Clinical Benefit of Using Molecular Profiling to Determine an Individualized Treatment Plan for Patients With High Grade Glioma

Inclusion Criteria: * Patients with newly diagnosed HGG (including midline HGG but excluding DIPG), who undergo tissue collection as part of standard of care. HGG is defined as either World Health Organization (WHO) grade III or IV, or testing positive for H3K27M mutation. Patients with disseminated disease are not eligible, and MRI of the spine must be performed if disseminated disease is suspected by the treating physician. Primary spinal cord tumors are eligible. * Enrollment within 3 weeks of the start of radiation therapy. * Start of radiation therapy within 6 weeks from initial tissue diagnosis. * Age ≤ 21 years * Karnofsky score ≥ 50 for patients ≥ 16 years of age and Lansky score ≥ 50 for patients ≤15 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 * Adequate tissue for molecular profiling (see Section 8 of the protocol for full details) * The effects of the current treatment paradigm on the developing human fetus are unknown. For this reason, females of child-bearing potential and males must agree to use adequate contraception: hormonal or barrier method of birth control; abstinence prior to study entry and for the duration of study participation, and 30 days after completion of study drug administration. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 30 days after completion of study drug administration. * Adequate neurologic function defined as: Patients with seizure disorder may be enrolled if seizures are well controlled. * Ability by patient or parent/legal guardian to understand a written informed consent document, and the willingness to sign it. Exclusion Criteria: * Patients who are currently enrolled on another therapeutic clinical trial. Individual cases should be discussed with the study chair. * Patients who are currently taking any anti-cancer directed therapy. Steroids are not considered anti-cancer therapy. The use of temozolomide during radiation therapy is allowed at standard dosing (maximum 75 to 90 mg/m\^2 daily for a total of 42 days). Any other schedule(s) need to be discussed with the study chair. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated). * Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy. Telemedicine visits are acceptable.