Memory Avoidance Whole Brain Radiotherapy vs Hippocampal Avoidance Whole Brain Radiotherapy (Athena 2 Trial)

NCT07248228 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: CASE7325
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Participants in this research study have cancer that has spread to their brain, called brain metastases. One treatment for this type of cancer is called whole brain radiotherapy that stays away from a specific neurocognitive substructure, called the hippocampus, combined with medication to preserve cognitive function. This study compares that approach to another approach of whole brain radiotherapy that stays away from additional structures that are thought to have a role in cognitive function. Researchers want to see if there is a difference in the preservation of cognitive function between these two approaches.

Conditions

Brain Metastases

Keywords

Whole brain radiotherapy; Memory-avoidance whole brain radiotherapy; Hippocampal-avoidance whole brain radiotherapy

Outcome Measures

Primary Outcomes (21)

• Time to neurocognitive failure (NCF)

  Time to NCF is defined as cognitive decline on the reliable change index (RCI) on at least one of the following tests: HVLT-R, TMT A/B, COWAT, BVMT-R. Tests are defined below.

  Up to 12 months

• Hopkins Verbal Learning Test-Revised (HVLT-R)

  The HVLT-R involves three learning trials: Total Recall, Delayed Recall, and Delayed Recognition. The HVLT-R is administered by the examiner reading a 12-item list of words and asking the participant to recall as many as possible (Total Recall). After a 20-25 minutes interval of unrelated tasks, the examiner asks the participant to recall as many words as possible from the original list (Delayed Recall). Then, the examiner reads a 24-item list of words, where 12 words were on the original list and 12 were not (Delayed Recognition). The examiner asks the participant to respond "yes" if the word was on the original list or "no" if it was not. The HVLT-R is scored by summing the number of correctly recalled words across the three trials. Higher scores indicate greater recall.

  Day 1 (prior to WBRT treatment)

• Hopkins Verbal Learning Test-Revised (HVLT-R)

  The HVLT-R involves three learning trials: Total Recall, Delayed Recall, and Delayed Recognition. The HVLT-R is administered by the examiner reading a 12-item list of words and asking the participant to recall as many as possible (Total Recall). After a 20-25 minutes interval of unrelated tasks, the examiner asks the participant to recall as many words as possible from the original list (Delayed Recall). Then, the examiner reads a 24-item list of words, where 12 words were on the original list and 12 were not (Delayed Recognition). The examiner asks the participant to respond "yes" if the word was on the original list or "no" if it was not. The HVLT-R is scored by summing the number of correctly recalled words across the three trials. Higher scores indicate greater recall.

  Month 3

• Hopkins Verbal Learning Test-Revised (HVLT-R)

  The HVLT-R involves three learning trials: Total Recall, Delayed Recall, and Delayed Recognition. The HVLT-R is administered by the examiner reading a 12-item list of words and asking the participant to recall as many as possible (Total Recall). After a 20-25 minutes interval of unrelated tasks, the examiner asks the participant to recall as many words as possible from the original list (Delayed Recall). Then, the examiner reads a 24-item list of words, where 12 words were on the original list and 12 were not (Delayed Recognition). The examiner asks the participant to respond "yes" if the word was on the original list or "no" if it was not. The HVLT-R is scored by summing the number of correctly recalled words across the three trials. Higher scores indicate greater recall.

  Month 6

• Hopkins Verbal Learning Test-Revised (HVLT-R)

  The HVLT-R involves three learning trials: Total Recall, Delayed Recall, and Delayed Recognition. The HVLT-R is administered by the examiner reading a 12-item list of words and asking the participant to recall as many as possible (Total Recall). After a 20-25 minutes interval of unrelated tasks, the examiner asks the participant to recall as many words as possible from the original list (Delayed Recall). Then, the examiner reads a 24-item list of words, where 12 words were on the original list and 12 were not (Delayed Recognition). The examiner asks the participant to respond "yes" if the word was on the original list or "no" if it was not. The HVLT-R is scored by summing the number of correctly recalled words across the three trials. Higher scores indicate greater recall.

  Month 9

• Hopkins Verbal Learning Test-Revised (HVLT-R)

  The HVLT-R involves three learning trials: Total Recall, Delayed Recall, and Delayed Recognition. The HVLT-R is administered by the examiner reading a 12-item list of words and asking the participant to recall as many as possible (Total Recall). After a 20-25 minutes interval of unrelated tasks, the examiner asks the participant to recall as many words as possible from the original list (Delayed Recall). Then, the examiner reads a 24-item list of words, where 12 words were on the original list and 12 were not (Delayed Recognition). The examiner asks the participant to respond "yes" if the word was on the original list or "no" if it was not. The HVLT-R is scored by summing the number of correctly recalled words across the three trials. Higher scores indicate greater recall.

  Month 12

• Controlled Oral Word Association Test (COWAT)

  The COWAT is a verbal fluency test that involves the examiner asking the participant to name as many words as they can that start with a designated letter, excluding proper nouns, for one minute. This is repeated three times. The examiner records the words provided by the participant, and the COWAT is scored by calculating the total number of acceptable words that the participant produced. Greater scores indicate a higher performance (greater cognitive capabilities) on the test.

  Day 1 (prior to WBRT treatment)

• Controlled Oral Word Association Test (COWAT)

  The COWAT is a verbal fluency test that involves the examiner asking the participant to name as many words as they can that start with a designated letter, excluding proper nouns, for one minute. This is repeated three times. The examiner records the words provided by the participant, and the COWAT is scored by calculating the total number of acceptable words that the participant produced. Greater scores indicate a higher performance (greater cognitive capabilities) on the test.

  Month 3

• Controlled Oral Word Association Test (COWAT)

  The COWAT is a verbal fluency test that involves the examiner asking the participant to name as many words as they can that start with a designated letter, excluding proper nouns, for one minute. This is repeated three times. The examiner records the words provided by the participant, and the COWAT is scored by calculating the total number of acceptable words that the participant produced. Greater scores indicate a higher performance (greater cognitive capabilities) on the test.

  Month 6

• Controlled Oral Word Association Test (COWAT)

  The COWAT is a verbal fluency test that involves the examiner asking the participant to name as many words as they can that start with a designated letter, excluding proper nouns, for one minute. This is repeated three times. The examiner records the words provided by the participant, and the COWAT is scored by calculating the total number of acceptable words that the participant produced. Greater scores indicate a higher performance (greater cognitive capabilities) on the test.

  Month 9

• Controlled Oral Word Association Test (COWAT)

  The COWAT is a verbal fluency test that involves the examiner asking the participant to name as many words as they can that start with a designated letter, excluding proper nouns, for one minute. This is repeated three times. The examiner records the words provided by the participant, and the COWAT is scored by calculating the total number of acceptable words that the participant produced. Greater scores indicate a higher performance (greater cognitive capabilities) on the test.

  Month 12

• Brief Visuospatial Memory Test-Revised (BVMT-R)

  The BVMT-R test involves a participant viewing a page of six figures for 10 seconds and then being asked to draw as many figures as they can remember in their correct places. This is repeated three times. Then, after a 25 minute interval, the examiner asks the participant to recall and draw the figures again. The BVMT-R is scored by summing how many items the participant correctly recalled for each trial. Higher scores indicate higher performance (greater cognitive capabilities) on the test.

  Day 1 (prior to WBRT treatment)

• Brief Visuospatial Memory Test-Revised (BVMT-R)

  The BVMT-R test involves a participant viewing a page of six figures for 10 seconds and then being asked to draw as many figures as they can remember in their correct places. This is repeated three times. Then, after a 25 minute interval, the examiner asks the participant to recall and draw the figures again. The BVMT-R is scored by summing how many items the participant correctly recalled for each trial. Higher scores indicate higher performance (greater cognitive capabilities) on the test.

  Month 3

• Brief Visuospatial Memory Test-Revised (BVMT-R)

  The BVMT-R test involves a participant viewing a page of six figures for 10 seconds and then being asked to draw as many figures as they can remember in their correct places. This is repeated three times. Then, after a 25 minute interval, the examiner asks the participant to recall and draw the figures again. The BVMT-R is scored by summing how many items the participant correctly recalled for each trial. Higher scores indicate higher performance (greater cognitive capabilities) on the test.

  Month 6

• Brief Visuospatial Memory Test-Revised (BVMT-R)

  The BVMT-R test involves a participant viewing a page of six figures for 10 seconds and then being asked to draw as many figures as they can remember in their correct places. This is repeated three times. Then, after a 25 minute interval, the examiner asks the participant to recall and draw the figures again. The BVMT-R is scored by summing how many items the participant correctly recalled for each trial. Higher scores indicate higher performance (greater cognitive capabilities) on the test.

  Month 9

• Brief Visuospatial Memory Test-Revised (BVMT-R)

  The BVMT-R test involves a participant viewing a page of six figures for 10 seconds and then being asked to draw as many figures as they can remember in their correct places. This is repeated three times. Then, after a 25 minute interval, the examiner asks the participant to recall and draw the figures again. The BVMT-R is scored by summing how many items the participant correctly recalled for each trial. Higher scores indicate higher performance (greater cognitive capabilities) on the test.

  Month 12

• Trail Making Test (TMT)

  The TMT consists of two parts: Part A and Part B. In Part A, participants are asked to connect 25 circles numbered 1-25 in ascending order. In Part B, participants are asked to connect 13 circles alternating between numbers and letters in ascending order. Participants are asked to complete these tasks as quickly as they can without lifting their pen from the paper. The TMT is measured by the time in seconds that it takes participant to complete the tasks. Higher times indicate greater cognitive impairment.

  Day 1 (prior to WBRT treatment)

• Trail Making Test (TMT)

  The TMT consists of two parts: Part A and Part B. In Part A, participants are asked to connect 25 circles numbered 1-25 in ascending order. In Part B, participants are asked to connect 13 circles alternating between numbers and letters in ascending order. Participants are asked to complete these tasks as quickly as they can without lifting their pen from the paper. The TMT is measured by the time in seconds that it takes participant to complete the tasks. Higher times indicate greater cognitive impairment.

  Month 3

• Trail Making Test (TMT)

  The TMT consists of two parts: Part A and Part B. In Part A, participants are asked to connect 25 circles numbered 1-25 in ascending order. In Part B, participants are asked to connect 13 circles alternating between numbers and letters in ascending order. Participants are asked to complete these tasks as quickly as they can without lifting their pen from the paper. The TMT is measured by the time in seconds that it takes participant to complete the tasks. Higher times indicate greater cognitive impairment.

  Month 6

• Trail Making Test (TMT)

  The TMT consists of two parts: Part A and Part B. In Part A, participants are asked to connect 25 circles numbered 1-25 in ascending order. In Part B, participants are asked to connect 13 circles alternating between numbers and letters in ascending order. Participants are asked to complete these tasks as quickly as they can without lifting their pen from the paper. The TMT is measured by the time in seconds that it takes participant to complete the tasks. Higher times indicate greater cognitive impairment.

  Month 9

• Trail Making Test (TMT)

  The TMT consists of two parts: Part A and Part B. In Part A, participants are asked to connect 25 circles numbered 1-25 in ascending order. In Part B, participants are asked to connect 13 circles alternating between numbers and letters in ascending order. Participants are asked to complete these tasks as quickly as they can without lifting their pen from the paper. The TMT is measured by the time in seconds that it takes participant to complete the tasks. Higher times indicate greater cognitive impairment.

  Month 12

Study Arms (2)

Memory Avoidance Whole Brain Radiation Therapy (MA-WBRT)

EXPERIMENTAL

Radiation: MA-WBRT (Memory Avoidance Whole Brain Radiation Therapy (MA-WBRT)); Drug: Memantine

Hippocampal Avoidance Whole Brain Radiation Therapy (HA-WBRT)

ACTIVE COMPARATOR

Radiation: HA-WBRT (Hippocampal Avoidance Whole Brain Radiation Therapy (HA-WBRT)); Drug: Memantine

Interventions

MA-WBRT (Memory Avoidance Whole Brain Radiation Therapy (MA-WBRT)) RADIATION

Participants will receive 10 daily fractions of WBRT per standard of care. Participants receiving MA-WBRT will receive WBRT that avoids the hippocampus, the amygdala, corpus callosum, fornix, hypothalamus, and pituitary.

Memory Avoidance Whole Brain Radiation Therapy (MA-WBRT)

Memantine DRUG

Memantine is prescribed per standard of care. Participants will continue on memantine for 24 weeks. The target dose for memantine is 20 mg (10 mg divided twice daily). Dose is escalated by 5 mg per week to target of 10 mg twice daily (i.e., 5 mg a day for week 1, then 5 mg twice daily for week 2, then 10 mg in the morning and 5 mg in the evening for week 3, then 10 mg in the morning and 10 mg in the evening by week 4). Participants will also be prescribed extended release memantine. The target dose for extended release memantine is 28 mg. Dose is escalated by 7 mg per week to target of 28 mg daily (i.e., 7 mg a day for week 1, then 14 mg a day for week 2, then 21 mg a day for week 3, then 28 mg a day for by week 4).

Hippocampal Avoidance Whole Brain Radiation Therapy (HA-WBRT); Memory Avoidance Whole Brain Radiation Therapy (MA-WBRT)

HA-WBRT (Hippocampal Avoidance Whole Brain Radiation Therapy (HA-WBRT)) RADIATION

Participants will receive 10 daily fractions of WBRT per standard of care. Participants receiving HA-WBRT will receive WBRT that avoids the hippocampus.

Hippocampal Avoidance Whole Brain Radiation Therapy (HA-WBRT)

Eligibility Criteria

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

You may qualify if:

• Participants must have histologically, cytologically, or radiographically confirmed diagnosis of solid tumor with brain metastases
• Age \>18 years
• Performance status: Karnofsky Performance Status (KPS) ≥ 70
• Estimated life expectancy of at least 3 months
• Participant must be considered a candidate for WBRT by the treating physician
• Participant must be a primary English speaker and have the ability to understand and the willingness to sign an English written informed consent document
• Participant has at least 10 brain metastases or is otherwise suitable for WBRT

You may not qualify if:

• Prior whole brain radiation
• Participant has Multiple Sclerosis, Alzheimer's, dementia, or mental disability
• Pregnant or breastfeeding women are excluded from this study.
• Participant is not able to receive an MRI
• Participant has metastasis within avoidance neurocognitive substructures (hippocampus, amygdala, fornix, corpus callosum, pituitary, amygdala)

Sponsors & Collaborators

• Case Comprehensive Cancer Center: lead

Study Sites (1)

University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

Location

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

• Haley Perlow, MD

  Case Comprehensive Cancer Center, University Hospitals

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Haley Perlow, MD

CONTACT

(216) 286-3906; haley.perlow@uhhospitals.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2025
• First Posted: November 25, 2025
• Study Start: May 1, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): November 1, 2028
• Last Updated: April 8, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Compiled and analyzed participant data will be published upon study completion. Publisher may request Protocol and Statistical Analysis Plan.

Locations

US (1)