for people ages 18 years and up (full criteria)
at La Jolla, California and other locations
study started
estimated completion



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.

Official Title

A Randomized Phase III Trial of Memantine and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Patients With Brain Metastases



  1. 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.


  1. 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.

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


  1. 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.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive memantine hydrochloride orally (PO) twice daily (BID) for 24 weeks. Patients undergo WBRT daily over approximately 2 weeks (10 fractions).

ARM II: Patients receive memantine hydrochloride as in Arm I. Patients undergo HA-WBRT using intensity modulated radiation therapy (IMRT) daily over approximately 2 weeks (10 fractions).

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


Cognitive Impairment Metastatic Malignant Neoplasm in the Brain Solid Neoplasm Cognitive Dysfunction Neoplasms Memantine Cognitive Assessment Intensity-Modulated Radiation Therapy Memantine Hydrochloride Quality-of-Life Assessment Whole-Brain Radiotherapy


You can join if…

Open to people ages 18 years and up

  • 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
  • The following baseline neurocognitive assessments must be completed prior to Step 2 registration: HVLT-R, TMT, and COWA; the neurocognitive assessment will be uploaded into the NRG RAVE System for evaluation by Dr. Wefel; once the upload is complete, a notification will be sent to proceed to Step 2; NOTE: completed baseline neurocognitive assessments can be uploaded at the time of Step 1 registration
  • 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

You CAN'T join if...

  • 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


  • UC San Diego Moores Cancer Center
    La Jolla California 92093 United States
  • University of California San Diego
    San Diego California 92103 United States


in progress, not accepting new patients
Start Date
Completion Date
NRG Oncology
Phase 3
Study Type
Last Updated