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A Study to See if Memantine Protects the Brain During Radiation Therapy Treatment for a Brain Tumor

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ClinicalTrials.gov Identifier: NCT04939597
Recruitment Status : Not yet recruiting
First Posted : June 25, 2021
Last Update Posted : June 25, 2021
Sponsor:
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:
This phase III trial compares memantine to usual treatment in treating patients with brain tumors that are newly diagnosed or has come back (recurrent). 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 brain tumor.

Condition or disease Intervention/treatment Phase
Brain Neoplasm Recurrent Brain Neoplasm Procedure: Cognitive Assessment Drug: Memantine Hydrochloride Drug: Placebo Administration Phase 3

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 version (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 30 and 60 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 (30 and 60 months Cogstate composite score).

V. To correlate COG Standardized Battery scores to Cogstate composite scores at 12, 30, and 60 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) twice daily (BID) for 24 weeks 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, 30, and 60 months.

ARM II: Patients receive placebo PO BID for 24 weeks 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, 30, and 60 months.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 162 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Estimated Study Start Date : September 1, 2021
Estimated Primary Completion Date : October 15, 2030
Estimated Study Completion Date : October 15, 2030

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Brain Tumors

Arm Intervention/treatment
Experimental: Arm I (memantine hydrochloride)
Patients receive memantine hydrochloride PO BID for 24 weeks 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, 30, and 60 months.
Procedure: Cognitive Assessment
Complete cognitive testing

Drug: Memantine Hydrochloride
Given PO
Other Names:
  • Ebixia
  • Namenda

Placebo Comparator: Arm II (placebo)
Patients receive placebo PO BID for 24 weeks 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, 30, and 60 months.
Procedure: Cognitive Assessment
Complete cognitive testing

Drug: Placebo Administration
Given PO




Primary Outcome Measures :
  1. 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.


Other Outcome Measures:
  1. Intelligence quotient score [ Time Frame: At 12 months post baseline ]
    Assessed by intelligence assessment.

  2. Processing speed score [ Time Frame: At 12 months post baseline ]
    Assessed by processing speed/attention assessment.

  3. 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.

  4. 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.

  5. Visual memory score: CMS [ Time Frame: At 12 months post baseline ]
    Assessed by CMS Faces assessment, using Immediate and Delayed.

  6. 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.

  7. Working memory score: WAIS-IV [ Time Frame: At 12 months post baseline ]
    Assessed by Wechsler Adult Intelligence Scale - Fourth Edition Digit Span assessments.

  8. 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.

  9. 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.

  10. Visual learning score [ Time Frame: At 12 months post baseline ]
    Assessed by CMS Dot Locations assessment, using Total, Learning, Delay.

  11. Executive functioning score [ Time Frame: At 12 months post baseline ]
    Assessed by Executive Function assessment using Cognitive Regulation Index.

  12. 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.

  13. 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.

  14. 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.

  15. Disease-free survival [ Time Frame: At 36 months ]
  16. Overall survival [ Time Frame: At 36 months ]
  17. Quantitative volumetric magnetic resonance imaging measurements of critical brain regions (hippocampus, frontal cortex) [ Time Frame: Up to 30 months ]
  18. 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.

  19. Incidence of composite cognitive score decline [ Time Frame: At 12 months post baseline ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   4 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must weigh 15 kg or greater at time of study entry
  • Newly diagnosed or recurrent primary brain tumors that have not received prior cranial radiotherapy
  • Planned focal, cranial or craniospinal radiation treatment for a primary brain 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 memantine
    • 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
    • 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 computerized neurocognitive assessments are not eligible to participate
    • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04939597


Sponsors and Collaborators
Children's Oncology Group
Investigators
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Principal Investigator: Nadia N Laack Children's Oncology Group
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Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT04939597    
Other Study ID Numbers: ACCL2031
NCI-2020-07502 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACCL2031 ( Other Identifier: Children's Oncology Group )
ACCL2031 ( Other Identifier: DCP )
ACCL2031 ( Other Identifier: CTEP )
U01CA246568 ( U.S. NIH Grant/Contract )
UG1CA189955 ( U.S. NIH Grant/Contract )
First Posted: June 25, 2021    Key Record Dates
Last Update Posted: June 25, 2021
Last Verified: June 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Central Nervous System Diseases
Brain Diseases
Nervous System Diseases
Memantine
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents