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Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2016 by NRG Oncology
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology
ClinicalTrials.gov Identifier:
NCT02360215
First received: February 5, 2015
Last updated: June 17, 2016
Last verified: June 2016
  Purpose
This randomized phase III trial compares memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing neurocognitive decline in patients with cancer that has spread from the primary site (place where it started) to the brain. Whole brain radiotherapy (WBRT) is the most common treatment for brain metastasis. Unfortunately, the majority of patients with brain metastases experience cognitive (such as learning and memory) deterioration after WBRT. Memantine hydrochloride may enhance cognitive function by binding to and inhibiting channels of receptors located in the central nervous system. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Using radiation techniques, such as intensity modulated radiotherapy to avoid the hippocampal region during WBRT, may reduce the radiation dose to the hippocampus and help limit the radiation-induced cognitive decline. It is not yet known whether giving memantine hydrochloride and WBRT with or without hippocampal avoidance works better in reducing neurocognitive decline in patients with brain metastases.

Condition Intervention Phase
Cognitive Impairment
Metastatic Malignant Neoplasm in the Brain
Solid Neoplasm
Other: Cognitive Assessment
Radiation: Intensity-Modulated Radiation Therapy
Drug: Memantine Hydrochloride
Other: Quality-of-Life Assessment
Radiation: Whole-Brain Radiotherapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Supportive Care
Official Title: A Randomized Phase III Trial of Memantine and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Patients With Brain Metastases

Resource links provided by NLM:


Further study details as provided by NRG Oncology:

Primary Outcome Measures:
  • Time to neurocognitive failure, as measured by neurocognitive decline on HVLT-R, COWA, and TMT Parts A and B [ Time Frame: At 6 months ]
    The cumulative incidence approach will be used to estimate the median time to neurocognitive failure to account for the competing risk of death. Gray's test will be used to test for statistically significant difference in the distribution of neurocognitive failure times. The cause-specific Cox proportional hazards regression model will be used to evaluate the effect of stratification variables (RPA class and prior therapy) and other baseline characteristics, such as Karnofsky performance score, DS-GPA grade, FLAIR volume change, and hippocampal volume, on time to neurocognitive decline.


Secondary Outcome Measures:
  • Health outcomes, as measured by the EQ-5D-5L [ Time Frame: Up to 12 months ]
    The 5-item utility score in EQ-5D-5L will be used for the cost-utility analysis. The Z-test will be used to test the hypothesis that the cost-utility in the 2 treatment arms is the same at 6 months after initiation of treatment with a significance level of 0.05 and a 2-sided test. The remaining time points in which the EQ-5D-5L is collected also will be assessed.

  • Incidence of adverse events (AE) as measured by CTCAE v4.0 [ Time Frame: Up to 12 months ]
    Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm.

  • Intracranial progression defined as progression in the brain or death [ Time Frame: At 6 months ]
    MRI scans at baseline and 6 months will be reviewed to determine intracranial progression centrally. The 6 month comparison in intracranial progression rates between the treatment arms will be compared using a test of proportions. It is expected that the rates will be similar in both treatment arms.

  • Overall survival [ Time Frame: From the date of randomization to the date of death, or, otherwise, the last follow-up date on which the patient was reported alive, assessed up to 12 months ]
    Estimated using the Kaplan-Meier method, and differences between treatment arms will be tested using the log rank test.

  • Preservation of neurocognitive function, as measured by neurocognitive decline on HVLT-R, COWA, and TMT Parts A and B, and Clinical Trial Battery Composite (CTB COMP) score [ Time Frame: Up to 12 months ]
    Compared between treatment arms at each follow-up time point using Fisher's exact test. A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics.

  • Symptom burden, as measured by the MDASI-BT [ Time Frame: Up to 12 months ]
    Four subscales (symptom severity, symptom interference, neurologic factor, and cognitive factor score) as well as certain individual items (fatigue, neurologic factor items, and cognitive factor items) of the MDASI-BT will be analyzed. For discrete time point analyses, the change from baseline to each follow-up time point (2, 4, 6, and 12 months from the start of treatment) will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data. Mixed effects models will be used to assess changes of the four subscale scores.

  • Time to intracranial progression [ Time Frame: From the date of randomization to the date of intracranial progression, death, or, otherwise, the last follow-up date on which the patient was reported alive, assessed up to 12 months ]
    Estimated using the Kaplan-Meier method, and differences between treatment arms will be tested using the log rank test.


Other Outcome Measures:
  • Anxiety/depression measured using the EQ-5D-5L [ Time Frame: Up to 12 months ]
    An exploratory analysis, beginning with correlation coefficients, will be used to assess the association of symptom burden and anxiety/depression with neurocognitive function at each time point. The symptom burden items of interest are the "distressed (upset)", "sad", and "mood" items. From the EQ-5D-5L, the depression/anxiety item will be of interest.

  • Effect of RTOG RPA and the diagnosis-specific graded prognostic assessment (DSGPA) on neurocognitive function [ Time Frame: Up to 12 months ]
    Neurocognitive function, as measured by the HVLT-R, COWA, and TMT, will be correlated with both the RTOG RPA and the DS-GPA classification systems. Baseline neurocognitive function for each test will be compared between both RPA classes using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.

  • Effect of white matter injury and hippocampal volume on neurocognitive function [ Time Frame: Up to 12 months ]
    Evaluated through MRI scans using physician-contoured and auto-contoured scores. Concordance rates will be assessed using Kappa statistics. The auto-contoured scores will be used for the remaining analyses due to the number of physicians reviewing the scans. White matter injury is measured by FLAIR volume change and is a continuous variable. Hippocampal volume is measured as a continuous variable also and both will be covariates considered in the Cox proportional hazards model to assess the impact on time to neurocognitive failure and the longitudinal modeling of neurocognitive function.

  • MDASI-BT mood variables [ Time Frame: Up to 12 months ]
    The relationship between EQ-5D-5L and MDASI-BT mood variables and neurocognitive function will be assessed.


Estimated Enrollment: 510
Study Start Date: July 2015
Estimated Primary Completion Date: November 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (memantine hydrochloride, WBRT)
Patients receive memantine hydrochloride PO BID for 24 weeks. Patients undergo WBRT daily over approximately 2 weeks (10 fractions).
Other: Cognitive Assessment
Ancillary studies
Drug: Memantine Hydrochloride
Given PO
Other Names:
  • Ebixia
  • Namenda
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Radiation: Whole-Brain Radiotherapy
Undergo WBRT
Other Names:
  • WBRT
  • whole-brain radiation therapy
Experimental: Arm II (memantine hydrochloride, HA-WBRT)
Patients receive memantine hydrochloride as in Arm I. Patients undergo HA-WBRT using IMRT daily over approximately 2 weeks (10 fractions).
Other: Cognitive Assessment
Ancillary studies
Radiation: Intensity-Modulated Radiation Therapy
Undergo HA-WBRT using IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
Drug: Memantine Hydrochloride
Given PO
Other Names:
  • Ebixia
  • Namenda
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Radiation: Whole-Brain Radiotherapy
Undergo HA-WBRT using IMRT
Other Names:
  • WBRT
  • whole-brain radiation therapy

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine whether the addition of whole-brain radiotherapy with hippocampal avoidance (HA-WBRT) increases time to neurocognitive failure at months 2, 4, 6, and 12 as measured by neurocognitive decline on a battery of tests: the Hopkins Verbal Learning Test-Revised (HVLT-R) for Total Recall, Delayed Recall, and Delayed Recognition, Controlled Oral Word Association (COWA), and the Trail Making Test (TMT) Parts A and B.

SECONDARY OBJECTIVES:

I. Determine whether the addition of HA-WBRT preserves neurocognitive function at months 2, 4, 6, and 12 as separately measured by each test, the HVLT-R for Total Recall, Delayed Recall, and Delayed Recognition; COWA; and TMT Parts A and B.

II. Evaluate the potential benefit of HA-WBRT in symptom burden, as measured by the M. D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT).

III. Assessment of quality adjusted survival and cost analysis using the five-level version of the EuroQol five-dimensional (EQ-5D-5L).

IV. Compare cumulative incidence of progression and overall survival after WBRT versus HA-WBRT.

V. Compare adverse events between the treatment arms according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 criteria.

TERTIARY OBJECTIVES:

I. Collect serum, plasma, and imaging studies for future translational research analyses.

II. Evaluate magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry at baseline and 6 months as potential predictors of neurocognitive decline and differential benefit from HA-WBRT as compared to WBRT.

III. Association of symptom burden and anxiety/depression with neurocognitive function.

IV. Evaluate the potential correlation between the prognostic scoring systems Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) and the diagnosis-specific graded prognostic assessment (DS-GPA) and neurocognitive function at baseline and overtime.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive memantine hydrochloride orally (PO) twice daily (BID) for 24 weeks. Patients undergo WBRT daily over approximately 2 weeks (10 fractions).

ARM II: Patients receive memantine hydrochloride as in Arm I. Patients undergo HA-WBRT using intensity modulated radiation therapy (IMRT) daily over approximately 2 weeks (10 fractions).

After completion of study treatment, patients are followed up at 12 months.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRIOR TO STEP 1 REGISTRATION:
  • Brain metastases outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed =< 21 days prior to Step 1 registration; an allowed exception, regarding ability to image brain metastases, would be that patients who had undergone radiosurgery or surgical resection and are planning adjuvant WBRT do not have to have visible disease but do need a pre-surgery MRI or computed tomography (CT) scan demonstrating brain metastases; however, the brain metastases could not have been within 5 mm of either hippocampus
  • Patients must have a gadolinium contrast-enhanced three-dimensional spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) axial MRI scan with standard axial and coronal gadolinium contrast-enhanced T1-weighted sequence and axial T2/FLAIR sequence acquisitions; to yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan should use the smallest possible axial slice thickness not exceeding 1.5 mm; the associated coronal and sagittal contrast-enhanced T1 sequences can be up to 2.5 mm in slice thickness; this MRI must be obtained =< 21 days prior to step 1 registration; the vendor specific MRI protocols are available for download from the Alzheimer's Disease Neuroimaging Initiative (ADNI)
  • Patients must provide study-specific informed consent prior to registration
  • PRIOR TO STEP 2 REGISTRATION:
  • The following baseline neurocognitive assessments must be completed prior to Step 2 registration: HVLT-R, TMT, and COWA; the neurocognitive assessment will be uploaded into the NRG RAVE System for evaluation by Dr. Wefel; once the upload is complete, a notification will be sent to proceed to Step 2; NOTE: completed baseline neurocognitive assessments can be uploaded at the time of Step 1 registration
  • Pathologically (histologically or cytologically) proven diagnosis of solid tumor malignancy within 5 years prior to Step 2 registration
  • History and physical examination within 28 days prior to Step 2 registration
  • Karnofsky performance status of >= 70 within 28 days prior to Step 2 registration
  • Serum creatinine =< 3 mg/dL (265 umol/L) and creatinine clearance >= 30 ml/min
  • Blood urea nitrogen (BUN) within institutional upper limit of normal (e.g. < 20 mg/dL)
  • Total bilirubin =< 2.5 mg/dL (43 umol/L)
  • Patients may have had prior therapy for brain metastasis, including radiosurgery and surgical resection; patients must have completed prior therapy by at least 14 days prior to Step 2 for surgical resection and 7 days for radiosurgery
  • Negative serum pregnancy test (in women of childbearing potential) =< 14 days prior to Step 2; women of childbearing potential and men who are sexually active must practice adequate contraception while on study
  • Patients who are primary English or French speakers are eligible

Exclusion Criteria:

  • Prior external beam radiation therapy to the brain or whole brain radiation therapy
  • Planned cytotoxic chemotherapy during the WBRT only; patients may have had prior chemotherapy
  • Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt
  • 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 acute respiratory illness precluding study therapy at the time of registration
    • Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
    • Renal tubular acidosis or metabolic acidosis
    • Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration; Note also that HIV testing is not required for eligibility for this protocol
  • Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
  • Prior allergic reaction to memantine (memantine hydrochloride)
  • Current alcohol or drug abuse (may exacerbate lethargy/dizziness with memantine)
  • Intractable seizures while on adequate anticonvulsant therapy—more than 1 seizure per month for the past 2 months
  • Patients with definitive leptomeningeal metastases
  • Patients with brain metastases from primary germ cell tumors, small cell carcinoma, unknown primary, or lymphoma
  • Contraindication to magnetic resonance (MR) imaging such as implanted metal devices or foreign bodies
  • Contraindication to gadolinium contrast administration during MR imaging, such as allergy or insufficient renal function
  • Current use of (other N-methyl D-aspartate [NMDA] antagonists) amantadine, ketamine, or dextromethorphan
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02360215

  Show 103 Study Locations
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
Principal Investigator: Paul Brown NRG Oncology
  More Information

Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT02360215     History of Changes
Other Study ID Numbers: NRG-CC001
NCI-2015-00030 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-CC001 ( Other Identifier: NRG Oncology )
NRG-CC001 ( Other Identifier: DCP )
NRG-CC001 ( Other Identifier: CTEP )
UG1CA189867 ( US NIH Grant/Contract Award Number )
Study First Received: February 5, 2015
Last Updated: June 17, 2016

Additional relevant MeSH terms:
Neoplasms
Cognition Disorders
Neoplasms, Second Primary
Brain Neoplasms
Neurocognitive Disorders
Mental Disorders
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Memantine
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents

ClinicalTrials.gov processed this record on April 27, 2017