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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 : Not yet recruiting
First Posted : July 24, 2020
Last Update Posted : September 16, 2020
Sponsor:
Collaborators:
Novartis Pharmaceuticals
Pediatric Brain Tumor Foundation
The Lilabean Foundation for Pediatric Brain Cancer Research
Information provided by (Responsible Party):
Sabine Mueller, MD, PhD, University of California, San Francisco

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 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.

Condition or disease Intervention/treatment Phase
Recurrent World Health Organization (WHO) Grade II Glioma Drug: Everolimus Drug: Trametinib Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : October 31, 2020
Estimated Primary Completion Date : March 1, 2023
Estimated Study Completion Date : March 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: Everolimus
Given PO
Other Names:
  • 42-O-(2-Hydroxy)ethyl Rapamycin
  • Afinitor
  • Certican
  • RAD 001
  • RAD001
  • Votubia
  • Zortress

Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist




Primary Outcome Measures :
  1. 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).

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

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


Contacts
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Contact: Aubrie Drecshler 415-502-1600 PNOC_Regulatory@ucsf.edu
Contact: Sabine Mueller, MD, MPH 877-827-3222 cancertrials@ucsf.edu

Locations
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United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
Contact: Aubrie Drechsler    415-502-1600    PNOC_Regulatory@ucsf.edu   
Contact: Sabine Mueller, MD, MPH    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Sabine Mueller, MD, MPH         
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
Contact: Lindsay Kilburn, MD    202-476-5973    lkilburn@cnmc.org   
Principal Investigator: Lindsay Kilburn, MD         
Sub-Investigator: Roger Packer, MD         
Sponsors and Collaborators
University of California, San Francisco
Novartis Pharmaceuticals
Pediatric Brain Tumor Foundation
The Lilabean Foundation for Pediatric Brain Cancer Research
Investigators
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Principal Investigator: Sabine Mueller University of California, San Francisco
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Responsible Party: Sabine Mueller, MD, PhD, Principal Investigator, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04485559    
Other Study ID Numbers: 190819
NCI-2020-04097 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: July 24, 2020    Key Record Dates
Last Update Posted: September 16, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Everolimus
Trametinib
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action