<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03775330</url>
  </required_header>
  <id_info>
    <org_study_id>BRAIN METS SRS</org_study_id>
    <nct_id>NCT03775330</nct_id>
  </id_info>
  <brief_title>Radiosurgery With or Without Whole Brain Radiation for Multiple Metastases</brief_title>
  <official_title>Parallel Prospective Observational Cohorts Evaluating Stereotactic Radiosurgery Alone (SRS) and Whole Brain Radiotherapy (WBRT) Plus SRS for Patients With 5 to 30 Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sunnybrook Health Sciences Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sunnybrook Health Sciences Centre</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical study is a parallel, prospective observational single-centre trial in patients&#xD;
      presenting with 5 to 30 brain metastases. Patients to receive either stereotactic&#xD;
      radiosurgery (SRS) alone or SRS plus whole brain radiation (WBRT) will be enrolled.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The current standard of care for patients with limited brain metastases (1 to 4) is&#xD;
      stereotactic radiosurgery (SRS) alone. This has evolved from the traditional standard of care&#xD;
      in treating patients with whole brain radiation (WBRT). Studies in patients with limited&#xD;
      (less than 5) brain metastases have shown that WBRT is harmful with respect to neurocognition&#xD;
      and does not improve patient survival compared to SRS alone. As a result, SRS alone now is&#xD;
      considered the standard of care treatment for patients with limited metastases. However,&#xD;
      there is a lack of high quality prospective randomized evidence on the role of SRS in&#xD;
      patients with 5 or more brain metastases to guide treatment.&#xD;
&#xD;
      Therefore, this study seeks to prospectively compare SRS alone versus SRS plus WBRT in&#xD;
      patients with 5 to 30 brain metastases.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 20, 2020</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Neurocognitive function</measure>
    <time_frame>2 months post treatment</time_frame>
    <description>Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall using the Reliable Change Index (RCI)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function - HVLT-R</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Hopkins Verbal Learning Test-Revised (HVLT-R) (Total Recall, Delayed Recall, Delayed Recognition)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function - Trail Making Test</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Trail Making Test (TMT, Part A and Part B)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function - Controlled Oral Word Association</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Controlled Oral Word Association (COWA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function - Clinical Trial Battery Composite</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Clinical Trial Battery Composite (CTB COMP) score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Local control of sites initially treated by SRS</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Defined by the response criteria stipulated in the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria guideline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Distant tumour control within the brain</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Distant brain failure is defined as the appearance of one or more new lesions on a diagnostic-quality, contrast-enhanced MRI within the brain at sites other than those initially treated by SRS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall central nervous system (CNS) response</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Response will be recorded for each individual target lesion and for overall central nervous system (CNS) response as a composite of radiographical CNS target and non-target lesion responses, corticosteroid use, and clinical status defined as per RANO-BM criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From date of randomization until the date of death from any cause, whichever came first, assessed up to 36 months</time_frame>
    <description>Response recorded for survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure of Quality of Life</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Health-Related QoL as measured by Functional Assessment of Cancer Therapy - Brain (FACT-Br) instrument</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Brain Salvage therapy During Follow-up</measure>
    <time_frame>2 months, 4 months, 6 months, and 9 months</time_frame>
    <description>Number/proportion of patients requiring salvage therapy and type of salvage therapy, for progressive intracranial disease during follow-up</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">126</enrollment>
  <condition>Brain Metastases</condition>
  <arm_group>
    <arm_group_label>SRS</arm_group_label>
    <description>Stereotactic radiosurgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SRS plus WBRT</arm_group_label>
    <description>Stereotactic radiosurgery plus whole brain radiation</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic Radiosurgery (SRS)</intervention_name>
    <description>SRS or hypofractionated stereotactic radiation delivered via the Leksell Gammknife Perfexion/Icon radiosurgery system. Hypofractionated stereotactic radiotherapy 25-32.5 Gy in 5 fractions or 24-27 Gy in 3 fractions at the discretion of the radiation oncologist&#xD;
Maximum diameter of metastasis (doses in single fraction):&#xD;
≤ 2 cm: 15-20 Gy &gt; 2 cm and ≤ 3 cm: 15-18 Gy &gt; 3 cm and ≤ 4 cm: 15 Gy&#xD;
Tumour location (doses in single fraction):&#xD;
Brainstem: 15 Gy&#xD;
Hypofractionated stereotactic radiotherapy 25-32.5 Gy in 5 fractions may be used for lesions &gt; 2 cm at the discretion of the radiation oncologist&#xD;
Note: SRS dosing reduced by 20% (for all prescriptions &gt; 15 Gy) when patient is randomized to SRS + WBRT arm</description>
    <arm_group_label>SRS</arm_group_label>
    <arm_group_label>SRS plus WBRT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Whole brain radiation (WBRT)</intervention_name>
    <description>WBRT 20 Gy in 5 fractions or 30 Gy in 10 fractions at the discretion of the radiation oncologist</description>
    <arm_group_label>SRS plus WBRT</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        The participant population will be patients who have MRI-documented 5 to 30, inclusive,&#xD;
        brain metastases at time of enrollment and who are suitable for receiving stereotactic&#xD;
        radiosurgery (SRS) and whole brain radiation (WBRT), with or without hippocampal-avoidance.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologic or cytologic diagnosis of non-hematopoietic malignancy (excluding germ cell&#xD;
             malignancies and small cell carcinoma).&#xD;
&#xD;
          -  Patients with ≥ 5 but ≤ 30 de novo brain metastases seen on a diagnostic-quality&#xD;
             contrast-enhanced MRI obtained within 30 days prior to enrollment (or randomization if&#xD;
             previously randomized). Patients who are found to have 31-50 metastatic lesions at the&#xD;
             time of treatment planning may still participate in the study. Disease progression&#xD;
             such that &gt; 50 brain metastases are detected after initial MRI prior to enrollment but&#xD;
             before SRS will be treated off-protocol as per discretion of the treating physician.&#xD;
&#xD;
          -  Patients with ≥ 5 but ≤ 30 new brain metastases who have undergone prior SRS for 4 or&#xD;
             less brain metastases with stable intracranial disease as per diagnostic MRI for at&#xD;
             least 6 months post last course of SRS. Patients who are found to have 31-50 new&#xD;
             metastatic lesions at the time of treatment planning may still participate in the&#xD;
             study. Disease progression such that &gt; 50 new brain metastases are detected after&#xD;
             initial MRI prior to enrollment but before SRS will be treated off-protocol as per&#xD;
             discretion of the treating physician.&#xD;
&#xD;
          -  Age ≥ 18.&#xD;
&#xD;
          -  Karnofsky Performance Status (KPS) ≥ 70.&#xD;
&#xD;
          -  Baseline HVLT-R above ≥ 6&#xD;
&#xD;
          -  Patients must be able to tolerate WBRT, and all brain lesions must be eligible for&#xD;
             treatment with SRS as determined by the radiation oncologist.&#xD;
&#xD;
          -  Patient consent must be appropriately obtained in accordance with applicable local and&#xD;
             regulatory requirements. Each patient must sign a consent form prior to enrollment in&#xD;
             the trial to document their willingness to participate.&#xD;
&#xD;
          -  Patient is able to read, speak, and understand (i.e. sufficiently fluent) English in&#xD;
             order to allow completion and meaningful analyses of the neurocognitive tests and&#xD;
             quality of life questionnaires.&#xD;
&#xD;
          -  Patients must be accessible for treatment and follow up. Investigators must assure&#xD;
             themselves the patients registered on this trial will be available for complete&#xD;
             documentation of the treatment, adverse events, and follow-up.&#xD;
&#xD;
          -  Patients who are on immunotherapy must have immunotherapy held at least 1 week before&#xD;
             and after completion of radiotherapy. Other targeted agents/therapy must be held at&#xD;
             least 1 day before and after SRS. Systemic chemotherapy must be held one week prior to&#xD;
             treatment and re-started one week after treatment is complete.&#xD;
&#xD;
          -  Protocol treatment is to begin within 4 weeks of patient enrollment (or randomization&#xD;
             if previously randomized).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with brain metastases resulting from germ cell malignancies, small cell&#xD;
             carcinoma, or hematologic malignancies.&#xD;
&#xD;
          -  Prior SRS for 5 or more brain metastases or any SRS for brain metastases within the&#xD;
             last 6 months.&#xD;
&#xD;
          -  Any prior WBRT or radiotherapy for brain metastases such that the study interventions&#xD;
             cannot be delivered.&#xD;
&#xD;
          -  Prior surgical resection of metastatic cancer from the brain.&#xD;
&#xD;
          -  Patients with evidence of leptomeningeal disease.&#xD;
&#xD;
          -  Patients who have a pacemaker or other contraindications, such that&#xD;
             gadolinium-enhanced MRI cannot be performed or treatment cannot be delivered safely.&#xD;
&#xD;
          -  Patients who have received chemotherapy or immunotherapy within 1 week prior to&#xD;
             administration of protocol radiotherapy or who are expected / planned to receive&#xD;
             chemotherapy within one week of completing protocol radiotherapy.&#xD;
&#xD;
          -  Patients with &lt; 5 or &gt; 30 de novo or new brain metastases at time of enrollment, or &gt;&#xD;
             50 brain metastases at time of treatment planning.&#xD;
&#xD;
          -  Patients who are pregnant (women of child-bearing age must have negative pregnancy&#xD;
             urine test within 7 days of enrollment or randomization).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chia-Lin Tseng, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sunnybrook Health Sciences Centre</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Diana Ristevski</last_name>
    <phone>416-480-5000</phone>
    <phone_ext>85841</phone_ext>
    <email>diana.ristevski@sunnybrook.ca</email>
  </overall_contact>
  <location>
    <facility>
      <name>Sunnybrook Odette Cancer Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Diana Ristevski, BSc</last_name>
      <phone>416-480-5000</phone>
      <phone_ext>85841</phone_ext>
      <email>diana.ristevski@sunnybrook.ca</email>
    </contact>
    <investigator>
      <last_name>Chia-Lin (Eric) Tseng, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>March 21, 2018</study_first_submitted>
  <study_first_submitted_qc>December 12, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 13, 2018</study_first_posted>
  <last_update_submitted>June 29, 2022</last_update_submitted>
  <last_update_submitted_qc>June 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 5, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03775330
org study id: BRAIN METS SRS
nct id: NCT03775330
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This clinical study is a parallel, prospective observational single-centre trial in patients
      presenting with 5 to 30 brain metastases. Patients to receive either stereotactic
      radiosurgery (SRS) alone or SRS plus whole brain radiation (WBRT) will be enrolled.
The current standard of care for patients with limited brain metastases (1 to 4) is
      stereotactic radiosurgery (SRS) alone. This has evolved from the traditional standard of care
      in treating patients with whole brain radiation (WBRT). Studies in patients with limited
      (less than 5) brain metastases have shown that WBRT is harmful with respect to neurocognition
      and does not improve patient survival compared to SRS alone. As a result, SRS alone now is
      considered the standard of care treatment for patients with limited metastases. However,
      there is a lack of high quality prospective randomized evidence on the role of SRS in
      patients with 5 or more brain metastases to guide treatment.

      Therefore, this study seeks to prospectively compare SRS alone versus SRS plus WBRT in
      patients with 5 to 30 brain metastases.
observational model: Other
time perspective: Prospective
measure: Neurocognitive function
time frame: 2 months post treatment
description: Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall using the Reliable Change Index (RCI)
measure: Neurocognitive function - HVLT-R
time frame: 2 months, 4 months, 6 months, and 9 months
description: Hopkins Verbal Learning Test-Revised (HVLT-R) (Total Recall, Delayed Recall, Delayed Recognition)
measure: Neurocognitive function - Trail Making Test
time frame: 2 months, 4 months, 6 months, and 9 months
description: Trail Making Test (TMT, Part A and Part B)
measure: Neurocognitive function - Controlled Oral Word Association
time frame: 2 months, 4 months, 6 months, and 9 months
description: Controlled Oral Word Association (COWA)
measure: Neurocognitive function - Clinical Trial Battery Composite
time frame: 2 months, 4 months, 6 months, and 9 months
description: Clinical Trial Battery Composite (CTB COMP) score
measure: Local control of sites initially treated by SRS
time frame: 2 months, 4 months, 6 months, and 9 months
description: Defined by the response criteria stipulated in the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria guideline
measure: Distant tumour control within the brain
time frame: 2 months, 4 months, 6 months, and 9 months
description: Distant brain failure is defined as the appearance of one or more new lesions on a diagnostic-quality, contrast-enhanced MRI within the brain at sites other than those initially treated by SRS
measure: Overall central nervous system (CNS) response
time frame: 2 months, 4 months, 6 months, and 9 months
description: Response will be recorded for each individual target lesion and for overall central nervous system (CNS) response as a composite of radiographical CNS target and non-target lesion responses, corticosteroid use, and clinical status defined as per RANO-BM criteria
measure: Overall survival
time frame: From date of randomization until the date of death from any cause, whichever came first, assessed up to 36 months
description: Response recorded for survival
measure: Measure of Quality of Life
time frame: 2 months, 4 months, 6 months, and 9 months
description: Health-Related QoL as measured by Functional Assessment of Cancer Therapy - Brain (FACT-Br) instrument
measure: Incidence of Brain Salvage therapy During Follow-up
time frame: 2 months, 4 months, 6 months, and 9 months
description: Number/proportion of patients requiring salvage therapy and type of salvage therapy, for progressive intracranial disease during follow-up
arm group label: SRS
description: Stereotactic radiosurgery
arm group label: SRS plus WBRT
description: Stereotactic radiosurgery plus whole brain radiation
intervention type: Radiation
intervention name: Stereotactic Radiosurgery (SRS)
description: SRS or hypofractionated stereotactic radiation delivered via the Leksell Gammknife Perfexion/Icon radiosurgery system. Hypofractionated stereotactic radiotherapy 25-32.5 Gy in 5 fractions or 24-27 Gy in 3 fractions at the discretion of the radiation oncologist
Maximum diameter of metastasis (doses in single fraction):
≤ 2 cm: 15-20 Gy > 2 cm and ≤ 3 cm: 15-18 Gy > 3 cm and ≤ 4 cm: 15 Gy
Tumour location (doses in single fraction):
Brainstem: 15 Gy
Hypofractionated stereotactic radiotherapy 25-32.5 Gy in 5 fractions may be used for lesions > 2 cm at the discretion of the radiation oncologist
Note: SRS dosing reduced by 20% (for all prescriptions > 15 Gy) when patient is randomized to SRS + WBRT arm
arm group label: SRS
arm group label: SRS plus WBRT
intervention type: Radiation
intervention name: Whole brain radiation (WBRT)
description: WBRT 20 Gy in 5 fractions or 30 Gy in 10 fractions at the discretion of the radiation oncologist
arm group label: SRS plus WBRT
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Chia-Lin Tseng, M.D.
role: Principal Investigator
affiliation: Sunnybrook Health Sciences Centre
last name: Diana Ristevski
phone: 416-480-5000
phone ext: 85841
email: diana.ristevski@sunnybrook.ca
facility: 
status: Recruiting
contact: 
investigator: 
country: Canada
responsible party type: Sponsor
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms
sharing ipd: No