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

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.

Study Overview

• Status: Terminated
• Conditions: Metastatic Renal Cell Carcinoma; Metastatic Lung Non-Small Cell Carcinoma; Anatomic Stage IV Breast Cancer AJCC v8; Metastatic Melanoma; Stage IV Lung Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8; Metastatic Malignant Solid Neoplasm; Metastatic Malignant Neoplasm in the Brain; Recurrent Brain Neoplasm; Metastatic Lung Small Cell Carcinoma; Metastatic Malignant Digestive System Neoplasm; Metastatic Malignant Breast Neoplasm
• Intervention / Treatment: Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Procedure: Magnetic Resonance Imaging; Procedure: Computed Tomography; Procedure: Biospecimen Collection; Drug: Memantine; Radiation: Whole-Brain Radiotherapy; Radiation: Stereotactic Radiosurgery

Detailed Description

PRIMARY OBJECTIVE:

I. 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:

I. 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.

V. 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:

I. 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.

V. 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 Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2X 3E4
      • CHUM - Centre Hospitalier de l'Universite de Montreal
• Hong Kong
  • Chai Wan, Hong Kong
    • Pamela Youde Nethersole Eastern Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Banner University Medical Center - Tucson
    • Tucson, Arizona, United States, 85719
      • University of Arizona Cancer Center-North Campus
  • California
    • Corona, California, United States, 92882
      • City of Hope Corona
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Irvine, California, United States, 92618
      • City of Hope at Irvine Lennar
    • Lancaster, California, United States, 93534
      • City of Hope Antelope Valley
    • Roseville, California, United States, 95661
      • Sutter Cancer Centers Radiation Oncology Services-Roseville
    • Roseville, California, United States, 95661
      • Sutter Roseville Medical Center
    • Sacramento, California, United States, 95816
      • Sutter Medical Center Sacramento
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center-Pacific Campus
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
    • Torrance, California, United States, 90503
      • City of Hope South Bay
    • Upland, California, United States, 91786
      • City of Hope Upland
  • Delaware
    • Newark, Delaware, United States, 19713
      • Helen F Graham Cancer Center
    • Newark, Delaware, United States, 19713
      • Delaware Clinical and Laboratory Physicians PA
    • Newark, Delaware, United States, 19713
      • Medical Oncology Hematology Consultants PA
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System-Christiana Hospital
  • Florida
    • Coral Gables, Florida, United States, 33146
      • UM Sylvester Comprehensive Cancer Center at Coral Gables
    • Deerfield Beach, Florida, United States, 33442
      • UM Sylvester Comprehensive Cancer Center at Deerfield Beach
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Pembroke Pines, Florida, United States, 33028
      • Memorial Hospital West
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Danville, Illinois, United States, 61832
      • Carle at The Riverfront
    • DeKalb, Illinois, United States, 60115
      • Northwestern Medicine Cancer Center Kishwaukee
    • Effingham, Illinois, United States, 62401
      • Carle Physician Group-Effingham
    • Geneva, Illinois, United States, 60134
      • Northwestern Medicine Cancer Center Delnor
    • Mattoon, Illinois, United States, 61938
      • Carle Physician Group-Mattoon/Charleston
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center
    • Urbana, Illinois, United States, 61801
      • The Carle Foundation Hospital
    • Warrenville, Illinois, United States, 60555
      • Northwestern Medicine Cancer Center Warrenville
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • MedStar Franklin Square Medical Center/Weinberg Cancer Institute
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
    • Bel Air, Maryland, United States, 21014
      • UM Upper Chesapeake Medical Center
    • Columbia, Maryland, United States, 21044
      • Central Maryland Radiation Oncology in Howard County
    • Glen Burnie, Maryland, United States, 21061
      • UM Baltimore Washington Medical Center/Tate Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Trinity Health Saint Joseph Mercy Hospital Ann Arbor
    • Brighton, Michigan, United States, 48114
      • Trinity Health IHA Medical Group Hematology Oncology - Brighton
    • Chelsea, Michigan, United States, 48118
      • Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
    • Chelsea, Michigan, United States, 48118
      • Chelsea Hospital
    • Ypsilanti, Michigan, United States, 48197
      • Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • City of Saint Peters, Missouri, United States, 63376
      • Siteman Cancer Center at Saint Peters Hospital
    • Creve Coeur, Missouri, United States, 63141
      • Siteman Cancer Center at West County Hospital
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • St Louis, Missouri, United States, 63129
      • Siteman Cancer Center-South County
    • St Louis, Missouri, United States, 63136
      • Siteman Cancer Center at Christian Hospital
  • New York
    • Lake Success, New York, United States, 11042
      • Northwell Health/Center for Advanced Medicine
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
    • Verona, New York, United States, 13478
      • Upstate Cancer Center at Verona
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Sanford Bismarck Medical Center
    • Fargo, North Dakota, United States, 58122
      • Sanford Roger Maris Cancer Center
    • Fargo, North Dakota, United States, 58122
      • Sanford Broadway Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Chadds Ford, Pennsylvania, United States, 19317
      • Christiana Care Health System-Concord Health Center
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Greensburg, Pennsylvania, United States, 15601
      • UPMC Cancer Centers - Arnold Palmer Pavilion
    • Lewisburg, Pennsylvania, United States, 17837
      • Geisinger Medical Oncology-Lewisburg
    • Media, Pennsylvania, United States, 19063
      • Riddle Memorial Hospital
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC-Shadyside Hospital
    • Pottsville, Pennsylvania, United States, 17901
      • Geisinger Cancer Services-Pottsville
    • Wynnewood, Pennsylvania, United States, 19096
      • Lankenau Medical Center
    • York, Pennsylvania, United States, 17408
      • UPMC Memorial
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Faris
  • Texas
    • Lubbock, Texas, United States, 79410
      • Covenant Medical Center-Lakeside
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Healthcare
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center - University Hospital
    • Menomonee Falls, Wisconsin, United States, 53051
      • Froedtert Menomonee Falls Hospital
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin
    • Oak Creek, Wisconsin, United States, 53154
      • Drexel Town Square Health Center
    • West Bend, Wisconsin, United States, 53095
      • Froedtert West Bend Hospital/Kraemer Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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
      • 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

Exclusion Criteria:

• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (memantine, HA-WBRT); 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.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Memantine; Given PO; Radiation: Whole-Brain Radiotherapy; Undergo HA-WBRT; Other Names: WBRT; whole-brain radiation therapy
Active Comparator: Arm II (SRS/fSRS); Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Radiation: Stereotactic Radiosurgery; Undergo SRS/fSRS; Other Names: Stereotactic External Beam Irradiation; stereotactic external-beam radiation therapy; Stereotactic Radiotherapy; stereotaxic radiation therapy; stereotaxic radiosurgery; Stereotactic Radiation Therapy; SRS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Collaborators and Investigators

• Sponsor: NRG Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Vinai Gondi, NRG Oncology

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2021
• Primary Completion (Actual): August 6, 2024
• Study Completion (Actual): August 6, 2024

Study Registration Dates

• First Submitted: October 7, 2020
• First Submitted That Met QC Criteria: October 13, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Respiratory Tract Diseases; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Lung Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Skin Diseases; Breast Diseases; Urologic Neoplasms; Carcinoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Kidney Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Central Nervous System Neoplasms; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Lung Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Gastrointestinal Neoplasms; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma; Melanoma; Brain Neoplasms; Organic Chemicals; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Hydrocarbons; Hydrocarbons, Cyclic; Chemistry Techniques, Analytical; Spectrum Analysis; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Adamantane; Bridged-Ring Compounds; Amantadine; Memantine; Specimen Handling; Magnetic Resonance Spectroscopy; Radiosurgery
• Other Study ID Numbers: NRG-BN009 (Other Identifier: CTEP); U10CA180868 (U.S. NIH Grant/Contract); NCI-2020-07375 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No