Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases
Condition: Cognitive Impairment; Metastatic Malignant Neoplasm in the Brain; Solid Neoplasm
MeSH terms: Neoplasms; Brain Neoplasms
Intervention: Whole brain radiation therapy with hippocampal avoidance; Memantine; Whole brain radiation therapy
Intervention description: 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.; 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 (WBRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately 2 weeks
Intervention MeSH terms: Memantine
Phase: Phase 3
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 518.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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