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

NCT04588246 | Terminated Phase 3 Results

• 3 other identifiers: NRG-BN009NCI-2020-07375U10CA180868
• Study Type: interventional
• Target: 19
• Locations: 3 countries
• Sites: 81

Brief 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. 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.

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; Metastatic Malignant Solid Neoplasm; Metastatic Melanoma; Metastatic Renal Cell Carcinoma; Recurrent Brain Neoplasm; Stage IV Lung Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Overall Survival

  Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.

• Intracranial Progression-Free Survival (IPFS)

  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)

  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

  Baseline and 4 months from treatment start

• Number of Participants With a Grade 3 or Higher Adverse Event

  Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Study Arms (2)

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.

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.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Radiation: Stereotactic Radiosurgery

Interventions

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Arm I (memantine, HA-WBRT); Arm II (SRS/fSRS)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Arm I (memantine, HA-WBRT); Arm II (SRS/fSRS)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Arm I (memantine, HA-WBRT); Arm II (SRS/fSRS)

Memantine DRUG

Given PO

Arm I (memantine, HA-WBRT)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Arm I (memantine, HA-WBRT); Arm II (SRS/fSRS)

Questionnaire Administration OTHER

Ancillary studies

Arm I (memantine, HA-WBRT); Arm II (SRS/fSRS)

Stereotactic Radiosurgery RADIATION

Undergo SRS/fSRS

Also known as: SRS, Stereotactic External Beam Irradiation, stereotactic external-beam radiation therapy, Stereotactic Radiation Therapy, Stereotactic Radiotherapy, stereotaxic radiation therapy, stereotaxic radiosurgery

Arm II (SRS/fSRS)

Whole-Brain Radiotherapy RADIATION

Undergo HA-WBRT

Also known as: WBRT, whole-brain radiation therapy

Arm I (memantine, HA-WBRT)

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• NRG Oncology: lead
• National Cancer Institute (NCI): collaborator

Study Sites (81)

Banner University Medical Center - Tucson

Tucson, Arizona, 85719, United States

Location

University of Arizona Cancer Center-North Campus

Tucson, Arizona, 85719, United States

Location

City of Hope Corona

Corona, California, 92882, United States

Location

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

City of Hope at Irvine Lennar

Irvine, California, 92618, United States

Location

City of Hope Antelope Valley

Lancaster, California, 93534, United States

Location

Sutter Cancer Centers Radiation Oncology Services-Roseville

Roseville, California, 95661, United States

Location

Sutter Roseville Medical Center

Roseville, California, 95661, United States

Location

Sutter Medical Center Sacramento

Sacramento, California, 95816, United States

Location

California Pacific Medical Center-Pacific Campus

San Francisco, California, 94115, United States

Location

City of Hope South Pasadena

South Pasadena, California, 91030, United States

Location

City of Hope South Bay

Torrance, California, 90503, United States

Location

City of Hope Upland

Upland, California, 91786, United States

Location

Delaware Clinical and Laboratory Physicians PA

Newark, Delaware, 19713, United States

Location

Helen F Graham Cancer Center

Newark, Delaware, 19713, United States

Location

Medical Oncology Hematology Consultants PA

Newark, Delaware, 19713, United States

Location

Christiana Care Health System-Christiana Hospital

Newark, Delaware, 19718, United States

Location

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida, 33146, United States

Location

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida, 33442, United States

Location

Mayo Clinic in Florida

Jacksonville, Florida, 32224-9980, United States

Location

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, 33136, United States

Location

Memorial Hospital West

Pembroke Pines, Florida, 33028, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, 60637, United States

Location

Carle at The Riverfront

Danville, Illinois, 61832, United States

Location

Northwestern Medicine Cancer Center Kishwaukee

DeKalb, Illinois, 60115, United States

Location

Carle Physician Group-Effingham

Effingham, Illinois, 62401, United States

Location

Northwestern Medicine Cancer Center Delnor

Geneva, Illinois, 60134, United States

Location

Carle Physician Group-Mattoon/Charleston

Mattoon, Illinois, 61938, United States

Location

Carle Cancer Center

Urbana, Illinois, 61801, United States

Location

The Carle Foundation Hospital

Urbana, Illinois, 61801, United States

Location

Northwestern Medicine Cancer Center Warrenville

Warrenville, Illinois, 60555, United States

Location

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, 21201, United States

Location

MedStar Franklin Square Medical Center/Weinberg Cancer Institute

Baltimore, Maryland, 21237, United States

Location

UM Upper Chesapeake Medical Center

Bel Air, Maryland, 21014, United States

Location

Central Maryland Radiation Oncology in Howard County

Columbia, Maryland, 21044, United States

Location

UM Baltimore Washington Medical Center/Tate Cancer Center

Glen Burnie, Maryland, 21061, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Trinity Health Saint Joseph Mercy Hospital Ann Arbor

Ann Arbor, Michigan, 48106, United States

Location

Trinity Health IHA Medical Group Hematology Oncology - Brighton

Brighton, Michigan, 48114, United States

Location

Chelsea Hospital

Chelsea, Michigan, 48118, United States

Location

Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital

Chelsea, Michigan, 48118, United States

Location

Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus

Ypsilanti, Michigan, 48197, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

Siteman Cancer Center at Saint Peters Hospital

City of Saint Peters, Missouri, 63376, United States

Location

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri, 63141, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Siteman Cancer Center-South County

St Louis, Missouri, 63129, United States

Location

Siteman Cancer Center at Christian Hospital

St Louis, Missouri, 63136, United States

Location

Northwell Health/Center for Advanced Medicine

Lake Success, New York, 11042, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

State University of New York Upstate Medical University

Syracuse, New York, 13210, United States

Location

Upstate Cancer Center at Verona

Verona, New York, 13478, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Sanford Bismarck Medical Center

Bismarck, North Dakota, 58501, United States

Location

Sanford Broadway Medical Center

Fargo, North Dakota, 58122, United States

Location

Sanford Roger Maris Cancer Center

Fargo, North Dakota, 58122, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Christiana Care Health System-Concord Health Center

Chadds Ford, Pennsylvania, 19317, United States

Location

Geisinger Medical Center

Danville, Pennsylvania, 17822, United States

Location

UPMC Cancer Centers - Arnold Palmer Pavilion

Greensburg, Pennsylvania, 15601, United States

Location

Geisinger Medical Oncology-Lewisburg

Lewisburg, Pennsylvania, 17837, United States

Location

Riddle Memorial Hospital

Media, Pennsylvania, 19063, United States

Location

UPMC-Shadyside Hospital

Pittsburgh, Pennsylvania, 15232, United States

Location

Geisinger Cancer Services-Pottsville

Pottsville, Pennsylvania, 17901, United States

Location

Lankenau Medical Center

Wynnewood, Pennsylvania, 19096, United States

Location

UPMC Memorial

York, Pennsylvania, 17408, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Prisma Health Cancer Institute - Faris

Greenville, South Carolina, 29605, United States

Location

Covenant Medical Center-Lakeside

Lubbock, Texas, 79410, United States

Location

Virginia Commonwealth University/Massey Cancer Center

Richmond, Virginia, 23298, United States

Location

West Virginia University Healthcare

Morgantown, West Virginia, 26506, United States

Location

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin, 53792, United States

Location

Froedtert Menomonee Falls Hospital

Menomonee Falls, Wisconsin, 53051, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Drexel Town Square Health Center

Oak Creek, Wisconsin, 53154, United States

Location

Froedtert West Bend Hospital/Kraemer Cancer Center

West Bend, Wisconsin, 53095, United States

Location

CHUM - Centre Hospitalier de l'Universite de Montreal

Montreal, Quebec, H2X 3E4, Canada

Location

Pamela Youde Nethersole Eastern Hospital

Chai Wan, Hong Kong

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma; Breast Neoplasms; Gastrointestinal Neoplasms; Brain Neoplasms; Neoplasm Metastasis; Melanoma; Carcinoma, Renal Cell; Lung Neoplasms

Interventions

Specimen Handling; Magnetic Resonance Spectroscopy; Memantine; Radiosurgery

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Amantadine; Adamantane; Bridged-Ring Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative

Limitations and Caveats

This study stopped accrual and data collection early due to unmet targeted accrual goals, with 19 participants enrolled out of 350 planned.

Results Point of Contact

• Title: Wendy Seiferheld
• Organization: NRG Oncology

seiferheldw@nrgoncology.org

215-574-3208

Study Officials

• Vinai Gondi

  NRG Oncology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 7, 2020
• First Posted: October 19, 2020
• Study Start: August 5, 2021
• Primary Completion: August 6, 2024
• Study Completion: August 6, 2024
• Last Updated: June 6, 2025
• Results First Posted: June 6, 2025

Record last verified: 2025-04

Locations

US (79); CA (1); HK (1)