Clinical trial NCT03550391: Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases
Official title: A Phase III Trial of Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Brain Metastases
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: Alliance for Clinical Trials in Oncology
name: NRG Oncology
First posted: 2018-06-08
Enrollment: 206
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is an international multi-centre, open-label, randomized phase III trial comparing stereotactic radiosurgery compared with hippocampal-avoidant whole brain radiotherapy (HA-WBRT) plus memantine for 5-15 brain metastases
Primary purpose: TREATMENT

Brief 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).

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: 4.5 years
measure: Neurocognitive progression-free survival
timeFrame: 4.5 years
Secondary outcomes:
measure: Time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine
timeFrame: 4.5 years
measure: Difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine
timeFrame: 4.5 years
measure: Number of salvage procedures following SRS in comparison to HA-WBRT + memantine
timeFrame: 4.5 years
measure: Neurocognitive progression-free survival in patients who receive SRS compared to HA-WBRT + memantine
timeFrame: 4.5 years
measure: Tabulate and descriptively compare the post-treatment adverse events associated with the interventions.
timeFrame: 4.5 years
measure: Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT + memantine
timeFrame: 4.5 years
measure: Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS
timeFrame: 4.5 years
measure: Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT + memantine.
timeFrame: 4.5 years
measure: 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)
timeFrame: 4.5 years
measure: Quality of life assessed by ECOG performance status
timeFrame: 4.5 years
measure: Quality of life, as assessed by EQ-5D-5L
timeFrame: 4.5 years
measure: Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases.
timeFrame: 4.5 years
measure: 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
timeFrame: 4.5 years
measure: Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis
timeFrame: 4.5 years
measure: Evaluate serial changes in imaging features found in routine MRI images (T2w changes, morphometry) that may predict tumour control and/or neurocognitive outcomes
timeFrame: 4.5 years
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center-Orange Grove Campus
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center-North Campus
state: Arizona
city: Corona
country: United States
facility: City of Hope Corona
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Irvine
country: United States
facility: City of Hope at Irvine Lennar
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Lancaster
country: United States
facility: City of Hope Antelope Valley
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Rancho Cordova
country: United States
facility: Kaiser Permanente-Rancho Cordova Cancer Center
state: California
city: Rohnert Park
country: United States
facility: Rohnert Park Cancer Center
state: California
city: Roseville
country: United States
facility: The Permanente Medical Group-Roseville Radiation Oncology
state: California
city: Sacramento
country: United States
facility: South Sacramento Cancer Center
state: California
city: Santa Clara
country: United States
facility: Kaiser Permanente Medical Center - Santa Clara
state: California
city: South Pasadena
country: United States
facility: City of Hope South Pasadena
state: California
city: South San Francisco
country: United States
facility: Kaiser Permanente Cancer Treatment Center
state: California
city: Torrance
country: United States
facility: City of Hope South Bay
state: California
city: Upland
country: United States
facility: City of Hope Upland
state: California
city: Boca Raton
country: United States
facility: Boca Raton Regional Hospital
state: Florida
city: Coral Gables
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Coral Gables
state: Florida
city: Deerfield Beach
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Deerfield Beach
state: Florida
city: Hollywood
country: United States
facility: Memorial Regional Hospital/Joe DiMaggio Children's Hospital
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Pembroke Pines
country: United States
facility: Memorial Hospital West
state: Florida
city: Plantation
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Plantation
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: O'Fallon
country: United States
facility: HSHS Saint Elizabeth's Hospital
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Center of Illinois
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Warrenville
country: United States
facility: Northwestern Medicine Cancer Center Warrenville
state: Illinois
city: Indianapolis
country: United States
facility: Community Cancer Center North
state: Indiana
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: Annapolis
country: United States
facility: Luminis Health Anne Arundel Medical Center
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Cape Girardeau
country: United States
facility: Saint Francis Medical Center
state: Missouri
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Billings
country: United States
facility: Billings Clinic Cancer Center
state: Montana
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
state: New Hampshire
city: Egg Harbor Township
country: United States
facility: AtlantiCare Surgery Center
state: New Jersey
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical Center-Community Campus
state: New York
city: Asheville
country: United States
facility: Mission Hospital
state: North Carolina
city: Greensboro
country: United States
facility: Cone Health Cancer Center
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center
state: North Dakota
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Legacy Good Samaritan Hospital and Medical Center
state: Oregon
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Furlong
country: United States
facility: Fox Chase Cancer Center Buckingham
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Geisinger Wyoming Valley/Henry Cancer Center
state: Pennsylvania
city: Greenwood
country: United States
facility: Self Regional Healthcare
state: South Carolina
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Saint Johnsbury
country: United States
facility: Dartmouth Cancer Center - North
state: Vermont
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: Arthur J E Child Comprehensive Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: BCCA-Vancouver Cancer Centre
state: British Columbia
city: Halifax
country: Canada
facility: QEII Health Sciences Centre/Nova Scotia Health Authority
state: Nova Scotia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Toronto
country: Canada
facility: University Health Network-Princess Margaret Hospital
state: Ontario
city: Greenfield Park
country: Canada
facility: CSSS Champlain-Charles Le Moyne
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: The Research Institute of the McGill University Health Centre (MUHC)
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ)
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
state: Quebec
Study officials:
affiliation: CHUM-Centre Hospitalier de l'Universite de Montreal
name: David Roberge
role: STUDY_CHAIR
affiliation: Wake Forest School of Medicine, Winston-Salem, NC
name: Michael Chan
role: STUDY_CHAIR
affiliation: Northwestern Medicine Cancer Center, Warrenville IL
name: Vina Gondi
role: STUDY_CHAIR
References: