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

Sponsor
Canadian Cancer Trials Group (Other)
Overall Status
Recruiting
CT.gov ID
NCT03550391
Collaborator
Alliance for Clinical Trials in Oncology (Other), NRG Oncology (Other)
206
Enrollment
73
Locations
2
Arms
61.2
Anticipated Duration (Months)
2.8
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Memantine
  • Radiation: Hippocampal-avoidant (HA-WBRT) Radiotherapy
  • Procedure: Stereotactic Radiosurgery (SRS)
 Phase 3

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).

Study Design

Study Type:
Interventional
Anticipated Enrollment :
206 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
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 metastasesThis 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
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
May 25, 2018
Anticipated Primary Completion Date :
Dec 31, 2022
Anticipated Study Completion Date :
Jun 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Hippocampal-avoidant (HA-WBRT) plus Memantine

WBRT 30Gy in 10 fractions + memantine

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
Experimental: Stereotactic Radiosurgery (SRS)

SRS 18-20 or 22Gy in single fraction

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

Outcome Measures

Primary Outcome Measures

  1. Overall Survival [4.5 years]

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

  2. Neurocognitive progression-free survival [4.5 years]

    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

Secondary Outcome Measures

  1. 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]

  2. 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]

  3. Number of salvage procedures following SRS in comparison to HA-WBRT + memantine [4.5 years]

  4. Neurocognitive progression-free survival in patients who receive SRS compared to HA-WBRT + memantine [4.5 years]

    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)

  5. Tabulate and descriptively compare the post-treatment adverse events associated with the interventions. [4.5 years]

  6. Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT + memantine [4.5 years]

  7. Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS [4.5 years]

    a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery

  8. Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT + memantine. [4.5 years]

    Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding)

  9. 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]

  10. Quality of life assessed by ECOG performance status [4.5 years]

  11. Quality of life, as assessed by EQ-5D-5L [4.5 years]

  12. 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]

  13. 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]

  14. Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis [4.5 years]

  15. 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]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy 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

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Arizona Cancer Center-Orange Grove Campus Tucson Arizona United States 85704
2 University of Arizona Cancer Center-North Campus Tucson Arizona United States 85719
3 UC Irvine Health/Chao Family Comprehensive Cancer Center Orange California United States 92868
4 Kaiser Permanente-Rancho Cordova Cancer Center Rancho Cordova California United States 95670
5 Rohnert Park Cancer Center Rohnert Park California United States 94928
6 The Permanente Medical Group-Roseville Radiation Oncology Roseville California United States 95678
7 South Sacramento Cancer Center Sacramento California United States 95823
8 Kaiser Permanente Medical Center - Santa Clara Santa Clara California United States 95051
9 Kaiser Permanente Cancer Treatment Center South San Francisco California United States 94080
10 Boca Raton Regional Hospital Boca Raton Florida United States 33486
11 UM Sylvester Comprehensive Cancer Center at Coral Gables Coral Gables Florida United States 33146
12 UM Sylvester Comprehensive Cancer Center at Deerfield Beach Deerfield Beach Florida United States 33442
13 Memorial Regional Hospital/Joe DiMaggio Children's Hospital Hollywood Florida United States 33021
14 Mayo Clinic in Florida Jacksonville Florida United States 32224-9980
15 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
16 Memorial Hospital West Pembroke Pines Florida United States 33028
17 Moffitt Cancer Center Tampa Florida United States 33612
18 Piedmont Hospital Atlanta Georgia United States 30309
19 Emory University Hospital/Winship Cancer Institute Atlanta Georgia United States 30322
20 Emory Saint Joseph's Hospital Atlanta Georgia United States 30342
21 Saint Alphonsus Cancer Care Center-Boise Boise Idaho United States 83706
22 Northwestern University Chicago Illinois United States 60611
23 Decatur Memorial Hospital Decatur Illinois United States 62526
24 Loyola University Medical Center Maywood Illinois United States 60153
25 Methodist Medical Center of Illinois Peoria Illinois United States 61636
26 Carle Cancer Center Urbana Illinois United States 61801
27 Northwestern Medicine Cancer Center Warrenville Warrenville Illinois United States 60555
28 Community Cancer Center North Indianapolis Indiana United States 46256
29 Iowa Methodist Medical Center Des Moines Iowa United States 50309
30 Anne Arundel Medical Center Annapolis Maryland United States 21401
31 Tufts Medical Center Boston Massachusetts United States 02111
32 University of Michigan Comprehensive Cancer Center Ann Arbor Michigan United States 48109
33 Mayo Clinic in Rochester Rochester Minnesota United States 55905
34 Saint Francis Medical Center Cape Girardeau Missouri United States 63703
35 Siteman Cancer Center at West County Hospital Creve Coeur Missouri United States 63141
36 Washington University School of Medicine Saint Louis Missouri United States 63110
37 Siteman Cancer Center-South County Saint Louis Missouri United States 63129
38 Missouri Baptist Medical Center Saint Louis Missouri United States 63131
39 Siteman Cancer Center at Saint Peters Hospital Saint Peters Missouri United States 63376
40 Billings Clinic Cancer Center Billings Montana United States 59101
41 Benefis Healthcare- Sletten Cancer Institute Great Falls Montana United States 59405
42 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States 03756
43 AtlantiCare Surgery Center Egg Harbor Township New Jersey United States 08234
44 State University of New York Upstate Medical University Syracuse New York United States 13210
45 SUNY Upstate Medical Center-Community Campus Syracuse New York United States 13215
46 Mission Hospital Asheville North Carolina United States 28801
47 Cone Health Cancer Center Greensboro North Carolina United States 27403
48 East Carolina University Greenville North Carolina United States 27834
49 Wake Forest University Health Sciences Winston-Salem North Carolina United States 27157
50 Sanford Bismarck Medical Center Bismarck North Dakota United States 58501
51 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
52 Legacy Good Samaritan Hospital and Medical Center Portland Oregon United States 97210
53 Geisinger Medical Center Danville Pennsylvania United States 17822
54 Fox Chase Cancer Center Buckingham Furlong Pennsylvania United States 18925
55 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111
56 Geisinger Wyoming Valley/Henry Cancer Center Wilkes-Barre Pennsylvania United States 18711
57 Self Regional Healthcare Greenwood South Carolina United States 29646
58 Huntsman Cancer Institute/University of Utah Salt Lake City Utah United States 84112
59 Norris Cotton Cancer Center-North Saint Johnsbury Vermont United States 05819
60 Medical College of Wisconsin Milwaukee Wisconsin United States 53226
61 Tom Baker Cancer Centre Calgary Alberta Canada T2N 4N2
62 Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
63 BCCA-Vancouver Cancer Centre Vancouver British Columbia Canada V5Z 4E6
64 QEII Health Sciences Centre/Nova Scotia Health Authority Halifax Nova Scotia Canada B3H 2Y9
65 Juravinski Cancer Centre at Hamilton Health Sciences Hamilton Ontario Canada L8V 5C2
66 London Regional Cancer Program London Ontario Canada N6A 4L6
67 University Health Network-Princess Margaret Hospital Toronto Ontario Canada M5G 2M9
68 CSSS Champlain-Charles Le Moyne Greenfield Park Quebec Canada J4V 2H1
69 CHUM - Centre Hospitalier de l'Universite de Montreal Montreal Quebec Canada H2X 3E4
70 The Research Institute of the McGill University Health Centre (MUHC) Montreal Quebec Canada H3H 2R9
71 Jewish General Hospital Montreal Quebec Canada H3T 1E2
72 CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ) Quebec City Quebec Canada G1R 2J6
73 Centre Hospitalier Universitaire de Sherbrooke-Fleurimont Sherbrooke Quebec Canada J1H 5N4

Sponsors and Collaborators

  • Canadian Cancer Trials Group
  • Alliance for Clinical Trials in Oncology
  • NRG Oncology

Investigators

  • Study Chair: David Roberge, CHUM-Centre Hospitalier de l'Universite de Montreal
  • Study Chair: Michael Chan, Wake Forest School of Medicine, Winston-Salem, NC
  • Study Chair: Vina Gondi, Northwestern Medicine Cancer Center, Warrenville IL

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Canadian Cancer Trials Group
ClinicalTrials.gov Identifier:
NCT03550391
Other Study ID Numbers:
  • CCTG CE.7
  • NCI-2018-00395
First Posted:
Jun 8, 2018
Last Update Posted:
Apr 14, 2022
Last Verified:
Jan 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
Yes
Product Manufactured in and Exported from the U.S.:
No
Additional relevant MeSH terms:
Neoplasm Metastasis
Brain Neoplasms
Memantine

Study Results

No Results Posted as of Apr 14, 2022