Inclusion Criteria:

• STEP 0: Patients must be >= 12 months and =< 21 years of age at the time of enrollment on Step 0.
• Please note:
• This age range includes pre-screening for all HGG patients. Individual treatment protocols may have different age criteria.
• Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are >= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).
• STEP 0: Patient is suspected of having localized, newly diagnosed HGG, excluding metastatic disease, OR patient has an institutional diagnosis of DIPG
• STEP 0:
• For patients with non-pontine tumors: Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
• For patients with DIPG: Patient and/or their parents or legal guardians have signed informed consent for ACNS1821.
• STEP 0:
• For patients with non-pontine tumors only, the specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably within 5 calendar days of definitive surgery
• STEP 1: Patients must be >= 12 months and =< 21 years of age at the time of enrollment
• STEP 1: Patients must have newly-diagnosed DIPG or HGG (including DMG).
• STEP 1: Stratum DIPG
• Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial T2 weighted image, are eligible. No histologic confirmation is required.
• Patients with pontine tumors that do not meet radiographic criteria for typical DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine cross-sectional area with or without extrapontine extension) are eligible if the tumors are biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, high-grade glioma not otherwise specified [NOS], and/or H3 K27M-mutant) by institutional diagnosis.
• STEP 1: Stratum DMG (with H3 K27M mutation)
• Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
• Note: Patients need not have either measurable or evaluable disease, i.e., DMG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in non-midline structures (e.g., cerebral hemispheres), these patients will be considered part of Stratum DMG.
• STEP 1: Stratum HGG (without H3 K27M mutation)
• Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
• Please note:
• Patients who fall in this category and who are >= 18 years of age are not eligible due to another standard-of-care regimen (radiation/temozolomide) that is available
• Patients need not have either measurable or evaluable disease, i.e., HGG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment
• STEP 1: 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. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• STEP 1: Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to step 1 enrollment)
• STEP 1: Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to step 1 enrollment)
• STEP 1: Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to step 1 enrollment)
• STEP 1: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to step 1 enrollment) or A serum creatinine based on age/gender as follows (within 7 days prior to step 1 enrollment):
• Age / Maximum Serum Creatinine (mg/dL)
• 1 to < 2 years / male: 0.6; female: 0.6
• 2 to < 6 years / male: 0.8; female: 0.8
• 6 to < 10 years / male: 1; female: 1
• 10 to < 13 years / male: 1.2; female: 1.2
• 13 to < 16 years / male: 1.5; female: 1.4
• >= 16 years / male: 1.7; female: 1.4
• STEP 1: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• STEP 1: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
• STEP 1: Serum amylase =< 1.5 x ULN
• STEP 1: Serum lipase =< 1.5 x ULN
• STEP 1: No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination.
• STEP 1: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
• STEP 1: Patients must be enrolled and protocol therapy must begin no later than 31 days after the date of radiographic diagnosis (in the case of non-biopsied DIPG patients only) or definitive surgery, whichever is the later date (Day 0). For patients who have a biopsy followed by resection, the date of resection will be considered the date of definitive diagnostic surgery. If a biopsy only was performed, the biopsy date will be considered the date of definitive diagnostic surgery.

Exclusion Criteria:

• STEP 1: Patients must not have received any prior therapy for their central nervous system (CNS) malignancy except for surgery and steroid medications.
• STEP 1: Patients who are currently receiving another investigational drug are not eligible.
• STEP 1: Patients who are currently receiving other anti-cancer agents are not eligible.
• STEP 1: Patients >=18 years of age who have H3 K27M-wild type HGG.
• STEP 1: Patients who have an uncontrolled infection.
• STEP 1: Patients who have received a prior solid organ transplantation.
• STEP 1: Patients with grade > 1 extrapyramidal movement disorder.
• STEP 1: Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
• STEP 1: Patients with metastatic disease are not eligible; MRI of spine with and without contrast must be performed if metastatic disease is suspected by the treating physician.
• STEP 1: Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the exception of H3 K27M-mutant bithalamic tumors.
• STEP 1: Patients who are not able to receive protocol specified radiation therapy.
• STEP 1:
• 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. It is not known whether selinexor is excreted in human milk.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use two effective methods of birth control (including a medically accepted barrier method of contraception, e.g., male or female condom) for the duration of their study participation and for 90 days after the last dose of selinexor. Abstinence is an acceptable method of birth control.

Inclusion Criteria:

• Patients must be greater than or equal to 3 years and less than 22 years of age at the time of enrollment
• Patients must be newly diagnosed and have:
• Eligibility confirmed by rapid central pathology and molecular screening review on APEC14B1 and via the Molecular Characterization Initiative:
• Classical histologic type (non LC/A) WNT medulloblastoma
• Positive nuclear beta-catenin by immunohistochemistry (IHC)
• Positive for CTNNB1 mutation
• Negative for MYC and MYCN by fluorescence in situ hybridization (FISH)
• Patient must have negative lumbar cerebrospinal fluid (CSF) cytology
• Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF; ideally, CSF should be obtained between day 14 and day 21 to allow for final staging status before enrollment onto the study; patients with positive CSF cytology obtained 0 to 14 days after surgery should have cytology repeated to determine eligibility and final CSF status; patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated; patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively
• Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1; patients must have =< 1.5 cm^2 maximal cross-sectional area of residual tumor; whole brain magnetic resonance imaging (MRI) with and without gadolinium and spine MRI with gadolinium must be performed
• Patients must be enrolled, and protocol therapy must be projected to begin, no later than 36 days after definitive diagnostic surgery (day 0)
• Peripheral absolute neutrophil count (ANC) >= 1000/uL
• Platelet count >= 100,000/uL (transfusion independent)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• 3 to < 6 years of age: maximum (max) serum creatinine 0.8 mg/dL (males and females)
• 6 to < 10 years of age: max serum creatinine 1 mg/dL (males and females)
• 10 to < 13 years of age: max serum creatinine 1.2 mg/dL (males and females)
• 13 to < 16 years of age: max serum creatinine 1.5 md/dL (males) and 1.4 md/dL (females)
• >= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)
• The threshold creatinine values were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC)
• Total or direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3x ULN); for the purpose of this study, the ULN for SGPT is 45 U/L
• Central nervous system function defined as:
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment
• Patients must have receptive and expressive language skills in English, French, or Spanish to complete the QoL and neurocognitive assessments; if a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted
• All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible; patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible
• Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids
• Pregnancy and Breast Feeding
• Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies
• Lactating females are not eligible unless they have agreed not to breastfeed their infants
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
• Patients with a history of moderate to profound intellectual disability (i.e., intelligence quotient [Q)]=< 55) are not eligible for enrollment; PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study. Children with posterior fossa syndrome (also known as cerebellar mutism) are eligible for this study

Inclusion Criteria:

• Patients must be >= 3 years and < 30 years at the time of study enrollment
• Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation of AFP above institutional normal or > 10 ng/mL or human chorionic gonadotropin (hCG) beta > 100 mIU/mL. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers and cytology must be within 21 days prior to enrollment and within 35 days prior to start of protocol therapy [repeat if necessary]. Serum tumor markers, AFP and hCGbeta must be within 7 days prior to enrollment and start of protocol therapy [repeat if necessary]). Basal ganglia or other primary sites are excluded
• Patients with any of the following pathological elements are eligible: endodermal sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant elements listed above are present. Patients with only mature teratoma are excluded. Patients with pure germinoma admixed with mature teratoma are excluded (would be eligible for pure germinoma protocols)
• Patients must have a cranial magnetic resonance imaging (MRI) with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post operative brain MRI with and without gadolinium. The post operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required (within 14 days prior to study enrollment)
• Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Spine MRI with and without gadolinium is recommended (within 14 days prior to study enrollment)
• Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery
• Patients must have CSF tumor markers obtained prior to enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first
• 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 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
• Age: Maximum serum creatinine (mg/dL)
• 3 to < 6 years: 0.8 (male), 0.8 (female)
• 6 to < 10 years: 1 (male), 1 (female)
• 10 to < 13 years: 1.2 (male), 1.2 (female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: male (1.7), 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment)
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• Central nervous system function defined as:
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
• Protocol therapy must begin within 31 calendar days of definitive surgery or clinical diagnosis. 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
• NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:
• English-, Spanish-, or French- speaking
• Note: Patients who speak a language other than English, Spanish, or French will be allowed to participate in ACNS2021 but will not complete the neurocognitive and quality of life assessments
• No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g., Down syndrome, fragile X, William syndrome, intellectual disability). Patients with NF1 will be allowed to participate
• Additional eligibility criteria for the COG Standardized Neuropsychological Battery only: must be at a site that has a psychologist to administer the battery
• Note: If not eligible for the COG Standardized Battery, patients should still complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior Assessment System Third Edition (ABAS-3), and Behavior Assessment System for Children, Third Edition (BASC-3) questionnaires

Exclusion Criteria:

• Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)
• Patients with only mature teratoma and non-elevated markers upon tumor sampling at diagnosis
• Patients who have received any prior tumor-directed therapy for their diagnosis of NGGCT other than surgical intervention and corticosteroids
• Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology or intraoperative evidence of dissemination)
• Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs
• Note: Serum and urine pregnancy tests may be falsely positive due to HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by institutional standards
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Inclusion Criteria:

• Patients must be >= 2 years and =< 21 years at the time of enrollment
• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have neurofibromatosis type 1 (NF1) based on clinical criteria and/or germline genetic testing
• Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGG that has not been treated with any modality other than surgery
• For patients with optic pathway gliomas (OPGs):
• Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms (including visual dysfunction, as defined below) or other exam findings associated with the tumor
• Previously-diagnosed patients with OPG are eligible if they have new or worsening neurologic symptoms (including visual dysfunction, as defined below) or have tumor growth
• For both newly-diagnosed and previously-diagnosed OPG, the patient may be eligible, irrespective of whether there has been tumor growth or other neurological symptoms or worsening, if they meet at least one of the following visual criteria:
• Visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year (by examination or history); OR
• Significant visual dysfunction (defined as VA worse than normal for age by 0.6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes)
• For patients with LGG in other locations (i.e., not OPGs):
• Newly-diagnosed patients with LGG are eligible if there are neurologic symptoms or other exam findings associated with the tumor
• NOTE: Newly-diagnosed patients with LGG without associated neurologic symptoms or exam findings are not eligible
• Previously-diagnosed patients with LGG are eligible if they have new or worsening neurologic symptoms or have tumor growth
• Although not required, if a biopsy/tumor resection is performed, eligible histologies will include all tumors considered LGG or low-grade astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHO classification of central nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma
• Patients must have two-dimensional measurable tumor >= 1 cm^2
• Patients with metastatic disease or multiple independent primary LGGs are allowed on study
• Creatinine clearance or radioisotope glomerular filtration Rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender (within 7 days prior to enrollment) as follows:
• Age; maximum serum creatinine (mg/dL)
• 2 to < 6 years; 0.8 (male) and 0.8 (female)
• 6 to < 10 years; 1 (male) and 1 (female)
• 10 to < 13 years; 1.2 (male) and 1.2 (female)
• 13 to < 16 years; 1.5 (male) and 1.4 (female)
• >= 16 years; 1.7 (male) and 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study regardless of their total and indirect [unconjugated] bilirubin levels as long as their direct [conjugated] bilirubin is < 3.1 mg/dL)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN) = 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (within 7 days prior to enrollment)
• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF result is given as a range of values, then the upper value of the range will be used) by echocardiogram (within 4 weeks prior to enrollment)
• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (within 4 weeks prior to enrollment)
• Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to enrollment)
• Platelets >= 100,000/uL (unsupported) (within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (may be supported) (within 7 days prior to enrollment)
• Patients with a known seizure disorder should be stable and should have not experienced a significant increase in seizure frequency within 2 weeks prior to enrollment
• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for age, height, and gender at the time of enrollment. Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the use of antihypertensive medications).
• Note: Adequate blood pressure can be achieved using medication for the treatment of hypertension
• All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to enrollment
• For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors) and/or spine (depending on the site(s) of primary disease) with and without contrast must be performed within 4 weeks prior to enrollment
• For patients who undergo a surgery on the target tumor (not required), a pre- and post-operative* MRI of the brain (with orbital cuts for optic pathway tumors) or spine (depending on the site(s) of primary disease) with and without contrast must also be performed within 4 weeks prior to enrollment
• The post-operative MRIs should be performed ideally within 48 hours after surgery if possible
• 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
• Patients must have the ability to swallow whole capsules
• Patients must have receptive and expressive language skills in English or Spanish to complete the quality of life (QOL) and neurocognitive assessments
• 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 must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention is permitted
• Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible
• Patients may not be receiving any other investigational agents
• Patients with any serious medical or psychiatric illness/ condition, including substance use disorders likely in the judgement of the investigator to interfere or limit compliance with study requirements/treatment are not eligible
• Patients who, in the opinion of the investigator, are not able to comply with the study procedures are not eligible
• Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants are not eligible
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible
• Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo
• Cardiac conditions:
• Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented
• Symptomatic heart failure
• New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• Ophthalmologic conditions:
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion or retinal detachment
• Patients with uncontrolled glaucoma
• If checking pressure is clinically indicated, patients with intraocular pressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible
• Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN), such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
• Treatments and/or medications patient is receiving that would make her/him ineligible, such as:
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of surgical placement for vascular access or cerebrospinal fluid (CSF) diverting procedures such as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP) shunt.
• Note: Patients must have healed from any prior surgery prior to enrollment
• Patients who have an uncontrolled infection are not eligible

Inclusion Criteria:

• >= 4 and < 18 years at time of study entry
• Patients must weigh 15 kg or greater at time of study entry
• Newly diagnosed or recurrent primary brain tumors that have not received prior cranial radiotherapy
• Planned focal, cranial or craniospinal radiation treatment for a primary brain tumor
• The patient must have receptive and expressive language skills in English, French or Spanish since the neurocognitive function and quality of life (QOL) assessment instruments are available in these languages only
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: 4 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 male; 0.8 female
• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 male; 1 female
• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 male; 1.2 female
• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 male; 1.4 female
• Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 male; 1.4 female
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• The patient must be able to undergo magnetic resonance imaging
• 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:

• Life expectancy of less than 18 months
• Pre-existing conditions:
• Any contraindication or allergy to memantine
• Intractable seizures while on adequate anticonvulsant therapy, defined as more than one seizure per month for the past 2 months or since initiating anticonvulsant therapy
• Co-morbid systemic illnesses, psychiatric conditions, social situations, or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or would limit compliance with the study requirements
• Patients with a motor, visual, or auditory condition that precludes computerized neurocognitive assessments are not eligible to participate
• Patients with any medical condition or taking medications that lead to alterations of urine pH towards the alkaline condition (e.g., renal tubular acidosis, carbonic anhydrase inhibitors, sodium bicarbonate)
• Personal history of prior cranial or craniospinal radiotherapy is not allowed
• Note: Prior anti-cancer therapy including surgery, chemotherapy, targeted agents are allowed as per standard of care clinical treatment guidelines
• Female patients who are pregnant are excluded since fetal toxicities and teratogenic effects have been noted for the study drug. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who do not agree to use an effective contraceptive method for the duration of their study participation

Inclusion Criteria:

• Feasibility phase: patients must be >= 2 years and =< 21 years of age at the time of enrollment
• Efficacy phase: patients must be >= 2 years and =< 25 years of age at the time of enrollment
• All patients > 21 years of age at the time of enrollment must have had initial diagnosis of low-grade glioma by 21 years of age
• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1
• Non-neurofibromatosis type 1 (non-NF1), non-tuberous sclerosis complex (non-TSC) low-grade glioma (LGG) without a BRAFV600E or IDH1 mutation
• Patients must have progressive or recurrent LGG. Note: Biopsy may be at either initial diagnosis or recurrence
• Patients must have measurable disease, defined as having a two-dimensional measurable tumor volume of >= 1 cm^2
• Tumor size will be measured to include both solid and cystic components of the tumor (whether or not tumor is enhancing) + fluid attenuated inversion recovery (FLAIR) signal
• Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (World Health Organization [WHO] grade 1 and II) by the WHO Classification of Tumors of the Central Nervous System - 4th Edition Revised, with the exception of subependymal giant cell astrocytoma
• Patients with metastatic disease or multiple independent primary LGGs are eligible
• Patients must be progressive or recurrent after having been treated with at least one prior tumor-directed therapy before enrollment
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea);
• Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent;
• Radiation therapy (RT): >= 2 weeks (wks) for local palliative RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 wks must have elapsed if other substantial bone marrow (BM) radiation;
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to =< grade 1;
• MEK inhibitor or vinblastine: Must not have received treatment with a MEK inhibitor or vinblastine within 6 months of study enrollment
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^ 2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
• 2 to < 6 years: 0.8 mg/dL (male) 0.8 mg/dL (female)
• 6 to < 10 years: 1 mg/dL (male) 1 mg/dL (female)
• 10 to < 13 years: 1.2 mg/dL (male) 1.2 mg/dL (female)
• 13 to < 16 years: 1.5 mg/dL (male) 1.4 mg/dL (female)
• >= 16 years: 1.7 mg/dL (male) 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study regardless of their total and indirect [unconjugated] bilirubin levels as long as their direct [conjugated] bilirubin is < 3.1 mg/dL)
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment)
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• Albumin >= 2 g/L (within 7 days prior to enrollment)
• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF result is given as a range of values, then the upper value of the range will be used) by echocardiogram (within 4 weeks prior to enrollment)
• Corrected QT interval (QTc interval) =< 450 msec by electrocardiogram (EKG) (within 4 weeks prior to enrollment)
• Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to enrollment)
• Platelets >= 100,000/uL (unsupported) (within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (may be supported) (within 7 days prior to enrollment)
• Patients with a known seizure disorder should be stable and should not have experienced a significant increase in seizure frequency within 2 weeks prior to enrollment
• Stable neurological examination for >= 1 week
• HYPERTENSION:
• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for age, height, and gender at the time of enrollment (with or without the use of anti-hypertensive medications);
• Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the use of anti-hypertensive medications)
• Note for patients of all ages: Adequate blood pressure can be achieved using medication for the treatment of hypertension
• All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to enrollment
• For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors) and/or spine (depending on the site[s] of primary disease) with and without contrast must be performed within 4 weeks prior to enrollment
• Note: If surgical resection or biopsy is performed at the time of progression or recurrence, a post-operative MRI is required
• 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
• Patients must have the ability to swallow whole capsules

Exclusion Criteria:

• Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following exceptions:
• Patients must not have had progressive disease while on therapy with vinblastine or a MEK inhibitor;
• Patients must not have discontinued vinblastine or selumetinib due to toxicity
• Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible
• Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals grade I/II histology
• Patients may not be receiving any other investigational agents
• Patients must not have known hypersensitivity to selumetinib, vinblastine, or similar compounds
• CYP3A4 agents: Patients must not have received fluconazole or drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment
• Patients with any serious medical or psychiatric illness/condition, including substance use disorders or ophthalmological conditions, likely in the judgment of the investigator to interfere or limit compliance with study requirements/treatment
• Patients who, in the opinion of the investigator, are not able to comply with the study procedures are not eligible
• PRE-EXISTING CONDITIONS (CARDIAC):
• Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented;
• Symptomatic heart failure
• New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• PRE-EXISTING CONDITIONS (OPHTHALMOLOGIC CONDITIONS):
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion or retinal detachment
• Patients with uncontrolled glaucoma
• If checking pressure is clinically indicated, patients with intraocular pressure (IOP) > 22 mmHg or upper limit of normal (ULN) adjusted by age are not eligible
• Any multivitamin containing vitamin E must be stopped prior to study enrollment even if it contains less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of a surgical biopsy, placement of a vascular access device or cerebrospinal fluid (CSF) diverting procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt
• Note: Patients must have healed from any prior surgery
• Patients who have an uncontrolled infection are not eligible
• Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible
• Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo
• 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

Inclusion Criteria:

• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patients must be >= 12 months and =< 21 years of age at the time of enrollment on Step 0
• Note: This age range encompasses pre-screening for all HGG patients. Individual treatment protocols may have different age 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): 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 =< 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 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.

• Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma
• Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC
• Measurable disease and/or non-measurable disease
• Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions
• Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment.
• Prior treatment
• Cohort A: No prior therapy received other than surgery
• Cohort B: Prior radiation therapy required (any type of prior radiation is allowed)
• For patients treated with external beam radiation therapy, interstitial brachytherapy or radiosurgery, an interval of >= 3 months must have elapsed from completion of radiation therapy to registration
• Recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity attributed to radiation with exception of alopecia, fatigue
• For patients enrolling on Cohort A or Cohort B:
• For patients treated with surgery, an interval of >= 21 days must have elapsed prior to registration
• No prior treatment with BRAF or MEK inhibitors
• Steroid dosing stable for at least 4 days prior to registration
• Not pregnant and not nursing; for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
• ECOG performance status =< 2
• Comorbid conditions
• No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of red blood) =< 8 weeks prior to registration
• No evidence of intracranial hemorrhage =< 4 weeks prior to registration
• Patients who have experienced thromboembolic event within 6 months prior to registration must be on stable therapeutic anticoagulation for at least 4 weeks prior to registration
• No symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registration
• No current unstable angina or uncontrolled arrhythmia
• No uncontrolled hypertension at time of registration (blood pressure [BP] > 150/95 despite antihypertensive therapy)
• No known history of prolonged QT syndrome
• No known history of ventricular arrhythmia within 6 months of registration
• No known history of uveitis or iritis =< 4 weeks prior to registration
• No known history of or evidence of retinal pathology that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration within 12 months of registration
• No known history of chronic lung disease
• Concomitant medications
• Chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitors is not allowed; patients must discontinue the drug at least 14 days prior to study registration
• Chronic concomitant treatment with CYP1A2 substrate is not allowed; patients must discontinue the drug at least 14 days prior to study registration
• Absolute neutrophil count >= 1500/mm^3
• Platelets >= 100,000/mm^3
• Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45mL/min
• Bilirubin =< 1.5 upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 ULN

Inclusion Criteria:

• STEP 1 REGISTRATION: No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered)
• STEP 1 REGISTRATION: Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Note that tissue for central pathology review and central MGMT assessment must be received by the NYU Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be received by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be conveyed to NRG Oncology within 10 business days of receipt of tissue. Note: In the event of an additional tumor resection(s), tissue must be received within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis
• STEP 1 REGISTRATION: Contrast-enhanced brain MRI after surgery
• STEP 1 REGISTRATION: Willing to use highly effective method of contraception for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 6 months after completing treatment; this inclusion is necessary because the treatment in this study may be significantly teratogenic
• STEP 1 REGISTRATION: The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
• STEP 2 REGISTRATION: Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review
• STEP 2 REGISTRATION: MGMT promoter with methylation confirmed by central pathology review (See Section 10 for details). Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or unmethylated MGMT promoter are excluded.
• STEP 2 REGISTRATION: IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)
• STEP 2 REGISTRATION: History/physical examination within 28 days prior to Step 2 registration
• STEP 2 REGISTRATION: Karnofsky performance status (KPS) >= 70 within 28 days prior to Step 2 registration
• STEP 2 REGISTRATION: Neurologic function assessment within 28 days prior to Step 2 registration
• STEP 2 REGISTRATION: Age 18-70 years Adequate hematologic, renal, and hepatic function within 14 days prior to STEP 2 REGISTRATION defined as follows:
• STEP 2 REGISTRATION: Hemoglobin >= 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) >= 10.0 g/dl is acceptable)
• STEP 2 REGISTRATION: Leukocytes >= 2,000/mm^3
• STEP 2 REGISTRATION: Absolute neutrophil count >= 1,500/mm^3
• STEP 2 REGISTRATION: Platelets >= 100,000/mm^3
• STEP 2 REGISTRATION: Total bilirubin =< 1.5 x institutional/lab upper limit of normal (ULN)
• STEP 2 REGISTRATION: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x ULN
• STEP 2 REGISTRATION: Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• STEP 2 REGISTRATION: Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula
• STEP 2 REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B)
• STEP 2 REGISTRATION: For patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Note: Known positive test for hepatitis C virus ribonucleic acid (HCV ribonucleic acid [RNA]) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy
• STEP 2 REGISTRATION: Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to step 2 registration are eligible for this trial. Testing is not required for entry into protocol
• STEP 2 REGISTRATION: Negative serum or urine pregnancy test (in persons of childbearing potential) within 14 days prior to Step 2 registration
• Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal

Exclusion Criteria:

• STEP 2 REGISTRATION: Prior therapy for tumor, except for resection or prior laser interstitial thermal therapy (LITT). For example, prior chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) as is Gliadel wafer, radiotherapy, radiosurgery, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery
• Note: 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent. Prior laser interstitial thermal therapy (LITT) is allowed.
• STEP 2 REGISTRATION: Current or planned treatment with any other investigational agents for the study cancer
• STEP 2 REGISTRATION: Definitive clinical or radiologic evidence of metastatic disease outside the brain
• STEP 2 REGISTRATION: Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2 years
• STEP 2 REGISTRATION: Prior radiotherapy to the head or neck that would result in overlap of radiation therapy fields
• STEP 2 REGISTRATION: Pregnancy and individuals unwilling to discontinue nursing due to the potential teratogenic effects and potential risk for adverse events in nursing infants
• STEP 2 REGISTRATION: History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or lomustine
• STEP 2 REGISTRATION: History of pulmonary fibrosis
• STEP 2 REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:
• Ongoing or active infection requiring IV antibiotics, IV antiviral, or IV antifungal treatment
• Symptomatic congestive heart failure, defined as New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
• Unstable angina pectoris within 6 months prior to Step 2 registration
• Uncontrolled cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study requirements
• STEP 2 REGISTRATION: No evidence of diffuse leptomeningeal disease that requires whole brain irradiation.