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A Study of the Drugs Selumetinib versus Carboplatin / Vincristine in Patients with Neurofibromatosis and Low-Grade Glioma

Trial Status: Active

This phase III trial studies if selumetinib works just as well as the standard treatment with carboplatine / vincristine (CV) for subjects with NF1-associated low grade glioma (LGG), and to see if selumetinib is better than CV in improving vision in subjects with LGG of the optic pathway (vision nerves). Selumetinib is a drug that works by blocking some enzymes that low grade glioma tumor cells need for their growth. This results in killing tumor cells. Drugs used as 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. It is not yet known whether selumetinib works better in treating patients with NF1-associated low-grade glioma compared to standard therapy with carboplatin and vincristine.

Inclusion Criteria

  • Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
  • Patients must have neurofibromatosis type 1 (NF1) based on clinical criteria and/or germline genetic testing
  • Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGG that has not been treated with any modality other than surgery
  • For patients with optic pathway gliomas (OPGs): * Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms (including visual dysfunction, as defined below) or other exam findings associated with the tumor * Previously-diagnosed patients with OPG are eligible if they have new or worsening neurologic symptoms (including visual dysfunction, as defined below) or have tumor growth * For both newly-diagnosed and previously-diagnosed OPG, the patient may be eligible, irrespective of whether there has been tumor growth or other neurological symptoms or worsening, if they meet at least one of the following visual criteria: ** Visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year (by examination or history); OR ** Significant visual dysfunction (defined as VA worse than normal for age by 0.6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes)
  • For patients with LGG in other locations (i.e., not OPGs): * Newly-diagnosed patients with LGG are eligible if there are neurologic symptoms or other exam findings associated with the tumor ** NOTE: Newly-diagnosed patients with LGG without associated neurologic symptoms or exam findings are not eligible * Previously-diagnosed patients with LGG are eligible if they have new or worsening neurologic symptoms or have tumor growth
  • Although not required, if a biopsy/tumor resection is performed, eligible histologies will include all tumors considered LGG 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 must have two-dimensional measurable tumor >= 1 cm^2
  • Patients with metastatic disease or multiple independent primary LGGs are allowed on study
  • Creatinine clearance or radioisotope glomerular filtration Rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender within 7 days prior to enrollment as follows: * Age; maximum serum creatinine (mg/dL) * 2 to < 6 years; 0.8 (male) and 0.8 (female) * 6 to < 10 years; 1 (male) and 1 (female) * 10 to < 13 years; 1.2 (male) and 1.2 (female) * 13 to < 16 years; 1.5 (male) and 1.4 (female) * >= 16 years; 1.7 (male) and 1.4 (female)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age 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 glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN) = 135 U/L within 7 days prior to enrollment. For the purpose of this study, the ULN for SGPT is 45 U/L
  • Albumin >= 2 g/dL 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 within 7 days prior to enrollment
  • Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) within 7 days prior to enrollment
  • Absolute neutrophil count >= 1,000/uL (unsupported) within 7 days prior to enrollment
  • Platelets >= 100,000/uL (unsupported) within 7 days prior to enrollment
  • Hemoglobin >= 8 g/dL (may be supported) within 7 days prior to enrollment
  • Patients with a known seizure disorder should be stable and should have not 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. Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the use of antihypertensive medications). * Note: 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 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
  • For patients who undergo a surgery on the target tumor (not required), a pre- and post-operative* MRI of the brain (with orbital cuts for optic pathway tumors) or spine (depending on the site(s) of primary disease) with and without contrast must also be performed within 4 weeks prior to enrollment * The post-operative MRIs should be performed ideally within 48 hours after surgery if possible
  • 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
  • Patients must have receptive and expressive language skills in English or Spanish to complete the quality of life (QOL) and neurocognitive assessments
  • 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.

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 may not be receiving any other investigational agents
  • Patients with any serious medical or psychiatric illness/ condition, including substance use disorders likely in the judgement of the investigator to interfere or limit compliance with study requirements/treatment are not eligible
  • 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
  • Cardiac conditions: * 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
  • 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 ULN adjusted by age are not eligible * Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN, such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
  • Treatments and/or medications patient is receiving that would make her/him ineligible, such as: * 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 placement for vascular access or cerebrospinal fluid (CSF) diverting procedures such as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP) shunt. ** Note: Patients must have healed from any prior surgery prior to enrollment
  • Patients who have an uncontrolled infection are not eligible

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

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

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
Jacksonville
Nemours Children's Clinic-Jacksonville
Status: ACTIVE
Contact: Site Public Contact
Phone: 904-697-3529

Georgia

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

Illinois

Springfield
Southern Illinois University School of Medicine
Status: ACTIVE
Contact: Site Public Contact
Phone: 217-545-7929

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

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

Michigan

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

Minnesota

Minneapolis
University of Minnesota / Masonic Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 612-624-2620

Missouri

Columbia
Columbia Regional
Status: ACTIVE
Contact: Site Public Contact
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

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
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
Cleveland
Rainbow Babies and Childrens Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 216-844-5437
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: TEMPORARILY_CLOSED_TO_ACCRUAL
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
San Antonio
Children's Hospital of San Antonio
Status: ACTIVE
Contact: Site Public Contact

Virginia

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

Nova Scotia

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

PRIMARY OBJECTIVES:

I. To determine whether the efficacy of treatment with selumetinib sulfate (selumetinib) as measured by event-free survival (EFS) is non-inferior to treatment with carboplatin/vincristine sulfate (vincristine) (CV) in previously untreated neurofibromatosis type 1 (NF1)-associated low-grade glioma (LGG).

II. To determine whether visual acuity (VA) using Teller acuity cards (TAC), in patients with NF1-associated LGG within the optic pathway, is better in those treated with selumetinib compared to CV.

SECONDARY OBJECTIVES:

I. To estimate tumor response rates and overall survival (OS) in each treatment regimen in previously untreated NF1-associated LGG.

II. To evaluate VA outcomes utilizing HOTV letter acuity testing in previously untreated NF1-associated LGG within the optic pathway in patients who are old enough to perform visual acuity testing utilizing HOTV (a recognition acuity measure).

III. To describe the improvement in motor function as measured by the Vineland scale in patients with previously untreated NF1-associated LGG that have documented motor deficits at enrollment.

IV. To prospectively evaluate and compare the quality of life among patients treated with selumetinib or CV.

V. To prospectively evaluate and compare the cognitive, social, emotional, and behavioral functioning of patients with NF1-associated LGG treated with either selumetinib or CV.

EXPLORATORY OBJECTIVES:

I. To evaluate optical coherence tomography (OCT) measures of retinal axon and ganglion cell thickness as a marker of treatment response in previously untreated NF1-associated LGG within the optic pathway.

II. To compare novel, semi-automated volumetric magnetic resonance imaging (MRI) measures to traditional measurements of treatment response (bi-dimensional MRI measurements) in NF1-associated optic pathway tumors.

III. To obtain paired blood and tumor tissue to be banked for future NF1-LGG biology studies involving comprehensive molecular analysis, including but not limited to whole exome and ribonucleic acid (RNA) sequencing.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I:

INDUCTION: Patients receive carboplatin intravenously (IV) over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 and vincristine IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive carboplatin IV over 60 minutes on days 1, 8, 15, and 22 and vincristine IV on days 1, 8, and 15. Treatment repeats every 6 weeks for 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 is continuous and repeats every 28 days for 27 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up with MRIs and physical exams every 3 months for 1 year, every 6 months for 2 years, and then once yearly for up to 10 years.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Children's Oncology Group

Principal Investigator
Jason R. Fangusaro

  • Primary ID ACNS1831
  • Secondary IDs NCI-2019-01396
  • Clinicaltrials.gov ID NCT03871257