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Memantine Hydrochloride and W...

Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases

Last Updated: 2025-04-23

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

518 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-07-31

Study Completion Date

2019-08-26

Brief Summary

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This randomized phase III trial compares memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing neurocognitive decline in patients with cancer that has spread from the primary site (place where it started) to the brain. Whole brain radiotherapy (WBRT) is the most common treatment for brain metastasis. Unfortunately, the majority of patients with brain metastases experience cognitive (such as learning and memory) deterioration after WBRT. Memantine hydrochloride may enhance cognitive function by binding to and inhibiting channels of receptors located in the central nervous system. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Using radiation techniques, such as intensity modulated radiotherapy to avoid the hippocampal region during WBRT, may reduce the radiation dose to the hippocampus and help limit the radiation-induced cognitive decline. It is not yet known whether giving memantine hydrochloride and WBRT with or without hippocampal avoidance works better in reducing neurocognitive decline in patients with brain metastases.

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Detailed Description

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PRIMARY OBJECTIVES:

I. Determine whether the addition of whole-brain radiotherapy with hippocampal avoidance (HA-WBRT) increases time to neurocognitive failure at months 2, 4, 6, and 12 as measured by neurocognitive decline on a battery of tests: the Hopkins Verbal Learning Test-Revised (HVLT-R) for Total Recall, Delayed Recall, and Delayed Recognition, Controlled Oral Word Association (COWA), and the Trail Making Test (TMT) Parts A and B.

SECONDARY OBJECTIVES:

I. Determine whether the addition of HA-WBRT preserves neurocognitive function at months 2, 4, 6, and 12 as separately measured by each test, the HVLT-R for Total Recall, Delayed Recall, and Delayed Recognition; COWA; and TMT Parts A and B.

II. Evaluate the potential benefit of HA-WBRT in symptom burden, as measured by the M. D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT).

III. Assessment of quality adjusted survival and cost analysis using the five-level version of the EuroQol five-dimensional (EQ-5D-5L).

IV. Compare cumulative incidence of progression and overall survival after WBRT versus HA-WBRT.

V. Compare adverse events between the treatment arms according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 criteria.

TERTIARY OBJECTIVES:

I. Collect serum, plasma, and imaging studies for future translational research analyses.

II. Evaluate magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry at baseline and 6 months as potential predictors of neurocognitive decline and differential benefit from HA-WBRT as compared to WBRT.

III. Association of symptom burden and anxiety/depression with neurocognitive function.

IV. Evaluate the potential correlation between the prognostic scoring systems Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) and the diagnosis-specific graded prognostic assessment (DS-GPA) and neurocognitive function at baseline and overtime.

After completion of study treatment, patients are followed up at 12 months.

Conditions

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Cognitive Impairment Metastatic Malignant Neoplasm in the Brain Solid Neoplasm

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

SUPPORTIVE_CARE

Blinding Strategy

NONE

Study Groups

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WBRT + Memantine

Whole brain radiation therapy (WBRT) and memantine

Group Type EXPERIMENTAL

Memantine

Intervention Type DRUG

Given PO daily during and after radiation therapy for a total of 24 weeks. Week 1: 5 mg in the AM, none in the PM; Week 2: 5 mg in the AM, 5 mg in the PM; Week 3: 10 mg in the AM, 5 mg in the PM; Weeks 4-24: 10 mg in the AM, 10 mg in the PM. Should start the same day as radiation therapy, at latest before the fourth radiation treatment.

Whole brain radiation therapy

Intervention Type RADIATION

Whole brain radiation therapy (WBRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately 2 weeks

HA-WBRT/IMRT+ Memantine

Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) using intensity modulated radiation therapy (IMRT) and memantine

Group Type EXPERIMENTAL

Whole brain radiation therapy with hippocampal avoidance

Intervention Type RADIATION

Intensity modulated radiation therapy (IMRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately two week; starting within 21 calendar days after randomization.

Memantine

Intervention Type DRUG

Interventions

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Whole brain radiation therapy with hippocampal avoidance

Intensity modulated radiation therapy (IMRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately two week; starting within 21 calendar days after randomization.

Intervention Type RADIATION

Memantine

Intervention Type DRUG

Whole brain radiation therapy

Whole brain radiation therapy (WBRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately 2 weeks

Intervention Type RADIATION

Other Intervention Names

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IMRT Intensity Modulated RT INTENSITY-MODULATED RADIATION THERAPY Intensity-Modulated Radiotherapy Whole-brain radiation therapy WBRT whole-brain radiotherapy HA-WBRT Ebixia Memantine Hydrochloride Namenda WBRT whole-brain radiation therapy whole-brain radiotherapy

Eligibility Criteria

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Inclusion Criteria

* PRIOR TO STEP 1 REGISTRATION:

* Brain metastases outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed =\< 21 days prior to Step 1 registration; an allowed exception, regarding ability to image brain metastases, would be that patients who had undergone radiosurgery or surgical resection and are planning adjuvant WBRT do not have to have visible disease but do need a pre-surgery MRI or computed tomography (CT) scan demonstrating brain metastases; however, the brain metastases could not have been within 5 mm of either hippocampus
* Patients must have a gadolinium contrast-enhanced three-dimensional spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) axial MRI scan with standard axial and coronal gadolinium contrast-enhanced T1-weighted sequence and axial T2/FLAIR sequence acquisitions; to yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan should use the smallest possible axial slice thickness not exceeding 1.5 mm; the associated coronal and sagittal contrast-enhanced T1 sequences can be up to 2.5 mm in slice thickness; this MRI must be obtained =\< 21 days prior to step 1 registration; the vendor specific MRI protocols are available for download from the Alzheimer's Disease Neuroimaging Initiative (ADNI)
* Patients must provide study-specific informed consent prior to registration
* PRIOR TO STEP 2 REGISTRATION:

* The following baseline neurocognitive assessments must be completed prior to Step 2 registration: HVLT-R, TMT, and COWA;
* Pathologically (histologically or cytologically) proven diagnosis of solid tumor malignancy within 5 years prior to Step 2 registration
* History and physical examination within 28 days prior to Step 2 registration
* Karnofsky performance status of \>= 70 within 28 days prior to Step 2 registration
* Serum creatinine =\< 3 mg/dL (265 umol/L) and creatinine clearance \>= 30 ml/min
* Blood urea nitrogen (BUN) within institutional upper limit of normal (e.g. \< 20 mg/dL)
* Total bilirubin =\< 2.5 mg/dL (43 umol/L)
* Patients may have had prior therapy for brain metastasis, including radiosurgery and surgical resection; patients must have completed prior therapy by at least 14 days prior to Step 2 for surgical resection and 7 days for radiosurgery
* Negative serum pregnancy test (in women of childbearing potential) =\< 14 days prior to Step 2; women of childbearing potential and men who are sexually active must practice adequate contraception while on study
* Patients who are primary English or French speakers are eligible

Exclusion Criteria

* Prior external beam radiation therapy to the brain or whole brain radiation therapy
* Planned cytotoxic chemotherapy during the WBRT only; patients may have had prior chemotherapy
* Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt
* Severe, active co-morbidity defined as follows:

* Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
* Transmural myocardial infarction within the last 6 months
* Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
* Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of registration
* Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
* Renal tubular acidosis or metabolic acidosis
* Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 count \< 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count \>= 200 cells/microliter within 30 days prior to registration; Note also that HIV testing is not required for eligibility for this protocol
* Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
* Prior allergic reaction to memantine (memantine hydrochloride)
* Current alcohol or drug abuse (may exacerbate lethargy/dizziness with memantine)
* Intractable seizures while on adequate anticonvulsant therapy-more than 1 seizure per month for the past 2 months
* Patients with definitive leptomeningeal metastases
* Patients with brain metastases from primary germ cell tumors, small cell carcinoma, unknown primary, or lymphoma
* Contraindication to magnetic resonance (MR) imaging such as implanted metal devices or foreign bodies
* Contraindication to gadolinium contrast administration during MR imaging, such as allergy or insufficient renal function
* Current use of (other N-methyl D-aspartate \[NMDA\] antagonists) amantadine, ketamine, or dextromethorphan

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Paul Brown

Role: PRINCIPAL_INVESTIGATOR

NRG Oncology

Locations

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Lewis and Faye Manderson Cancer Center

Tuscaloosa, Alabama, United States

Site Status

Banner MD Anderson Cancer Center

Gilbert, Arizona, United States

Site Status

Banner University Medical Center - Tucson

Tucson, Arizona, United States

Site Status

Providence Saint Joseph Medical Center/Disney Family Cancer Center

Burbank, California, United States

Site Status

Mercy San Juan Medical Center

Carmichael, California, United States

Site Status

City of Hope Comprehensive Cancer Center

Duarte, California, United States

Site Status

UC San Diego Moores Cancer Center

La Jolla, California, United States

Site Status

Kaiser Permanente Los Angeles Medical Center

Los Angeles, California, United States

Site Status

Los Angeles County-USC Medical Center

Los Angeles, California, United States

Site Status

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States

Site Status

Kaiser Permanente Oakland-Broadway

Oakland, California, United States

Site Status

Stanford Cancer Institute Palo Alto

Palo Alto, California, United States

Site Status

Kaiser Permanente-Rancho Cordova Cancer Center

Rancho Cordova, California, United States

Site Status

Rohnert Park Cancer Center

Rohnert Park, California, United States

Site Status

Sutter Cancer Centers Radiation Oncology Services-Roseville

Roseville, California, United States

Site Status

The Permanente Medical Group-Roseville Radiation Oncology

Roseville, California, United States

Site Status

Mercy Cancer Center - Sacramento

Sacramento, California, United States

Site Status

Sutter Medical Center Sacramento

Sacramento, California, United States

Site Status

University of California San Diego

San Diego, California, United States

Site Status

California Pacific Medical Center-Pacific Campus

San Francisco, California, United States

Site Status

Stanford Cancer Center South Bay

San Jose, California, United States

Site Status

Kaiser Permanente Medical Center - Santa Clara

Santa Clara, California, United States

Site Status

Kaiser Permanente Cancer Treatment Center

South San Francisco, California, United States

Site Status

Sutter Solano Medical Center/Cancer Center

Vallejo, California, United States

Site Status

Rocky Mountain Cancer Centers-Boulder

Boulder, Colorado, United States

Site Status

Penrose-Saint Francis Healthcare

Colorado Springs, Colorado, United States

Site Status

UCHealth Memorial Hospital Central

Colorado Springs, Colorado, United States

Site Status

Swedish Medical Center

Englewood, Colorado, United States

Site Status

Saint Vincent's Medical Center

Bridgeport, Connecticut, United States

Site Status

Helen F Graham Cancer Center

Newark, Delaware, United States

Site Status

Christiana Care Health System-Christiana Hospital

Newark, Delaware, United States

Site Status

Boca Raton Regional Hospital

Boca Raton, Florida, United States

Site Status

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida, United States

Site Status

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida, United States

Site Status

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, United States

Site Status

UF Cancer Center at Orlando Health

Orlando, Florida, United States

Site Status