PRIMARY OBJECTIVE:
I. To estimate the event-free survival (EFS) distribution for newly-diagnosed patients with
BRAFV600-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
BRAFV600-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 BRAFV600E-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 BRAFV600E-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.
Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or
unacceptable toxicity.
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.
Inclusion Criteria:
- PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient is suspected of having
localized newly-diagnosed HGG, excluding metastatic disease
- PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient and/or their parents or legal
guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
- PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Specimens obtained at the time of
diagnostic biopsy must be submitted through APEC14B1 as soon as possible (ASAP),
preferably within 13 calendar days of the procedure.
- Patients must be >= 3 years and =< 21 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 BRAFV600-mutation
- Positive or negative results for H3 K27M by immunohistochemistry (IHC)
- 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.
Cerebrospinal fluid (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 magnetic resonance imaging (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.
- 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.
- All patients and/or their parents or legal guardians must sign a written informed
consent.
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
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.
