Clinical Trials /

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

NCT04485559

Description:

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.

Related Conditions:
  • Low Grade Glioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 190819
  • SECONDARY ID: NCI-2020-04097
  • NCT ID: NCT04485559

Conditions

  • Recurrent World Health Organization (WHO) Grade II Glioma

Interventions

DrugSynonymsArms
Everolimus42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, ZortressTreatment (trametinib, everolimus)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (trametinib, everolimus)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
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.
  • Everolimus
  • Trametinib

Eligibility 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
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of trametinib in combination with everolimus for both continuous and intermittent dosing schedules
Time Frame:Up to 28 days
Safety Issue:
Description: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).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

July 22, 2020