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.