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

Trial Status: Active

This trial studies how well selumetinib works in treating patients with low-grade glioma. Selumetinib is a drug that works by blocking a protein (a basic building block of the human body) that lets tumor cells grow without stopping. Drugs used in 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. This trial studies if selumetinib works as well as carboplatin and vincristine for getting rid of or shrinking low-grade gliomas and stopping them from coming back.

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 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: * 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 (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. For the purpose of this study, the ULN for SGPT is 45 U/L
  • Albumin >= 2 g/dL
  • 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
  • Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG)
  • Absolute neutrophil count >= 1,000/uL (unsupported)
  • Platelets >= 100,000/uL (unsupported)
  • Hemoglobin >= 8 g/dL (may be supported)
  • 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
  • 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

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
  • Recent surgery within a minimum of 2 weeks prior to starting study 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

Arkansas

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

California

Oakland
Kaiser Permanente-Oakland
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org

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

Georgia

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

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: ACTIVE
Contact: Site Public Contact
Phone: 773-880-4562

Indiana

Indianapolis
Riley Hospital for Children
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-248-1199

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

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

Missouri

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 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
New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: ACTIVE
Contact: Site Public Contact
Phone: 212-263-4434

North Carolina

Durham
Duke University Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-275-3853
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
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

Tennessee

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
Fort Worth
Cook Children's Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 682-885-2103
Lubbock
UMC Cancer Center / UMC Health System
Status: ACTIVE
Contact: Site Public Contact
Phone: 806-775-8590

Washington

Seattle
Seattle Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 866-987-2000

Nova Scotia

Halifax
IWK Health Centre
Status: ACTIVE
Contact: Site Public Contact
Phone: 902-470-6767

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 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 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 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