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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 1 Year - 25 Years
Gender All
More Inclusion & Exclusion Criteria

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.
Biologic agents: Patient 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
  • - Patients may have received prior treatment with a MEK or mTOR inhibitor but must not have developed severe (grade III or IV) clinically significant toxicity.
(Patients 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: Patients must have received their last dose at least four weeks prior to study registration - Radiation: Patients 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: Patients must be: >= 6 months since allogeneic bone marrow transplant prior to registration; >= 3 months since autologous bone marrow/stem cell prior to registration - Corticosteroids: Patients who are receiving steroids must be on a stable or decreasing dose for at least 1 week prior to registration - Karnofsky >= 50 for subjects > 16 years of age and Lansky >= 50 for subjects =< 16 years of age.
Subjects 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: - 3 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 - Patients 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 patient 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
  • - Subjects with seizure disorder may be enrolled if well controlled.
Patients must be on non-enzyme inducing anticonvulsants which are not excluded on study therapy
  • - Patients 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 - Patients 3-17 years of age must have a blood pressure that is =< 95th percentile for age, height, and gender at the time of registration - Patients who are >= 18 years of age must have a blood pressure that is < 140/90 mm of Hg at the time of registration - Patients 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
  • - A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate per institutional guidelines

    Exclusion Criteria:

    - Subjects 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 - Patients 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)
  • - Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to enrollment - 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.
Patients should stop using all herbal medications at least 7 days prior to enrollment
  • - As part of the enrollment/informed consent procedures, the subject 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 subject is considering a new over-the-counter medicine or herbal product - Women of childbearing potential who are pregnant or breast-feeding - Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours of enrollment AND 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 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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04485559
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

University of California, San Francisco
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Sabine Mueller
Principal Investigator Affiliation University of California, San Francisco
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

OtherIndustryOtherOther
Overall Status Not yet recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Recurrent World Health Organization (WHO) Grade II Glioma
Additional Details

PRIMARY OBJECTIVES:

  • 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.
EXPLORATORY OBJECTIVES:
  • 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.

Arms & Interventions

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

Drug: - Everolimus

Given PO

Drug: - Trametinib

Given PO

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

University of California, San Francisco, San Francisco, California

Status

Address

University of California, San Francisco

San Francisco, California, 94143

Site Contact

Aubrie Drechsler

PNOC_Regulatory@ucsf.edu

415-502-1600

Children's National Medical Center, Washington, District of Columbia

Status

Address

Children's National Medical Center

Washington, District of Columbia, 20010

Site Contact

Lindsay Kilburn, MD

lkilburn@cnmc.org

202-476-5973

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