Neoplasms

All Conditions

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Glioma

Astrocytoma

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neurofibromatosis

Neurofibromatosis Type 1

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Carboplatin

Vincristine

Tubulin Modulators

Antimitotic Agents

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. Patients also undergo collection of blood and magnetic resonance imaging (MRI) at baseline and end of induction.

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. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up.

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. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up.

Biospecimen Collection

Magnetic Resonance Imaging

Quality-of-Life Assessment

Questionnaire Administration

Selumetinib Sulfate

Vincristine Sulfate

Site Public Contact

Joseph C. Torkildson

Lindsey M. Hoffman

David L. Becton

Albert Kheradpour

Nathan J. Robison

Fataneh (Fae) Majlessipour

Satiro N. De Oliveira

Aarati V. Rao

Elyssa M. Rubin

Jay Michael S. Balagtas

William D. Roberts

Alyssa T. Reddy

Jean M. Mulcahy Levy

Michael S. Isakoff

Asher M. Marks

Scott M. Bradfield

Jeffrey S. Dome

William B. Slayton

Iftikhar Hanif

Ziad A. Khatib

Fouad M. Hajjar

Jaime M. Libes-Bander

Jeffrey H. Schwartz

Stacie L. Stapleton

Jason R. Fangusaro

Wade T. Kyono

Martha M. Pacheco

Angela J. Waanders

Dipti S. Dighe

Wendy S. Darlington

Gregory P. Brandt

Sandeep Batra

Jessica F. Goodman

Samantha L. Mallory

David S. Dickens

James T. Badgett

Ashok B. Raj

Lolie C. Yu

Daniel L. Callaway

Stanley Chaleff

Kenneth J. Cohen

Allen I. Stering

David H. Ebb

Andrea T. Franson

Stephanie A. Toll

Kathleen J. Yost

Laura K. Gowans

Michael K. Richards

Christopher L. Moertel

Jonathan D. Schwartz

Betty L. Herrington

Keith J. August

William S. Ferguson

Andrew S. Cluster

Jill C. Beck

Kathryn L. Laurie

Lauren R. Weintraub

Matthew J. Barth

Chana L. Glasser

Mark P. Atlas

Elizabeth A. Raetz

Sameer Farouk Sait

Melanie A. Comito

Jessica C. Hochberg

David E. Kram

Joel A. Kaplan

Jessica M. Sun

Andrea R. Whitfield

Thomas W. McLean

Samuel J. Milanovich

Erin Wright

Peter M. de Blank

Duncan S. Stearns

Mark A. Ranalli

Mukund G. Dole

Rene Y. McNall-Knapp

Linda C. Stork

Jagadeesh Ramdas

Lisa M. McGregor

Michael J. Fisher

James T. Felker

Jennifer J. Welch

Jacqueline M. Kraveka

Stuart L. Cramer

Aniket Saha

Susan E. Spiller

Anna Vinitsky

Devang J. Pastakia

Shannon M. Cohn

Daniel C. Bowers

Benjamin Carcamo

Sibo Zhao

Murali M. Chintagumpala

Najat C. Daw

Peter M de Blank

This phase III 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.

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. Patients also undergo collection of blood and magnetic resonance imaging (MRI) at baseline and end of induction.

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. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up.

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. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up.

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.

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)

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

QOL scores for each domain of the PedsQL Generic module will be summarized by timepoint (4 timepoints) and treatment arm. Mean QOL scores will be reported with standard deviations. If scores do not follow normal distributions, medians and ranges will be reported instead.

Neurocognitive functioning scores for each index/scale of the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) will be summarized by timepoint (4 timepoints) and treatment arm. Mean scores will be reported with standard deviations. If scores do not follow normal distributions, medians and ranges will be reported instead.

The Kaplan-Meier method will be used to estimate EFS which is defined as the interval from randomization to first occurrence of clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause, or to the date of last follow-up. Estimates with 95% confidence intervals will be reported by treatment arm. The hazard ratio with a confidence interval will also be reported to compare treatment arms based on a Cox proportional hazards model stratified by BRAF status, tumor location and size of residual tumor.

Percentages of patients with responses (complete or partial response) will be reported by treatment arm with 95% confidence intervals. The result of an exact binomial test to test for the difference in response rates between treatment arm will also be reported.

The Kaplan-Meier method will be used to estimate OS by treatment arm, defined as the interval from randomization to death from any cause, or to the date of last follow-up. Estimates with confidence intervals will be reported by treatment arm.

Numbers of patients that show improvement in VA after 12 months of treatment will be reported by treatment arm. Patients with at least 1 impaired eye are evaluable. In a patient with a unilateral optic nerve glioma, only the affected eye is considered. In patients with bilateral visual impairment, if VA improves in 1 eye but worsens in the other, the patient will be coded as a treatment failure, whereas if 1 eye improves and the other is at least stable, the patient will be coded as a success.

Motor function is measured using the Vineland-3 Motor Scale. Only patients with motor function deficits at baseline are included. Magnitudes of change for each patient after 48 weeks of therapy from baseline will be calculated and medians (with ranges) by treatment arm will be reported.

QOL will be measured using the PedsQL Total Scale Score as measured from the validated PedsQL Generic Module (for children 2-21 years old). Mean differences in the total scale score between 9 months and baseline will be reported by treatment arm. The results of 2-sample t-test comparing differences in the QOL scores between the 2 arms will also be reported. If change scores do not follow normal distributions, non-parametric alternatives may be employed for analysis.

Measured by Wechsler Processing Speed Index (standard score). Scores at 9 months will be summarized by treatment arm and reported as means (with standard deviations) or medians (with ranges) depending on the data distribution.

Executive function will be measured by the BRIEF-2 Cognitive Regulation Index (CRI). Summary statistics for the differences in scores from baseline to 9 months will be reported by treatment arm.

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for metastatic low grade astrocytoma