Summary

This phase II trial studies how well the combination of dabrafenib and trametinib works after radiation therapy in children and young adults with high grade glioma who have a genetic change called BRAF V600 mutation. Radiation therapy uses high energy rays to kill tumor cells and reduce the size of tumors. Dabrafenib and trametinib may stop the growth of tumor cells by blocking BRAF and MEK, respectively, which are enzymes that tumor cells need for their growth. Giving dabrafenib with trametinib after radiation therapy may work better than treatments used in the past in patients with newly-diagnosed BRAF V600-mutant high-grade glioma.

Objectives

PRIMARY OBJECTIVE:
I. To estimate the event-free survival (EFS) distribution for newly-diagnosed patients with BRAF^V600-mutant high-grade glioma (HGG) without H3 K27M mutations excluding anaplastic pleomorphic xanthoastrocytoma (aPXA) and anaplastic ganglioglioma (aGG) treated with radiation therapy followed by a maintenance combination of dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) and to compare this EFS to contemporary historical controls.

SECONDARY OBJECTIVES:
I. To describe the overall survival (OS) distribution for newly-diagnosed patients with BRAF^V600-mutant HGG without H3 K27M mutations excluding aPXA and aGG treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib.
II. To describe the EFS and overall survival (OS) distribution for newly-diagnosed patients with BRAF^V600E-mutant aPXA and aGG without H3 K27M mutations treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib.
III. To describe the EFS and overall survival (OS) distribution for newly-diagnosed patients with BRAF^V600E-mutant HGG including aPXA and aGG with H3 K27M mutations treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib.
IV. To define and evaluate the toxicities of combination therapy with dabrafenib and trametinib after radiation therapy in newly-diagnosed patients with HGG.

EXPLORATORY OBJECTIVE:
I. To bank tumor specimens and body fluids (blood, urine and cerebrospinal fluid) for future studies.

OUTLINE:
Patients undergo standardized local radiation therapy (RT) 5 days a week (Monday-Friday) for 6-7 weeks. Four weeks after completion of RT, patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl sulfoxide PO once daily (QD) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a magnetic resonance imaging (MRI) at baseline, on day 1 of cycles 1, 3, 5, 7, 11, 14, 17, 20, and 23 while on treatment, then at time of relapse, every 3 months for year 1, every 4 months for year 3, every 6 months for year 3, and annually for years 4-5. Patients may also undergo lumbar puncture for cerebral spinal fluid (CSF) testing during treatment. Patients also undergo collection of blood on study.

After completion of study treatment, patients are followed up at disease relapse, every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, then annually for years 4-5.

Eligibility

1. 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.
2. PRE-ENROLLMENT ELIGIBILITY SCREENING: Patient is suspected of having localized newly-diagnosed HGG, excluding metastatic disease.
3. PRE-ENROLLMENT ELIGIBILITY SCREENING: Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
4. 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.
5. Patients must be >= 3 years and =< 25 years of age at the time of enrollment.
6. 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).
7. 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.
8. 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.
9. 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.
10. Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment).
11. Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment).
12. Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment).
13. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) or
14. 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)
15. Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and
16. 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.
17. Patients with a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study.
18. All patients and/or their parents or legal guardians must sign a written informed consent
19. 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.

Treatment Sites in Georgia