and/or corticosteroids. - Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor. - Patients with a history of a malignancy with confirmed activating RAS mutation. - History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients. - Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease, or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol. - Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs. - History of hepatitis B virus, or hepatitis C virus infection (patients with laboratory evidence of cleared hepatitis B virus and/or hepatitis C virus may be enrolled). - History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following: - Recent myocardial infarction (within the last 6 months); - Uncontrolled congestive heart failure; - Unstable angina (within last 6 months); - Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular [AV] block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to the first dose of study treatment; - Coronary angioplasty or stenting (within last 6 months); - Intra-cardiac defibrillators; - Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram. - Patients with a history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension). - Patients with presence of interstitial lung disease or pneumonitis. - Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities. - Lactating females are not eligible unless they have agreed not to breastfeed their infants for the duration of the study and for 4 months following discontinuation of study therapy. - Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained. - Sexually active patients of reproductive potential (male or female) are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months following discontinuation of study therapy. Male patients (including those who have had a vasectomy) taking dabrafenib and trametinib combination therapy must use a condom during intercourse while on study and for 16 weeks after stopping treatment, and should not father a child during these periods. Women of childbearing potential should use effective non-hormonal contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib in patients taking combination therapy. Women should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used.