Skip to main content

A Study to Compare Treatment with the Drug Selumetinib Alone versus Selumetinib and Vinblastine in Patients with Recurrent or Progressive Low-Grade Glioma

Trial Status: Active

This phase III trial investigates the best dose of vinblastine in combination with selumetinib and the benefit of adding vinblastine to selumetinib compared to selumetinib alone in treating children and young adults with low-grade glioma (a common type of brain cancer) that has come back after prior treatment (recurrent) or does not respond to therapy (progressive). Selumetinib is a drug that works by blocking a protein that lets tumor cells grow without stopping. Vinblastine blocks cell growth by stopping cell division and may kill cancer cells. Giving selumetinib in combination with vinblastine may work better than selumetinib alone in treating recurrent or progressive low-grade glioma.

Inclusion Criteria

  • Feasibility phase: patients must be >= 2 years and =< 21 years of age at the time of enrollment
  • Efficacy phase: patients must be >= 2 years and =< 25 years of age at the time of enrollment * All patients > 21 years of age at the time of enrollment must have had initial diagnosis of low-grade glioma by 21 years of age
  • Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
  • Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1 * Non-neurofibromatosis type 1 (non-NF1), non-tuberous sclerosis complex (non-TSC) low-grade glioma (LGG) without a BRAFV600E or IDH1 mutation * Patients must have progressive or recurrent LGG. Note: Biopsy may be at either initial diagnosis or recurrence * Patients must have measurable disease, defined as having a two-dimensional measurable tumor volume of >= 1 cm^2 ** Tumor size will be measured to include both solid and cystic components of the tumor (whether or not tumor is enhancing) + fluid attenuated inversion recovery (FLAIR) signal * Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (World Health Organization [WHO] Grade 1 and II) by the WHO Classification of Tumors of the Central Nervous System – 4th Edition Revised, with the exception of subependymal giant cell astrocytoma * Patients with metastatic disease or multiple independent primary LGGs are eligible
  • Patients must be progressive or recurrent after having been treated with at least one prior tumor-directed therapy before enrollment
  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study * Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea); * Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent; * Radiation therapy (RT): >= 2 weeks (wks) for local palliative RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 wks must have elapsed if other substantial bone marrow (BM) radiation; * Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to =< grade 1; * MEK inhibitor or vinblastine: Must not have received treatment with a MEK inhibitor or vinblastine within 6 months of study enrollment
  • 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: * 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 * Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 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 interval (QTc interval) =< 450 msec by electrocardiogram (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
  • Stable neurological examination for >= 1 week
  • HYPERTENSION: * 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, an 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 * Note: If surgical resection or biopsy is performed at the time of progression or recurrence, a post-operative MRI is required
  • 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

  • Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following exceptions: * Patients must not have had progressive disease while on therapy with vinblastine or a MEK inhibitor; * Patients must not have discontinued vinblastine or selumetinib due to toxicity
  • 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 must not have known hypersensitivity to selumetinib, vinblastine, or similar compounds
  • CYP3A4 agents: Patients must not have received fluconazole or drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment
  • 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
  • PRE-EXISTING CONDITIONS (CARDIAC): * 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
  • PRE-EXISTING CONDITIONS (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 upper limit of normal (ULN) adjusted by age are not eligible
  • Any multivitamin containing vitamin E must be stopped prior to study enrollment even if it contains less than 100% of the daily recommended dosing for vitamin E
  • Surgery within 2 weeks prior to enrollment, with the exception of a surgical biopsy, placement of a vascular access device or cerebrospinal 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
  • 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
  • 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
  • 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

Alabama

Birmingham
Children's Hospital of Alabama
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
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

Los Angeles
Children's Hospital Los Angeles
Status: ACTIVE
Contact: Site Public Contact
Phone: 323-361-4110
Oakland
Kaiser Permanente-Oakland
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org

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: 302-651-5572

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: 302-651-5572
Orlando
Arnold Palmer Hospital for Children
Status: ACTIVE
Contact: Site Public Contact
Phone: 321-841-5357
Nemours Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-651-5572

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: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 773-702-8222

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

Maine

Scarborough
Maine Children's Cancer Program
Status: ACTIVE
Contact: Site Public Contact
Phone: 207-396-7581

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 410-955-8804
Bethesda
Walter Reed National Military Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 301-319-2100

Michigan

Royal Oak
Beaumont Children's Hospital-Royal Oak
Status: ACTIVE
Contact: Site Public Contact
Phone: 248-551-7695

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

Nebraska

Omaha
Children's Hospital and Medical Center of Omaha
Status: ACTIVE
Contact: Site Public Contact
Phone: 402-955-3949
University of Nebraska Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 402-559-6941

New Jersey

Morristown
Morristown Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 973-971-5900
New Brunswick
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 732-235-8675

New York

Albany
Albany Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 518-262-5513
New Hyde Park
The Steven and Alexandra Cohen Children's Medical Center of New York
Status: ACTIVE
Contact: Site Public Contact
Phone: 718-470-3460
New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: ACTIVE
Contact: Site Public Contact
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 212-639-7592
Syracuse
State University of New York Upstate Medical University
Status: ACTIVE
Contact: Site Public Contact
Phone: 315-464-5476

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
Columbus
Nationwide Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 614-722-6039
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

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

South Carolina

Columbia
Prisma Health Richland Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-241-6251
Greenville
BI-LO Charities Children's Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-241-6251

Tennessee

Knoxville
East Tennessee Childrens Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 865-541-8266
Nashville
Vanderbilt University / Ingram Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-811-8480

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
San Antonio
Children's Hospital of San Antonio
Status: ACTIVE
Contact: Site Public Contact
Phone: 210-704-2894

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

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: 253-968-6144

West Virginia

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

Wisconsin

Madison
University of Wisconsin Carbone Cancer Center
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

Quebec

Montreal
Centre Hospitalier Universitaire Sainte-Justine
Status: ACTIVE
Contact: Site Public Contact
Phone: 514-345-4931
Quebec
Centre Hospitalier Universitaire de Quebec
Status: ACTIVE
Contact: Site Public Contact
Phone: 418-525-4444

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of selumetinib sulfate (selumetinib) + vinblastine sulfate (vinblastine) for children with progressive or recurrent low-grade gliomas (LGGs).

II. To determine if selumetinib + vinblastine will lead to improved event-free survival (EFS) outcome compared with selumetinib alone for children with progressive or recurrent LGGs.

SECONDARY OBJECTIVES:

I. To estimate the objective response rates and overall survival associated with treatment with selumetinib + vinblastine versus single-agent selumetinib.

II. To estimate the difference in EFS and response rate between patients with BRAF rearranged LGG and patients with non-BRAF rearranged LGG after treatment with selumetinib + vinblastine versus single-agent selumetinib.

III. To evaluate toxicities associated with selumetinib + vinblastine and single-agent selumetinib for children with progressive or recurrent LGGs.

IV. To compare the quality of life among patients treated with selumetinib + vinblastine and single-agent selumetinib.

V. To examine the vision outcomes among patients with optic pathway gliomas (OPGs) treated with selumetinib + vinblastine and single-agent selumetinib.

EXPLORATORY OBJECTIVE:

I. To obtain paired blood and tumor specimens for future biology studies, including studies to correlate genomic drivers to response.

OUTLINE: This is a dose-escalation feasibility study of vinblastine sulfate in combination with selumetinib, followed by a randomized efficacy study. Patients in the feasibility study are assigned to Arm I, while patients in the efficacy study are randomized to Arm I or Arm II.

ARM I: Patients receive vinblastine sulfate intravenously (IV) over 1 minute or IV infusion on days 1, 8, 15, and 22 and selumetinib sulfate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days. Patients receive selumetinib and vinblastine for a total duration of 17 cycles followed by 10 additional cycles of selumetinib alone in the absence of disease progression or unacceptable toxicity.

ARM II: 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.

After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and annually for years 4-5.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Children's Oncology Group

Principal Investigator
Daniel Charles Bowers

  • Primary ID ACNS1931
  • Secondary IDs NCI-2020-07549
  • Clinicaltrials.gov ID NCT04576117