Anatomic Stage IV Breast Cancer AJCC v8Phase 3NCT04588246
Comparing Whole Brain Radiotherapy Using a Technique That Avoids the Hippocampus to Stereotactic Radiosurgery in Patients With Cancer That Has Spread to the Brain and Come Back in Other Areas of the Brain After Earlier Stereotactic Radiosurgery
A Phase 3 study testing Biospecimen Collection, Computed Tomography and Magnetic Resonance Imaging in people with Anatomic Stage IV Breast Cancer AJCC v8 and Metastatic Lung Non-Small Cell Carcinoma, run by NRG Oncology at 81 sites in 3 countries.
Trial summary
This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Small Cell Carcinoma
- What is being tested?
- Biospecimen Collection, Computed Tomography and Magnetic Resonance Imaging
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 81 sitesin 3 countries
- Study dates
- 5 Aug 2021to 6 Aug 2024
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have developed their distant brain relapse(s) at least 8 weeks after last SRS and within 21 days prior to randomization
- Distant brain relapse lesions to be treated must measure =< 3.0 cm in maximal extent and total volume of distant brain relapses to be treated must measure < 30 mL on the contrast-enhanced diagnostic MRI brain scan obtained within 21 days prior to randomization
- "last SRS" refers to the most recent SRS procedure that the patient received prior to enrollment on this study
- Distant brain relapse lesions must be diagnosed on MRI, which will include the following elements:
- REQUIRED MRI ELEMENTS
- Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization-prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (brain volume imaging) or 3D fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm
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- Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged)
- A minimum of one axial T2 fluid attenuated inversion recovery (FLAIR) (preferred) or T2 sequence is required. This can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the axial plane
- ADDITIONAL RECOMMENDATIONS
- Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence
- Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1
- Recommendation is that imaging be performed on a 3 Tesla (3T) MRI
- Recommendation is that the study participants be scanned on the same MRI instrument at each time point
- Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020
- If additional sequences are obtained, total imaging time should not exceed 60 minutes
- Brain metastasis velocity (BMV) since last SRS must be >= 4 brain metastases/year
- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
- Pathologically (histologically or cytologically) proven diagnosis of small cell cancer, non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or gastrointestinal cancer within 10 years prior to randomization. If the original histologic proof of malignancy is greater than 10 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)
- Other histologies are not permitted
- History and physical examination within 28 days prior to randomization
- Age >= 18
- Karnofsky performance status of >= 70 within 28 days prior to randomization
- Calculated creatinine clearance (CrCl) >= 30 ml/min (within 28 days prior to randomization)
- Blood urea nitrogen (BUN) within 1.5 times the institutional upper limit of normal (ULN) (e.g., if the ULN is 20 mg/dL, then BUN up to 30 mg/dL is permitted) (within 28 days prior to randomization)
- Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to randomization
Who cannot join
- BMV >= 4 brain metastases/year at time of any SRS prior to enrollment.
- Patients are permitted to have undergone multiple SRS treatments to different brain metastases so long as prior BMV has been less than 4 brain metastases/year
- Prior WBRT or prophylactic cranial irradiation
- Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed)
- Brain metastases from primary germ cell tumor or lymphoma
- Definitive leptomeningeal metastasis
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- Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; concurrent immunotherapy is permitted
- Radiographic evidence of enlargement or other architectural distortion of the lateral ventricles, including placement of external ventricular drain or ventriculoperitoneal shunt
- Known history of demyelinating disease such as multiple sclerosis
- Inability to swallow pills
- Contraindication to MR imaging such as non-MR conditional implanted metal devices or unknown metallic foreign bodies, or contraindication to gadolinium contrast administration during MR imaging, such as anaphylactic allergy that cannot be adequately addressed with pre-contrast medications or acute kidney injury
- Contraindications to memantine, including:
- Allergy, including prior allergic reaction to memantine
- Intractable seizures on adequate anticonvulsive therapy-more than 1 seizure per month for the past 2 months
- Current use of N-methyl-D-asparatate (NMDA) agonist
- Current alcohol or drug abuse, which can exacerbate lethargy/dizziness with memantine
- Severe, active co-morbidity defined as follows:
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
- Transmural myocardial infarction within the last 6 months
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of randomization
- Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization
- Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
- Renal tubular acidosis or metabolic acidosis
- Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to randomization. Note also that HIV testing is not required for eligibility for this protocol
- Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the medication and radiation involved in this study has unknown effects on the unborn fetus
Trial locations and contacts
81 sites in 3 countries.
81 sites in 3 countries
United States79 sites
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
Ann Arbor, Michigan, 48106
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, 21201
MedStar Franklin Square Medical Center/Weinberg Cancer Institute
Baltimore, Maryland, 21237
UM Upper Chesapeake Medical Center
Bel Air, Maryland, 21014
Sanford Bismarck Medical Center
Bismarck, North Dakota, 58501
Tufts Medical Center
Boston, Massachusetts, 02111
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan, 48114
Christiana Care Health System-Concord Health Center
Chadds Ford, Pennsylvania, 19317
Medical University of South Carolina
Charleston, South Carolina, 29425
Chelsea Hospital
Chelsea, Michigan, 48118
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan, 48118
Northwestern University
Chicago, Illinois, 60611
Rush University Medical Center
Chicago, Illinois, 60612
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Central Maryland Radiation Oncology in Howard County
Columbia, Maryland, 21044
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146
City of Hope Corona
Corona, California, 92882
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
Carle at The Riverfront
Danville, Illinois, 61832
Geisinger Medical Center
Danville, Pennsylvania, 17822
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442
Northwestern Medicine Cancer Center Kishwaukee
DeKalb, Illinois, 60115
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
Carle Physician Group-Effingham
Effingham, Illinois, 62401
Sanford Broadway Medical Center
Fargo, North Dakota, 58122
Sanford Roger Maris Cancer Center
Fargo, North Dakota, 58122
Northwestern Medicine Cancer Center Delnor
Geneva, Illinois, 60134
UM Baltimore Washington Medical Center/Tate Cancer Center
Glen Burnie, Maryland, 21061
UPMC Cancer Centers - Arnold Palmer Pavilion
Greensburg, Pennsylvania, 15601
Prisma Health Cancer Institute - Faris
Greenville, South Carolina, 29605
City of Hope at Irvine Lennar
Irvine, California, 92618
University of Mississippi Medical Center
Jackson, Mississippi, 39216
Mayo Clinic in Florida
Jacksonville, Florida, 32224-9980
Northwell Health/Center for Advanced Medicine
Lake Success, New York, 11042
City of Hope Antelope Valley
Lancaster, California, 93534
Geisinger Medical Oncology-Lewisburg
Lewisburg, Pennsylvania, 17837
Covenant Medical Center-Lakeside
Lubbock, Texas, 79410
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, 61938
Riddle Memorial Hospital
Media, Pennsylvania, 19063
Froedtert Menomonee Falls Hospital
Menomonee Falls, Wisconsin, 53051
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
West Virginia University Healthcare
Morgantown, West Virginia, 26506
Delaware Clinical and Laboratory Physicians PA
Newark, Delaware, 19713
Helen F Graham Cancer Center
Newark, Delaware, 19713
Medical Oncology Hematology Consultants PA
Newark, Delaware, 19713
Christiana Care Health System-Christiana Hospital
Newark, Delaware, 19718
Drexel Town Square Health Center
Oak Creek, Wisconsin, 53154
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Memorial Hospital West
Pembroke Pines, Florida, 33028
UPMC-Shadyside Hospital
Pittsburgh, Pennsylvania, 15232
Geisinger Cancer Services-Pottsville
Pottsville, Pennsylvania, 17901
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, 23298
University of Rochester
Rochester, New York, 14642
Sutter Cancer Centers Radiation Oncology Services-Roseville
Roseville, California, 95661
Sutter Roseville Medical Center
Roseville, California, 95661
Sutter Medical Center Sacramento
Sacramento, California, 95816
California Pacific Medical Center-Pacific Campus
San Francisco, California, 94115
City of Hope South Pasadena
South Pasadena, California, 91030
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
State University of New York Upstate Medical University
Syracuse, New York, 13210
City of Hope South Bay
Torrance, California, 90503
Banner University Medical Center - Tucson
Tucson, Arizona, 85719
University of Arizona Cancer Center-North Campus
Tucson, Arizona, 85719
City of Hope Upland
Upland, California, 91786
Carle Cancer Center
Urbana, Illinois, 61801
The Carle Foundation Hospital
Urbana, Illinois, 61801
Upstate Cancer Center at Verona
Verona, New York, 13478
Northwestern Medicine Cancer Center Warrenville
Warrenville, Illinois, 60555
Froedtert West Bend Hospital/Kraemer Cancer Center
West Bend, Wisconsin, 53095
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
Lankenau Medical Center
Wynnewood, Pennsylvania, 19096
UPMC Memorial
York, Pennsylvania, 17408
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
Ypsilanti, Michigan, 48197
Canada1 site
CHUM - Centre Hospitalier de l'Universite de Montreal
Montreal, Quebec, H2X 3E4
About this study
Official title: Phase III Trial of Stereotactic Radiosurgery (SRS) or Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for Distant Brain Relapse With Brain Metastasis Velocity >/= 4 Brain Metastases/Year
This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to the hippocampus, which is a brain structure that is important for memory. The medicine memantine is also often given with whole brain radiation therapy because it may decrease the risk of side effects of radiation on neurocognitive function (including thinking and memory). Stereotactic radiosurgery delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Adding whole brain radiotherapy with hippocampal avoidance and memantine may be effective in reducing the size of the cancer or keeping the cancer the same size when it has spread to the brain and/or come back in other areas of the brain compared to stereotactic radiosurgery.
Read the detailed description
PRIMARY OBJECTIVE:
- To determine if hippocampal-avoidant plus whole brain radiotherapy (HA-WBRT) in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs time to neurologic death as compared to stereotactic radiosurgery (SRS).
SECONDARY OBJECTIVES:
- To determine if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs overall survival as compared to SRS.
II. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs intracranial progression-free survival as compared to SRS.
III. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year improves brain metastasis velocity at subsequent relapse as compared to SRS.
IV. To assess perceived difficulties in cognitive abilities, symptom burden and health status after HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year.
- To compare neurocognitive function outcomes following HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year.
VI. To tabulate and descriptively compare the adverse events associated with the interventions.
VII. To tabulate and descriptively compare the number of salvage procedures used to manage recurrent intracranial disease following the interventions.
EXPLORATORY OBJECTIVES:
- To collect serum, plasma, and whole blood for translational research analyses.
II. To collect baseline and all follow-up magnetic resonance (MR) imaging for hippocampal volume, memory center substructures, axial T2 volumes, and quantitative texture analysis.
III. To collect baseline and follow-up MR imaging to extract whole brain volume, white matter volume and volume of metastatic disease to correlate with cognitive change at 4 months.
IV. To evaluate dose-volume histogram parameters to correlate with radiation toxicity.
- To assess in patients receiving immunotherapy or targeted therapy, if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year at time improves brain metastasis velocity and/or overall survival at subsequent relapse as compared to SRS.
VI. To compare the estimated cost of brain-related therapies and quality-adjusted life years in patients who receive HA-WBRT, as compared to SRS, in patients with distant brain failure with metastasis velocity >= 4 new brain metastases/year.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine orally (PO) once daily (QD) or twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) and may undergo blood sample collection throughout the trial.
ARM II: Patients undergo single fraction SRS or fractionated SRS (fSRS) on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Patients are followed up at 2, 4, 6, 9, and 12 months from the start of SRS/fSFS or HA-WBRT and then every 6 months after month 12 and within 21 days after patient death.
- Conditions
- Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Small Cell Carcinoma, Metastatic Malignant Breast Neoplasm, Metastatic Malignant Digestive System Neoplasm, Metastatic Malignant Neoplasm in the Brain
- Being tested
- Biospecimen Collection, Computed Tomography, Magnetic Resonance Imaging, Memantine, Quality-of-Life Assessment
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung, Small Cell Lung Carcinoma, Breast Neoplasms, Gastrointestinal Neoplasms, Brain Neoplasms, Neoplasm Metastasis, Melanoma, Carcinoma, Renal Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection
Undergo blood sample collection
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
MemantineDrug
Given PO
Quality-of-Life AssessmentOther
Also called Quality of Life Assessment
Ancillary studies
Questionnaire AdministrationOther
Ancillary studies
Stereotactic RadiosurgeryRadiation
Also called SRS, Stereotactic External Beam Irradiation, stereotactic external-beam radiation therapy, Stereotactic Radiation Therapy
Undergo SRS/fSRS
Whole-Brain RadiotherapyRadiation
Also called WBRT, whole-brain radiation therapy
Undergo HA-WBRT
| Study group | Role | What they receive |
|---|---|---|
| Arm I (memantine, HA-WBRT) | Experimental | Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial. Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Memantine; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Radiation: Whole-Brain Radiotherapy |
| Arm II (SRS/fSRS) | Active comparator | Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial. Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Radiation: Stereotactic Radiosurgery |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants With Neurologic Death
Neurologic death defined as 1) Progressive neurologic decline or new neurologic symptoms/signs at time of death irrespective of status of extracranial disease OR 2) Death from inter-current disease in patients with severe neurologic dysfunction. Neurologic death rates were to be estimated using the cumulative incidence method, treating non-neurologic deaths as competing risks, and otherwise censoring participants alive at time of analysis. Analysis was to occur after 127 neurologic death events overall. The primary comparison of treatment arms would be a one-sided 0.05-level test for cause-specific hazard ratio (CHR) in a Cox proportional hazards model. Given the small number of participants due to early study closure, only the number of patients with neurologic death is reported and no statistical testing was done.
Measured: From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Secondary outcomes (6)
Overall Survival
Survival rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a stratified log-rank test. Given the small number of participants due to early study closure, only the number of patients alive at time of study termination is reported, and no statistical testing was done.
Measured: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Intracranial Progression-Free Survival (IPFS)
IPFS rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a stratified log-rank test. Given the small number of participants due to early study closure, only the number of patients with alive without intracranial progression is reported, and no statistical testing was done. Per the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, intracranial progression is defined as local progression of lesions treated with prior radiation or distant progression/development of a new brain lesion. Given the small number of participants due to early study closure, only the number of patients alive without intracranial progression is reported and no statistical testing was done.
Measured: Baseline to intracranial progression, death, or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Brain Metastasis Velocity at Subsequent Relapse (BMVs)
BMVs = [total number of new brain metastases since on-study SRS/HA-WBRT] / (years since on-study SRS/HA-WBRT). BMVs is calculated at the time of distant brain relapse. Higher BMVs is associated with lower rates of survival and higher rates of neurologic death.
Measured: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score
The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the presence and severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 ("not present") to 10 ("as bad as you can imagine") and is rated as the worst occurrence in the last 24 hours. The Symptom Severity subscale score is the average of the symptom severity items, ranging from 0 (best) to 10 (worst). Change from baseline is calculated as score at 4 months minus score at baseline. A negative change value indicates improvement in symptom severity, while a positive change value indicates worsening.
Measured: Baseline and 4 months from treatment start
Number of Participants With a Grade 3 or Higher Adverse Event
Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Adverse events reported as possibly, probably, or definitely related to treatment are considered to be treatment-related adverse events. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Measured: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Number of Participants Who Received Salvage Procedures
Salvage procedures are defined as procedures for the purpose of managing recurrent intracranial disease following protocol treatment.
Measured: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2020
- Study start5 Aug 2021
- Primary completion6 Aug 2024
- Study completion6 Aug 2024
Why it stopped: Inadequate accrual rate
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Anatomic Stage IV Breast Cancer AJCC v8Studies of the same condition, open and under way.
- More trials run by NRG OncologyThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Investigator
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- NRG Oncology
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Vinai Gondi, Principal investigator, NRG Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04588246
- Sponsor's protocol ID
- NRG-BN009
- Other IDs
- NCI-2020-07375, NRG-BN009, NRG-BN009, NRG-BN009, U10CA180868
- Status last verified
- Apr 2025
- First submitted
- 7 Oct 2020
- Last updated
- 20 May 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
Study at a glance
From the registry record, last updated by the sponsor on 20 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase III Trial of Stereotactic Radiosurgery (SRS) or Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for Distant Brain Relapse With Brain Metastasis Velocity >/= 4 Brain Metastases/Year
- ClinicalTrials.gov ID
- NCT04588246
- Acronym / sponsor ID
- NRG-BN009
- Conditions
- Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Small Cell Carcinoma, Metastatic Malignant Breast Neoplasm, Metastatic Malignant Digestive System Neoplasm, Metastatic Malignant Neoplasm in the Brain
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Inadequate accrual rate
- Enrolment
- 19 participants (actual)
- Lead sponsor
- NRG OncologyUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- 5 Aug 2021 (actual)
- Primary completion
- 6 Aug 2024 (actual)
- Study completion
- 6 Aug 2024 (actual)
- First posted
- 19 Oct 2020 (actual)
- Results
- Posted 6 Jun 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to the hippocampus, which is a brain structure that is important for memory. The medicine memantine is also often given with whole brain radiation therapy because it may decrease the risk of side effects of radiation on neurocognitive function (including thinking and memory). Stereotactic radiosurgery delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Adding whole brain radiotherapy with hippocampal avoidance and memantine may be effective in reducing the size of the cancer or keeping the cancer the same size when it has spread to the brain and/or come back in other areas of the brain compared to stereotactic radiosurgery.
Detailed description
PRIMARY OBJECTIVE:
- To determine if hippocampal-avoidant plus whole brain radiotherapy (HA-WBRT) in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs time to neurologic death as compared to stereotactic radiosurgery (SRS).
SECONDARY OBJECTIVES:
- To determine if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs overall survival as compared to SRS.
II. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs intracranial progression-free survival as compared to SRS.
III. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year improves brain metastasis velocity at subsequent relapse as compared to SRS.
IV. To assess perceived difficulties in cognitive abilities, symptom burden and health status after HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year.
- To compare neurocognitive function outcomes following HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year.
VI. To tabulate and descriptively compare the adverse events associated with the interventions.
VII. To tabulate and descriptively compare the number of salvage procedures used to manage recurrent intracranial disease following the interventions.
EXPLORATORY OBJECTIVES:
- To collect serum, plasma, and whole blood for translational research analyses.
II. To collect baseline and all follow-up magnetic resonance (MR) imaging for hippocampal volume, memory center substructures, axial T2 volumes, and quantitative texture analysis.
III. To collect baseline and follow-up MR imaging to extract whole brain volume, white matter volume and volume of metastatic disease to correlate with cognitive change at 4 months.
IV. To evaluate dose-volume histogram parameters to correlate with radiation toxicity.
- To assess in patients receiving immunotherapy or targeted therapy, if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year at time improves brain metastasis velocity and/or overall survival at subsequent relapse as compared to SRS.
VI. To compare the estimated cost of brain-related therapies and quality-adjusted life years in patients who receive HA-WBRT, as compared to SRS, in patients with distant brain failure with metastasis velocity >= 4 new brain metastases/year.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine orally (PO) once daily (QD) or twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) and may undergo blood sample collection throughout the trial.
ARM II: Patients undergo single fraction SRS or fractionated SRS (fSRS) on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Patients are followed up at 2, 4, 6, 9, and 12 months from the start of SRS/fSFS or HA-WBRT and then every 6 months after month 12 and within 21 days after patient death.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm I (memantine, HA-WBRT) | Experimental | Procedure: Biospecimen Collection, Procedure: Computed Tomography, Procedure: Magnetic Resonance Imaging, Drug: Memantine, Other: Quality-of-Life Assessment, Other: Questionnaire Administration, Radiation: Whole-Brain RadiotherapyPatients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial. |
| Arm II (SRS/fSRS) | Active comparator | Procedure: Biospecimen Collection, Procedure: Computed Tomography, Procedure: Magnetic Resonance Imaging, Other: Quality-of-Life Assessment, Other: Questionnaire Administration, Radiation: Stereotactic RadiosurgeryPatients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- Patients must have developed their distant brain relapse(s) at least 8 weeks after last SRS and within 21 days prior to randomization
- Brain metastasis velocity (BMV) since last SRS must be >= 4 brain metastases/year
- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
- Pathologically (histologically or cytologically) proven diagnosis of small cell cancer, non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or gastrointestinal cancer within 10 years prior to randomization. If the original histologic proof of malignancy is greater than 10 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)
- History and physical examination within 28 days prior to randomization
Key exclusion criteria (25 listed)
- BMV >= 4 brain metastases/year at time of any SRS prior to enrollment.
- Prior WBRT or prophylactic cranial irradiation
- Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed)
- Brain metastases from primary germ cell tumor or lymphoma
- Definitive leptomeningeal metastasis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Biospecimen CollectionAlso: Biological Sample Collection, Biospecimen Collected, Specimen CollectionUndergo blood sample collection | Procedure or surgery | Arm I (memantine, HA-WBRT), Arm II (SRS/fSRS) |
| Computed TomographyAlso: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial TomographyUndergo CT | Procedure or surgery | Arm I (memantine, HA-WBRT), Arm II (SRS/fSRS) |
| Magnetic Resonance ImagingAlso: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging ScanUndergo MRI | Procedure or surgery | Arm I (memantine, HA-WBRT), Arm II (SRS/fSRS) |
| MemantineGiven PO | Drug | Arm I (memantine, HA-WBRT) |
| Quality-of-Life AssessmentAlso: Quality of Life AssessmentAncillary studies | Other | Arm I (memantine, HA-WBRT), Arm II (SRS/fSRS) |
| Questionnaire AdministrationAncillary studies | Other | Arm I (memantine, HA-WBRT), Arm II (SRS/fSRS) |
| Stereotactic RadiosurgeryAlso: SRS, Stereotactic External Beam Irradiation, stereotactic external-beam radiation therapy, Stereotactic Radiation TherapyUndergo SRS/fSRS | Radiation | Arm II (SRS/fSRS) |
| Whole-Brain RadiotherapyAlso: WBRT, whole-brain radiation therapyUndergo HA-WBRT | Radiation | Arm I (memantine, HA-WBRT) |
Primary outcome
Percentage of Participants With Neurologic Death
Time frame: From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Neurologic death defined as 1) Progressive neurologic decline or new neurologic symptoms/signs at time of death irrespective of status of extracranial disease OR 2) Death from inter-current disease in patients with severe neurologic dysfunction. Neurologic death rates were to be estimated using the cumulative incidence method, treating non-neurologic deaths as competing risks, and otherwise censoring participants alive at time of analysis. Analysis was to occur after 127 neurologic death events overall. The primary comparison of treatment arms would be a one-sided 0.05-level test for cause-specific hazard ratio (CHR) in a Cox proportional hazards model. Given the small number of participants due to early study closure, only the number of patients with neurologic death is reported and no statistical testing was done.
6 secondary outcomes
Overall Survival
Time frame: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Intracranial Progression-Free Survival (IPFS)
Time frame: Baseline to intracranial progression, death, or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Brain Metastasis Velocity at Subsequent Relapse (BMVs)
Time frame: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score
Time frame: Baseline and 4 months from treatment start
Number of Participants With a Grade 3 or Higher Adverse Event
Time frame: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Number of Participants Who Received Salvage Procedures
Time frame: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 May 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vinai Gondi principal investigator
NRG Oncology
81 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Biospecimen Collection, Computed Tomography and Magnetic Resonance Imaging in people with Anatomic Stage IV Breast Cancer AJCC v8 and Metastatic Lung Non-Small Cell Carcinoma, run by NRG Oncology at 81 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 81 sites in United States, Canada, Hong Kong. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Jun 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With Neurologic Death (time frame: From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 May 2026.