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

NCT02360215

Description:

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.

Related Conditions:
  • Brain metastasis
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases
  • Official Title: A Randomized Phase III Trial of Memantine and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Patients With Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: NRG-CC001
  • SECONDARY ID: NCI-2015-00030
  • SECONDARY ID: NRG-CC001
  • SECONDARY ID: NRG-CC001
  • SECONDARY ID: NRG-CC001
  • SECONDARY ID: UG1CA189867
  • NCT ID: NCT02360215

Conditions

  • Cognitive Impairment
  • Metastatic Malignant Neoplasm in the Brain
  • Solid Neoplasm

Interventions

DrugSynonymsArms
Memantine HydrochlorideEbixia, NamendaArm I (memantine hydrochloride, WBRT)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (memantine hydrochloride, WBRT)ExperimentalPatients receive memantine hydrochloride PO BID for 24 weeks. Patients undergo WBRT daily over approximately 2 weeks (10 fractions).
  • Memantine Hydrochloride
Arm II (memantine hydrochloride, HA-WBRT)ExperimentalPatients receive memantine hydrochloride as in Arm I. Patients undergo HA-WBRT using IMRT daily over approximately 2 weeks (10 fractions).
  • Memantine Hydrochloride

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Time to neurocognitive failure, as measured by neurocognitive decline on HVLT-R, COWA, and TMT Parts A and B
Time Frame:At 6 months
Safety Issue:
Description: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

Measure:Health outcomes, as measured by the EQ-5D-5L
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure:Incidence of adverse events (AE) as measured by CTCAE v4.0
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure:Intracranial progression defined as progression in the brain or death
Time Frame:At 6 months
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Estimated using the Kaplan-Meier method, and differences between treatment arms will be tested using the log rank test.
Measure: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
Safety Issue:
Description: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.
Measure:Symptom burden, as measured by the MDASI-BT
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Estimated using the Kaplan-Meier method, and differences between treatment arms will be tested using the log rank test.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NRG Oncology

Last Updated

February 9, 2018