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

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.

Study Overview

• Status: Recruiting
• Conditions: High Grade Glioma; Low-grade Glioma; Recurrent World Health Organization (WHO) Grade II Glioma
• Intervention / Treatment: Drug: Trametinib; Drug: Everolimus

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 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:

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 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.

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
• Enrollment (Estimated): 50
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Sabine Mueller, MD, PhD, MAS; Phone Number: 877-827-3222; Email: cancertrials@ucsf.edu
• Study Contact Backup: Name: Aubrie Dreschler; Phone Number: 415-502-1600; Email: PNOC021@ucsf.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • University of Alabama at Birmingham, Children's of Alabama
      • Contact: Girish Dhall, MD; Phone Number: 205-638-9285; Email: gdhall@peds.uab.edu
      • Contact: Gregory Friedman, MD; Email: gfriedman@peds.uab.edu
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital Los Angeles
      • Sub-Investigator: Tom Davidson, MD
      • Contact: Ashley Margol, MD; Phone Number: 323-361-8147; Email: amargol@chla.usc.edu
      • Principal Investigator: Ashley Margol, MD
    • San Diego, California, United States, 92123
      • Recruiting
      • University of California, San Diego Rady Children's Hospital
      • Contact: Jennifer Elster, MD; Email: jelster@rchsd.org
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Principal Investigator: Sabine Mueller, MD, PhD, MAS
      • Contact: Sabine Mueller, MD, MPH; Phone Number: 877-827-3222; Email: cancertrials@ucsf.edu
      • Contact: Aubrie Drechsler; Phone Number: 415-502-1600; Email: PNOC021@ucsf.edu
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: Lindsay Kilburn, MD; Phone Number: 202-476-5973; Email: lkilburn@cnmc.org
      • Principal Investigator: Lindsay Kilburn, MD
      • Sub-Investigator: Roger Packer, MD
  • Florida
    • Gainesville, Florida, United States, 32610-0265
      • Recruiting
      • University of Florida
      • Contact: Elias Sayour, MD, PhD; Phone Number: 352-294-8347
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Ann & Robert H. Lurie Children's Hospital of Chicago
      • Contact: Angela Waanders, MD, MPH; Phone Number: 312-227-4873; Email: awaanders@luriechildrens.org
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Riley Hospital for Children
      • Contact: Scott Coven, DO, MPH; Phone Number: 317-944-8784; Email: scoven@iu.edu
      • Principal Investigator: Scott Coven, DO, MPH
      • Sub-Investigator: Daniel Runco, MD, MS
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • John Hopkins University
      • Contact: Kenneth Cohen, MD, MBA; Phone Number: 410-614-5055; Email: kcohen@jhmi.edu
      • Contact: Eric Raabe, MD, PhD; Phone Number: 410-502-5157; Email: eraabe2@jhmi.edu
      • Principal Investigator: Kenneth Cohen, MD, MBA
      • Sub-Investigator: Eric Raabe, MD, PhD
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
      • Contact: Susan Chi; Email: susan_chi@dfci.harvard.edu
      • Sub-Investigator: Tabitha Cooney
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Recruiting
      • Children's Minnesota
      • Principal Investigator: Anne Bendel, MD
      • Contact: Anne Bendel, MD; Phone Number: 612-626-2778; Email: anne.bendel@childrensmn.org
      • Sub-Investigator: Maggie Skrypek, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University in St. Louis
      • Contact: Mohamad AbdelBaki, MD; Phone Number: 314-454-6018; Email: Mohameda@wustl.edu
      • Contact: Josh Rubin, MD, PhD; Phone Number: 314-286-2790; Email: rubin_j@wustl.edu
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Recruiting
      • Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center
      • Contact: Derek Hanson, MD; Phone Number: 551-996-5437; Email: Derek.Hanson@HMHN.org
      • Contact: Katharine Offer, MD; Email: Katharine.Offer@HMHN.org
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • New York University
      • Contact: Sharon Gardner, MD; Phone Number: 212-263-9913; Email: Sharon.Gardner@nyulangone.org
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Doernbecher Children's Hospital Oregon Health & Science University
      • Principal Investigator: Matthew Miller, MD
      • Contact: Matthew Miller, MD; Phone Number: 503-494-1543; Email: milmatth@ohsu.edu
      • Sub-Investigator: Christopher Park, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Contact: Cassie Kline, MD, MAS; Phone Number: 267-426-5026; Email: klinec@email.chop.edu
      • Principal Investigator: Cassie Kline, MD, MAS
      • Sub-Investigator: Jane Mintrum, MD, PhD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital
      • Contact: Daniela Westerhold; Phone Number: 832-824-4552; Email: diwester@txch.org
      • Contact: Faryal Dina; Phone Number: (832) 824-4167; Email: fxdina@texaschildrens.org
      • Sub-Investigator: Donald W Parsons, MD, PHD
      • Principal Investigator: Patricia Baxter, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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
• 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 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Trametinib; Given PO; Other Names: Mekinist; GSK1120212; JTP-74057; MEK Inhibitor GSK1120212; Drug: Everolimus; Given PO; Other Names: 42-O-(2-Hydroxy)ethyl Rapamycin; Afinitor; Certican; RAD 001; RAD001; Votubia; Zortress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to 28 days
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.	Up to 30 days after the last day of treatment
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.	Up to 28 days
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.	Up to 28 days
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.	Up to 5 years
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.	Up to 5 years

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Novartis Pharmaceuticals; Pediatric Brain Tumor Foundation; The Lilabean Foundation for Pediatric Brain Cancer Research
• Investigators: Principal Investigator: Sabine Mueller, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2020
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: July 13, 2020
• First Submitted That Met QC Criteria: July 22, 2020
• First Posted (Actual): July 24, 2020

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: MAPK; PI3K; phosphatidylinositol 3-kinase (PI3K); Mitogen-activated protein kinase (MAPK)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Recurrence; Glioma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; MTOR Inhibitors; Everolimus; Trametinib
• Other Study ID Numbers: 190819; NCI-2020-04097 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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