Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Neurocognitive Outcome of Bilateral or Unilateral Hippocampal Avoidance WBRT With Memantine for Brain Metastases

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04801342
Recruitment Status : Recruiting
First Posted : March 17, 2021
Last Update Posted : March 17, 2021
Sponsor:
Information provided by (Responsible Party):
National Taiwan University Hospital

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.


Condition or disease Intervention/treatment Phase
Metastatic Malignant Neoplasm to Brain Radiation: Conformal Whole Brain Radiotherapy with Unilateral Hippocampal Avoidance Radiation: Conformal Whole Brain Radiotherapy with Bilateral Hippocampal Avoidance Drug: Memantine Hydrochloride Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
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
Estimated Study Start Date : April 1, 2021
Estimated Primary Completion Date : January 1, 2024
Estimated Study Completion Date : February 28, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Unilateral Hippocampal Avoidance WBRT with Memantine
Conformal whole brain radiotherapy with unilateral hippocampal avoidance and Concurrent use of Memantine HCL
Radiation: Conformal Whole Brain Radiotherapy with Unilateral Hippocampal Avoidance
Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Unilateral Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy
Other Name: Unilateral HA-WBRT

Drug: Memantine Hydrochloride
Start from day 1 of WBRT orally for 24 weeks and escalating doses over the first 4 weeks
Other Name: Memantine

Active Comparator: Bilateral Hippocampal Avoidance WBRT with Memantine
Conformal whole brain radiotherapy with bilateral hippocampal avoidance and Concurrent use of Memantine HCL
Radiation: Conformal Whole Brain Radiotherapy with Bilateral Hippocampal Avoidance
Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Bilateral Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy
Other Name: Bilateral HA-WBRT

Drug: Memantine Hydrochloride
Start from day 1 of WBRT orally for 24 weeks and escalating doses over the first 4 weeks
Other Name: Memantine




Primary Outcome Measures :
  1. Hopkins Verbal Learning Test-Revised (HVLT-R) memory score [ Time Frame: At 6 months after WBRT ]
    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 :
  1. Neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R) [ 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 ]
    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.

  2. Neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A & B [ 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 ]
    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.

  3. Neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test [ 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 ]
    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.

  4. Patient reported outcome (Quality of Life questionnaire) [ 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 ]
    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.

  5. Patient reported outcome (Cognitive Functioning questionnaire) [ 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 ]
    Function Assessment Cancer Therapy for patients with Cognitive function issue

  6. Acute toxicity (Common Toxicity Criteria for Adverse Events version 4) [ Time Frame: From date of WBRT until 90 days after radiotherapy starts ]
    Common Toxicity Criteria for Adverse Events version 4

  7. Late toxicity (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 ]
    Common Toxicity Criteria for Adverse Events version 4

  8. Intracranial progression (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 ]
    Number of participant with intracranial progression on MRI of brain

  9. Overall survival [ Time Frame: From date of enrollment until the date of death from any cause, assessed up to 60 months ]
    Number of patients died


Other Outcome Measures:
  1. Genomic risk of neurocognitive decline after WBRT [ Time Frame: At 4 months after radiotherapy ]
    Number of participants with Genomic risk of neurocognitive impairment after WBRT



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

    1. Uncontrolled active infection requiring intravenous antibiotics at the time of registration
    2. Transmural myocardial infarction ≤ 6 months prior to registration
    3. Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
    4. Life-threatening uncontrolled clinically significant cardiac arrhythmias
    5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
    6. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
    7. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04801342


Contacts
Layout table for location contacts
Contact: Feng-Ming Hsu, MD, PhD +886-2-23123456 ext 67061 hsufengming@ntuh.gov.tw

Locations
Layout table for location information
Taiwan
National Taiwan University Hospital Recruiting
Taipei, Taiwan, 100
Contact: Feng-Ming Hsu, MD    +886-2-23123456 ext 67061    hsufengming@ntuh.gov.tw   
Sponsors and Collaborators
National Taiwan University Hospital
Investigators
Layout table for investigator information
Principal Investigator: Feng-Ming Hsu, MD, PhD National Taiwan University Hospital
Layout table for additonal information
Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT04801342    
Other Study ID Numbers: 201901084MINA
First Posted: March 17, 2021    Key Record Dates
Last Update Posted: March 17, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
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
Keywords provided by National Taiwan University Hospital:
Brain Metastases
Hippocampal Avoidance Whole Brain Radiotherapy
Neurocognitive function
Additional relevant MeSH terms:
Layout table for MeSH terms
Neoplasm Metastasis
Brain Neoplasms
Neoplasms
Neoplastic Processes
Pathologic Processes
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