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

Phase 3

Completed

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

Interventions: Other: Placebo
Drug: Memantine
Radiation: Whole brain radiation therapy

Registration Number: NCT00566852

Lead Sponsor: Radiation Therapy Oncology Group

Brief 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 554

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
WBRT+Memantine	Whole brain radiation therapy	Whole brain radiation therapy (WBRT) and memantine
WBRT+Placebo	Placebo	Whole brain radiation therapy (WBRT) and placebo
WBRT+Placebo	Whole brain radiation therapy	Whole brain radiation therapy (WBRT) and placebo
WBRT+Memantine	Memantine	Whole brain radiation therapy (WBRT) and memantine

Primary Outcome Measures

Name	Time	Method
Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 24 Weeks	Baseline and 24 weeks from the start of drug treatment	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.

Secondary Outcome Measures

Name	Time	Method
Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks	Baseline, 8, 16, and 52 weeks from the start of drug treatment	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.
Median Time to Neurocognitive Failure	Baseline to 12 months from the start of drug treatment	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.
Change in Functional Assessment of Cancer Therapy With Brain Subscale (FACT-Br) at 24 Weeks	Baseline and 24 weeks from start of treatment	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.
Median Progression-free Survival Time	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.	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.
Overall Survival	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.	Failure for overall survival is death from any cause. Median survival was estimated using the Kaplan-Meier method.

Trial Locations

Locations (235): MBCCOP - Gulf Coast
🇺🇸
Mobile, Alabama, United States
Providence Cancer Center at Providence Hospital
🇺🇸
Mobile, Alabama, United States
Arizona Oncology Services Foundation
🇺🇸
Phoenix, Arizona, United States
Mayo Clinic Scottsdale
🇺🇸
Scottsdale, Arizona, United States
Arizona Oncology - Tucson
🇺🇸
Tucson, Arizona, United States
Arizona Cancer Center at University of Arizona Health Sciences Center
🇺🇸
Tucson, Arizona, United States
Auburn Radiation Oncology
🇺🇸
Auburn, California, United States
Providence Saint Joseph Medical Center - Burbank
🇺🇸
Burbank, California, United States
Radiation Oncology Centers - Cameron Park
🇺🇸
Cameron Park, California, United States
Mercy Cancer Center at Mercy San Juan Medical Center
🇺🇸
Carmichael, California, United States
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MBCCOP - Gulf Coast
🇺🇸Mobile, Alabama, United States