Trametinib and Everolimus for the Treatment of Pediatric and Young Adult Patients With Recurrent Low Grade Gliomas (PNOC021)
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|ClinicalTrials.gov Identifier: NCT04485559|
Recruitment Status : Recruiting
First Posted : July 24, 2020
Last Update Posted : September 14, 2021
|Condition or disease||Intervention/treatment||Phase|
|Recurrent World Health Organization (WHO) Grade II Glioma||Drug: Everolimus Drug: Trametinib||Phase 1|
I. To estimate the recommended phase 2 dose (RP2D) of trametinib given orally in combination with everolimus in pediatric and young adult patients with low-grade gliomas (LGGs).
II. 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 LGGs.
III. To characterize the pharmacokinetic profile of trametinib and everolimus when given in combination.
I. To describe the objective response rate and the 2-year progression-free survival (PFS) of LGGs to this therapy in the context of a phase I study.
II. To assess quality of life (QOL) and cognitive measures in pediatric and young adult patients with LGGs.
III. To identify potential predictive biomarkers to targeted therapy in pediatric and young adult patients with LGGs.
IV. To assess endocrine outcomes in pediatric and young adult patients with LGGs.
V. To explore magnetic resonance (MR) quantitative measures of relative cerebral blood volume, permeability and apparent diffusion coefficient within the region of hyperintensity on T2-weighted images as markers of disease response and/or progression in comparison to institutional evaluation of disease response and/or progression and quantitative measures of tumor response as determined by central review (based upon both area and volumetric measures).
OUTLINE: This is a dose-escalation study.
Patients receive a combination of trametinib orally (PO) and everolimus in either of two dosing scheduled (continuous and intermittent). Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, then every 6 months for 5 years from the start of therapy.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||PNOC021: A Phase I Trial Evaluating the Combination of Trametinib and Everolimus in Pediatric and Young Adult Patients With Recurrent Low-Grade Gliomas|
|Actual Study Start Date :||December 9, 2020|
|Estimated Primary Completion Date :||March 1, 2023|
|Estimated Study Completion Date :||March 1, 2023|
Experimental: Treatment (trametinib, everolimus)
Patients receive dosing per their assigned dose level. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
- Maximum tolerated dose (MTD) of trametinib in combination with everolimus for both continuous and intermittent dosing schedules [ Time Frame: Up to 28 days ]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 [ Time Frame: Up to 30 days after the last day of treatment ]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 [ Time Frame: Up to 28 days ]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) [ Time Frame: Up to 28 days ]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.
- Maximum Concentration (Cmax) of trametinib and everolimus [ Time Frame: Up to 5 years ]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.
- Area Under the Curve (AUC) of trametinib and everolimus [ Time Frame: Up to 5 years ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04485559
|Contact: Krystal Pryor||415-502-1600||PNOC021@ucsf.edu|
|Contact: Sabine Mueller, MD, PhD, MASemail@example.com|
|United States, California|
|University of California, San Diego Rady Children's Hospital||Recruiting|
|San Diego, California, United States, 92123|
|Contact: John Crawford, MD, MS firstname.lastname@example.org|
|University of California, San Francisco||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Aubrie Drechsler 415-502-1600 PNOC_Regulatory@ucsf.edu|
|Contact: Sabine Mueller, MD, MPH 877-827-3222 email@example.com|
|Principal Investigator: Sabine Mueller, MD, PhD, MAS|
|United States, District of Columbia|
|Children's National Medical Center||Recruiting|
|Washington, District of Columbia, United States, 20010|
|Contact: Lindsay Kilburn, MD 202-476-5973 firstname.lastname@example.org|
|Principal Investigator: Lindsay Kilburn, MD|
|Sub-Investigator: Roger Packer, MD|
|United States, Illinois|
|Ann & Robert H. Lurie Children's Hospital of Chicago||Recruiting|
|Chicago, Illinois, United States, 60611|
|Contact: Angela Waanders, MD, MPH 312-227-4873 email@example.com|
|United States, Missouri|
|Washington University in St. Louis||Recruiting|
|Saint Louis, Missouri, United States, 63110|
|Contact: Mohamad AbdelBaki, MD 314-454-6018 Mohameda@wustl.edu|
|Contact: Josh Rubin, MD, PhD 314-286-2790 firstname.lastname@example.org|
|Principal Investigator:||Sabine Mueller||University of California, San Francisco|