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This phase III trial compares memantine to placebo 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.

Primary Objective:

1. 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:

1. 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.

2. 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.

3. 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.

4. 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).

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

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

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

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

9. 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.

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