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

NCT04801342 | Unknown Phase 2 DMC FDA Drug FDA Device

• 1 other identifier: 201901084MINA
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Malignant Neoplasm to Brain

Keywords

Brain Metastases; Hippocampal Avoidance Whole Brain Radiotherapy; Neurocognitive function

Outcome Measures

Primary Outcomes (1)

• 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

  At 6 months after WBRT

Secondary Outcomes (9)

• Neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R)

  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

• Neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A & B

  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

• Neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test

  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

• Patient reported outcome (Quality of Life questionnaire)

  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

• Patient reported outcome (Cognitive Functioning questionnaire)

  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

Other Outcomes (1)

• Genomic risk of neurocognitive decline after WBRT

  At 4 months after radiotherapy

Study Arms (2)

Unilateral Hippocampal Avoidance WBRT with Memantine

EXPERIMENTAL

Conformal whole brain radiotherapy with unilateral hippocampal avoidance and Concurrent use of Memantine HCL

Radiation: Conformal Whole Brain Radiotherapy with Unilateral Hippocampal Avoidance; Drug: Memantine Hydrochloride

Bilateral Hippocampal Avoidance WBRT with Memantine

ACTIVE COMPARATOR

Conformal whole brain radiotherapy with bilateral hippocampal avoidance and Concurrent use of Memantine HCL

Radiation: Conformal Whole Brain Radiotherapy with Bilateral Hippocampal Avoidance; Drug: Memantine Hydrochloride

Interventions

Conformal Whole Brain Radiotherapy with Unilateral Hippocampal Avoidance RADIATION

Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Unilateral Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy

Also known as: Unilateral HA-WBRT

Unilateral Hippocampal Avoidance WBRT with Memantine

Conformal Whole Brain Radiotherapy with Bilateral Hippocampal Avoidance RADIATION

Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Bilateral Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy

Also known as: Bilateral HA-WBRT

Bilateral Hippocampal Avoidance WBRT with Memantine

Memantine Hydrochloride DRUG

Start from day 1 of WBRT orally for 24 weeks and escalating doses over the first 4 weeks

Also known as: Memantine

Bilateral Hippocampal Avoidance WBRT with Memantine; Unilateral Hippocampal Avoidance WBRT with Memantine

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Pregnant or breast-feeding women

Sponsors & Collaborators

• National Taiwan University Hospital: lead

Study Sites (1)

National Taiwan University Hospital

Taipei, 100, Taiwan

RECRUITING

MeSH Terms

Conditions

Brain Neoplasms

Interventions

Memantine

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Amantadine; Adamantane; Bridged-Ring Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Feng-Ming Hsu, MD, PhD

  National Taiwan University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Feng-Ming Hsu, MD, PhD

CONTACT

+886-2-23123456; hsufengming@ntuh.gov.tw

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2019
• First Posted: March 17, 2021
• Study Start: April 1, 2021
• Primary Completion: January 1, 2024
• Study Completion: February 28, 2025
• Last Updated: March 17, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)