Recruiting

Phase 1

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

Sponsor:

UCLA

Code:

NCT04485559

Conditions

Recurrent World Health Organization (WHO) Grade II Glioma

Low-grade Glioma

High-Grade Glioma (HGG)

Eligibility Criteria

Sex: All

Age: 1 - 25

Healthy Volunteers: Not accepted

Interventions

Everolimus

Trametinib

Study Details

Brief 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. 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.

Conditions

Recurrent World Health Organization (WHO) Grade II Glioma

Low-grade Glioma

High-Grade Glioma (HGG)

Study ID

NCT04485559

Start date

Dec 9, 2020

Status verified date

Aug, 2026

Completion date

Dec 31, 2027

Anticipated

Primary completion date

Dec 31, 2027

Anticipated

Eligibility Criteria

Sex: All

Age: 1 - 25

Healthy Volunteers: Not accepted

Inclusion Criteria:

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
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

Exclusion Criteria:

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
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

Study Design

Enrollment

50 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

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.

Interventions

Everolimus

Given PO

Trametinib

Given PO

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 ]
Incidence of adverse events for both continuous and intermittent dosing schedules [ Time Frame: Up to 30 days after the last day of treatment ]
Dose limiting toxicities (DLTs) of the combination for both continuous and intermittent dosing schedules [ Time Frame: Up to 28 days ]
Recommended phase 2 dose (RP2D) [ Time Frame: Up to 28 days ]
Maximum Concentration (Cmax) of trametinib and everolimus [ Time Frame: Up to 5 years ]
Area Under the Curve (AUC) of trametinib and everolimus [ Time Frame: Up to 5 years ]

Central Contacts and Locations

Central contacts

PNOC Operations

415-502-1600 PNOC021@ucsf.edu

Sabine Mueller, MD, PhD, MAS

877-827-3222 cancertrials@ucsf.edu

Locations

University of Alabama at Birmingham, Children's of Alabama

Recruiting

Birmingham, Alabama, United States, 35233

Contacts

Girish Dhall, MD

205-638-9285 gdhall@peds.uab.edu

Gregory Friedman, MD

gfriedman@peds.uab.edu

Children's Hospital Los Angeles

Recruiting

Los Angeles, California, United States, 90027

Contacts

Ashley Margol, MD

(323) 361- 8147 amargol@chla.usc.edu

Principal Investigator:

Ashley Margol, MD

University of California, San Diego Rady Children's Hospital

Recruiting

San Diego, California, United States, 92123

Contacts

Jennifer Elster, MD

jelster@rchsd.org

University of California, San Francisco

Recruiting

San Francisco, California, United States, 94143

Contacts

PNOC Operations

415-502-1600 PNOC021@ucsf.edu

Sabine Mueller, MD, MPH

877-827-3222 cancertrials@ucsf.edu

Principal Investigator:

Sabine Mueller, MD, PhD, MAS

Children's National Medical Center

Recruiting

Washington D.C., District of Columbia, United States, 20010

Contacts

Lindsay Kilburn, MD

202-476-5973 lkilburn@cnmc.org

Principal Investigator:

Lindsay Kilburn, MD

University of Florida

Recruiting

Gainesville, Florida, United States, 32610-0265

Contacts

Elias Sayour, MD, PhD

352-294-8347

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

Recruiting

Chicago, Illinois, United States, 60611

Contacts

Angela Waanders, MD, MPH

(312) 227-4873 awaanders@luriechildrens.org

Riley Hospital for Children

Recruiting

Indianapolis, Indiana, United States, 46202

Contacts

Scott Coven, DO, MPH

317-944-8784 scoven@iu.edu

Principal Investigator:

Scott Coven, DO, MPH

John Hopkins University

Recruiting

Baltimore, Maryland, United States, 21287

Contacts

Kenneth Cohen, MD, MBA

(410) 614-5055 kcohen@jhmi.edu

Eric Raabe, MD, PhD

410-502-5157 eraabe2@jhmi.edu

Principal Investigator:

Kenneth Cohen, MD, MBA

Children's Minnesota

Recruiting

Minneapolis, Minnesota, United States, 55404

Contacts

Anne Bendel, MD

(612) 626-2778 anne.bendel@childrensmn.org

Principal Investigator:

Anne Bendel, MD

Washington University in St. Louis

Recruiting

St Louis, Missouri, United States, 63110

Contacts

Mohamad AbdelBaki, MD

(314) 454-6018 Mohameda@wustl.edu

Josh Rubin, MD, PhD

314-286-2790 rubin_j@wustl.edu

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

Recruiting

Hackensack, New Jersey, United States, 07601

Contacts

Derek Hanson, MD

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

Katharine Offer, MD

Katharine.Offer@HMHN.org

New York University

Recruiting

New York, New York, United States, 10016

Contacts

Sharon Gardner, MD

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

Children's Hospital of Philadelphia

Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contacts

Cassie Kline, MD, MAS

(267) 426- 5026 klinec@email.chop.edu

Principal Investigator:

Cassie Kline, MD, MAS

University Of Texas Southwestern Medical Center

Recruiting

Dallas, Texas, United States, 75235

Contacts

Laura Klesse, MD

214-456-2382 laura.klesse@utsouthwestern.edu

More Information

Sponsor

University of California, San Francisco

Last update posted

Aug 18, 2026

Last verified

Aug, 2026

Keywords

Mitogen-activated protein kinase (MAPK)
phosphatidylinositol 3-kinase (PI3K)
MAPK
PI3K

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by University of California, San Francisco on 2026-08-18.