A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma

Study Overview
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Brief Summary
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This phase III trial compares the effect of selumetinib versus the standard of care treatment with carboplatin and vincristine (CV) in treating patients with newly diagnosed or previously untreated low-grade glioma (LGG) that does not have a genetic abnormality called BRAFV600E mutation and is not associated with systemic neurofibromatosis type 1. Selumetinib works by blocking some of the enzymes needed for cell growth and may kill tumor cells. Carboplatin and vincristine are chemotherapy drugs that work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. The overall goal of this study is to see if selumetinib works just as well as the standard treatment of CV for patients with LGG. Another goal of this study is to compare the effects of selumetinib versus CV in subjects with LGG to find out which is better. Additionally, this trial will also examine if treatment with selumetinib improves the quality of life for subjects who take it.

Detailed Description
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PRIMARY OBJECTIVE: I. To demonstrate that the efficacy of treatment with selumetinib as measured by event-free survival (EFS) is non-inferior compared to treatment with carboplatin/vincristine (CV) in previously-untreated low-grade glioma (LGG) not associated with BRAFV600E mutations or systemic neurofibromatosis type 1 (NF1). SECONDARY OBJECTIVES: I. To estimate tumor response rates to each regimen of chemotherapy. II. To evaluate visual acuity (VA) outcomes utilizing Teller Acuity Cards (TAC) and HOTV letter acuity testing in previously-untreated optic pathway gliomas (OPGs). III. To describe the improvement in motor function as measured by the Vineland Scale in children with previously-untreated LGG that have motor deficits at enrollment. IV. To estimate the difference in EFS and tumor response rate between BRAF rearranged and non-BRAF rearranged patients treated on each chemotherapy regimen. V. To prospectively evaluate the quality of life of children with LGG not associated with BRAFV600E or systemic NF1 treated with either CV or selumetinib. VI. To prospectively evaluate the cognitive, social, emotional, and behavioral functioning of children with LGG not associated with BRAFV600E or systemic NF1 treated with either CV or selumetinib. EXPLORATORY OBJECTIVE: I. To obtain paired blood and tumor specimens for future biology studies, including studies to correlate genomic drivers to response. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: INDUCTION: Patients receive vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64, and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and magnetic resonance imaging (MRI) at baseline and end of induction. MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15, and carboplatin IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 42 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up. ARM II: Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up. After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and then annually for years 4-10.

Official Title
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A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine Versus Selumetinib (NSC# 748727) in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) Not Associated With BRAFV600E Mutations or Systemic Neurofibromatosis Type 1 (NF1)

Conditions
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Low Grade Astrocytoma, Low Grade Glioma, Metastatic Low Grade Astrocytoma, Metastatic Low Grade Glioma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* 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 non-neurofibromatosis type 1 (non-NF1) low-grade glioma (LGG) without a BRAFV600E mutation as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1 (NCT02402244) and that has not been treated with any modality besides surgery. Note: Patients may be newly-diagnosed OR previously diagnosed, and there is no required time frame between biopsy/surgery and treatment initiation. Patients with residual tumor after resection or progressive tumor after initial diagnosis (with or without surgery) who have not received treatment (chemotherapy and/or radiation) are eligible Patients must have two-dimensional measurable tumor >= 1 cm^2 to be eligible Eligible histologies will include all tumors considered low-grade glioma 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 with metastatic disease or multiple independent primary LGG are eligible Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows (performed within 7 days prior to enrollment): Age: Maximum Serum Creatinine (mg/dL) 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female) 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female) 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female) 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female) >= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female) Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (performed 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 glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (performed within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L Albumin >= 2 g/dL (performed 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 (performed within 4 weeks prior to enrollment) Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (performed within 4 weeks prior to enrollment) Absolute neutrophil count >= 1,000/uL (unsupported) (performed within 7 days prior to enrollment) Platelets >= 100,000/uL (unsupported) (performed within 7 days prior to enrollment) Hemoglobin >= 8 g/dL (may be supported) (performed within 7 days prior to enrollment) Patients with a known seizure disorder should be stable and should not have 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 (with or without the use of anti-hypertensive medications) Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the use of anti-hypertensive medications) Note for patients of all ages: 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, a magnetic resonance imaging (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 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 All patients have signed an appropriate consent form and Health Insurance Portability and Accountability Act (HIPAA) authorization form (if applicable) All patients and/or their parents or legal guardians must sign a written informed consent All patients have been consented and enrolled on APEC14B1 (NCT02402244) followed by enrollment on the ACNS1833 Pre-Enrollment Eligibility Screening (Step 0) on the same day to complete the Rapid Central Review 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 with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals grade I/II histology Patients may not be receiving any other investigational agents Patients with any serious medical or psychiatric illness/condition, including substance use disorders or ophthalmological conditions, likely in the judgment of the investigator to interfere or limit compliance with study requirements/treatment 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 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 Health Association (NYHA) class II-IV prior or current cardiomyopathy Severe valvular heart disease History of atrial fibrillation 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 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 biopsy, placement of a vascular access device or cerebral spinal fluid (CSF) diverting procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt. Note: Patients must have healed from any prior surgery 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 (vincristine sulfate, carboplatin)<br>INDUCTION: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64, and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and magnetic resonance imaging (MRI) at baseline and end of induction. MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15, and carboplatin IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 42 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;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<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm II (selumetinib sulfate)<br>Patients receive selumetinib sulfate PO BID on days 1-28. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;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) | The Kaplan-Meier method will be used to estimate EFS which is defined as the interval from randomization to first occurrence of clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause, or to the date of last follow-up. Estimates with 95% confidence intervals will be reported by treatment arm. The hazard ratio with a confidence interval will also be reported to compare treatment arms based on a Cox proportional hazards model stratified by BRAF status, tumor location and size of residual tumor. | Up to 10 years from date of randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic tumor response rate | Percentages of patients with responses (complete or partial response) will be reported by treatment arm with 95% confidence intervals. The result of an exact binomial test to test for the difference in response rates between treatment arm will also be reported. | Up to 10 years | 
| Overall survival (OS) | The Kaplan-Meier method will be used to estimate OS by treatment arm, defined as the interval from randomization to death from any cause, or to the date of last follow-up. Estimates with confidence intervals will be reported by treatment arm. | Up to 10 years from date of randomization | 
| Number of patients who experience an improvement in visual acuity (VA) | Numbers of patients that show improvement in VA after 12 months of treatment will be reported by treatment arm. Patients with at least 1 impaired eye are evaluable. In a patient with a unilateral optic nerve glioma, only the affected eye is considered. In patients with bilateral visual impairment, if VA improves in 1 eye but worsens in the other, the patient will be coded as a treatment failure, whereas if 1 eye improves and the other is at least stable, the patient will be coded as a success. | After the first 12 months of treatment | 
| Change in motor function | Motor function is measured using the Vineland-3 Motor Scale. Only patients with motor function deficits at baseline are included. Magnitudes of change for each patient after 48 weeks of therapy from baseline will be calculated and medians (with ranges) by treatment arm will be reported. | After 48 weeks of therapy | 
| Change in quality of life (QOL) | QOL will be measured using the PedsQL Total Scale Score as measured from the validated PedsQL Generic Module (for children 2-21 years old). Mean differences in the total scale score between 9 months and baseline will be reported by treatment arm. The results of 2-sample t-test comparing differences in the QOL scores between the 2 arms will also be reported. If change scores do not follow normal distributions, non-parametric alternatives may be employed for analysis. | Baseline and 9 months after treatment initiation | 
| Processing speed function | Measured by Wechsler Processing Speed Index (standard score). Scores at 9 months will be summarized by treatment arm and reported as means (with standard deviations) or medians (with ranges) depending on the data distribution. | Up to 9 months post-treatment initiation | 
| Change in executive function | Executive function will be measured by the BRIEF-2 Cognitive Regulation Index (CRI). Summary statistics for the differences in scores from baseline to 9 months will be reported by treatment arm. | Baseline and 9-months |