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.
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
