Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma

Inclusion Criteria:

• PRE-ENROLLMENT ELIGIBILITY SCREENING: Patients must be =< 25 years of age at thetime of enrollment on APEC14B1 Part A CNS/HGG pre-enrollment eligibility screening.

• Note: This required age range applies to the pre-enrollment eligibilityscreening for all HGG patients. Individual treatment protocols may havedifferent age criteria.

• PRE-ENROLLMENT ELIGIBILITY SCREENING: Patient is suspected of having localizednewly-diagnosed HGG, excluding metastatic disease.

• PRE-ENROLLMENT ELIGIBILITY SCREENING: Patient and/or their parents or legalguardians have signed informed consent for eligibility screening on APEC14B1 Part A.

• PRE-ENROLLMENT ELIGIBILITY SCREENING: The specimens obtained at the time ofdiagnostic 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 detailedinstructions 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 MolecularScreening 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. CSFcytology by lumbar puncture must be done if clinically indicated and determined tobe safe prior to study enrollment. If cytology proves positive, the patient would beconsidered to have metastatic disease and would, therefore, be ineligible.

• A pre- and post-operative brain MRI with and without contrast and a baseline spineMRI with contrast must be obtained prior to enrollment. The requirement for apost-operative MRI is waived for patients who undergo biopsy only. If the spine MRIis positive, the patient would be considered to have metastatic disease and would beineligible.

• Patients must have a performance status corresponding to Eastern CooperativeOncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years ofage and Lansky for patients =< 16 years of age.

• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior toenrollment).

• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior toenrollment).

• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7days prior to enrollment).

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 (within 7 days prior to enrollment) or

• A serum creatinine based on age/sex 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)

• The threshold creatinine values in this table were derived from theSchwartz formula for estimating GFR utilizing child length and staturedata published by the Centers for Disease Control and Prevention (CDC).

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior toenrollment), and

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN forSGPT is 45 U/L.

• Patients with a seizure disorder may be enrolled if their seizures are wellcontrolled while on non-enzyme inducing anticonvulsants permitted on this study.

• Patients must be enrolled and protocol therapy must be projected to begin no laterthan 31 days after definitive surgery (day 0). If a biopsy only was performed, thebiopsy date will be considered the date of definitive surgery. For patients who havea biopsy or incomplete resection at diagnosis followed by additional surgery, thedate of the last resection will be considered the date of definitive surgery.

• All patients and/or their parents or legal guardians must sign a written informedconsent.

Exclusion Criteria:

• Patients with intrinsic brainstem or primary spinal cord tumors will be excluded.

• Patients with metastatic disease (defined as neuraxis dissemination either byimaging or by cytology) will be excluded.

• Patients must not have received any prior tumor-directed therapy includingchemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for thetreatment of HGG other than surgical intervention and/or corticosteroids.

• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or anotherMEK 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 orbiologic composition to dabrafenib, trametinib, and their excipients.

• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liverdisease, or uncontrolled infection), psychological, familial, sociological, orgeographical conditions that do not permit compliance with the protocol; orunwillingness or inability to follow the procedures required in the protocol.

• Presence of active gastrointestinal (GI) disease or other condition (e.g., smallbowel or large bowel resection) that will interfere significantly with theabsorption of drugs.

• History of hepatitis B virus, or hepatitis C virus infection (patients withlaboratory evidence of cleared hepatitis B virus and/or hepatitis C virus may beenrolled).

• History or current diagnosis of cardiac disease indicating significant risk ofsafety for patients participating in the study such as uncontrolled or significantcardiac 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 orthird degree atrioventricular [AV] block without a pacemaker) except sinusarrhythmia 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) orcentral 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 availableinformation regarding human fetal or teratogenic toxicities.

• Lactating females are not eligible unless they have agreed not to breastfeed theirinfants for the duration of the study and for 4 months following discontinuation ofstudy therapy.

• Female patients of childbearing potential are not eligible unless a negativepregnancy test result has been obtained.

• Sexually active patients of reproductive potential (male or female) are not eligibleunless they have agreed to use an effective contraceptive method for the duration oftheir study participation and for 4 months following discontinuation of studytherapy. Male patients (including those who have had a vasectomy) taking dabrafeniband trametinib combination therapy must use a condom during intercourse while onstudy and for 16 weeks after stopping treatment, and should not father a childduring these periods. Women of childbearing potential should use effectivenon-hormonal contraception during therapy and for 4 weeks following discontinuationof dabrafenib and at least 4 months following the last dose of trametinib inpatients taking combination therapy. Women should be advised that dabrafenib maydecrease the efficacy of hormonal contraceptives and an alternate method ofcontraception, such as barrier methods, should be used.