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

• ClinicalTrials.gov Identifier: NCT04939597
• Recruitment Status: Recruiting
• First Posted: June 25, 2021
• Last Update Posted: February 29, 2024
• Sponsor: Children's Oncology Group
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: October 1, 2020
• First Posted Date: June 25, 2021
• Last Update Posted Date: February 29, 2024
• Actual Study Start Date: November 15, 2021
• Estimated Primary Completion Date: September 30, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 5, 2024)

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) [ Time Frame: Up-to 12 months post baseline ]

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.

Original Primary Outcome Measures (submitted: June 17, 2021)

Estimate the difference in change of Cogstate composite Z scores over time between 2 treatment arms [ Time Frame: From baseline up to 13 months after baseline ]

Cogstate composite Z score is an average of Detection Z scores, Identification Z scores, and One-back Z scores calculated using Cogstate age-based normative data. The difference in slopes of Cogstate composite Z scores over time will be estimated via a mixed model.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: March 14, 2023)

• Intelligence quotient score (assessed by age-appropriate Wechsler Intelligence Scale) [ Time Frame: At 12-months post baseline ]
  We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
• Processing speed score (assessed by processing speed/attention subtests of age-appropriate Wechsler Intelligence Scale) [ Time Frame: At 12-months post baseline ]
  We will estimate the difference in mean standard scores and will provide a point estimate and corresponding 95% confidence interval.
• 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) [ Time Frame: At 12-months post baseline ]
  We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
• Visual memory score (assessed by CMS or WMS-IV Faces subtest scores, Immediate and Delayed, depending on age) [ Time Frame: At 12-months post baseline ]
  We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
• Working memory score (assessed by Digit Span subtests of age-appropriate Wechsler Intelligence Scales) [ Time Frame: At 12-months post baseline ]
  We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
• 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) [ Time Frame: At 12-months post baseline ]
  We will estimate the difference in mean standard scores and will provide a point estimate and corresponding 95% confidence interval.
• Visual learning score (assessed by CMS Dot Locations subtest or WMS-IV Symbol Span subtest, depending on age) [ Time Frame: At 12-months post baseline ]
  We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
• Executive functioning score (assessed by the Cognitive Regulation Index of the Brief Rating Inventory of Executive Function) [ Time Frame: At 12-months post baseline ]
  We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
• Disease-free survival [ Time Frame: Up-to 36 months post baseline ]
  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.
• Overall survival [ Time Frame: Up-to 36 months post baseline ]
  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.
• Quantitative volumetric magnetic resonance imaging (MRI) measurements of critical brain regions (hippocampus, frontal cortex) [ Time Frame: At 12-months post baseline ]
  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).
• Number of patients who consented to biobanking [ Time Frame: Up-to 12 months post baseline ]
  The number of patients who agree to be in the biobanking part of the study future research.
• Composite cognitive score decline (0.5 standard deviation or more decline in Cogstate composite score relative to baseline) [ Time Frame: At 12-months post 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.

Original Other Pre-specified Outcome Measures (submitted: June 17, 2021)

• Intelligence quotient score [ Time Frame: At 12 months post baseline ]
  Assessed by intelligence assessment.
• Processing speed score [ Time Frame: At 12 months post baseline ]
  Assessed by processing speed/attention assessment.
• Verbal memory score: CMS [ Time Frame: At 12 months post baseline ]
  From Children's Memory Scale (CMS) Stories assessment, using Immediate, Delayed, and Recognition scores; and from the Wechsler Memory Scale - Fourth Edition (WMS-IV) using Logical Memory I and II.
• Verbal memory score: WMS-IV [ Time Frame: At 12months post baseline ]
  Assessed by the Wechsler Memory Scale - Fourth Edition (WMS-IV) using Logical Memory I and II.
• Visual memory score: CMS [ Time Frame: At 12 months post baseline ]
  Assessed by CMS Faces assessment, using Immediate and Delayed.
• Working memory score: WISC-V [ Time Frame: At 12 months post baseline ]
  Assessed by Wechsler Intelligence Scale for Children-Fifth Edition Digit Span and Wechsler Adult Intelligence Scale - Fourth Edition Digit Span assessments, using forwards, backwards, sequencing.
• Working memory score: WAIS-IV [ Time Frame: At 12 months post baseline ]
  Assessed by Wechsler Adult Intelligence Scale - Fourth Edition Digit Span assessments.
• Verbal score: CVLT-C [ Time Frame: At 12 months post baseline ]
  Assessed by the California Verbal Learning Test - Children's Version (CVLT-C) and 2nd Edition (CVLT-II) assessment, using the List A Trials 1-5 Total T-score.
• Verbal score: CVLT-II [ Time Frame: At 12months post baseline ]
  Assessed by the 2nd Edition (CVLT-II) assessment, using the List A Trials 1-5 Total T-score.
• Visual learning score [ Time Frame: At 12 months post baseline ]
  Assessed by CMS Dot Locations assessment, using Total, Learning, Delay.
• Executive functioning score [ Time Frame: At 12 months post baseline ]
  Assessed by Executive Function assessment using Cognitive Regulation Index.
• Estimate the difference in change of Cogstate composite Z scores over time between 2 treatment arms [ Time Frame: From baseline up to 7 months after baseline ]
  Cogstate composite Z score is an average of Detection Z scores, Identification Z scores, and One-back Z scores calculated using Cogstate age-based normative data.
• Cogstate composite Z score: 30 months [ Time Frame: At 30 months post baseline ]
  The difference in slopes of Cogstate composite Z scores over time will be estimated via a mixed model. Cogstate composite Z score is an average of Detection Z scores, Identification Z scores, and One-back Z scores calculated using Cogstate age-based normative data.
• Cogstate composite Z score: 60 months [ Time Frame: At 60 months post baseline ]
  Cogstate composite Z score is an average of Detection Z scores, Identification Z scores, and One-back Z scores calculated using Cogstate age-based normative data.
• Disease-free survival [ Time Frame: At 36 months ]
• Overall survival [ Time Frame: At 36 months ]
• Quantitative volumetric magnetic resonance imaging measurements of critical brain regions (hippocampus, frontal cortex) [ Time Frame: Up to 30 months ]
• Number of patients who consented to Biobanking [ Time Frame: At Baseline ]
  The number of patients who agree to be in the Biobanking part of the study future research.
• Incidence of composite cognitive score decline [ Time Frame: At 12 months post baseline ]

Descriptive Information

• Brief Title: A Study to See if Memantine Protects the Brain During Radiation Therapy Treatment for Primary Central Nervous System Tumors
• 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
• Brief 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.

Detailed 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Supportive Care
• Condition: Central Nervous System Carcinoma

Intervention

• Procedure: Biospecimen Collection
  Undergo blood sample collection
  Other Names:

  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
• Procedure: Cognitive Assessment
  Complete cognitive testing
• Procedure: Magnetic Resonance Imaging
  Undergo MRI
  Other Names:

  • Magnetic Resonance
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • MRIs
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • sMRI
  • Structural MRI
• Drug: Memantine Hydrochloride
  Given PO
  Other Names:

  • Ebixia
  • Namenda
• Drug: Placebo Administration
  Given PO
• Other: Questionnaire Administration
  Ancillary studies

Study Arms

• Experimental: Arm I (memantine hydrochloride)
  Patients receive memantine hydrochloride orally 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.
  Interventions:

  • Procedure: Biospecimen Collection
  • Procedure: Cognitive Assessment
  • Procedure: Magnetic Resonance Imaging
  • Drug: Memantine Hydrochloride
  • Other: Questionnaire Administration
• Placebo Comparator: Arm II (placebo)
  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.
  Interventions:

  • Procedure: Biospecimen Collection
  • Procedure: Cognitive Assessment
  • Procedure: Magnetic Resonance Imaging
  • Drug: Placebo Administration
  • Other: Questionnaire Administration

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 30, 2023): 192
• Original Estimated Enrollment (submitted: June 17, 2021): 162
• Estimated Study Completion Date: September 30, 2027
• Estimated Primary Completion Date: September 30, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT04939597
• Other Study ID Numbers: ACCL2031; NCI-2020-07502 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ACCL2031 ( Other Identifier: Children's Oncology Group ); COG-ACCL2031 ( Other Identifier: DCP ); ACCL2031 ( Other Identifier: CTEP ); U01CA246568 ( U.S. NIH Grant/Contract ); U24CA196173 ( U.S. NIH Grant/Contract ); UG1CA189955 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Nadia N Laack; Children's Oncology Group

• PRS Account: Children's Oncology Group
• Verification Date: January 2024