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

Brain Metastases Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03550391
• Other study ID #: CCTG CE.7
• Secondary ID: NCI-2018-00395
• Status: Recruiting
• Phase: Phase 3
• Start date: November 22, 2018
• Est. completion date: December 31, 2027

Study information

• Verified date: March 2024
• Source: Canadian Cancer Trials Group
• Contact: Chris O'Callaghan
• Phone: 613-533-6430
• Email: cocallaghan[@]ctg.queensu.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 206
• Est. completion date: December 31, 2027
• Est. primary completion date: June 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Metastases
• Brain Neoplasms
• Neoplasm Metastasis

Intervention

Drug:
• Memantine
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:

Radiation:
• Hippocampal-avoidant (HA-WBRT) Radiotherapy
30Gy in 10 fractions

Procedure:
• Stereotactic Radiosurgery (SRS)
18-20 or 22 Gy in single fraction

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	CSSS Champlain-Charles Le Moyne	Greenfield Park	Quebec
Canada	QEII Health Sciences Centre/Nova Scotia Health Authority	Halifax	Nova Scotia
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	London Regional Cancer Program	London	Ontario
Canada	CHUM - Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec
Canada	CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ)	Quebec City	Quebec
Canada	Centre Hospitalier Universitaire de Sherbrooke-Fleurimont	Sherbrooke	Quebec
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
Canada	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Luminis Health Anne Arundel Medical Center	Annapolis	Maryland
United States	Mission Hospital	Asheville	North Carolina
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Boca Raton Regional Hospital	Boca Raton	Florida
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Tufts Medical Center	Boston	Massachusetts
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Northwestern University	Chicago	Illinois
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	City of Hope Corona	Corona	California
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	AtlantiCare Surgery Center	Egg Harbor Township	New Jersey
United States	Fox Chase Cancer Center Buckingham	Furlong	Pennsylvania
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Cone Health Cancer Center	Greensboro	North Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Self Regional Healthcare	Greenwood	South Carolina
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Community Cancer Center North	Indianapolis	Indiana
United States	City of Hope at Irvine Lennar	Irvine	California
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	City of Hope Antelope Valley	Lancaster	California
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Loyola University Medical Center	Maywood	Illinois
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Memorial Hospital West	Pembroke Pines	Florida
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California
United States	South Sacramento Cancer Center	Sacramento	California
United States	Dartmouth Cancer Center - North	Saint Johnsbury	Vermont
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Regions Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	City of Hope South Pasadena	South Pasadena	California
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	SUNY Upstate Medical Center-Community Campus	Syracuse	New York
United States	Moffitt Cancer Center	Tampa	Florida
United States	City of Hope South Bay	Torrance	California
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	University of Arizona Cancer Center-Orange Grove Campus	Tucson	Arizona
United States	City of Hope Upland	Upland	California
United States	Carle Cancer Center	Urbana	Illinois
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Canadian Cancer Trials Group	Alliance for Clinical Trials in Oncology, NRG Oncology

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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	4.5 years
Primary	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	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		4.5 years
Secondary	Difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine		4.5 years
Secondary	Number of salvage procedures following SRS in comparison to HA-WBRT + memantine		4.5 years
Secondary	Neurocognitive progression-free survival in patients who receive SRS compared to HA-WBRT + memantine	measured from date the patient is randomized to date at which there is a drop of at least 1.5 standard deviations from baseline in two of the six neurocognitive tests (all tests are standardized based on published norms)	4.5 years
Secondary	Tabulate and descriptively compare the post-treatment adverse events associated with the interventions.		4.5 years
Secondary	Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT + memantine		4.5 years
Secondary	Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS	a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery	4.5 years
Secondary	Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT + memantine.	Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding)	4.5 years
Secondary	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)		4.5 years
Secondary	Quality of life assessed by ECOG performance status		4.5 years
Secondary	Quality of life, as assessed by EQ-5D-5L		4.5 years
Secondary	Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases.		4.5 years
Secondary	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		4.5 years
Secondary	Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis		4.5 years
Secondary	Evaluate serial changes in imaging features found in routine MRI images (T2w changes, morphometry) that may predict tumour control and/or neurocognitive outcomes		4.5 years