memantine in preventing side effects in patients undergoing whole-brain radiation therapy for brain metastases from solid tumors

Conditions: Cognitive/Functional Effects; Metastatic Cancer; Neurotoxicity; Unspecified Adult Solid Tumor, Protocol Specific

Summary: rationale: memantine may be able to decrease side effects caused by whole-brain radiation therapy. it is not yet known if memantine is effective in preventing side effects caused by whole-brain radiation therapy. purpose: this randomized phase iii trial is studying memantine to see how well it works compared to a placebo in preventing side effects caused by whole-brain radiation therapy in patients with brain metastases from solid tumors.

objectives: primary * determine whether the addition of memantine hydrochloride to whole-brain radiotherapy (wbrt) preserves cognitive function, specifically memory, as measured by the hopkins verbal learning test for delayed recall (hvlt-delayed recall), over that of placebo and wbrt in patients with brain metastases at 24 weeks from the start of drug treatment. secondary * determine whether the addition of memantine hydrochloride preserves cognitive function, specifically memory, as measured by the hvlt-delayed recall at 8 weeks, 16 weeks, and 12 months from the start of drug treatment. * determine whether the addition of memantine hydrochloride increases time to neurocognitive failure as measured by cognitive decline on a battery of tests including the hvlt for free recall, delayed recall, and delayed recognition; the controlled word association test (cowat); the trail making test parts a and b (tmt); the medical outcomes scale-cognitive functioning subscale (mos); and the mini-mental status examination (mmse). * evaluate the potential benefit of memantine hydrochloride in change and overall quality of life, as measured by the functional assessment of cancer therapy-brain (fact-br) subscale. * determine whether the addition of memantine hydrochloride increases progression-free survival. * determine whether the addition of memantine hydrochloride increases overall survival. * compare adverse events between the treatment arms according to the ctcae v3.0 criteria. * collect serum, plasma, buffy coat cells, urine, and cerebrospinal fluid (csf) for future translational research analyses. outline: this is a multicenter study. patients are stratified according to recursive partitioning analysis (rpa) prognostic class (class i vs class ii with controlled systemic disease) and prior surgical therapy (none vs radiosurgery or surgical resection). patients are randomized to 1 of 2 treatment arms. * arm i: patients undergo whole-brain radiotherapy (wbrt) 5 days a week for 3 weeks (15 fractions). patients also receive oral memantine hydrochloride once daily beginning on day 1 of wbrt and continuing for 24 weeks. * arm ii: patients undergo wbrt as in arm i. patients also receive oral placebo once daily beginning on day 1 of wbrt and continuing for 24 weeks. after completion of study treatment, patients are followed at 6 months, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Eligibility criteria:
disease characteristics: * histologically or cytologically confirmed diagnosis of a solid tumor malignancy within the past 5 years * if the original histologic proof of malignancy is \> 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis) * brain metastases must be visible on contrast-enhanced mri or a contrast enhanced ct scan (for patients unable to undergo mri within the past 28 days) * patients unable to undergo mri imaging because of non-compatible devices are eligible, provided the contrast-enhanced ct scans are obtained and are of sufficient quality * patients who had undergone radiosurgery or surgical resection and are planning adjuvant whole-brain radiotherapy do not have to have visible disease but do need a baseline mri * must have stable systemic disease (i.e. no evidence of systemic disease progression within the past 3 months) * patients with brain metastases at initial presentation are eligible and do not need to demonstrate 3 months of stable scans patient characteristics: inclusion * karnofsky performance status 70-100% * serum creatinine ≤ 3 mg/dl and creatinine clearance ≥ 30 ml/min * total bilirubin ≤ 2.5 mg/dl * blood urea nitrogen (bun) \< 20 mg/dl * mini-mental status exam score ≥ 18 * negative serum pregnancy test * fertile patients must practice adequate contraception exclusion * 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 respiratory illness requiring hospitalization or precluding study therapy at the time of registration * hepatic insufficiency resulting in clinical jaundice and/or coagulation defects * pregnant or lactating women * prior allergic reaction to memantine hydrochloride * current alcohol or drug abuse * intractable seizures while on adequate anticonvulsant therapy (i.e., more than one seizure per month for the past 2 months) prior concurrent therapy: inclusion * at least 14 days but no more than 56 days since prior therapy for brain metastasis, including radiosurgery and surgical resection * no systemic chemotherapy for 14 days prior, during, or for 14 days after completion of whole-brain radiotherapy (wbrt) exclusion * prior cranial radiotherapy * patients may have received up to 3 prior wbrt treatments and still be registered and randomized on the protocol provided wbrt parameters meet protocol requirements * chronic short-acting benzodiazepine use

Keywords: cognitive/functional effects neurotoxicity tumors metastatic to brain unspecified adult solid tumor, protocol specific