A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma

Study Overview
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Brief Summary
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This phase III trial studies if selumetinib works just as well as the standard treatment with carboplatin/vincristine (CV) for subjects with NF1-associated low grade glioma (LGG), and to see if selumetinib is better than CV in improving vision in subjects with LGG of the optic pathway (vision nerves). Selumetinib is a drug that works by blocking some enzymes that low-grade glioma tumor cells need for their growth. This results in killing tumor cells. Drugs used as chemotherapy, such as carboplatin and vincristine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether selumetinib works better in treating patients with NF1-associated low-grade glioma compared to standard therapy with carboplatin and vincristine.

Detailed Description
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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.

Official Title
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A Phase 3 Randomized Study of Selumetinib Versus Carboplatin/Vincristine in Newly Diagnosed or Previously Untreated Neurofibromatosis Type 1 (NF1) Associated Low-Grade Glioma (LGG)

Conditions
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Low Grade Glioma, Neurofibromatosis Type 1, Visual Pathway Glioma

Intervention / Treatment
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* Drug: Carboplatin
* Procedure: Magnetic Resonance Imaging
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Selumetinib Sulfate
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (carboplatin, vincristine)<br>INDUCTION: Patients receive carboplatin 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. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Vincristine Sulfate<br>* Given IV or IV push<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm II (selumetinib sulfate)<br>Patients receive selumetinib sulfate PO 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. | Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Selumetinib Sulfate<br>* Given PO<br>* Other names: Selumetinib Sulphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | EFS is defined as time from randomization to the first occurrence of any of the following events: clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause. Patients who are event-free will be censored at the time of last follow-up. Hazard ratio based on a stratified Cox proportional hazards model will be reported, along with a 90% confidence interval. | From randomization to the first occurrence of any of the following events: clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause, assessed up to 3 years after accrual completion | 
| Number of participants with visual acuity (VA) improvement per arm | VA will be assessed using Teller acuity cards (TAC). A significant improvement in VA will be defined as a decrease of >= 0.2 logMAR (corrected for age) from baseline (pre-treatment baseline) to end of about 12 months of treatment. The primary analysis will be based on per subject outcome (rather than per eye). | Baseline and end of about 12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic tumor response rate | Tumors will be classified into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Radiologic response rates will be summarized per arm and be tested for a difference between the two arms using an exact binomial test. | Assessed up to 3 years after accrual completion | 
| Overall survival (OS) | OS is defined as the time from randomization until death from any cause or till the time of last follow-up for patients who are alive at the time of analysis. Hazard ratio will be reported, along with a 90% confidence interval. | From randomization until death from any cause or till the time of last follow-up for patients who are alive at the time of analysis, assessed up to 3 years after accrual completion | 
| Change in VA using HOTV letter acuity testing | HOTV is a recognition acuity measure. It will be conducted on patients who are developmentally able to perform this testing. | Baseline and end of about 12 months of treatment | 
| Change in motor function | The Vineland-3 Motor Scale from the Comprehensive Parent Rating Form will be used to assess motor deficits. Change in Vineland motor scale from baseline to about 12 months of treatment will be compared between two treatment arms. | Baseline and approximately 12 months of treatment | 
| Change in quality of life (QOL) | Will be measured by Pain and Hurt subscale score. QOL will be assessed by Pediatric Quality of Life (PedsQL) Generic and Brain Tumor modules. Analysis will be based on a 2-sample t-test comparing change in Pain and Hurt subscale score from baseline to 12 months for the two arms. | Baseline and 12 months of treatment | 
| Change in quality of life (QOL) | Will be measured by Movement and Balance subscale score. QOL will be assessed by Pediatric Quality of Life (PedsQL) Generic and Brain Tumor modules. Analysis will be based on a 2-sample t-test comparing change in Movement and Balance subscale score from baseline to 12 months for the two arms. | Baseline and 12 months of treatment | 
| Change in executive function | Will be measured by BRIEF Cognitive Regulation Index (CRI). Executive function will be measured by age-appropriate Behavior Rating Inventory of Executive Function (BRIEF) questionnaire. Analysis will be based on a 2-sample t-test comparing change in the designated score from baseline to 24 months for the two arms. | Baseline and 24 months of treatment | 
| Change in neurocognitive function | Will be measured by Cogstate composite score. Neurocognitive function will be measured by a computerized battery (Cogstate) testing. Analysis will be based on a 2-sample t-test comparing change in Cogstate composite score from baseline to 24 months for the two arms. | Baseline and 24 months of treatment |