Trametinib and Everolimus for the Treatment of Pediatric and Young Adult Patients With Recurrent Low Grade Gliomas (PNOC021)

1. Subjects must have histologically confirmed diagnosis of a LGG (World Health Organization [WHO] grade I-II) that is recurrent or progressive after prior treatment (biologic, chemotherapy or radiation therapy)
   1. Patients who have had surgery alone are not eligible
   2. Patients with neurofibromatosis type 1 (NF1) are eligible but must have available tissue per study requirements NF status will be collected
   3. Patients with spinal cord primaries or disseminated disease are eligible
   4. Patients with a known K27M mutation are considered by current WHO as grade IV and are ineligible for this study
2. 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
   1. 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
3. Patients must have evaluable disease
4. Prior therapy: Patients 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
   1. Myelosuppressive chemotherapy: Patients 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: Patient 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
      1. Patients may have received prior treatment with a MEK or mTOR inhibitor but must not have developed severe (grade III or IV) clinically significant toxicity. (Patients 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)
   2. Monoclonal antibody treatment: Patients must have received their last dose at least four weeks prior to study registration
   3. Radiation: Patients 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
   4. Bone marrow transplant: Patients must be: >= 6 months since allogeneic bone marrow transplant prior to registration; >= 3 months since autologous bone marrow/stem cell prior to registration
   5. Corticosteroids: Patients who are receiving steroids must be on a stable or decreasing dose for at least 1 week prior to registration
5. Karnofsky >= 50 for subjects > 16 years of age and Lansky >= 50 for subjects =< 16 years of age. Subjects 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
6. Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (unsupported)
7. Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
8. Hemoglobin >= 8 m/dL (may be supported)
9. International normalized ratio (INR) =< 1.5
10. 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. 3 to < 6 years: 0.8 (male), 0.8 (female)
    2. 6 to < 10 years: 1 (male), 1 (female)
    3. 10 to < 13 years: 1.2 (male), 1.2 (female)
    4. 13 to < 16 years: 1.5 (male), 1.4 (female)
    5. >= 16 years: 1.7 (male), 1.4 (female)
11. Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
12. Serum glutamate pyruvate transaminase (SGPT) alanine aminotransferase (ALT) =< 3 x ULN
13. Serum albumin >= 2 g/dL
14. Sodium, potassium, calcium and magnesium within 1.5 x institutional lower limit of normal (LLN) or ULN
15. Patients 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 patient 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
16. Subjects with seizure disorder may be enrolled if well controlled. Patients must be on non-enzyme inducing anticonvulsants which are not excluded on study therapy
17. Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration
18. Corrected QT (QTc) interval =< 450 msecs
19. Left ventricular ejection fraction (LVEF) >= 50%
20. Pulse oximeter (Ox) > 93% on room air
21. Hypertension
    1. Patients 3-17 years of age must have a blood pressure that is =< 95th percentile for age, height, and gender at the time of registration
    2. Patients who are >= 18 years of age must have a blood pressure that is < 140/90 mm of Hg at the time of registration
22. Patients 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
23. A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate per institutional guidelines

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

1. Subjects who are receiving any other investigational agent for treatment of their tumor
2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus or trametinib
3. Patients without available tissue from prior surgery. (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)
4. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to enrollment
   1. Known strong inducers or inhibitors of CYP3A4/5, including enzyme inducing anti-convulsant drugs (EIACDs), grapefruit, grapefruit hybrids, pomelos, starfruit, and Seville oranges
   2. Substrates of CYP3A4/5 with a narrow therapeutic index
   3. Herbal preparations/medications (except for vitamins) including, but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. Patients should stop using all herbal medications at least 7 days prior to enrollment
   4. As part of the enrollment/informed consent procedures, the subject and/or legal parent or guardian will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the subject is considering a new over-the-counter medicine or herbal product
5. Women of childbearing potential who are pregnant or breast-feeding
   1. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours of enrollment AND prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
6. Human immunodeficiency virus (HIV) positive patients will be ineligible if HIV therapy regimen has not been stable for at least 4 weeks or there is intent to change the regimen within 8 weeks following enrollment, or if they are severely immunocompromised
7. Patients with known hepatitis B or C are not eligible
8. Patients with any clinically significant unrelated systemic illness (serious infectious or significant cardiac, pulmonary, hepatic or other organ dysfunction), which in the opinion of the investigator would interfere with the study procedures or results
9. Patients with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class II or above are excluded

For the most up-to-date list of criteria, please visit clinicaltrials.gov.