Memantine in Preventing Side Effects in Patients Undergoing Whole-Brain Radiation Therapy for Brain Metastases From Solid Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized, Phase III, Double-Blind, Placebo-Controlled Trial of Memantine for Prevention of Cognitive Dysfunction in Patients Receiving Whole-Brain Radiotherapy

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

Intervention / Treatment
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* Drug: Memantine
* Other: Placebo
* Radiation: Whole brain radiation therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WBRT+Memantine<br>Whole brain radiation therapy (WBRT) and memantine | Drug: Memantine<br>* Patients began taking memantine(by mouth) while receiving radiation therapy. Patients continued taking memantine for 24 weeks or until doctor thinks it is in their best interest to stop. They started with 5 mg once a day. After a week dose increased to 5 mg twice a day. At week 3, dose increased to 10 mg in the morning and 5 mg in the evening. Weeks 4-24, dose was 10 mg twice a day.<br>Radiation: Whole brain radiation therapy<br>* Whole brain radiation therapy (WBRT) once a day (2.5Gy), five days a week (Monday to Friday) for three weeks, for total fifteen treatments and 37.5 Gy<br>|
| Active Comparator: WBRT+Placebo<br>Whole brain radiation therapy (WBRT) and placebo | Other: Placebo<br>* Patients began taking placebo(by mouth) while receiving radiation therapy. Patients continued taking placebo for 24 weeks or until doctor thinks it is in their best interest to stop. They started with 5 mg once a day. After a week dose increased to 5 mg twice a day. At week 3, dose increased to 10 mg in the morning and 5 mg in the evening. Weeks 4-24, dose was 10 mg twice a day.<br>Radiation: Whole brain radiation therapy<br>* Whole brain radiation therapy (WBRT) once a day (2.5Gy), five days a week (Monday to Friday) for three weeks, for total fifteen treatments and 37.5 Gy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 24 Weeks | The HVLT-R consists of 3 parts. Free call has a range of 0 to 36, delayed recall has a range from 0 to 12, and delayed recognition has a range of -12 to 12. Higher scores indicating better function in all 3 parts. Standardized scores are used by calculating an average standardized z score for each part of the HVLT-R. Change is calculated by subtracting baseline value from 24-week value. Imputation methods were used to determine values for all alive patients missing the 24 week assessment. This tool is being used to measure cognitive function, specifically memory. | Baseline and 24 weeks from the start of drug treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks | The HVLT-R consists of 3 parts. Free call has a range of 0 to 36, delayed recall has a range from 0 to 12, and delayed recognition has a range of -12 to 12. Higher scores indicating better function in all 3 parts. Standardized scores are used by calculating an average standardized z score for each part of the HVLT-R. Change is calculated by subtracting baseline value from the respective later time point value. Imputation methods were used to determine values for all alive patients missing the post-baseline assessments. This tool is being used to measure cognitive function, specifically memory. | Baseline, 8, 16, and 52 weeks from the start of drug treatment | 
| Median Time to Neurocognitive Failure | Neurocognitive failure is defined as the first cognitive failure on any of the neurocognitive tests: the HVLT-R for immediate recall, delayed recognition, and delayed recall; the Controlled Oral Word Association Test (COWAT); the Trail-Making Test (TMT) Parts A and B. Cognitive failure for each test is defined as a post-treatment score that meets one of the following criteria: follow-up score is at least 2 standard deviations worse than the patient's personal baseline score or the patient's raw score change is greater than the reliable change index. The cumulative incidence approach was used to estimate the median time to neurocognitive failure to account for the competing risks of disease progression and death. | Baseline to 12 months from the start of drug treatment | 
| Change in Functional Assessment of Cancer Therapy With Brain Subscale (FACT-Br) at 24 Weeks | The FACT-Br is a 50-question self-report questionnaire contains the following domains (scales): Physical well-being (7 questions), social/family well-being (7 questions), emotional well-being (6 questions), functional well-being (7 questions) and brain cancer subscale which contains concerns relevant to patients with brain tumors (23 questions). Each question has a value 0-4. For some questions a higher indicates better outcome and others are the opposite. The former are summed as is, the latter are reversed in value before adding, such that each domain ranges from 0 to 4 times the number of questions in the domain, with 0 indicating worst and the highest possible value indicating best outcome. The FACT-Br total is obtained by adding all domains together if the overall question response rate is greater than 80%. Total scores on the FACT-Br range from 0 to 184 with lower scores indicating declining quality of life. Change is calculated as baseline score subtracted from 24-week score. | Baseline and 24 weeks from start of treatment | 
| Median Progression-free Survival Time | Disease progression is defined as the first of the following events: an increase of at least 50% for lesions less than or equal to 1cm, an increase of least 25% for lesions greater than 1cm, appearance of any new brain metastases. Failure for progression-free survival is disease progression or death. Median progression-free survival was estimated using the Kaplan-Meier method. | From randomization to date of progression, death or last follow-up. Analysis occurs at the same time as the primary outcome. Patients are followed until death and all follow-up collected at time of analysis is used. | 
| Overall Survival | Failure for overall survival is death from any cause. Median survival was estimated using the Kaplan-Meier method. | From randomization to date of death or last follow-up. Analysis occurs at the same time as the primary outcome. Patients are followed until death and all follow-up collected at time of analysis is used. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive/functional effects, neurotoxicity, tumors metastatic to brain, unspecified adult solid tumor, protocol specific