PNOC021: A Phase I Trial Evaluating the Combination of Trametinib and Everolimus in Pediatric and Young Adult Patients With Recurrent Low-Grade Gliomas and High Grade Gliomas

• Participants must have histologically confirmed diagnosis of an LGG (WHO grade I-II) that is recurrent or progressive after prior treatment (biologic, chemotherapy or radiation therapy) or must have a histologically confirmed diagnosis of a high grade glioma (HGG) (WHO grade III-VI)

‣ Participants with LGG who have had surgery alone are not eligible.

⁃ Participants with neurofibromatosis type 1 (NF-1) are eligible but must have available tissue per study requirements neurofibromatosis (NF) status will be collected

⁃ Participants with spinal cord primaries or disseminated disease are eligible

• For enrollment, snap frozen tissue (150 mg) or 10 unstained 10 um formalin-fixed, paraffin-embedded (FFPE) slides for comprehensive genomic testing or results of prior testing is required

‣ If clinical comprehensive testing has already been performed, the requirement for submission of tissue may be waived after discussion and review of results with study chairs

• Participants must have evaluable disease

• Prior therapy: Participants must have received prior therapy other than surgery and must have fully recovered from the acute toxic effects of all prior chemotherapy, biologics, immunotherapy, or radiotherapy prior to entering this study

‣ Myelosuppressive chemotherapy: Participants must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks if they had received nitrosourea. Biologic agents: Participant must have recovered from any acute toxicity potentially related to the agent and received their last dose of the biologic agent \>= 7 days prior to study registration. For biologic agents that have a prolonged half-life, at least three half-lives must have elapsed prior to registration

∙ Participants may have received prior treatment with a mitogen-activated extracellular signal-regulated kinase (MEK) or Mechanistic target of rapamycin (mTOR) inhibitor but must not have developed severe (grade III or IV) clinically significant toxicity. (Participants who developed grade III or IV toxicity which was not presumed by the treating physician to be medically significant should be discussed with the study chair or co-chair)

⁃ Monoclonal antibody treatment: Participants must have received their last dose at least four weeks prior to study registration

⁃ Radiation: Participants must have: had their last fraction of local irradiation to the primary tumor, craniospinal irradiation (\> 24 Gy) or total body irradiation \> 12 weeks prior to registration; investigators are reminded to review potentially eligible cases to confirm disease progression and avoid confusion with pseudo-progression

⁃ Bone marrow transplant: Participants must be: \>= 6 months since allogeneic bone marrow transplant prior to registration; \>= 3 months since autologous bone marrow/stem cell prior to registration

⁃ Corticosteroids: Participants who are receiving steroids must be on a stable or decreasing dose for at least 1 week prior to registration

• Karnofsky \>= 50 for participants \> 16 years of age and Lansky \>= 50 for participants =\< 16 years of age. Participants 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

• Peripheral absolute neutrophil count (ANC) \>= 1000/mm\^3 (unsupported)

• Platelet count \>= 100,000/mm\^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

• Hemoglobin \>= 8 m/dL (may be supported)

• International normalized ratio (INR) =\< 1.5

• Creatinine clearance or radioisotope growth factor receptor (rGFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows:

‣ 1 to \< 2 years: 0.6 (male), 0.6 (female)

⁃ \>= 16 years: 1.7 (male), 1.4 (female)

• Bilirubin (sum of conjugated + unconjugated) =\< 1.5 x upper limit of normal (ULN) for age

• Serum glutamate pyruvate transaminase (SGPT) alanine aminotransferase (ALT) =\< 3 x ULN

• Serum albumin \>= 2 g/dL

• Sodium, potassium, calcium and magnesium within 1.5 x institutional lower limit of normal (LLN) or ULN

• Participants must have cholesterol level \< 350 mg/dL and triglycerides \< 400 mg/dL before starting therapy. In case one or both of these are exceeded, the participant can only be included after initiation of appropriate lipid lowering medication and documentation of cholesterol \< 350 mg/dL and triglycerides \< 400mg/dl before start of therapy

• Participants with seizure disorder may be enrolled if well controlled. Participants must be on non-enzyme inducing anticonvulsants which are not excluded on study therapy

• Participants with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration

• Corrected QT (QTc) interval =\< 450 msecs

• Left ventricular ejection fraction (LVEF) \>= 50%

• Pulse oximeter (Ox) \> 93% on room air

• Hypertension

‣ Participants 3-17 years of age must have a blood pressure that is =\< 95th percentile for age, height, and gender at the time of registration

⁃ Participants who are \>= 18 years of age must have a blood pressure that is \< 140/90 mm of Hg at the time of registration

• Participants must agree to use adequate contraception: The effects of trametinib and everolimus on the developing human fetus are unknown. For this reason, women of child-bearing potential and males of child fathering potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 4 months after completion of trametinib and everolimus administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate per institutional guidelines