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NCT04166409PHASE3Recruiting

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

National Cancer Institute (NCI)

Start Date

1/31/2020

Completion Date

12/31/2030

Summary

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 is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Vincristine is in a class of medications called vinca alkaloids. It works by stopping tumor cells from growing and dividing and may kill them. 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

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 as well as data from Molecular Characterization Initiative (MCI) testing, to correlate genomic drivers to efficacy outcomes. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: INDUCTION: Patients receive vincristine sulfate intravenously (IV) 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) throughout the trial. MAINTENANCE: Patients receive vincristine sulfate IV on days 1, 8, and 15, and carboplatin IV over 60 minutes on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 42 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and MRI throughout the trial. ARM II: Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) at baseline and undergo collection of blood and MRI throughout the trial. 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.

Eligibility Criteria

Age Range: 2 years to 21 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 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) Childhood Cancer Data Initiative (CCDI)-MCI, or accepted Clinical Laboratory Improvement Act (CLIA)-certified test 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 * Patients with ependymoma are not 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/sex 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 must be stable and must 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 sex 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 8 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 8 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 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 * All patients have signed an appropriate consent form and Health Insurance Portability and Accountability Act (HIPAA) authorization form (if applicable) * All patients have been consented and enrolled on APEC14B1 (NCT02402244) Part A for Pre-Enrollment Eligibility Screening for ACNS1833 Exclusion Criteria: * Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention (with the exclusion of laser interstitial thermal therapy \[LITT\]) 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 1 week after stopping study therapy are not eligible. * Note: Women study participants of child-bearing potential must use acceptable contraception during the study and for 1 week (7 days) after the last dose of selumetinib. Men study participants with sexual partners who are pregnant or who are of child-bearing potential must use acceptable contraception during the study and for 1 week (7 days) after the last dose of study agent. Acceptable contraception includes implants, injectables, or oral contraceptives (all combined with barrier methods), some intrauterine devices (IUDs), vasectomy or abstinence * 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

Interventions

PROCEDURE

Biospecimen Collection

DRUG

Carboplatin

PROCEDURE

Echocardiography Test

PROCEDURE

Magnetic Resonance Imaging

OTHER

Questionnaire Administration

DRUG

Selumetinib Sulfate

DRUG

Vincristine Sulfate

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Conditions

Low Grade AstrocytomaLow Grade GliomaMetastatic Low Grade AstrocytomaMetastatic Low Grade GliomaWHO Grade 1 GliomaWHO Grade 2 Glioma

Locations

Children's Hospital of Alabama

Birmingham, Alabama 35233

United States

Banner Children's at Desert

Mesa, Arizona 85202

United States

Phoenix Childrens Hospital

Phoenix, Arizona 85016

United States

Arkansas Children's Hospital

Little Rock, Arkansas 72202-3591

United States

Loma Linda University Medical Center

Loma Linda, California 92354

United States

Miller Children's and Women's Hospital Long Beach

Long Beach, California 90806

United States

Children's Hospital Los Angeles

Los Angeles, California 90027

United States

Cedars-Sinai Medical Center

Los Angeles, California 90048

United States

Mattel Children's Hospital UCLA

Los Angeles, California 90095

United States

Kaiser Permanente-Oakland

Oakland, California 94611

United States

Children's Hospital of Orange County

Orange, California 92868

United States

Lucile Packard Children's Hospital Stanford University

Palo Alto, California 94304

United States

Rady Children's Hospital - San Diego

San Diego, California 92123

United States

UCSF Medical Center-Mission Bay

San Francisco, California 94158

United States

Children's Hospital Colorado

Aurora, Colorado 80045

United States

Connecticut Children's Medical Center

Hartford, Connecticut 06106

United States

Yale University

New Haven, Connecticut 06520

United States

Alfred I duPont Hospital for Children

Wilmington, Delaware 19803

United States

Children's National Medical Center

Washington D.C., District of Columbia 20010

United States

Golisano Children's Hospital of Southwest Florida

Fort Myers, Florida 33908

United States

UF Health Cancer Institute - Gainesville

Gainesville, Florida 32610

United States

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

Hollywood, Florida 33021

United States

Nemours Children's Clinic-Jacksonville

Jacksonville, Florida 32207

United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida 33136

United States

Nicklaus Children's Hospital

Miami, Florida 33155

United States

AdventHealth Orlando

Orlando, Florida 32803

United States

Arnold Palmer Hospital for Children

Orlando, Florida 32806

United States

Nemours Children's Hospital

Orlando, Florida 32827

United States

Nemours Children's Clinic - Pensacola

Pensacola, Florida 32504

United States

Sacred Heart Hospital

Pensacola, Florida 32504

United States

Johns Hopkins All Children's Hospital

St. Petersburg, Florida 33701

United States

Saint Joseph's Hospital/Children's Hospital-Tampa

Tampa, Florida 33607

United States

Children's Healthcare of Atlanta - Arthur M Blank Hospital

Atlanta, Georgia 30329

United States

Kapiolani Medical Center for Women and Children

Honolulu, Hawaii 96826

United States

Saint Luke's Cancer Institute - Boise

Boise, Idaho 83712

United States

Lurie Children's Hospital-Chicago

Chicago, Illinois 60611

United States

University of Illinois

Chicago, Illinois 60612

United States

University of Chicago Comprehensive Cancer Center

Chicago, Illinois 60637

United States

OSF Children's Hospital of Illinois

Peoria, Illinois 61637

United States

Southern Illinois University School of Medicine

Springfield, Illinois 62702

United States

Riley Hospital for Children

Indianapolis, Indiana 46202

United States

Ascension Saint Vincent Indianapolis Hospital

Indianapolis, Indiana 46260

United States

Blank Children's Hospital

Des Moines, Iowa 50309

United States

University of Iowa/Holden Comprehensive Cancer Center

Iowa City, Iowa 52242

United States

University of Kentucky/Markey Cancer Center

Lexington, Kentucky 40536

United States

Norton Children's Hospital

Louisville, Kentucky 40202

United States

Children's Hospital New Orleans

New Orleans, Louisiana 70118

United States

Eastern Maine Medical Center

Bangor, Maine 04401

United States

Maine Children's Cancer Program

Scarborough, Maine 04074

United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland 21287

United States

Walter Reed National Military Medical Center

Bethesda, Maryland 20889-5600

United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts 02114

United States

Dana-Farber Cancer Institute

Boston, Massachusetts 02215

United States

C S Mott Children's Hospital

Ann Arbor, Michigan 48109

United States

Children's Hospital of Michigan

Detroit, Michigan 48201

United States

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital

Grand Rapids, Michigan 49503

United States

Corewell Health Children's

Royal Oak, Michigan 48073

United States

Children's Hospitals and Clinics of Minnesota - Minneapolis

Minneapolis, Minnesota 55404

United States

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota 55455

United States

Mayo Clinic in Rochester

Rochester, Minnesota 55905

United States

University of Mississippi Medical Center

Jackson, Mississippi 39216

United States

Children's Mercy Hospitals and Clinics

Kansas City, Missouri 64108

United States

Cardinal Glennon Children's Medical Center

St Louis, Missouri 63104

United States

Washington University School of Medicine

St Louis, Missouri 63110

United States

Children's Hospital and Medical Center of Omaha

Omaha, Nebraska 68114

United States

University of Nebraska Medical Center

Omaha, Nebraska 68198

United States

Morristown Medical Center

Morristown, New Jersey 07960

United States

Albany Medical Center

Albany, New York 12208

United States

Roswell Park Cancer Institute

Buffalo, New York 14263

United States

NYU Langone Hospital - Long Island

Mineola, New York 11501

United States

The Steven and Alexandra Cohen Children's Medical Center of New York

New Hyde Park, New York 11040

United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York 10016

United States

Memorial Sloan Kettering Cancer Center

New York, New York 10065

United States

University of Rochester

Rochester, New York 14642

United States

State University of New York Upstate Medical University

Syracuse, New York 13210

United States

New York Medical College

Valhalla, New York 10595

United States

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina 27599

United States

Carolinas Medical Center/Levine Cancer Institute

Charlotte, North Carolina 28203

United States

Duke University Medical Center

Durham, North Carolina 27710

United States

East Carolina University

Greenville, North Carolina 27834

United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina 27157

United States

Sanford Broadway Medical Center

Fargo, North Dakota 58122

United States

Children's Hospital Medical Center of Akron

Akron, Ohio 44308

United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio 45229

United States

Rainbow Babies and Childrens Hospital

Cleveland, Ohio 44106

United States

Nationwide Children's Hospital

Columbus, Ohio 43205

United States

Dayton Children's Hospital

Dayton, Ohio 45404

United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma 73104

United States

Oregon Health and Science University

Portland, Oregon 97239

United States

Geisinger Medical Center

Danville, Pennsylvania 17822

United States

Penn State Children's Hospital

Hershey, Pennsylvania 17033

United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania 19104

United States

Saint Christopher's Hospital for Children

Philadelphia, Pennsylvania 19134

United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania 15224

United States

Rhode Island Hospital

Providence, Rhode Island 02903

United States

Medical University of South Carolina

Charleston, South Carolina 29425

United States

Prisma Health Richland Hospital

Columbia, South Carolina 29203

United States

BI-LO Charities Children's Cancer Center

Greenville, South Carolina 29605

United States

East Tennessee Childrens Hospital

Knoxville, Tennessee 37916

United States

Saint Jude Children's Research Hospital

Memphis, Tennessee 38105

United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee 37232

United States

Dell Children's Medical Center of Central Texas

Austin, Texas 78723

United States

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas 75390

United States

El Paso Children's Hospital

El Paso, Texas 79905

United States

Cook Children's Medical Center

Fort Worth, Texas 76104

United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas 77030

United States

UT MD Anderson Cancer Center

Houston, Texas 77030

United States

Covenant Children's Hospital

Lubbock, Texas 79410

United States

UMC Cancer Center / UMC Health System

Lubbock, Texas 79415

United States

Children's Hospital of San Antonio

San Antonio, Texas 78207

United States

Methodist Children's Hospital of South Texas

San Antonio, Texas 78229

United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas 78229

United States

Primary Children's Hospital

Salt Lake City, Utah 84113

United States

University of Vermont and State Agricultural College

Burlington, Vermont 05405

United States

Children's Hospital of The King's Daughters

Norfolk, Virginia 23507

United States

VCU Massey Comprehensive Cancer Center

Richmond, Virginia 23298

United States

Carilion Children's

Roanoke, Virginia 24014

United States

Seattle Children's Hospital

Seattle, Washington 98105

United States

Providence Sacred Heart Medical Center and Children's Hospital

Spokane, Washington 99204

United States

Mary Bridge Children's Hospital and Health Center

Tacoma, Washington 98405

United States

Madigan Army Medical Center

Tacoma, Washington 98431

United States

West Virginia University Healthcare

Morgantown, West Virginia 26506

United States

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin 53792

United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin 53226

United States

British Columbia Children's Hospital

Vancouver, British Columbia V6H 3V4

Canada

Janeway Child Health Centre

St. John's, Newfoundland and Labrador A1B 3V6

Canada

IWK Health Centre

Halifax, Nova Scotia B3K 6R8

Canada

The Montreal Children's Hospital of the MUHC

Montreal, Quebec H3H 1P3

Canada

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec H3T 1C5

Canada

Centre Hospitalier Universitaire de Sherbrooke-Fleurimont

Sherbrooke, Quebec J1H 5N4

Canada

CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)

Québec, G1V 4G2

Canada

HIMA San Pablo Oncologic Hospital

Caguas, 00726

Puerto Rico