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

A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine Versus Selumetinib (NSC# 748727) in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) Not Associated With BRAFV600E Mutations or Systemic Neurofibromatosis Type 1 (NF1)

Patrocinadores

Patrocinador principal: National Cancer Institute (NCI)

Fuente National Cancer Institute (NCI)
Resumen breve

This phase III 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.

Descripción detallada

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.

Estado general Recruiting
Fecha de inicio January 3, 2020
Fecha de Terminación December 31, 2026
Fecha de finalización primaria December 31, 2026
Fase Phase 3
Tipo de estudio Interventional
Resultado primario
Medida Periodo de tiempo
Event-free survival (EFS) Time from randomization to the first occurrence of clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause, assessed up to 10 years
Resultado secundario
Medida Periodo de tiempo
Radiographic tumor response rate Up to 10 years
Overall survival (OS) Time from randomization until death from any cause or until the time of last follow-up for patients who are alive at time of analysis
Proportion of patients who experience an improvement in visual acuity (VA) After first 12 months of treatment
Motor function assessment At baseline and after 48 weeks of therapy
Change in parent and patient-reported quality of life (QOL) over time Baseline and at 9 months after treatment initiation
Inscripción 200
Condición
Intervención

Tipo de intervención: Drug

Nombre de intervención: Carboplatin

Descripción: Given IV

Etiqueta de grupo de brazo: Arm I (vincristine sulfate, carboplatin)

Tipo de intervención: Other

Nombre de intervención: Quality-of-Life Assessment

Descripción: Ancillary studies

Otro nombre: Quality of Life Assessment

Tipo de intervención: Other

Nombre de intervención: Questionnaire Administration

Descripción: Ancillary studies

Tipo de intervención: Drug

Nombre de intervención: Selumetinib Sulfate

Descripción: Given PO

Etiqueta de grupo de brazo: Arm II (selumetinib sulfate)

Tipo de intervención: Drug

Nombre de intervención: Vincristine Sulfate

Descripción: Given IV

Etiqueta de grupo de brazo: Arm I (vincristine sulfate, carboplatin)

Elegibilidad

Criterios:

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

- 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

Género: All

Edad mínima: 2 Years

Edad máxima: 21 Years

Voluntarios Saludables: No

Oficial general
Apellido Papel Afiliación
Peter M de Blank Principal Investigator Children's Oncology Group
Ubicación
Instalaciones: Estado: Contacto: Investigador:
Children's Hospital of Alabama | Birmingham, Alabama, 35233, United States Recruiting Site Public Contact 205-638-9285 [email protected] Matthew A. Kutny Principal Investigator
Arkansas Children's Hospital | Little Rock, Arkansas, 72202-3591, United States Recruiting Site Public Contact 501-364-7373 David L. Becton Principal Investigator
Mattel Children's Hospital UCLA | Los Angeles, California, 90095, United States Recruiting Site Public Contact 310-825-6708 William A. May Principal Investigator
Kaiser Permanente-Oakland | Oakland, California, 94611, United States Recruiting Site Public Contact 877-642-4691 [email protected] Laura A. Campbell Principal Investigator
UCSF Medical Center-Mission Bay | San Francisco, California, 94158, United States Recruiting Site Public Contact 877-827-3222 Alyssa T. Reddy Principal Investigator
Children's Hospital Colorado | Aurora, Colorado, 80045, United States Recruiting Site Public Contact 303-764-5056 [email protected] Jean M. Mulcahy Levy Principal Investigator
Connecticut Children's Medical Center | Hartford, Connecticut, 06106, United States Recruiting Site Public Contact 860-545-9981 Michael S. Isakoff Principal Investigator
Alfred I duPont Hospital for Children | Wilmington, Delaware, 19803, United States Recruiting Site Public Contact 302-651-6884 [email protected] Scott M. Bradfield Principal Investigator
Nemours Children's Clinic-Jacksonville | Jacksonville, Florida, 32207, United States Recruiting Site Public Contact 904-697-3529 Scott M. Bradfield Principal Investigator
University of Miami Miller School of Medicine-Sylvester Cancer Center | Miami, Florida, 33136, United States Recruiting Site Public Contact 305-243-2647 Julio C. Barredo Principal Investigator
Johns Hopkins All Children's Hospital | Saint Petersburg, Florida, 33701, United States Recruiting Site Public Contact 727-767-4784 [email protected] Stacie L. Stapleton Principal Investigator
Children's Healthcare of Atlanta - Egleston | Atlanta, Georgia, 30322, United States Recruiting Site Public Contact 404-785-2025 [email protected] Jason R. Fangusaro Principal Investigator
Lurie Children's Hospital-Chicago | Chicago, Illinois, 60611, United States Recruiting Site Public Contact 773-880-4562 Angela J. Waanders Principal Investigator
Riley Hospital for Children | Indianapolis, Indiana, 46202, United States Recruiting Site Public Contact 800-248-1199 Sandeep Batra Principal Investigator
Saint Vincent Hospital and Health Care Center | Indianapolis, Indiana, 46260, United States Recruiting Site Public Contact 317-338-2194 [email protected] Jessica F. Goodman Principal Investigator
University of Iowa/Holden Comprehensive Cancer Center | Iowa City, Iowa, 52242, United States Recruiting Site Public Contact 800-237-1225 Mariko Sato Principal Investigator
University of Kentucky/Markey Cancer Center | Lexington, Kentucky, 40536, United States Recruiting Site Public Contact 859-257-3379 James T. Badgett Principal Investigator
Children's Hospital New Orleans | New Orleans, Louisiana, 70118, United States Recruiting Site Public Contact [email protected] Lolie C. Yu Principal Investigator
Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore, Maryland, 21287, United States Recruiting Site Public Contact 410-955-8804 [email protected] Kenneth J. Cohen Principal Investigator
Dana-Farber Cancer Institute | Boston, Massachusetts, 02215, United States Recruiting Site Public Contact 877-442-3324 Susan N. Chi Principal Investigator
Helen DeVos Children's Hospital at Spectrum Health | Grand Rapids, Michigan, 49503, United States Recruiting Site Public Contact 616-391-1230 [email protected] Kathleen J. Yost Principal Investigator
Children's Mercy Hospitals and Clinics | Kansas City, Missouri, 64108, United States Recruiting Site Public Contact 816-302-6808 [email protected] Keith J. August Principal Investigator
Cardinal Glennon Children's Medical Center | Saint Louis, Missouri, 63104, United States Recruiting Site Public Contact 314-268-4000 William S. Ferguson Principal Investigator
Washington University School of Medicine | Saint Louis, Missouri, 63110, United States Recruiting Site Public Contact 800-600-3606 [email protected] Andrew S. Cluster Principal Investigator
Albany Medical Center | Albany, New York, 12208, United States Recruiting Site Public Contact 518-262-5513 Lauren R. Weintraub Principal Investigator
Roswell Park Cancer Institute | Buffalo, New York, 14263, United States Recruiting Site Public Contact 800-767-9355 [email protected] Matthew J. Barth Principal Investigator
NYU Winthrop Hospital | Mineola, New York, 11501, United States Recruiting Site Public Contact 516-663-3115 Mark E. Weinblatt Principal Investigator
Laura and Isaac Perlmutter Cancer Center at NYU Langone | New York, New York, 10016, United States Recruiting Site Public Contact 212-263-4434 [email protected] Sharon L. Gardner Principal Investigator
Duke University Medical Center | Durham, North Carolina, 27710, United States Recruiting Site Public Contact 888-275-3853 Lars M. Wagner Principal Investigator
Wake Forest University Health Sciences | Winston-Salem, North Carolina, 27157, United States Recruiting Site Public Contact 336-713-6771 David E. Kram Principal Investigator
Sanford Broadway Medical Center | Fargo, North Dakota, 58122, United States Recruiting Site Public Contact 701-323-5760 [email protected] Samuel J. Milanovich Principal Investigator
Children's Hospital Medical Center of Akron | Akron, Ohio, 44308, United States Recruiting Site Public Contact 330-543-3193 Steven J. Kuerbitz Principal Investigator
Cincinnati Children's Hospital Medical Center | Cincinnati, Ohio, 45229, United States Recruiting Site Public Contact 513-636-2799 [email protected] Peter M. de Blank Principal Investigator
Rainbow Babies and Childrens Hospital | Cleveland, Ohio, 44106, United States Recruiting Site Public Contact 216-844-5437 Duncan S. Stearns Principal Investigator
Dayton Children's Hospital | Dayton, Ohio, 45404, United States Recruiting Site Public Contact 800-228-4055 Ayman A. El-Sheikh Principal Investigator
University of Oklahoma Health Sciences Center | Oklahoma City, Oklahoma, 73104, United States Recruiting Site Public Contact 405-271-8777 [email protected] Rene Y. McNall-Knapp Principal Investigator
Oregon Health and Science University | Portland, Oregon, 97239, United States Recruiting Site Public Contact 503-494-1080 [email protected] Kellie J. Nazemi Principal Investigator
Children's Hospital of Philadelphia | Philadelphia, Pennsylvania, 19104, United States Recruiting Site Public Contact 267-425-5544 [email protected] Michael J. Fisher Principal Investigator
Children's Hospital of Pittsburgh of UPMC | Pittsburgh, Pennsylvania, 15224, United States Recruiting Site Public Contact 412-692-8570 [email protected] James T. Felker Principal Investigator
Saint Jude Children's Research Hospital | Memphis, Tennessee, 38105, United States Recruiting Site Public Contact 888-226-4343 [email protected] Anna Vinitsky Principal Investigator
Dell Children's Medical Center of Central Texas | Austin, Texas, 78723, United States Recruiting Site Public Contact 512-628-1902 [email protected] Shannon M. Cohn Principal Investigator
UT Southwestern/Simmons Cancer Center-Dallas | Dallas, Texas, 75390, United States Recruiting Site Public Contact 214-648-7097 [email protected] Daniel C. Bowers Principal Investigator
Cook Children's Medical Center | Fort Worth, Texas, 76104, United States Recruiting Site Public Contact 682-885-2103 [email protected] Sibo Zhao Principal Investigator
UMC Cancer Center / UMC Health System | Lubbock, Texas, 79415, United States Recruiting Site Public Contact 806-775-8590 Mohamad M. Al-Rahawan Principal Investigator
Children's Hospital of San Antonio | San Antonio, Texas, 78207, United States Recruiting Site Public Contact [email protected] Timothy C. Griffin Principal Investigator
Seattle Children's Hospital | Seattle, Washington, 98105, United States Recruiting Site Public Contact 866-987-2000 Sarah E. Leary Principal Investigator
Providence Sacred Heart Medical Center and Children's Hospital | Spokane, Washington, 99204, United States Recruiting Site Public Contact 800-228-6618 [email protected] Judy L. Felgenhauer Principal Investigator
West Virginia University Healthcare | Morgantown, West Virginia, 26506, United States Recruiting Site Public Contact 304-293-7374 [email protected] Stephan R. Paul Principal Investigator
University of Wisconsin Hospital and Clinics | Madison, Wisconsin, 53792, United States Recruiting Site Public Contact 800-622-8922 Kenneth B. De Santes Principal Investigator
IWK Health Centre | Halifax, Nova Scotia, B3K 6R8, Canada Recruiting Site Public Contact 902-470-6767 Conrad V. Fernandez Principal Investigator
Ubicacion Paises

Canada

United States

Fecha de verificación

July 2020

Fiesta responsable

Tipo: Sponsor

Tiene acceso ampliado No
Condición Examinar
Número de brazos 2
Grupo de brazo

Etiqueta: Arm I (vincristine sulfate, carboplatin)

Tipo: Active Comparator

Descripción: INDUCTION: Patients receive vincristine sulfate 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.

Etiqueta: Arm II (selumetinib sulfate)

Tipo: Experimental

Descripción: 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.

Datos del paciente Yes
Información de diseño del estudio

Asignación: Randomized

Modelo de intervención: Parallel Assignment

Propósito primario: Treatment

Enmascaramiento: None (Open Label)

Fuente: ClinicalTrials.gov