Patients 1-25 years of age with a histologically confirmed diagnosis of low grade gliomas (LGGs) (WHO grade I-II) that is progressive after prior treatment or high grade gliomas.

A combination of trametinib and everolimus will be administered in two dosing schedules (continuous and intermittent). The first will evaluate a continuous dosing schedule, and the second, an intermittent dosing schedule, given there is evidence of tolerability with potential efficacy at reduced doses.

Mitogen activated protein kinase (MAPK) inhibitors have demonstrated efficacy in the Phase I/II setting for the treatment of pediatric LGG with both clinical and radiographic improvements reported as well as stable disease after completion of therapy.  However, not all patients respond to single agent therapy and many patients develop progression after completion of therapy.  Thus, evaluation of potential combination therapies which may enhance efficacy or prolong disease stabilization are warranted. Mammalian target of rapamycin (mTOR) inhibitors have also shown efficacy in the clinical setting in patients with low grade glioma although disease stabilization is a more common outcome.  Both the MAPK and mTOR pathways also show activation in high grade glioma and thus this combination is also of interest for that patient population where novel therapies remain greatly needed.  Adult data and preclinical data in several tumor models suggest that combination therapy with MEK and mTOR inhibition may improve efficacy and avoid resistance to therapy. Further, both trametinib and everolimus have available safety and dosing data in pediatric patients as well as pediatric friendly dosing formulations which are critical for development in this patient population.  Although initial clinical development of this combination in adults was halted due to toxicity concerns when trying to achieve full doses of both agents, lower or intermittent doses were tolerated and did provide some efficacy in a refractory patient population. Preclinical data supports improved efficacy of the combination in a model of pediatric LGG even at reduced doses.  Conducting an initial phase I dose escalation followed by a dose expansion in patients with low grade glioma at the recommended Phase 2 dose (RP2D) will provide essential data to guide the use of this combination in pediatric patients with glioma and may also support renewed interest in further development in other clinical settings.

• To estimate the recommended Phase 2 dose (RP2D) of trametinib given orally in combination with everolimus in pediatric and young adult patients with glioma
• To describe the toxicity profile and define the dose limiting toxicities (DLTs) of the combination of trametinib and everolimus in pediatric and young adult patients with recurrent low-grade gliomas (LGGs) or high-grade glioma (HGG)
• To characterize the pharmacokinetic profile of trametinib and everolimus when given in combination

Eligibility Criteria:

Subjects must have baseline evaluations performed prior to start of protocol treatment and must meet all inclusion and none of the exclusion criteria. In addition, the patient and/or their legal guardian must be thoroughly informed about all aspects of the study, including the study visit schedule, required evaluations and all regulatory requirements. The written informed consent must be obtained from the patient or their legal guardian prior to enrollment. The following criteria apply to all patients enrolled onto the study unless otherwise specified.

INCLUSION CRITERIA:

• Participants must have histologically confirmed diagnosis of a 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 HGG (WHO grade III-VI)
  • Participants with LGG who have had surgery alone are not eligible.
  • Participants with NF-1 are eligible but must have available tissue per study requirements 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 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 fully recovered from the acute toxic effects of all prior chemotherapy, biologic or targeted therapy, 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 or targeted agents: Participants must have recovered from any acute toxicity potentially related to the agent and received their last dose of the biologic/targeted agent ≥ 7 days prior to study registration. For 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 MEK or mTOR inhibitor but must not have developed severe (grade III or IV) clinically significant toxicity. (Participants who developed grade III or IV toxicity which the treating physician did not feel 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 (>24Gy) or total body irradiation > 8 weeks prior to registration; investigators are reminded to review potentially eligible cases with LGG 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.
• Age: Participants must be > 1 years but < 25 years of age at registration
• Performance Score: Karnofsky ³ 50 for participants > 16 years of age and Lansky ³ 50 for participants £ 16 years of age (See Appendix A). 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.
• Organ function requirements
  • Adequate bone marrow function
  • Adequate renal function
  • Adequate liver function
• 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 < 350mg/dL and triglycerides < 400mg/dl before start of therapy.
• Adequate Neurologic Function Defined as:
  • 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. See Appendix B for a list of recommended non-enzyme inducing anticonvulsants.
• Participants with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration.
• Participants must have adequate cardiac function defined as:
  • QTc interval ≤450 msecs
  • Left Ventricular Ejection Fraction (LVEF) ≥ 50%
• Pulse 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.

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.

EXCLUSION CRITERIA

• Participants who are receiving any other investigational agent for treatment of their tumor
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus or trametinib
• Participants 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)
• Participants receiving any of the following medications within 7 days prior to enrollment (see Appendix B for details). If patients require (re)initiation of these agents after enrollment and prior to start of therapy, they will not be eligible to initiate study therapy:
  • Known strong inducers or inhibitors of CYP3A4/5, including enzyme inducing anti-convulsant drugs (EIACDs), grapefruit, grapefruit hybrids, pomelos, star-fruit, and Seville oranges
  • Substrates of CYP3A4/5 with a narrow therapeutic index
  • 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. Participants should stop using all herbal medications at least 7 days prior to enrollment.
  • Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians’ Desk Reference may also provide this information.  As part of the enrollment/informed consent procedures, the participant 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 participant is considering a new over-the-counter medicine or herbal product.
• Women of childbearing potential who are pregnant or breast-feeding.
  • Female participants of childbearing potential must have a negative serum or urine pregnancy test within 72 hours of enrollment AND within 72 hours 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.
• Human immunodeficiency virus- (HIV) positive participants 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.
• Participants with known Hepatitis B or C are not eligible
• Participants 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
• Participants 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.

Important note: The eligibility criteria listed above are interpreted literally and cannot be waived.

Funding is provided by A Kids Brain Tumor Foundation (aka The Pediatric Low Grade Glioma Foundation) and The LilaBean Foundation.