SMART Trial: Cognitive Sparing Brain Radiotherapy for Multiple Brain Metastases

1. Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases
2. Patients with brain metastasis outside a 5-mm margin around either hippocampus or corpus callosum on gadolinium contrast-enhanced MRI obtained within 30 days prior to registration
3. Patients with 6 or more active or progressive brain metastases that have not been treated by radiotherapy or radiosurgery
4. No evidence of diffuse leptomeningeal metastasis on gadolinium-enhanced MRI within 30 days prior registration
5. Age ≥ 18 years
6. Karnofsky Performance Status ≥ 60%
7. Life expectancy ≥ 6 months.
8. Women of childbearing potential and male participants must practice adequate contraception
9. Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent

Exclusion Criteria:

1. Prior radiotherapy to brain or radiosurgery to > 5 intracranial metastatic lesion(s)
2. Clinical diagnosis of symptomatic leptomeningeal metastsases
3. Contraindication to MR imaging such as implanted metal devices or foreign bodies, severe claustrophobia

4. Severe, active comorbidities 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 adverse events of the protocol, or limit compliance with study requirements, defined as follows:

   1. Uncontrolled active infection requiring intravenous antibiotics at the time of registration
   2. Transmural myocardial infarction ≤ 6 months prior to registration
   3. Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
   4. Life-threatening uncontrolled clinically significant cardiac arrhythmias
   5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
   6. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
   7. Uncontrolled psychiatric disorder
5. Will receive any other investigation agent or chemotherapy during cranial radiotherapy or radiosurgery
6. Current use of Memantine HCL or Allergy to Memantine HCL
7. Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic
8. Pregnant or breast-feeding women