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

Trial Status: Active

This phase 3 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.

Inclusion Criteria

  • 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 7 days prior to enrollment)
  • Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (performed within 7 days 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)
  • All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to 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 anti-hypertensive medications)
  • Note for patients of all ages: Adequate blood pressure can be achieved using medication for the treatment of hypertension
  • 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

Alabama

Birmingham
Children's Hospital of Alabama
Status: ACTIVE
Contact: Site Public Contact
Phone: 205-638-9285

Arizona

Phoenix
Phoenix Childrens Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 602-546-0920

Arkansas

Little Rock
Arkansas Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 501-364-7373

California

Loma Linda
Loma Linda University Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 909-558-4050
Los Angeles
Children's Hospital Los Angeles
Status: ACTIVE
Contact: Site Public Contact
Phone: 323-361-4110
Mattel Children's Hospital UCLA
Status: ACTIVE
Contact: Site Public Contact
Phone: 310-825-6708
Oakland
Kaiser Permanente-Oakland
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org
San Francisco
UCSF Medical Center-Mission Bay
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-827-3222

Colorado

Aurora
Children's Hospital Colorado
Status: ACTIVE
Contact: Site Public Contact
Phone: 303-764-5056

Connecticut

Hartford
Connecticut Children's Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 860-545-9981

Delaware

Wilmington
Alfred I duPont Hospital for Children
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-651-6884

District of Columbia

Washington
Children's National Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 202-884-2549

Florida

Gainesville
University of Florida Health Science Center - Gainesville
Status: ACTIVE
Contact: Site Public Contact
Phone: 352-273-8010
Hollywood
Memorial Regional Hospital / Joe DiMaggio Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 954-265-1847
Email: OHR@mhs.net
Jacksonville
Nemours Children's Clinic-Jacksonville
Status: ACTIVE
Contact: Site Public Contact
Phone: 904-697-3529
Miami
Nicklaus Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-624-2778
University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: APPROVED
Contact: Site Public Contact
Phone: 305-243-2647
Orlando
AdventHealth Orlando
Status: ACTIVE
Contact: Site Public Contact
Phone: 407-303-2090
Arnold Palmer Hospital for Children
Status: ACTIVE
Contact: Site Public Contact
Phone: 321-841-2008
Saint Petersburg
Johns Hopkins All Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 727-767-4784

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-785-2025

Idaho

Boise
Saint Luke's Cancer Institute - Boise
Status: ACTIVE
Contact: Site Public Contact
Phone: 208-381-2774

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: ACTIVE
Contact: Site Public Contact
Phone: 773-880-4562
University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 773-702-8222
University of Illinois
Status: ACTIVE
Contact: Site Public Contact
Phone: 312-355-3046

Indiana

Indianapolis
Riley Hospital for Children
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-248-1199
Saint Vincent Hospital and Health Care Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 317-338-2194

Iowa

Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-237-1225

Kentucky

Lexington
University of Kentucky / Markey Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 859-257-3379
Louisville
Norton Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 502-629-5500

Louisiana

New Orleans
Children's Hospital New Orleans
Status: ACTIVE
Contact: Site Public Contact

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 410-955-8804

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-442-3324

Michigan

Grand Rapids
Helen DeVos Children's Hospital at Spectrum Health
Status: ACTIVE
Contact: Site Public Contact
Phone: 616-391-1230

Minnesota

Minneapolis
Children's Hospitals and Clinics of Minnesota - Minneapolis
Status: ACTIVE
Contact: Site Public Contact
Phone: 612-813-5193
University of Minnesota / Masonic Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 612-624-2620

Mississippi

Jackson
University of Mississippi Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 601-815-6700

Missouri

Kansas City
Children's Mercy Hospitals and Clinics
Status: ACTIVE
Contact: Site Public Contact
Phone: 816-302-6808
Email: rryan@cmh.edu
Saint Louis
Cardinal Glennon Children's Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-268-4000
Washington University School of Medicine
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606

New Jersey

Morristown
Morristown Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 973-971-5900

New York

Albany
Albany Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 518-262-5513
Buffalo
Roswell Park Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-767-9355
Mineola
NYU Winthrop Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 646-754-4624
New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: ACTIVE
Contact: Site Public Contact
Phone: 212-263-4434
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 212-639-7592

North Carolina

Charlotte
Carolinas Medical Center / Levine Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-804-9376
Durham
Duke University Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-275-3853
Greenville
East Carolina University
Status: ACTIVE
Contact: Site Public Contact
Phone: 252-744-1015
Winston-Salem
Wake Forest University Health Sciences
Status: ACTIVE
Contact: Site Public Contact
Phone: 336-713-6771

North Dakota

Fargo
Sanford Broadway Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 701-323-5760

Ohio

Akron
Children's Hospital Medical Center of Akron
Status: ACTIVE
Contact: Site Public Contact
Phone: 330-543-3193
Cincinnati
Cincinnati Children's Hospital Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 513-636-2799
Cleveland
Rainbow Babies and Childrens Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 216-844-5437
Columbus
Nationwide Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 614-072-2657
Dayton
Dayton Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-228-4055

Oklahoma

Oklahoma City
University of Oklahoma Health Sciences Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 405-271-8777

Oregon

Portland
Oregon Health and Science University
Status: ACTIVE
Contact: Site Public Contact
Phone: 503-494-1080

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: ACTIVE
Contact: Site Public Contact
Phone: 267-425-5544
Pittsburgh
Children's Hospital of Pittsburgh of UPMC
Status: ACTIVE
Contact: Site Public Contact
Phone: 412-692-8570

Puerto Rico

Caguas
HIMA San Pablo Oncologic Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 787-653-3434

Rhode Island

Providence
Rhode Island Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 401-444-1488

South Carolina

Greenville
BI-LO Charities Children's Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-522-2066

Tennessee

Knoxville
East Tennessee Childrens Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 865-541-8266
Memphis
Saint Jude Children's Research Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-226-4343

Texas

Austin
Dell Children's Medical Center of Central Texas
Status: ACTIVE
Contact: Site Public Contact
Phone: 512-628-1902
Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: ACTIVE
Contact: Site Public Contact
Phone: 214-648-7097
El Paso
El Paso Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 915-298-5444
Fort Worth
Cook Children's Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 682-885-2103
Houston
Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 713-798-1354
M D Anderson Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-632-6789
Lubbock
Covenant Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
UMC Cancer Center / UMC Health System
Status: ACTIVE
Contact: Site Public Contact
Phone: 806-775-8590
San Antonio
Children's Hospital of San Antonio
Status: ACTIVE
Contact: Site Public Contact
Methodist Children's Hospital of South Texas
Status: ACTIVE
Contact: Site Public Contact
Phone: 210-575-6240

Utah

Salt Lake City
Primary Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 801-585-5270

Virginia

Norfolk
Children's Hospital of The King's Daughters
Status: ACTIVE
Contact: Site Public Contact
Phone: 757-668-7243
Richmond
Virginia Commonwealth University / Massey Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 804-628-1914

Washington

Seattle
Seattle Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 866-987-2000
Spokane
Providence Sacred Heart Medical Center and Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-228-6618
Tacoma
Madigan Army Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 253-968-0129
Mary Bridge Children's Hospital and Health Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 253-403-1461

West Virginia

Morgantown
West Virginia University Healthcare
Status: ACTIVE
Contact: Site Public Contact
Phone: 304-293-7374

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-622-8922
Milwaukee
Children's Hospital of Wisconsin
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-955-4727

Nova Scotia

Halifax
IWK Health Centre
Status: ACTIVE
Contact: Site Public Contact
Phone: 902-470-8037

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.

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.

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.

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.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Children's Oncology Group

Principal Investigator
Peter Matthew Kennedy de Blank

  • Primary ID ACNS1833
  • Secondary IDs NCI-2019-07600
  • Clinicaltrials.gov ID NCT04166409