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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

Phase 3
18 Years
Open (Enrolling)
Cognitive/Functional Effects, Metastatic Cancer, Neurotoxicity, Unspecified Adult Solid Tumor, Protocol Specific

Thank you

Trial Information

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



- 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.


- 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)

- Determine whether the addition of memantine hydrochloride increases progression-free

- 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 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.

Inclusion Criteria


- 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



- Karnofsky performance status 70-100%

- Serum creatinine ≤ 3 mg/dL and creatinine clearance ≥ 30 mL/min

- Total bilirubin ≤ 2.5 mg/dL

- BUN < 20 mg/dL

- Mini-mental status exam score ≥ 18

- Negative serum pregnancy test

- Fertile patients must practice adequate contraception


- 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

- 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)



- 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)


- 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

- Chronic short-acting benzodiazepine use

Type of Study:


Study Design:

Allocation: Randomized, Masking: Double-Blind, Primary Purpose: Supportive Care

Outcome Measure:

Cognitive function, specifically memory, 24 weeks from the start of drug treatment as measured by the Hopkins Verbal Learning Test-Revised for delayed recall (HVLT-R-delayed recall)

Safety Issue:


Principal Investigator

Paul D. Brown, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic


United States: Federal Government

Study ID:




Start Date:

March 2008

Completion Date:

Related Keywords:

  • Cognitive/Functional Effects
  • Metastatic Cancer
  • Neurotoxicity
  • Unspecified Adult Solid Tumor, Protocol Specific
  • cognitive/functional effects
  • neurotoxicity
  • tumors metastatic to brain
  • unspecified adult solid tumor, protocol specific
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary
  • Neurotoxicity Syndromes



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