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Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5-15 Brain Metastases

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ClinicalTrials.gov Identifier: NCT03550391
Recruitment Status : Recruiting
First Posted : June 8, 2018
Last Update Posted : November 10, 2020
Sponsor:
Collaborators:
Alliance for Clinical Trials in Oncology
NRG Oncology
Information provided by (Responsible Party):
Canadian Cancer Trials Group

Tracking Information
First Submitted Date  ICMJE April 30, 2018
First Posted Date  ICMJE June 8, 2018
Last Update Posted Date November 10, 2020
Actual Study Start Date  ICMJE May 25, 2018
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
  • Overall Survival [ Time Frame: 3.5 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
  • Neurocognitive progression-free survival [ Time Frame: 3.5 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
Original Primary Outcome Measures  ICMJE
 (submitted: June 6, 2018)
  • Overall Survival [ Time Frame: 3.5 years ]
    To compare the overall survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive WBRT
  • Neurocognitive progression-free survival [ Time Frame: 3.5 years ]
    To compare the neurocognitive progression-free survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive WBRT
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
  • 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: 3.5 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: 3.5 years ]
  • Number of salvage procedures following SRS in comparison to HA-WBRT + memantine [ Time Frame: 3.5 years ]
  • Neurocognitive progression-free survival in patients who receive SRS compared to HA-WBRT + memantine [ Time Frame: 3.5 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)
  • Tabulate and descriptively compare the post-treatment adverse events associated with the interventions. [ Time Frame: 3.5 years ]
  • Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT + memantine [ Time Frame: 3.5 years ]
  • Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS [ Time Frame: 3.5 years ]
    a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery
  • Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT + memantine. [ Time Frame: 3.5 years ]
    Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding)
  • 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: 3.5 years ]
  • Quality of life assessed by ECOG performance status [ Time Frame: 3.5 years ]
  • Quality of life, as assessed by EQ-5D-5L [ Time Frame: 3.5 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: 3.5 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: 3.5 years ]
  • Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis [ Time Frame: 3.5 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: 3.5 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2018)
  • Time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive WBRT [ Time Frame: 3.5 years ]
  • Difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive WBRT [ Time Frame: 3.5 years ]
  • Number of salvage procedures following SRS in comparison to WBRT [ Time Frame: 3.5 years ]
  • Neurocognitive progression-free survival in patients who receive SRS compared to WBRT [ Time Frame: 3.5 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)
  • Tabulate and descriptively compare the post-treatment adverse events associated with the interventions. [ Time Frame: 3.5 years ]
  • Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to WBRT [ Time Frame: 3.5 years ]
  • Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS [ Time Frame: 3.5 years ]
    a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery
  • Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive WBRT. [ Time Frame: 3.5 years ]
    Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding)
  • 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: 3.5 years ]
  • Quality of life assessed by ECOG performance status [ Time Frame: 3.5 years ]
  • Quality of life, as assessed by EQ-5D [ Time Frame: 3.5 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: 3.5 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: 3.5 years ]
  • Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis [ Time Frame: 3.5 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: 3.5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5-15 Brain Metastases
Official Title  ICMJE A Phase III Trial of Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5-15 Brain Metastases
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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 metastases
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Brain Metastases
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Hippocampal-avoidant (HA-WBRT) plus Memantine
    WBRT 30Gy in 10 fractions + memantine
    Interventions:
    • Drug: Memantine
    • Radiation: Hippocampal-avoidant (HA-WBRT) Radiotherapy
  • Experimental: Stereotactic Radiosurgery (SRS)
    SRS 18-20 or 22Gy in single fraction
    Intervention: Procedure: Stereotactic Radiosurgery (SRS)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 6, 2018)
206
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Chris O'Callaghan 613-533-6430 cocallaghan@ctg.queensu.ca
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03550391
Other Study ID Numbers  ICMJE CCTG CE.7
NCI-2018-00395 ( Other Identifier: NCI CTRP )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Canadian Cancer Trials Group
Study Sponsor  ICMJE Canadian Cancer Trials Group
Collaborators  ICMJE
  • Alliance for Clinical Trials in Oncology
  • NRG Oncology
Investigators  ICMJE
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
PRS Account Canadian Cancer Trials Group
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP