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Stereotactic Radiosurgery or Hippocampus Avoidance Whole-Brain Radiation Therapy with Memantine in Treating Patients with 5-15 Brain Metastases

Trial Status: Active

This phase III trial studies stereotactic radiosurgery to see how well it works compared to hippocampus avoidance whole-brain radiation therapy with memantine in treating patients with 5-15 brain tumors that have spread from other places in the body. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Hippocampus avoidance whole-brain radiation therapy delivers radiation to the entire brain except for the hippocampus. The hippocampus is a brain structure that is important for memory. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to this area. Memantine is often given with whole brain radiation therapy and may decrease the risk of cognitive side effects after radiation therapy to the brain. It is not yet known whether stereotactic radiosurgery or whole-brain radiation therapy works better in treating patients with 5-15 brain metastases.

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 * The total tumor volume must be 30 cm^3 or less; lesion volume will be approximated by measuring the lesion’s three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2); alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume
  • Center must have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system, or access to a center at which the trial is open which can treat with using one of these systems
  • 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; the baseline assessment must be completed within required timelines, prior to randomization * Patient must also be able and willing to complete the neurocognitive testing without assistance from family and companions; patients must be fluent in English or French, and fully testable in one of those languages * A patient that is able but unwilling to complete the questionnaires will be considered ineligible
  • 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
  • The enrolling facility is credentialed by Imaging and Radiation Oncology Core (IROC) to perform SRS and HA-WBRT - or have access to a center where these treatments are credentialed and the study is open; the treating center must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients; the treating center must have completed intensity-modulated radiation therapy (IMRT) credentialing of the specific IMRT system(s) 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 enrollment 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 Canadian Cancer Trials Group (CCTG) policy, protocol treatment is to begin within 14 days of patient enrollment
  • Women/men of childbearing potential must have agreed to use a highly effective contraceptive method; a woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy / vasectomized partner; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures * Women of childbearing potential will have a pregnancy test to determine eligibility as part of the pre-study evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected; for example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumor production of human chorionic gonadotropin (hCG), as seen with some cancers; patient will be considered eligible if an ultrasound is negative for pregnancy

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 tumor, 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 tumor 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^3 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, or hypersensitivity to any excipients of memantine
  • Current alcohol or drug abuse
  • Current use of N-methyl-D-aspartate (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)
  • Clinically significant untreated or uncontrolled cardiovascular conditions, and/or symptomatic cardiac dysfunction (i.e. unstable angina, congestive heart failure, myocardial infarction within the previous year, cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects, uncontrolled hypertension)
  • Current active or uncontrolled urinary tract infections (UTI)
  • History of epilepsy or seizures, and not currently taking anti-epileptic medication
  • Any other serious intercurrent illness or medical condition judged by the local investigator to compromise the patient's safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines
  • Patients with architectural distortion of lateral ventricular systems which, in the opinion of the local investigator, makes hippocampal delineation challenging

Arizona

Tucson
University of Arizona Cancer Center-North Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-327-2873
University of Arizona Cancer Center-Orange Grove Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 520-694-8900

California

Orange
UC Irvine Health / Chao Family Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-827-8839
Rancho Cordova
Kaiser Permanente-Rancho Cordova Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org
Rohnert Park
Rohnert Park Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org
Roseville
The Permanente Medical Group-Roseville Radiation Oncology
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org
Sacramento
South Sacramento Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org
Santa Clara
Kaiser Permanente Medical Center - Santa Clara
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org
South San Francisco
Kaiser Permanente Cancer Treatment Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-642-4691
Email: Kpoct@kp.org

Florida

Boca Raton
Boca Raton Regional Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 561-955-4800
Coral Gables
UM Sylvester Comprehensive Cancer Center at Coral Gables
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Deerfield Beach
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Hollywood
Memorial Regional Hospital / Joe DiMaggio Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 954-265-1847
Email: OHR@mhs.net
Jacksonville
Mayo Clinic in Florida
Status: ACTIVE
Contact: Site Public Contact
Phone: 855-776-0015
Miami
University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Pembroke Pines
Memorial Hospital West
Status: ACTIVE
Contact: Site Public Contact
Phone: 954-265-4325
Tampa
Moffitt Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-679-0775

Georgia

Atlanta
Emory Saint Joseph's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-851-7115
Emory University Hospital / Winship Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-778-1868

Idaho

Boise
Saint Alphonsus Cancer Care Center-Boise
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 734-712-3671

Illinois

Chicago
Northwestern University
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 312-695-1301
Decatur
Decatur Memorial Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 217-876-4740
Maywood
Loyola University Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 708-226-4357
Peoria
Methodist Medical Center of Illinois
Status: ACTIVE
Contact: Site Public Contact
Phone: 309-243-3605
Urbana
Carle Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
Warrenville
Northwestern Medicine Cancer Center Warrenville
Status: ACTIVE
Contact: Site Public Contact
Phone: 630-352-5360

Indiana

Indianapolis
Community Cancer Center North
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 317-497-2823

Iowa

Des Moines
Iowa Methodist Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-241-6727

Maryland

Annapolis
Anne Arundel Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 443-481-1320

Massachusetts

Boston
Tufts Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 617-636-5000

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-865-1125

Minnesota

Rochester
Mayo Clinic in Rochester
Status: ACTIVE
Contact: Site Public Contact
Phone: 855-776-0015

Missouri

Cape Girardeau
Saint Francis Medical Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 573-334-2230
Email: sfmc@sfmc.net
Creve Coeur
Siteman Cancer Center at West County Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606
Saint Louis
Missouri Baptist Medical Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 314-996-5569
Siteman Cancer Center-South County
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606
Washington University School of Medicine
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606
Saint Peters
Siteman Cancer Center at Saint Peters Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-600-3606

Montana

Billings
Billings Clinic Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-996-2663
Great Falls
Benefis Healthcare- Sletten Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 406-969-6060

New Hampshire

Lebanon
Dartmouth Hitchcock Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 800-639-6918

New Jersey

Egg Harbor Township
AtlantiCare Surgery Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 609-748-7200

New York

Syracuse
SUNY Upstate Medical Center-Community Campus
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 888-823-5923
State University of New York Upstate Medical University
Status: ACTIVE
Contact: Site Public Contact
Phone: 315-464-5476

North Carolina

Asheville
Mission Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 828-775-7211
Greensboro
Cone Health Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 336-832-0821
Greenville
East Carolina University
Status: ACTIVE
Contact: Site Public Contact
Phone: 252-744-1015
Winston-Salem
Wake Forest University Health Sciences
Status: ACTIVE
Contact: Site Public Contact
Phone: 336-713-6771

North Dakota

Bismarck
Sanford Bismarck Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 701-323-5760

Oklahoma

Oklahoma City
University of Oklahoma Health Sciences Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 405-271-8777

Oregon

Portland
Legacy Good Samaritan Hospital and Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-220-4937

Pennsylvania

Danville
Geisinger Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 570-271-5251
Wilkes-Barre
Geisinger Wyoming Valley / Henry Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 570-271-5251

South Carolina

Greenwood
Self Regional Healthcare
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 864-725-4771

Utah

Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-424-2100

Vermont

Saint Johnsbury
Norris Cotton Cancer Center-North
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 802-473-4100

Wisconsin

Milwaukee
Medical College of Wisconsin
Status: ACTIVE
Contact: Site Public Contact
Phone: 414-805-3666

Alberta

Calgary
Tom Baker Cancer Centre
Status: ACTIVE
Contact: Site Public Contact
Phone: 403-521-3433
Edmonton
Cross Cancer Institute
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 780-432-8500

British Columbia

Vancouver
BCCA-Vancouver Cancer Centre
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-939-3333

Nova Scotia

Halifax
QEII Health Sciences Centre / Nova Scotia Health Authority
Status: ACTIVE
Contact: Site Public Contact
Phone: 902-473-6000

Ontario

Hamilton
Juravinski Cancer Centre at Hamilton Health Sciences
Status: ACTIVE
Contact: Site Public Contact
Phone: 905-387-9495
London
London Regional Cancer Program
Status: ACTIVE
Contact: Site Public Contact
Phone: 519-685-8600
Toronto
University Health Network-Princess Margaret Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 416-946-4501

Quebec

Greenfield Park
CSSS Champlain-Charles Le Moyne
Status: ACTIVE
Contact: Site Public Contact
Phone: 450-466-5065
Montreal
CHUM - Centre Hospitalier de l'Universite de Montreal
Status: ACTIVE
Contact: Site Public Contact
Phone: 514-890-8000ext12725
Jewish General Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 514-340-8222ext8248
The Research Institute of the McGill University Health Centre (MUHC)
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 514-934-1934ext48354
Quebec City
CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ)
Status: ACTIVE
Contact: Site Public Contact
Sherbrooke
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
Status: ACTIVE
Contact: Site Public Contact
Phone: 819-820-6480

PRIMARY OBJECTIVES:

I. To compare the overall survival in patients with five to fifteen brain metastases who receive stereotactic radiosurgery (SRS) compared to patients who receive hippocampal-avoidant whole-brain radiation therapy (HA-WBRT) plus memantine hydrochloride (memantine).

II. 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 plus memantine.

SECONDARY OBJECTIVES:

I. To compare time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.

II. To evaluate if there is any difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.

III. To evaluate number of salvage procedures following SRS in comparison to HA-WBRT plus memantine.

IV. To evaluate the individual cognitive test results following SRS in comparison to HA-WBRT plus memantine.

V. To tabulate and descriptively compare the post-treatment adverse events associated with the interventions.

VI. To evaluate the time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT plus memantine.

VII. To prospectively validate a predictive nomogram for distant brain failure.

VIII. To compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.

IX. To evaluate patient’s quality of life, as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) + Brain Cancer Module (BN20), European Quality of Life-5-Dimensional (EQ-5D), Eastern Cooperative Oncology Group (ECOG) performance status, for those who receive SRS compared to those who receive HA-WBRT plus memantine.

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

XI. 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.

XII. Collect whole-brain dosimetry on all patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis (hippocampal dosimetry will be retrospectively assessed).

XIII. Collect imaging parameters and workflow details relating to the radiosurgery planning MRIs (including timing of MR prior to radiosurgery, magnet field strength, contrast type/dose/timing, use of image post-processing, and formal reviewed by radiology) to be prospectively correlated with tumor control outcomes (local control, intracranial control).

XIV. Evaluate serial changes in imaging features found in routine magnetic resonance imaging (MRI) images (T2w changes, morphometry) that may predict tumor control and/or neurocognitive outcomes

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM I: Patients receive memantine hydrochloride orally (PO) twice daily (BID) for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo 10 fractions of HA-WBRT daily for up to 3 weeks.

ARM II: Patients undergo 1 fraction of SRS.

After completion of study treatment, patients are followed up at 8 weeks, 4, 6, 9, 12, 16, and 24 months, then annually afterwards.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Canadian Cancer Trials Group

Principal Investigator
David Roberge

  • Primary ID CCTG CE.7
  • Secondary IDs NCI-2018-00395, CE.7
  • Clinicaltrials.gov ID NCT03550391