This phase I trial studies the side effects and best dose of trametinib and everolimus in treating pediatric and young adult patients with gliomas that have come back (recurrent). Trametinib acts by targeting a protein in cells called MEK and disrupting tumor growth. Everolimus is a drug that may block another pathway in tumor cells that can help tumors grow. Giving trametinib and everolimus may work better to treat low and high-grade gliomas compared to trametinib or everolimus alone.
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
Participants that have received prior therapy with a MEK inhibitor in combination with an mTOR inhibitor
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)
Single group
Everolimus
DrugGiven PO
Trametinib
DrugGiven PO
Maximum tolerated dose (MTD) of trametinib in combination with everolimus for both continuous and intermittent dosing schedules
We will employ the Bayesian optimal interval (BOIN) design to find the MTD for both continuous and intermittent dosing schedules. The BOIN design is implemented in a simple way similar to the traditional 3+3 design, but is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model-based designs, such as the continual reassessment method (CRM).
Incidence of adverse events for both continuous and intermittent dosing schedules
Toxicities will be graded based on Common Terminology Criteria for Adverse Events (CTCAE) V5 .0 and followed for 30 days after last treatment or until resolution or returned to baseline values.
Dose limiting toxicities (DLTs) of the combination for both continuous and intermittent dosing schedules
Any treatment related adverse event during the first cycle of therapy that leads to a dose reduction or results in delay of treatment \> 7 days or which results in the permanent cessation of therapy will be considered dose limiting.
Recommended phase 2 dose (RP2D)
The RP2D rate is selected based on isotonic regression as specified in Liu and Yuan (2015). This computation is implemented by the shiny app "BOIN" available at http://www.trialdesign.org. Specifically, select as the RP2D the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.
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University of California, San Francisco
Lead sponsor
Novartis Pharmaceuticals
Collaborator
Pediatric Brain Tumor Foundation
Collaborator
The Lilabean Foundation for Pediatric Brain Cancer Research
Collaborator
