This phase I trial studies the side effects and best dose of trametinib and everolimus in treating pediatric and young adult patients with low grade gliomas that has 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 grade gliomas compared to trametinib or everolimus alone.
Name: Everolimus
Name: Trametinib
Description: 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).
Measure: Maximum tolerated dose (MTD) of trametinib in combination with everolimus for both continuous and intermittent dosing schedules Time: Up to 28 daysDescription: 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.
Measure: Incidence of adverse events for both continuous and intermittent dosing schedules Time: Up to 30 days after the last day of treatmentDescription: 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.
Measure: Dose limiting toxicities (DLTs) of the combination for both continuous and intermittent dosing schedules Time: Up to 28 daysDescription: 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.
Measure: Recommended phase 2 dose (RP2D) Time: Up to 28 daysDescription: Plasma trametinib and everolimus concentration-time data will be analyzed using a classic non-compartmental approach and/or population-based compartmental methods using non-linear mixed effects modeling. Individual pharmacokinetic parameters of interest after single and repeated doses (i.e., maximum plasma concentration Cmax from 0 to 24h will be calculated from the pharmacokinetic model. Trametinib and everolimus pharmacokinetics after single dose will be compared to trametinib and everolimus pharmacokinetics after repeated doses.
Measure: Maximum Concentration (Cmax) of trametinib and everolimus Time: Up to 5 yearsDescription: Plasma trametinib and everolimus concentration-time data will be analyzed using a classic non-compartmental approach and/or population-based compartmental methods using non-linear mixed effects modeling. Individual pharmacokinetic parameters of interest after single and repeated doses (i.e., area under the curve from 0 to 24h will be calculated from the pharmacokinetic model. Trametinib and everolimus pharmacokinetics after single dose will be compared to trametinib and everolimus pharmacokinetics after repeated doses.
Measure: Area Under the Curve (AUC) of trametinib and everolimus Time: Up to 5 yearsAllocation: N/A
Single Group Assignment
There is one SNP
Trametinib and everolimus pharmacokinetics after single dose will be compared to trametinib and everolimus pharmacokinetics after repeated doses.. Inclusion Criteria: - 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) - Patients who have had surgery alone are not eligible - Patients with neurofibromatosis type 1 (NF1) are eligible but must have available tissue per study requirements NF status will be collected - Patients with spinal cord primaries or disseminated disease are eligible - Patients with a known K27M mutation are considered by current WHO as grade IV and are ineligible for this study - 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 - Patients must have evaluable disease - 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 - 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. --- K27M ---
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - 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 - Patients with known hepatitis B or C are not eligible - 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 - 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 Inclusion Criteria: - 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) - Patients who have had surgery alone are not eligible - Patients with neurofibromatosis type 1 (NF1) are eligible but must have available tissue per study requirements NF status will be collected - Patients with spinal cord primaries or disseminated disease are eligible - Patients with a known K27M mutation are considered by current WHO as grade IV and are ineligible for this study - 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 - Patients must have evaluable disease - 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 - 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. --- K27M ---