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RecruitingInterventionalPhase 3

A Phase III Trial of Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases

NCT ID: NCT03550391Sponsor: Canadian Cancer Trials GroupLast updated: 2026-06-09

Summary

Stereotactic radiosurgery (SRS) is a commonly used treatment for brain tumors. It is a one-day (or in some cases two day), out-patient procedure during which a high dose of radiation is delivered to small spots in the brain while excluding the surrounding normal brain. Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) is when radiation therapy is given to the whole brain, while trying to decrease the amount of radiation that is delivered to the area of the hippocampus. The hippocampus is a brain structure that is important for memory. Memantine is a drug that is given to help relieve symptoms that can be caused by WBRT, including problems with memory and other mental symptoms. Health Canada, the regulatory body that oversees the use of drugs in Canada, has not approved the sale or use of memantine in combination with WBRT to treat this kind of cancer, although they have allowed its use in this study.

Detailed description

The purpose of this research study is to compare the effects (good or bad) of receiving stereotactic radiosurgery (SRS) versus receiving hippocampal-avoidant whole brain radiotherapy (HA-WBRT) plus a drug called memantine, on brain metastases. Receiving SRS could control cancer that has spread to the brain. This study will allow the researchers to know whether this different approach is better, the same, or worse than the usual approach. To decide if it is better, the study doctors will be looking to see if the stereotactic radiosurgery (SRS) helps to either slow the growth of cancer or stop it from coming back, compared to the usual approach. Doctors will also look to see if this new approach increases the life span of patients with this type of cancer, and if it helps with quality of life and cancer related symptoms. The usual approach for patients who are not in a study is treatment with whole brain radiation therapy alone (WBRT).

Arms & interventions

  • DrugMemantine

    20 mg (10 mg divided twice daily). Dose will be escalated by 5 mg per week. Memantine should start at 5 mg, and then increased in 5 mg increments at the following schedule, depending on the patient's response and tolerance:

  • RadiationHippocampal-avoidant (HA-WBRT) Radiotherapy

    30Gy in 10 fractions

  • ProcedureStereotactic Radiosurgery (SRS)

    18-20 or 22 Gy in single fraction

Outcome measures

Primary

  • Overall Survival

    To compare the overall survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive HA-WBRT + memantine

    Time frame: 4.5 years

  • Neurocognitive progression-free survival

    To compare the neurocognitive progression-free survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive HA-WBRT + memantine

    Time frame: 4.5 years

Secondary

  • Time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine

    Time frame: 4.5 years

  • Difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine

    Time frame: 4.5 years

  • Number of salvage procedures following SRS in comparison to HA-WBRT + memantine

    Time frame: 4.5 years

  • Neurocognitive progression-free survival in patients who receive SRS compared to HA-WBRT + memantine

    Time frame: 4.5 years

  • Tabulate and descriptively compare the post-treatment adverse events associated with the interventions.

    Time frame: 4.5 years

  • Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT + memantine

    Time frame: 4.5 years

  • Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS

    Time frame: 4.5 years

  • Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT + memantine.

    Time frame: 4.5 years

  • Quality of life, as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) with brain cancer module (BN20)

    Time frame: 4.5 years

  • Quality of life assessed by ECOG performance status

    Time frame: 4.5 years

  • Quality of life, as assessed by EQ-5D-5L

    Time frame: 4.5 years

  • Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases.

    Time frame: 4.5 years

  • Analysis of serum samples for inflammatory biomarker C-reactive protein and brain-derived-neurotrophic factor (BDNF) to elucidate molecular/genomic mechanisms of neurocognitive decline and associated radiographic changes

    Time frame: 4.5 years

  • Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis

    Time frame: 4.5 years

  • Evaluate serial changes in imaging features found in routine MRI images (T2w changes, morphometry) that may predict tumour control and/or neurocognitive outcomes

    Time frame: 4.5 years

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No
Inclusion Criteria: * Patients must have 5 or more brain metastases as counted on a T1 contrast enhanced MRI obtained ≤ 30 days from randomization (maximum 15 brain metastases). * Patients must have a pathological diagnosis (cytological or histological) of a non-hematopoietic malignancy. * The largest brain metastasis must measure \<2.5 cm in maximal diameter. * Centre must have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system. * Patient must be \> 18 years of age. * Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French either alone or with assistance. * ECOG performance status 0, 1, or 2. * Creatinine clearance must be ≥ 30 ml/min within 28 days prior to registration. * The Neurocognitive Testing examiner must have credentialing confirming completion of the neurocognitive testing training. * Facility is credentialed by IROC to perform SRS and HA-WBRT. The treating centre must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients. The treating centre must have completed IMRT credintialing of this specific IMRT systems to be used in study patients for the purposes of HA-WBRT. * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate. * A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedures. * Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. * In accordance with CCTG policy, protocol treatment is to begin within 14 days of patient enrolment. * Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. Exclusion Criteria: * Pregnant or nursing women. * Men or women of childbearing potential who are unwilling to employ adequate contraception. * Inability to complete a brain MRI. * Known allergy to gadolinium. * Prior cranial radiation therapy. * Planned cytotoxic chemotherapy within 48 hours prior or after the SRS or HA-WBRT. * Primary germ cell tumour, small cell carcinoma, or lymphoma. * Widespread definitive leptomeningeal metastasis. This includes cranial nerve palsy, leptomeningeal carcinomatosis, ependymal involvement, cranial nerve involvement on imaging, suspicious linear meningeal enhancement, or cerebrospinal fluid (CSF) positive for tumour cells. * A brain metastasis that is located ≤ 5 mm of the optic chiasm or either optic nerve. * Surgical resection of a brain metastasis (stereotactic biopsies will be allowed). * More than 15 brain metastases on a volumetric T1 contrast MRI (voxels of 1mm or smaller) performed within the past 14 days, or more than 10 metastases in the case of a non-volumetric MRI. * Prior allergic reaction to memantine. * Current alcohol or drug abuse. * Current use of NMDA antagonists, such as amantadine, ketamine, or dextromethorphan. * Diagnosis of chronic liver disease/cirrhosis of the liver (e.g. Child-Pugh class B or C). * Patients with architectural distortion of lateral ventricular systems, which, in the opinion of the local investigator, makes hippocampal delineation challenging

Study locations (73)

University of Arizona Cancer Center-Orange Grove Campus

Tucson, Arizona, 85704

Recruiting
Site Public Contact · Contact
520-694-8900
Baldassarre Stea · Principal Investigator

University of Arizona Cancer Center-North Campus

Tucson, Arizona, 85719

Recruiting
Site Public Contact · Contact
UACC-IIT@uacc.arizona.edu
Baldassarre Stea · Principal Investigator

City of Hope Corona

Corona, California, 92882

Recruiting
Site Public Contact · Contact
626-256-4673becomingapatient@coh.org
Sean Szeja · Principal Investigator

City of Hope Comprehensive Cancer Center

Duarte, California, 91010

Recruiting
Site Public Contact · Contact
800-826-4673becomingapatient@coh.org
Sean Szeja · Principal Investigator

City of Hope at Irvine Lennar

Irvine, California, 92618

Recruiting
Site Public Contact · Contact
877-467-3411
Sean Szeja · Principal Investigator

UC San Diego Moores Cancer Center

La Jolla, California, 92093

Suspended

City of Hope Antelope Valley

Lancaster, California, 93534

Recruiting
Site Public Contact · Contact
800-826-4673becomingapatient@coh.org
Sean Szeja · Principal Investigator

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868

Active Not Recruiting

Kaiser Permanente-Rancho Cordova Cancer Center

Rancho Cordova, California, 95670

Active Not Recruiting

Rohnert Park Cancer Center

Rohnert Park, California, 94928

Active Not Recruiting

The Permanente Medical Group-Roseville Radiation Oncology

Roseville, California, 95678

Active Not Recruiting

South Sacramento Cancer Center

Sacramento, California, 95823

Active Not Recruiting

Kaiser Permanente Medical Center - Santa Clara

Santa Clara, California, 95051

Active Not Recruiting

City of Hope South Pasadena

South Pasadena, California, 91030

Recruiting
Site Public Contact · Contact
800-826-4673becomingapatient@coh.org
Sean Szeja · Principal Investigator

Kaiser Permanente Cancer Treatment Center

South San Francisco, California, 94080

Active Not Recruiting

City of Hope South Bay

Torrance, California, 90503

Recruiting
Site Public Contact · Contact
877-467-3411
Sean Szeja · Principal Investigator

City of Hope Upland

Upland, California, 91786

Recruiting
Site Public Contact · Contact
800-826-4673becomingapatient@coh.org
Sean Szeja · Principal Investigator

Boca Raton Regional Hospital

Boca Raton, Florida, 33486

Active Not Recruiting

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida, 33146

Recruiting
Site Public Contact · Contact
305-243-2647
Benjamin J. Rich · Principal Investigator

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida, 33442

Recruiting
Site Public Contact · Contact
305-243-2647
Benjamin J. Rich · Principal Investigator

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

Hollywood, Florida, 33021

Active Not Recruiting

Mayo Clinic in Florida

Jacksonville, Florida, 32224-9980

Active Not Recruiting

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, 33136

Recruiting
Site Public Contact · Contact
305-243-2647
Benjamin J. Rich · Principal Investigator

Memorial Hospital West

Pembroke Pines, Florida, 33028

Active Not Recruiting

UM Sylvester Comprehensive Cancer Center at Plantation

Plantation, Florida, 33324

Recruiting
Site Public Contact · Contact
305-243-2647
Benjamin J. Rich · Principal Investigator

Moffitt Cancer Center

Tampa, Florida, 33612

Active Not Recruiting

Piedmont Hospital

Atlanta, Georgia, 30309

Active Not Recruiting

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322

Suspended

Emory Saint Joseph's Hospital

Atlanta, Georgia, 30342

Suspended

Saint Alphonsus Cancer Care Center-Boise

Boise, Idaho, 83706

Suspended

Northwestern University

Chicago, Illinois, 60611

Active Not Recruiting

Decatur Memorial Hospital

Decatur, Illinois, 62526

Recruiting
Site Public Contact · Contact
217-876-4762morganthaler.jodi@mhsil.com
Bryan A. Faller · Principal Investigator

Loyola University Medical Center

Maywood, Illinois, 60153

Suspended

HSHS Saint Elizabeth's Hospital

O'Fallon, Illinois, 62269

Recruiting
Site Public Contact · Contact
217-876-4762morganthaler.jodi@mhsil.com
Bryan A. Faller · Principal Investigator

Methodist Medical Center of Illinois

Peoria, Illinois, 61636

Recruiting
Site Public Contact · Contact
309-243-3605andersonj@illinoiscancercare.com
Bryan A. Faller · Principal Investigator

OSF Saint Francis Medical Center

Peoria, Illinois, 61637

Recruiting
Site Public Contact · Contact
309-243-3605andersonj@illinoiscancercare.com
Bryan A. Faller · Principal Investigator

Carle Cancer Center

Urbana, Illinois, 61801

Recruiting
Site Public Contact · Contact
800-446-5532Research@carle.com
Daniel H. Barnett · Principal Investigator

Northwestern Medicine Cancer Center Warrenville

Warrenville, Illinois, 60555

Active Not Recruiting

Community Cancer Center North

Indianapolis, Indiana, 46256

Active Not Recruiting

Iowa Methodist Medical Center

Des Moines, Iowa, 50309

Recruiting
Site Public Contact · Contact
515-241-6727
Seema Harichand-Herdt · Principal Investigator

Luminis Health Anne Arundel Medical Center

Annapolis, Maryland, 21401

Active Not Recruiting

Walter Reed National Military Medical Center

Bethesda, Maryland, 20889-5600

Recruiting
Site Public Contact · Contact
301-319-2100
Corbin A. Helis · Principal Investigator

Tufts Medical Center

Boston, Massachusetts, 02111

Recruiting
Site Public Contact · Contact
617-636-5000ContactUsCancerCenter@TuftsMedicalCenter.org
John E. Mignano · Principal Investigator

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109

Recruiting
Site Public Contact · Contact
800-865-1125CancerAnswerLine@med.umich.edu
Michelle M. Kim · Principal Investigator

Mayo Clinic in Rochester

Rochester, Minnesota, 55905

Active Not Recruiting

Regions Hospital

Saint Paul, Minnesota, 55101

Suspended

Saint Francis Medical Center

Cape Girardeau, Missouri, 63703

Recruiting
Site Public Contact · Contact
573-334-2230sfmc@sfmc.net
Bryan A. Faller · Principal Investigator

Siteman Cancer Center at Saint Peters Hospital

City of Saint Peters, Missouri, 63376

Recruiting
Site Public Contact · Contact
800-600-3606info@siteman.wustl.edu
Jiayi Huang · Principal Investigator

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri, 63141

Recruiting
Site Public Contact · Contact
800-600-3606info@siteman.wustl.edu
Jiayi Huang · Principal Investigator

Washington University School of Medicine

St Louis, Missouri, 63110

Recruiting
Site Public Contact · Contact
800-600-3606info@siteman.wustl.edu
Jiayi Huang · Principal Investigator

Siteman Cancer Center-South County

St Louis, Missouri, 63129

Recruiting
Site Public Contact · Contact
800-600-3606info@siteman.wustl.edu
Jiayi Huang · Principal Investigator

Missouri Baptist Medical Center

St Louis, Missouri, 63131

Recruiting
Site Public Contact · Contact
314-996-5569
Bryan A. Faller · Principal Investigator

Billings Clinic Cancer Center

Billings, Montana, 59101

Suspended

Benefis Sletten Cancer Institute

Great Falls, Montana, 59405

Recruiting
Site Public Contact · Contact
406-969-6060mccinfo@mtcancer.org
John M. Schallenkamp · Principal Investigator

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center

Lebanon, New Hampshire, 03756

Active Not Recruiting

AtlantiCare Surgery Center

Egg Harbor, New Jersey, 08234

Recruiting
Site Public Contact · Contact
609-748-7200
James C. Wurzer · Principal Investigator

State University of New York Upstate Medical University

Syracuse, New York, 13210

Recruiting
Site Public Contact · Contact
315-464-5476
Michael D. Mix · Principal Investigator

SUNY Upstate Medical Center-Community Campus

Syracuse, New York, 13215

Suspended

Mission Hospital

Asheville, North Carolina, 28801

Active Not Recruiting

Cone Health Cancer Center

Greensboro, North Carolina, 27403

Recruiting
Site Public Contact · Contact
336-832-0836stacey.phelps@conehealth.com
Sarah E. Squire · Principal Investigator

East Carolina University

Greenville, North Carolina, 27834

Active Not Recruiting

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157

Recruiting
Site Public Contact · Contact
336-713-6771
Michael D. Chan · Principal Investigator

Sanford Bismarck Medical Center

Bismarck, North Dakota, 58501

Recruiting
Site Public Contact · Contact
701-323-5760OncologyClinicalTrialsFargo@sanfordhealth.org
Daniel Almquist · Principal Investigator

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104

Active Not Recruiting

Legacy Good Samaritan Hospital and Medical Center

Portland, Oregon, 97210

Recruiting
Site Public Contact · Contact
800-220-4937cancer@lhs.org
Andrew Y. Kee · Principal Investigator

Geisinger Medical Center

Danville, Pennsylvania, 17822

Recruiting
Site Public Contact · Contact
570-271-5251HemonCCTrials@geisinger.edu
Heath B. Mackley · Principal Investigator

Fox Chase Cancer Center Buckingham

Furlong, Pennsylvania, 18925

Active Not Recruiting

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111

Active Not Recruiting

Geisinger Wyoming Valley/Henry Cancer Center

Wilkes-Barre, Pennsylvania, 18711

Recruiting
Site Public Contact · Contact
570-271-5251HemonCCTrials@geisinger.edu
Heath B. Mackley · Principal Investigator

Self Regional Healthcare

Greenwood, South Carolina, 29646

Active Not Recruiting

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112

Active Not Recruiting

Dartmouth Cancer Center - North

Saint Johnsbury, Vermont, 05819

Active Not Recruiting

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226

Recruiting
Site Public Contact · Contact
414-805-3666
Michael W. Straza · Principal Investigator