NTS-WBRT VS HA-WBRT in Brain Metastases

Study Overview
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Brief Summary
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This research is being done to compare quality of life and symptom burden in participants who receive two different types of radiation therapy (normal tissue sparing whole brain radiation therapy (NTS-WBRT) or standard of care hippocampal avoidance whole brain radiation Therapy (HA-WBRT). This research study involves: NTS-WBRT (normal tissue sparing whole brain radiation therapy) HA-WBRT (hippocampal avoidance whole brain radiation Therapy) Memantine standard of care drug

Detailed Description
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This is a Phase 2 randomized trial testing the safety and effectiveness of NTS-WBRT (normal tissue sparing whole brain radiation therapy) as compared to HA-WBRT (hippocampal avoidance whole brain radiation Therapy) in treating brain metastases. NTS-WBRT is a targeted radiation therapy that further reduces radiation dose to tissue that does not need radiation therapy treatment. HA-WBRT is a targeted radiation therapy that avoids the hippocampus (part of the brain that controls learning and memory) tissue during radiation therapy treatment. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. It is expected that about 100 people will take part in this research study.

Official Title
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Randomized Phase II Trial of Normal Tissue Sparing Whole Brain Radiation Therapy (NTS-WBRT) Versus Hippocampal Avoidance Whole Brain Radiation Therapy (HA-WBRT) in Patients With Brain Metastases

Conditions
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Brain Metastases

Intervention / Treatment
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* Radiation: NTS-WBRT (normal tissue sparing whole brain radiation therapy)
* Radiation: HA-WBRT (hippocampal avoidance whole brain radiation therapy)
* Drug: Memantine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient with a solid tumor diagnosis and any number of brain metastasis clinically indicated for cranial irradiation with whole brain radiation therapy Age ≥ 18 Karnofsky Performance Status ≥ 70 Prior stereotactic radiosurgery (SRS) permissible per physician discretion Prior craniotomy permissible per physician discretion. Protocol radiation therapy should be initiated ≥2 weeks after craniotomy. Prior partial brain radiation therapy permissible if target volume < 50% brain and per physician discretion Expectant > 6 months survival Ability to understand and the willingness to sign a written informed consent document. Fluency in English, able to complete questionnaires and neurocognitive testing Ability to undergo MRI with gadolinium examination Ability to return for follow-up examinations throughout the course of this study for a maximum of 2 years after radiation treatment completion Any prior, concomitant, or post-radiotherapy systemic therapy is permitted at discretion of treating physicians Negative pregnancy test for premenopausal women Exclusion Criteria: Leptomeningeal disease (by any one or more of clinical assessment, radiographic assessment, or cerebrospinal fluid study) Prior whole brain radiation therapy Pre-existing or current use of memantine or other NMDA antagonists Known allergy to contrast used in imaging studies and/or inability to have MRI imaging Uncontrolled intercurrent illness that could significantly affect baseline cognitive function as determined by the enrolling clinician, such as symptomatic congestive heart failure, unstable angina pectoris, prior CVA, significant uncontrolled epilepsy or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or unwilling to use appropriate contraception to prevent pregnancy during the time of radiation therapy Concurrent participation in an investigational systemic therapy protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NTS-WBRT (normal tissue sparing whole brain radiation therapy) + Memantine<br>Participants will be randomly assigned to NTS-WBRT (normal tissue sparing whole brain radiation therapy) administration group and receive: NTS-WBRT for 5 days (Monday-Friday) for either 2 or 3 weeks. Memantine per standard of care, 1-2x daily for up to 24 weeks Specific participant administration schedules will be determined by study doctor | Radiation: NTS-WBRT (normal tissue sparing whole brain radiation therapy)<br>* Radiation<br>* Other names: Radiation Therapy;Drug: Memantine<br>* Capsule, taken orally<br>* Other names: Namenda XR Titration Pack;|
| Experimental: HA-WBRT (hippocampal avoidance whole brain radiation Therapy) + Memantine<br>Participants will be randomly assigned to HA-WBRT (hippocampal avoidance whole brain radiation Therapy) administration group and receive: HA-WBRT for 5 days (Monday-Friday) for either 2 or 3 weeks. Memantine per standard of care, 1-2x daily for up to 24 weeks Specific participant administration schedules will be determined by study doctor | Radiation: HA-WBRT (hippocampal avoidance whole brain radiation therapy)<br>* Radiation<br>* Other names: Radiation Therapy;Drug: Memantine<br>* Capsule, taken orally<br>* Other names: Namenda XR Titration Pack;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient Reported Quality of Life between NTS-WBRT (normal tissue sparing whole brain radiation therapy) and HA-WBRT (hippocampal avoidance whole brain radiation Therapy) | Assessed by Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire. Score range is 0-200 and the higher the score, the better the outcome. | 4 Months | 
| Change in Patient Reported Symptom Burden between NTS-WBRT (normal tissue sparing whole brain radiation therapy) and HA-WBRT (hippocampal avoidance whole brain radiation Therapy) | Assessed by Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire. Score range is 0-200 and the higher the score, the better the outcome. | 4 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor local control Rates between NTS-WBRT+SIB and HA-WBRT | Estimated by the cumulative incidence function treating death as a competing risk, compared using Gray's test | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Intracranial- Progression Free Survival (PFS) between NTS-WBRT+SIB and HA-WBRT | Estimated using the Kaplan-Meier method, compared using the logrank test | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Overall survival (OS) between NTS-WBRT+SIB and HA-WBRT | Estimated using the Kaplan-Meier method, compared using the logrank test | The date of randomization to the date of death, or otherwise censored at the last follow-up date for patients still alive up to 24 months | 
| Change in Neurocognitive function between NTS-WBRT+SIB and HA-WBRT | Assessed longitudinally by the HADS-D and HADS-A questionnaires | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Change in Mood between NTS-WBRT+SIB and HA-WBRT | Mixed effects models with treatment arm as a fixed effect will be used to compare changes in depression (HADS-D) and anxiety (HADS-A) scores over time | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Change in Fatigue between NTS-WBRT+SIB and HA-WBRT | Mixed effects models with treatment arm as a fixed effect will be used to compare changes in the fatigue score over time | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Change in Neuroendocrine function between NTS-WBRT+SIB and HA-WBRT | Estimated by the cumulative incidence function treating intracranial progression and death as competing risks; compared using Gray's test. | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Change in Hearing between NTS-WBRT+SIB and HA-WBRT Assessed by Pure Tone Average | Changes in pure tone average (PTA) from baseline to each subsequent assessment will be compared between treatment arms using Wilcox rank-sum test. Pure tone thresholds are found by presenting tones using standard headphones and methods in a sound treated booth. Pure tone thresholds will be tested by both bone (500, 1000, 2000 and 4000 Hz) and air conduction (250, 500, 1000, 2000, 3000, 4000, 6000, 8000, 10000, 12000, and 14000 Hz). Masking will be applied sufficient to determine the ear responsible for each value. The results of this testing will be used to determine the sensorineural hearing level. If significant conductive loss is found, bone conduction threshold will be used to report sensory ototoxicity. Threshold effects across frequency will be combined into a Pure Tone Average (PTA), defined as the average of audiometric thresholds at 500, 1000, 2000, and 4000. A significant decrease in Pure Tone Average is defined as an increase > 10 dB in relation to baseline threshold. | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Change in Hearing between NTS-WBRT+SIB and HA-WBRT Assessed by Word Recognition Score | Changes in word recognition score (WRS) from baseline to each subsequent assessment will be compared between treatment arms using Wilcox rank-sum test. Word recognition is defined as the percent correct on a standard, 50-item word list of English monosyllables: CID W-22, NU#6 or CNC. A significant decrease in word recognition is defined as a score exceeding the 95% critical difference from the table of Thornton and Raffin. | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Change in Hearing between NTS-WBRT+SIB and HA-WBRT Assessed by Otoacoustic Emissions | The rates of absent otoacoustic emissions (OAE) will be compared between treatment arms using Fisher's exact test. The OAE (Otoacoustic Emissions) test checks part of the inner ear's response to sound. Otoacoustic emissions are sounds given off by one small part of the cochlea when it is stimulated by soft clicking sounds. When the sound stimulates the cochlea, the outer hair cells vibrate. The vibration produces a nearly inaudible sound that echoes back into the middle ear. The results are either present or absent. Present OAEs are consistent with normal to near normal hearing. Absent OAEs may be a sign of a problem related to study treatment. | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Alopecia Rates between NTS-WBRT+SIB and HA-WBRT | Assessed by patient report and visual inspection with documented photography; compared by Fisher's exact test | baseline, 2, 4, 6, 9, 12, 18 and 24 months | 
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0 | The number and proportion of adverse events, graded as defined by CTCAE version 5.0 will be tabulated by type and grade, compared using Fisher's exact test. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Metastases