PRIMARY OBJECTIVES:
I. To determine whether the efficacy of treatment with selumetinib sulfate (selumetinib) as measured by event-free survival (EFS) is non-inferior to treatment with carboplatin/vincristine sulfate (vincristine) (CV) in previously untreated neurofibromatosis type 1 (NF1)-associated low-grade glioma (LGG).
II. To determine whether visual acuity (VA) using Teller acuity cards (TAC), in patients with NF1-associated LGG within the optic pathway, is better in those treated with selumetinib compared to CV.
SECONDARY OBJECTIVES:
I. To estimate tumor response rates and overall survival (OS) in each treatment regimen in previously untreated NF1-associated LGG.
II. To evaluate VA outcomes utilizing HOTV letter acuity testing in previously untreated NF1-associated LGG within the optic pathway in patients who are old enough to perform visual acuity testing utilizing HOTV (a recognition acuity measure).
III. To describe the improvement in motor function as measured by the Vineland scale in patients with previously untreated NF1-associated LGG that have documented motor deficits at enrollment.
IV. To prospectively evaluate and compare the quality of life among patients treated with selumetinib or CV.
V. To prospectively evaluate and compare the cognitive, social, emotional, and behavioral functioning of patients with NF1-associated LGG treated with either selumetinib or CV.
EXPLORATORY OBJECTIVES:
I. To evaluate optical coherence tomography (OCT) measures of retinal axon and ganglion cell thickness as a marker of treatment response in previously untreated NF1-associated LGG within the optic pathway.
II. To compare novel, semi-automated volumetric magnetic resonance imaging (MRI) measures to traditional measurements of treatment response (bi-dimensional MRI measurements) in NF1-associated optic pathway tumors.
III. To obtain paired blood and tumor tissue to be banked for future NF1-LGG biology studies involving comprehensive molecular analysis, including but not limited to whole exome and ribonucleic acid (RNA) sequencing.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I:
INDUCTION: Patients receive carboplatin intravenously (IV) over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 and vincristine IV or IV push over 1 minute on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and on study.
MAINTENANCE: Patients receive carboplatin IV over 60 minutes on days 1, 8, 15, and 22 and vincristine IV or IV push over 1 minute on days 1, 8, and 15. Treatment repeats every 6 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study and during follow-up.
ARM II: Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-28. Treatment is continuous and repeats every 28 days for 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.
After completion of study treatment, patients are followed up with MRIs and physical exams every 3 months for 1 year, every 6 months for 2 years, and then once yearly for up to 10 years.
Inclusion Criteria:
- Patients must be >= 2 years and =< 21 years at the time of enrollment
- Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
- Patients must have neurofibromatosis type 1 (NF1) based on clinical criteria and/or
germline genetic testing
- Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGG that
has not been treated with any modality other than surgery
- For patients with optic pathway gliomas (OPGs):
- Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms
(including visual dysfunction, as defined below) or other exam findings
associated with the tumor
- Previously-diagnosed patients with OPG are eligible if they have new or worsening
neurologic symptoms (including visual dysfunction, as defined below) or have
tumor growth
- For both newly-diagnosed and previously-diagnosed OPG, the patient may be
eligible, irrespective of whether there has been tumor growth or other
neurological symptoms or worsening, if they meet at least one of the following
visual criteria:
- Visual worsening, defined as worsening of visual acuity (VA) or visual
fields (VF) documented within the past year (by examination or history); OR
- Significant visual dysfunction (defined as VA worse than normal for age by
0.6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes)
- For patients with LGG in other locations (i.e., not OPGs):
- Newly-diagnosed patients with LGG are eligible if there are neurologic symptoms
or other exam findings associated with the tumor
- NOTE: Newly-diagnosed patients with LGG without associated neurologic
symptoms or exam findings are not eligible
- Previously-diagnosed patients with LGG are eligible if they have new or worsening
neurologic symptoms or have tumor growth
- Although not required, if a biopsy/tumor resection is performed, eligible histologies
will include all tumors considered LGG or low-grade astrocytoma (World Health
Organization [WHO] grade I and II) by 5th edition WHO classification of central
nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma
- Patients must have two-dimensional measurable tumor >= 1 cm^2
- Patients with metastatic disease or multiple independent primary LGGs are allowed on
study
- Creatinine clearance or radioisotope glomerular filtration Rate (GFR) >= 70
mL/min/1.73 m^2 OR a serum creatinine based on age/gender (within 7 days prior to
enrollment) as follows:
- Age; maximum serum creatinine (mg/dL)
- 2 to < 6 years; 0.8 (male) and 0.8 (female)
- 6 to < 10 years; 1 (male) and 1 (female)
- 10 to < 13 years; 1.2 (male) and 1.2 (female)
- 13 to < 16 years; 1.5 (male) and 1.4 (female)
- >= 16 years; 1.7 (male) and 1.4 (female)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study
regardless of their total and indirect [unconjugated] bilirubin levels as long as
their direct [conjugated] bilirubin is < 3.1 mg/dL)
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
upper limit of normal (ULN) = 135 U/L (within 7 days prior to enrollment). For the
purpose of this study, the ULN for SGPT is 45 U/L
- Albumin >= 2 g/dL (within 7 days prior to enrollment)
- Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF
result is given as a range of values, then the upper value of the range will be used)
by echocardiogram (within 4 weeks prior to enrollment)
- Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (within 4 weeks
prior to enrollment)
- Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to
enrollment)
- Platelets >= 100,000/uL (unsupported) (within 7 days prior to enrollment)
- Hemoglobin >= 8 g/dL (may be supported) (within 7 days prior to enrollment)
- Patients with a known seizure disorder should be stable and should have not
experienced a significant increase in seizure frequency within 2 weeks prior to
enrollment
- Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for
age, height, and gender at the time of enrollment. Patients >= 18 years of age must
have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the
use of antihypertensive medications).
- Note: Adequate blood pressure can be achieved using medication for the treatment
of hypertension
- All patients must have ophthalmology toxicity assessments performed within 4 weeks
prior to enrollment
- For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors)
and/or spine (depending on the site(s) of primary disease) with and without contrast
must be performed within 4 weeks prior to enrollment
- For patients who undergo a surgery on the target tumor (not required), a pre- and
post-operative* MRI of the brain (with orbital cuts for optic pathway tumors) or spine
(depending on the site(s) of primary disease) with and without contrast must also be
performed within 4 weeks prior to enrollment
- The post-operative MRIs should be performed ideally within 48 hours after surgery
if possible
- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age
- Patients must have the ability to swallow whole capsules
- Patients must have receptive and expressive language skills in English or Spanish to
complete the quality of life (QOL) and neurocognitive assessments
- All patients and/or their parents or legal guardians must sign a written informed
consent.
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
Exclusion Criteria:
- Patients must not have received any prior tumor-directed therapy including
chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior
surgical intervention is permitted
- Patients with a concurrent malignancy or history of treatment (other than surgery) for
another tumor within the last year are ineligible
- Patients may not be receiving any other investigational agents
- Patients with any serious medical or psychiatric illness/ condition, including
substance use disorders likely in the judgement of the investigator to interfere or
limit compliance with study requirements/treatment are not eligible
- Patients who, in the opinion of the investigator, are not able to comply with the
study procedures are not eligible
- Female patients who are pregnant are not eligible since fetal toxicities and
teratogenic effects have been noted for several of the study drugs. A pregnancy test
is required for female patients of childbearing potential
- Lactating females who plan to breastfeed their infants are not eligible
- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
12 weeks after stopping study therapy are not eligible
- Note: Women of child-bearing potential and males with sexual partners who are
pregnant or who could become pregnant (i.e., women of child-bearing potential)
should use effective methods of contraception for the duration of the study and
for 12 weeks after stopping study therapy to avoid pregnancy and/or potential
adverse effects on the developing embryo
- Cardiac conditions:
- Known genetic disorder that increases risk for coronary artery disease. Note: The
presence of dyslipidemia in a family with a history of myocardial infarction is
not in itself an exclusion unless there is a known genetic disorder documented
- Symptomatic heart failure
- New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy
- Severe valvular heart disease
- History of atrial fibrillation
- Ophthalmologic conditions:
- Current or past history of central serous retinopathy
- Current or past history of retinal vein occlusion or retinal detachment
- Patients with uncontrolled glaucoma
- If checking pressure is clinically indicated, patients with intraocular
pressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible
- Ophthalmological findings secondary to long-standing optic pathway glioma (such
as visual loss, optic nerve pallor, or strabismus) or longstanding
orbito-temporal plexiform neurofibroma (PN), such as visual loss, strabismus)
will NOT be considered a significant abnormality for the purposes of the study
- Treatments and/or medications patient is receiving that would make her/him ineligible,
such as:
- Supplementation with vitamin E greater than 100% of the daily recommended dose.
Any multivitamin containing vitamin E must be stopped prior to study enrollment
even if less than 100% of the daily recommended dosing for vitamin E
- Surgery within 2 weeks prior to enrollment, with the exception of surgical
placement for vascular access or cerebrospinal fluid (CSF) diverting procedures
such as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP)
shunt.
- Note: Patients must have healed from any prior surgery prior to enrollment
- Patients who have an uncontrolled infection are not eligible
