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.
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
