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Recurrent World Health Organization (WHO) Grade II GliomaPhase 1NCT04485559

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

A Phase 1 study testing Everolimus and Trametinib in people with Recurrent World Health Organization (WHO) Grade II Glioma and Low-grade Glioma, run by University of California, San Francisco at 17 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 1 year to 25 years
What is being tested?
Everolimus and Trametinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
50 participants
Where
17 sitesUnited States
Study dates
9 Dec 2020to 31 Dec 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 25 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
  • 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
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  • Participants must have evaluable disease
  • Prior therapy: Participants 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: 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 agents: Participant 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
  • Participants may have received prior treatment with a mitogen-activated extracellular signal-regulated kinase (MEK) or Mechanistic target of rapamycin (mTOR) inhibitor but must not have developed severe (grade III or IV) clinically significant toxicity. (Participants 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)
  • 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 (> 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
  • 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
  • Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants =< 16 years of age. 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
  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (unsupported)
  • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Hemoglobin >= 8 m/dL (may be supported)
  • International normalized ratio (INR) =< 1.5
  • 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 to < 2 years: 0.6 (male), 0.6 (female)
  • 2 to < 6 years: 0.8 (male), 0.8 (female)
  • 6 to < 10 years: 1 (male), 1 (female)
  • 10 to < 13 years: 1.2 (male), 1.2 (female)
  • 13 to < 16 years: 1.5 (male), 1.4 (female)
  • >= 16 years: 1.7 (male), 1.4 (female)
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) alanine aminotransferase (ALT) =< 3 x ULN
  • Serum albumin >= 2 g/dL
  • Sodium, potassium, calcium and magnesium within 1.5 x institutional lower limit of normal (LLN) or ULN
  • 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 < 350 mg/dL and triglycerides < 400mg/dl before start of therapy
  • 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
  • Participants with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration
  • Corrected QT (QTc) interval =< 450 msecs
  • Left ventricular ejection fraction (LVEF) >= 50%
  • Pulse oximeter (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
  • Participants must also enroll in a separate observational study to examine the effects of cancer therapies on them, if it is open to accrual at their site of enrollment
  • 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

Who cannot join

  • 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)
  • Participant is receiving any of the following medications within 7 days prior to enrollment (If participants 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, starfruit, and Seville oranges
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  • 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
  • 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

Trial locations and contacts

17 sites in 1 country. Contact the study team or a site near you to ask about taking part.

PNOC Operations contact

415-502-1600

PNOC021@ucsf.edu

Sabine Mueller, MD, PhD, MAS contact

877-827-3222

cancertrials@ucsf.edu

17 sites in 1 country

United States17 sites, 15 recruiting

  • John Hopkins University

    Baltimore, Maryland, 21287

    Kenneth Cohen, MD, MBA, (410) 614-5055, kcohen@jhmi.edu

    Eric Raabe, MD, PhD, 410-502-5157, eraabe2@jhmi.edu

    Recruiting

  • University of Alabama at Birmingham, Children's of Alabama

    Birmingham, Alabama, 35233

    Girish Dhall, MD, 205-638-9285, gdhall@peds.uab.edu

    Gregory Friedman, MD, gfriedman@peds.uab.edu

    Recruiting

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

    Withdrawn

  • Ann & Robert H. Lurie Children's Hospital of Chicago

    Chicago, Illinois, 60611

    Angela Waanders, MD, MPH, (312) 227-4873, awaanders@luriechildrens.org

    Recruiting

  • University Of Texas Southwestern Medical Center

    Dallas, Texas, 75235

    Laura Klesse, MD, 214-456-2382, laura.klesse@utsouthwestern.edu

    Recruiting

  • University of Florida

    Gainesville, Florida, 32610-0265

    Elias Sayour, MD, PhD, 352-294-8347

    Recruiting

  • Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center

    Hackensack, New Jersey, 07601

    Derek Hanson, MD, 551-996-5437, Derek.Hanson@HMHN.org

    Katharine Offer, MD, Katharine.Offer@HMHN.org

    Recruiting

  • Riley Hospital for Children

    Indianapolis, Indiana, 46202

    Scott Coven, DO, MPH, 317-944-8784, scoven@iu.edu

    Scott Coven, DO, MPH

    Recruiting

  • Children's Hospital Los Angeles

    Los Angeles, California, 90027

    Ashley Margol, MD, (323) 361- 8147, amargol@chla.usc.edu

    Ashley Margol, MD

    Recruiting

  • Children's Minnesota

    Minneapolis, Minnesota, 55404

    Anne Bendel, MD, (612) 626-2778, anne.bendel@childrensmn.org

    Anne Bendel, MD

    Recruiting

  • New York University

    New York, New York, 10016

    Sharon Gardner, MD, (212) 263-9913, Sharon.Gardner@nyulangone.org

    Recruiting

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

    Cassie Kline, MD, MAS, (267) 426- 5026, klinec@email.chop.edu

    Cassie Kline, MD, MAS

    Recruiting

  • Doernbecher Children's Hospital Oregon Health & Science University

    Portland, Oregon, 97239

    Active, not recruiting

  • University of California, San Diego Rady Children's Hospital

    San Diego, California, 92123

    Jennifer Elster, MD, jelster@rchsd.org

    Recruiting

  • University of California, San Francisco

    San Francisco, California, 94143

    PNOC Operations, 415-502-1600, PNOC021@ucsf.edu

    Sabine Mueller, MD, MPH, 877-827-3222, cancertrials@ucsf.edu

    Recruiting

  • Washington University in St. Louis

    St Louis, Missouri, 63110

    Mohamad AbdelBaki, MD, (314) 454-6018, Mohameda@wustl.edu

    Josh Rubin, MD, PhD, 314-286-2790, rubin_j@wustl.edu

    Recruiting

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

    Lindsay Kilburn, MD, 202-476-5973, lkilburn@cnmc.org

    Lindsay Kilburn, MD

    Recruiting

Other trials in United States

About this study

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 and High-Grade Gliomas

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To estimate the recommended phase 2 dose (RP2D) of trametinib given orally in combination with everolimus in pediatric and young adult patients with gliomas.

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 low-grade gliomas (LGG) or high-grade glioma (HGG).

III. To characterize the pharmacokinetic profile of trametinib and everolimus when given in combination.

EXPLORATORY OBJECTIVES:

  1. 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 LGG or HGG.

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.

  1. 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.

Being tested
Everolimus, Trametinib
Keywords
Mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), MAPK, PI3K
Medical subject headings
Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EverolimusDrug

    Also called 42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001

    Given PO

  • TrametinibDrug

    Also called GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

    Given PO

Study groups in NCT04485559
Study groupRoleWhat they receive
Treatment (trametinib, everolimus)ExperimentalPatients 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.
Receives: Drug: Everolimus; Drug: Trametinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: Up to 28 days

  2. 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.

    Measured: Up to 30 days after the last day of treatment

  3. 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.

    Measured: Up to 28 days

  4. 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.

    Measured: Up to 28 days

  5. Maximum Concentration (Cmax) of trametinib and everolimus

    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.

    Measured: Up to 5 years

  6. Area Under the Curve (AUC) of trametinib and everolimus

    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.

    Measured: Up to 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Jul 2020
  2. Study start9 Dec 2020
  3. Primary completion31 Dec 2027 (estimated)
  4. Study completion31 Dec 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
50 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04485559
Sponsor's protocol ID
190819
Other IDs
NCI-2020-04097
Status last verified
Aug 2026
First submitted
13 Jul 2020
Last updated
18 Aug 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Everolimus and Trametinib in people with Recurrent World Health Organization (WHO) Grade II Glioma and Low-grade Glioma, run by University of California, San Francisco at 17 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 42 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 18 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact PNOC Operations (415-502-1600, PNOC021@ucsf.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (MTD) of trametinib in combination with everolimus for both continuous and intermittent dosing schedules (time frame: Up to 28 days). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04485559.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Aug 2026.

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