A Study to See if Memantine Protects the Brain During Radiation Therapy Treatment for Primary Central Nervous System Tumors

Central Nervous System Carcinoma Clinical Trial

Official title:

A Phase 3 Randomized, Placebo-Controlled Trial Evaluating Memantine for Neurocognitive Protection in Children Undergoing Cranial Radiotherapy as Part of Treatment for Primary Central Nervous System Tumors

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04939597
• Other study ID #: ACCL2031
• Secondary ID: NCI-2020-07502AC
• Status: Recruiting
• Phase: Phase 3
• Start date: May 10, 2022
• Est. completion date: September 30, 2027

Study information

• Verified date: January 2024
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase III trial compares memantine to usual treatment in treating patients with primary central nervous system tumors. Memantine may block receptors (parts of nerve cells) in the brain known to contribute to a decline in cognitive function. Giving memantine may make a difference in cognitive function (attention, memory, or other thought processes) in children and adolescents receiving brain radiation therapy to treat a primary central nervous system tumors.

Description:

PRIMARY OBJECTIVE:

I. To determine the efficacy, as measured by the slope of change of the Cogstate composite Z score from baseline to 12 months, of oral memantine hydrochloride (memantine) administered for a period of 6 months, when compared to placebo, in children ages 4-18 receiving cranial or craniospinal radiotherapy for primary central nervous system tumors.

EXPLORATORY OBJECTIVES:

I. To determine if memantine is associated with improved cognitive function as measured for participants in the optional Children's Oncology Group (COG) Standardized Battery at 12 months.

II. To determine if memantine is associated with change in cognitive function versus (vs.) placebo as measured by Cogstate composite score at end of radiation therapy (RT), 3 and 6 months.

III. To determine if memantine is associated with differences in cognitive function vs. placebo as measured by Cogstate composite score at 24 and 48 months for participants in the optional COG Standardized Battery.

IV. To correlate early cognitive changes (end of RT, 3, 6, 12 months Cogstate composite score) with late cognitive function (24 and 48 months Cogstate composite score).

V. To correlate COG Standardized Battery scores to Cogstate composite scores at 12, 24, and 48 months.

VI. To estimate the 36-month disease-free and overall survival (of primary brain tumor) after memantine treatment compared to placebo.

VII. To correlate changes in quantitative volumetric magnetic resonance imaging (MRI) measurements of critical brain regions with cognitive function over time.

VIII. To evaluate impact of memantine versus placebo on molecular biomarkers associated with cognitive decline after radiotherapy.

IX. To determine whether oral memantine, when compared to placebo, is associated with reduction in the incidence of decline of composite Cogstate score at 12 months in children ages 4-18 receiving cranial radiotherapy for primary central nervous system tumors.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive memantine hydrochloride orally (PO) once daily (QD) for week 1 and then twice daily (BID) for weeks 2-24 in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 24, and 48 months. Patients undergo MRI and may optionally undergo blood sample collection throughout the trial.

ARM II: Patients receive placebo PO QD for week 1 and then BID for weeks 2-24 in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 24, and 48 months. Patients undergo MRI and may optionally undergo blood sample collection throughout the trial.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 192
• Est. completion date: September 30, 2027
• Est. primary completion date: September 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 17 Years

Eligibility

Inclusion Criteria:

• >= 4 and < 18 years at time of study entry

• Patients must weigh 15 kg or greater at time of study entry

• Primary central nervous system tumors that have not received prior cranial radiotherapy

• Planned focal, cranial or craniospinal radiation treatment for a primary central nervous system tumor

• The patient must have receptive and expressive language skills in English, French or Spanish since the neurocognitive function and quality of life (QOL) assessment instruments are available in these languages only

• 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: 4 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 male; 0.8 female

• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 male; 1 female

• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 male; 1.2 female

• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 male; 1.4 female

• Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 male; 1.4 female

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

• Serum glutamate pyruvate 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

• The patient must be able to undergo magnetic resonance imaging

• 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:

• Life expectancy of less than 18 months

• Pre-existing conditions:

• Any contraindication or allergy to study drug (memantine or placebo)

• Intractable seizures while on adequate anticonvulsant therapy, defined as more than one seizure per month for the past 2 months or since initiating anticonvulsant therapy

• History of neurodevelopmental disorder such as Down syndrome, Fragile X, William's Syndrome, intellectual disability (presumed intelligence quotient [IQ] < 70), etc

• Co-morbid systemic illnesses, psychiatric conditions, social situations, or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or would limit compliance with the study requirements

• Patients with a motor, visual, or auditory condition that precludes participation in computerized neurocognitive assessments

• Patients with any medical condition or taking medications that lead to alterations of urine pH towards the alkaline condition (e.g., renal tubular acidosis, carbonic anhydrase inhibitors, sodium bicarbonate)

• Personal history of prior cranial or craniospinal radiotherapy is not allowed

• Note: Prior anti-cancer therapy including surgery, chemotherapy, targeted agents are allowed as per standard of care clinical treatment guidelines

• Female patients who are pregnant are excluded since fetal toxicities and teratogenic effects have been noted for the study drug. 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 do not agree to use an effective contraceptive method for the duration of their study participation

Related Conditions & MeSH terms

• Central Nervous System Carcinoma
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Cognitive Assessment
Complete cognitive testing
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Memantine Hydrochloride
Given PO
• Placebo Administration
Given PO

Other:
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
Puerto Rico	HIMA San Pablo Oncologic Hospital	Caguas
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Maimonides Medical Center	Brooklyn	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Columbia Regional	Columbia	Missouri
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	El Paso Children's Hospital	El Paso	Texas
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Banner Children's at Desert	Mesa	Arizona
United States	Miami Cancer Institute	Miami	Florida
United States	Nicklaus Children's Hospital	Miami	Florida
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Carilion Children's	Roanoke	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Tampa General Hospital	Tampa	Florida
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Children's Oncology Group

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Intelligence quotient score (assessed by age-appropriate Wechsler Intelligence Scale)	We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.	At 12-months post baseline
Other	Processing speed score (assessed by processing speed/attention subtests of age-appropriate Wechsler Intelligence Scale)	We will estimate the difference in mean standard scores and will provide a point estimate and corresponding 95% confidence interval.	At 12-months post baseline
Other	Verbal memory score (assessed by Children's Memory Scale [CMS] Stories subtest, or the Wechsler Memory Scale - Fourth Edition [WMS-IV] Logical Memory I and II subtests, depending on age)	We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.	At 12-months post baseline
Other	Visual memory score (assessed by CMS or WMS-IV Faces subtest scores, Immediate and Delayed, depending on age)	We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.	At 12-months post baseline
Other	Working memory score (assessed by Digit Span subtests of age-appropriate Wechsler Intelligence Scales)	We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.	At 12-months post baseline
Other	Verbal score (assessed by the California Verbal Learning Test - Children's Version [CVLT-C] or 2nd Edition [CVLT-II] based on age, using the List A Trials 1-5 Total T-score)	We will estimate the difference in mean standard scores and will provide a point estimate and corresponding 95% confidence interval.	At 12-months post baseline
Other	Visual learning score (assessed by CMS Dot Locations subtest or WMS-IV Symbol Span subtest, depending on age)	We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.	At 12-months post baseline
Other	Executive functioning score (assessed by the Cognitive Regulation Index of the Brief Rating Inventory of Executive Function)	We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.	At 12-months post baseline
Other	Disease-free survival	We will estimate the hazard ratio comparing time-to-relapse of primary brain tumor or death due to any cause in the memantine relative to placebo arm and will provide a point estimate and corresponding 95% confidence interval.	Up-to 36 months post baseline
Other	Overall survival	We will estimate the hazard ratio comparing time-to- death due to any cause in the memantine relative to placebo arm and will provide a point estimate and corresponding 95% confidence interval.	Up-to 36 months post baseline
Other	Quantitative volumetric magnetic resonance imaging (MRI) measurements of critical brain regions (hippocampus, frontal cortex)	We will estimate a correlation coefficient between changes in quantitative volumetric MRI measurements for the three regions of interest and changes in Cogstate composite Z scores (from baseline to 12 months post baseline).	At 12-months post baseline
Other	Number of patients who consented to biobanking	The number of patients who agree to be in the biobanking part of the study future research.	Up-to 12 months post baseline
Other	Composite cognitive score decline (0.5 standard deviation or more decline in Cogstate composite score relative to baseline)	We will estimate the proportion of patients who experience composite cognitive score decline in the memantine and placebo arms and will provide corresponding 95% confidence intervals.	At 12-months post baseline
Primary	The mean slope of the Cogstate composite Z score (an average of detection, Identification, and one-back Z scores, each Z score calculated using Cogstate age-based normative data)	We will estimate the difference in mean Cogstate composite Z score slopes (reflecting change in Cogstate composite Z scores from baseline to 12 months post baseline taking into account measurements at those time points as well as end of radiation therapy and 3 and 6-months post baseline between the treatment and control arms using a generalized estimating equation model with compound symmetry correlation structure and will provide a point estimate and corresponding 95% confidence interval.	Up-to 12 months post baseline