Back to resultsNeurocognitive Outcome of Bilateral or Unilateral Hippocampal Avoidance WBRT With Memantine for Brain Metastases
Primary Purpose
Metastatic Malignant Neoplasm to Brain
Status
Recruiting
Phase
Phase 2
Locations
Taiwan
Study Type
Interventional
Intervention
Conformal Whole Brain Radiotherapy with Unilateral Hippocampal Avoidance
Conformal Whole Brain Radiotherapy with Bilateral Hippocampal Avoidance
Memantine Hydrochloride
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Malignant Neoplasm to Brain focused on measuring Brain Metastases, Hippocampal Avoidance Whole Brain Radiotherapy, Neurocognitive function
Eligibility Criteria
Inclusion Criteria:
- Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases
- Patients with brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast enhanced MRI obtained within 30 days prior to registration
- Patients with brain metastasis who have not been or will not be treated with SRS, or have received SRS for ≤ 5 intracranial metastatic lesion(s)
- No evidence of diffuse leptomeningeal metastasis on gadolinium- enhanced MRI within 30 days prior registration
- Age ≥ 20 years
- Karnofsky Performance Status ≥ 60%
- Life expectancy of ≥ 6 months.
- Women of childbearing potential and male participants must practice adequate contraception
- Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent
Exclusion Criteria:
- Prior radiotherapy to brain or radiosurgery to > 5 intracranial metastatic lesion(s) or the biological equivalent dose in 2-Gy fractions was greater than 7.3Gy to 40% of the volume of bilateral hippocampus from prior radiosurgery
- Serum creatinine > 2.0 mg/dL within 30 days prior registration
- Serum urea nitrogen > 20 mg/dL within 30 days prior registration
- Contraindication to MR imaging such as implanted metal devices or foreign bodies, severe claustrophobia
Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:
- Uncontrolled active infection requiring intravenous antibiotics at the time of registration
- Transmural myocardial infarction ≤ 6 months prior to registration
- Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
- Life-threatening uncontrolled clinically significant cardiac arrhythmias
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
- Uncontrolled psychiatric disorder
- Will receive any other investigational agent or chemotherapy during WBRT
- Current use of Memantine HCL or Allergy to Memantine HCL
- Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic
- Pregnant or breast-feeding women
Sites / Locations
- National Taiwan University HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Unilateral Hippocampal Avoidance WBRT with Memantine
Bilateral Hippocampal Avoidance WBRT with Memantine
Arm Description
Conformal whole brain radiotherapy with unilateral hippocampal avoidance and Concurrent use of Memantine HCL
Conformal whole brain radiotherapy with bilateral hippocampal avoidance and Concurrent use of Memantine HCL
Outcomes
Primary Outcome Measures
Hopkins Verbal Learning Test-Revised (HVLT-R) memory score
Decline in Hopkins Verbal Learning Test-Revised (HVLT-R) memory score (sum of total recall and recognition index) from baseline to 6 months after the start of conformal whole brain radiotherapy (WBRT) with bilateral or unilateral hippocampal avoidance for multiple brain metastases. HVLT-R Total recall raw scores ranged from 0 to 36, recognition index ranged from 0 to 12. The higher the score indicated better short term memory preservation
Secondary Outcome Measures
Neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R)
Evaluate neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R) with Total recall score (range from 0 to 36), delayed recall score (range from 0 to 12) and recognition index (range from 0 to 12). The higher the score indicated better short term memory preservation.
Neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A & B
Evaluate neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A & B. TMT-A and B tested the executive function documented with time needed for complete test with no upper limit of range. The longer the time needed, the worse executive function patients preserved.
Neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test
Evaluate neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test. Patients are given one phoneme at a time and instructed to say aloud as many words beginning with that phoneme as they could within 1 minute, for a total of three phonemes in 3 minutes. The more the words patients able to say in limit time, the better outcome presented.
Patient reported outcome (Quality of Life questionnaire)
EORTC Quality of Life-Core 30 questionnaire module (at question 1 to 27, range from 1 to 4; at question 29 and 30, range from 1 to 7) Quality of Life questionnaire-Brain.
Patient reported outcome (Cognitive Functioning questionnaire)
Function Assessment Cancer Therapy for patients with Cognitive function issue
Acute toxicity (Common Toxicity Criteria for Adverse Events version 4)
Common Toxicity Criteria for Adverse Events version 4
Late toxicity (Common Toxicity Criteria for Adverse Events version 4)
Common Toxicity Criteria for Adverse Events version 4
Intracranial progression (Number of participant with intracranial progression on MRI of brain)
Number of participant with intracranial progression on MRI of brain
Overall survival
Number of patients died
Full Information
NCT ID
NCT04801342
First Posted
April 28, 2019
Last Updated
March 14, 2021
Sponsor
National Taiwan University Hospital
1. Study Identification
Unique Protocol Identification Number
NCT04801342
Brief Title
Neurocognitive Outcome of Bilateral or Unilateral Hippocampal Avoidance WBRT With Memantine for Brain Metastases
Official Title
Neurocognitive Outcome of Conformal Whole Brain Radiotherapy With Bilateral or Unilateral Hippocampal Avoidance Plus Memantine for Brain Metastases: A Phase II Single Blind Randomized Trial
Study Type
Interventional
2. Study Status
Record Verification Date
January 2021
Overall Recruitment Status
Recruiting
Study Start Date
April 1, 2021 (Anticipated)
Primary Completion Date
January 1, 2024 (Anticipated)
Study Completion Date
February 28, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Taiwan University Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Brain metastases are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness.
Whole brain radiotherapy (WBRT) is the treatment of choice for the majority of patients with brain metastases. WBRT yields high radiologic response rate (27~56%) and is effective in rapid palliation of neurologic symptoms as well as prolongs time to neurocognitive function decline caused by intracranial lesions. By using conventional fractionation, more than one- third of patients developed late neurocognitive toxicity while memory impairment was the most common symptom. The incidence is even higher when a formal and sensitive neurocognitive assessment was prospectively evaluated. With more long-term survivors nowadays, it has become increasingly important to minimize neurocognitive function decline and maintain quality of life in patients with brain metastasis.
The function of hippocampus is cooperation in learning, consolidation and retrieval of information and essential for formation of new memories. Bilateral and unilateral radiation injury of the hippocampus is known to alter learning and memory formation. Several preclinical studies support the hypothesis of hippocampus-mediated cognitive dysfunction by ionizing radiation. Clinical studies show increase in radiation dose to hippocampus is associated with subsequent neurocognitive function impairment in adult and pediatric patients. Furthermore, the result of phase III randomized trials suggested hippocampal avoidance plus Memantine significantly reduce the risk of neurocognitive impairment at 6 months from 68.2% in control arm with standard WBRT to 59.5% in experimental arm. In the investigator's prior investigation, patients received conformal WBRT with bilateral hippocampal avoidance also had significant less declines in verbal memory at 6 months.
Previous studies showed the right and left hippocampus exert different neurocognitive functions. Several retrospective studies also demonstrated that the radiation dose to the left hippocampus is more related to neurocognitive impairment. Planning study and investigation showed that by avoiding the left hippocampus alone, the radiation dose to the spared unilateral hippocampus is further decreased. In present study, a single blind randomized phase II trial is designed to investigate the effectiveness of neurocognitive function preservation using conformal WBRT with bilateral or unilateral hippocampal avoidance and memantine.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Malignant Neoplasm to Brain
Keywords
Brain Metastases, Hippocampal Avoidance Whole Brain Radiotherapy, Neurocognitive function
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
72 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Unilateral Hippocampal Avoidance WBRT with Memantine
Arm Type
Experimental
Arm Description
Conformal whole brain radiotherapy with unilateral hippocampal avoidance and Concurrent use of Memantine HCL
Arm Title
Bilateral Hippocampal Avoidance WBRT with Memantine
Arm Type
Active Comparator
Arm Description
Conformal whole brain radiotherapy with bilateral hippocampal avoidance and Concurrent use of Memantine HCL
Intervention Type
Radiation
Intervention Name(s)
Conformal Whole Brain Radiotherapy with Unilateral Hippocampal Avoidance
Other Intervention Name(s)
Unilateral HA-WBRT
Intervention Description
Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Unilateral Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy
Intervention Type
Radiation
Intervention Name(s)
Conformal Whole Brain Radiotherapy with Bilateral Hippocampal Avoidance
Other Intervention Name(s)
Bilateral HA-WBRT
Intervention Description
Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Bilateral Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy
Intervention Type
Drug
Intervention Name(s)
Memantine Hydrochloride
Other Intervention Name(s)
Memantine
Intervention Description
Start from day 1 of WBRT orally for 24 weeks and escalating doses over the first 4 weeks
Primary Outcome Measure Information:
Title
Hopkins Verbal Learning Test-Revised (HVLT-R) memory score
Description
Decline in Hopkins Verbal Learning Test-Revised (HVLT-R) memory score (sum of total recall and recognition index) from baseline to 6 months after the start of conformal whole brain radiotherapy (WBRT) with bilateral or unilateral hippocampal avoidance for multiple brain metastases. HVLT-R Total recall raw scores ranged from 0 to 36, recognition index ranged from 0 to 12. The higher the score indicated better short term memory preservation
Time Frame
At 6 months after WBRT
Secondary Outcome Measure Information:
Title
Neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R)
Description
Evaluate neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R) with Total recall score (range from 0 to 36), delayed recall score (range from 0 to 12) and recognition index (range from 0 to 12). The higher the score indicated better short term memory preservation.
Time Frame
at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Title
Neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A & B
Description
Evaluate neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A & B. TMT-A and B tested the executive function documented with time needed for complete test with no upper limit of range. The longer the time needed, the worse executive function patients preserved.
Time Frame
at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Title
Neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test
Description
Evaluate neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test. Patients are given one phoneme at a time and instructed to say aloud as many words beginning with that phoneme as they could within 1 minute, for a total of three phonemes in 3 minutes. The more the words patients able to say in limit time, the better outcome presented.
Time Frame
at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Title
Patient reported outcome (Quality of Life questionnaire)
Description
EORTC Quality of Life-Core 30 questionnaire module (at question 1 to 27, range from 1 to 4; at question 29 and 30, range from 1 to 7) Quality of Life questionnaire-Brain.
Time Frame
at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Title
Patient reported outcome (Cognitive Functioning questionnaire)
Description
Function Assessment Cancer Therapy for patients with Cognitive function issue
Time Frame
at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Title
Acute toxicity (Common Toxicity Criteria for Adverse Events version 4)
Description
Common Toxicity Criteria for Adverse Events version 4
Time Frame
From date of WBRT until 90 days after radiotherapy starts
Title
Late toxicity (Common Toxicity Criteria for Adverse Events version 4)
Description
Common Toxicity Criteria for Adverse Events version 4
Time Frame
From 90 days after WBRT starts until the date of death from any cause, up to 60 months
Title
Intracranial progression (Number of participant with intracranial progression on MRI of brain)
Description
Number of participant with intracranial progression on MRI of brain
Time Frame
From date of enrolment until the date of first documented intracranial progression or date of death from any cause, whichever came first, assessed up to 60 months
Title
Overall survival
Description
Number of patients died
Time Frame
From date of enrollment until the date of death from any cause, assessed up to 60 months
Other Pre-specified Outcome Measures:
Title
Genomic risk of neurocognitive decline after WBRT
Description
Number of participants with Genomic risk of neurocognitive impairment after WBRT
Time Frame
At 4 months after radiotherapy
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases
Patients with brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast enhanced MRI obtained within 30 days prior to registration
Patients with brain metastasis who have not been or will not be treated with SRS, or have received SRS for ≤ 5 intracranial metastatic lesion(s)
No evidence of diffuse leptomeningeal metastasis on gadolinium- enhanced MRI within 30 days prior registration
Age ≥ 20 years
Karnofsky Performance Status ≥ 60%
Life expectancy of ≥ 6 months.
Women of childbearing potential and male participants must practice adequate contraception
Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent
Exclusion Criteria:
Prior radiotherapy to brain or radiosurgery to > 5 intracranial metastatic lesion(s) or the biological equivalent dose in 2-Gy fractions was greater than 7.3Gy to 40% of the volume of bilateral hippocampus from prior radiosurgery
Serum creatinine > 2.0 mg/dL within 30 days prior registration
Serum urea nitrogen > 20 mg/dL within 30 days prior registration
Contraindication to MR imaging such as implanted metal devices or foreign bodies, severe claustrophobia
Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:
Uncontrolled active infection requiring intravenous antibiotics at the time of registration
Transmural myocardial infarction ≤ 6 months prior to registration
Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
Life-threatening uncontrolled clinically significant cardiac arrhythmias
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
Uncontrolled psychiatric disorder
Will receive any other investigational agent or chemotherapy during WBRT
Current use of Memantine HCL or Allergy to Memantine HCL
Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic
Pregnant or breast-feeding women
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Feng-Ming Hsu, MD, PhD
Phone
+886-2-23123456
Ext
67061
Email
hsufengming@ntuh.gov.tw
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Feng-Ming Hsu, MD, PhD
Organizational Affiliation
National Taiwan University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Taiwan University Hospital
City
Taipei
ZIP/Postal Code
100
Country
Taiwan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Feng-Ming Hsu, MD
Phone
+886-2-23123456
Ext
67061
Email
hsufengming@ntuh.gov.tw
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Neurocognitive Outcome of Bilateral or Unilateral Hippocampal Avoidance WBRT With Memantine for Brain Metastases
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