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

S
Scott Coven

Primary Investigator

Enrolling By Invitation
1-25 years
All
Phase 1
50 participants needed
1 Location

Brief description of study

What is the purpose of this study?
This phase I trial studies the side effects and best dose of trametinib and everolimus ing 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.verolimus 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 comparedb or everolimus alone.

THIS STUDY IS ENROLLING BY INVITATION ONLY - Consistent with most oncology trials, patients are not actively “recruited,” but are screened by their physician for appropriate clinical trial(s) at the time of their routine clinic visit. Occasionally, a patient may be a self-referral or physician referral, but are still screened for appropriate clinical trials at the time of their routine clinic visit. PI and staff may send copies of relevant consent forms to these patients to look over prior to actually consenting or enrolling them. This may take place at the patient's visit at which the consent is presented or the patient's next visit to the outpatient hematology/oncology clinic.

Interested in participating? For more information about this research study or other cancer-related clinical trials at IU Simon Comprehensive Cancer Center, please contact:
IU Clinical Trials Office 
Phone: (317) 278-5632

Detailed description of study

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 thebination of trametinib and everolimus in pediatric and young adult patients with recurrentw-grade gliomas (LGG) or high grade glioma (HGG).
III. To characterize the pharmacokinetic profile of trametinib and everolimus when given inbination.
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 adultwith LGG or HGG.
III. To identify potential predictive biomarkers to targeted therapy in pediatric and youngdult 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 hyperintensityT2-weighted images as markers of disease response and/or progression in comparison toutional evaluation of disease response and/or progression and quantitative measures ofumor response as determined by central review (based upon both area and volumetricures).

What will happen during the study?
  • 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 26ycles 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.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Riley, Recurrent World Health Organization (WHO) Grade II Glioma, Low-grade Glioma, High Grade Glioma
  • Age: Between 1 Year - 25 Years
  • Gender: All

Inclusion Criteria:
  • Participants must have histologically confirmed diagnosis of an LGG (WHO grade I-II)hat is recurrent or progressive after prior treatment (biologic, chemotherapy ordiation therapy) or must have a histologically confirmed diagnosis of a high gradeglioma (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 havevailable tissue per study requirements neurofibromatosis (NF) status will bed
    • 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 priorg is required
    • If clinical comprehensive testing has already been performed, the requirement forubmission of tissue may be waived after discussion and review of results withudy chairs
  • Participants must have evaluable disease
  • Prior therapy: Participants must have received prior therapy other than surgery andust 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 ofknown myelosuppressive anticancer chemotherapy at least three weeks prior toudy registration or at least six weeks if they had received nitrosourea.Biologic agents: Participant must have recovered from any acute toxicityy related to the agent and received their last dose of the biologicgent >= 7 days prior to study registration. For biologic agents that have aged half-life, at least three half-lives must have elapsed prior togistration
      • Participants may have received prior treatment with a mitogen-activatedular signal-regulated kinase (MEK) or Mechanistic target ofycin (mTOR) inhibitor but must not have developed severe (grade III orV) clinically significant toxicity. (Participants who developed grade IIIV toxicity which was not presumed by the treating physician to bedically 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 irradiationhe primary tumor, craniospinal irradiation (> 24 Gy) or total bodydiation > 12 weeks prior to registration; investigators are reminded toview potentially eligible cases to confirm disease progression and avoidusion with pseudo-progression
    • Bone marrow transplant: Participants must be: >= 6 months since allogeneic bonew transplant prior to registration; >= 3 months since autologous bonew/stem cell prior to registration
    • Corticosteroids: Participants who are receiving steroids must be on a stable ordecreasing 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 whoup in a wheelchair, will be considered ambulatory for the purpose of assessing the
  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (unsupported)
  • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receivingusions 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/1.73^2 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(LLN) or ULN
  • Participants must have cholesterol level < 350 mg/dL and triglycerides < 400 mg/dLbefore starting therapy. In case one or both of these are exceeded, the participanty be included after initiation of appropriate lipid lowering medication anddocumentation of cholesterol < 350 mg/dL and triglycerides < 400mg/dl before start ofherapy
  • Participants with seizure disorder may be enrolled if well controlled. Participantsust be on non-enzyme inducing anticonvulsants which are not excluded on study therapy
  • Participants with neurological deficits should have deficits that are stable for aum 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 =< 95thge, 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 ofhild-bearing potential and males of child fathering potential must agree to usedequate contraception (hormonal or barrier method of birth control; abstinence) priorudy entry, for the duration of study participation and 4 months after completionb and everolimus administration. Should a woman become pregnant or suspecthe is pregnant while she or her partner is participating in this study, she shouldher treating physician immediately
  • A legal parent/guardian or participant must be able to understand, and willing togn, a written informed consent and assent document, as appropriate per institutionalguidelines
Exclusion Criteria:
  • Participants who are receiving any other investigational agent for treatment of theirumor
  • History of allergic reactions attributed to compounds of similar chemical or biologicverolimus or trametinib
  • Participants without available tissue from prior surgery. (If clinical comprehensiveg has already been performed, the requirement for submission of tissue may bewaived after discussion and review of results with study chairs)
  • Participant is receiving any of the following medications within 7 days prior to(If participants require (re)initiation of these agents after enrollmentd prior to start of therapy they will not be eligible to initiate study therapy):
    • Known strong inducers or inhibitors of CYP3A4/5, including enzyme inducingvulsant drugs (EIACDs), grapefruit, grapefruit hybrids, pomelos,uit, and Seville oranges
    • Substrates of CYP3A4/5 with a narrow therapeutic index
    • Herbal preparations/medications (except for vitamins) including, but not limited: 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
    • As part of the enrollment/informed consent procedures, the participant and/orgal parent or guardian will be counseled on the risk of interactions with othergents, and what to do if new medications need to be prescribed or if thedering 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 urinegnancy test within 72 hours of enrollment AND within 72 hours prior toving the first dose of study medication. If the urine test is positive orbe 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 changehe regimen within 8 weeks following enrollment, or if they are severelyunocompromised
  • Participants with known hepatitis B or C are not eligible
  • Participants with any clinically significant unrelated systemic illness (seriousus or significant cardiac, pulmonary, hepatic or other organ dysfunction),which in the opinion of the investigator would interfere with the study procedures orults
  • Participants with other factors that increase the risk of QT prolongation orhythmic events (e.g., heart failure, hypokalemia, family history of long QTval syndrome) including heart failure that meets New York Heart Association(NYHA) class II or above are excluded

Updated on 12 Sep 2024. Study ID: 190819, PHO-PNOC-PNOC021, 12381
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