<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/NCT02220491</url>
  </required_header>
  <id_info>
    <org_study_id>H14-02032</org_study_id>
    <nct_id>NCT02220491</nct_id>
  </id_info>
  <brief_title>Whole Brain Radiotherapy Versus Volumetric Modulated Arc Therapy for Brain Metastases</brief_title>
  <acronym>Amadeus</acronym>
  <official_title>A Randomized Phase II Study of 20 Gy in 5 Fractions Whole Brain Radiotherapy Versus 15 Gy in 1 Fraction Volumetric Modulated Arc Therapy for One to Ten Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>British Columbia Cancer Agency</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>British Columbia Cancer Agency</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with brain metastases with expected life expectancy of 3-6 months are typically&#xD;
      treated with radiotherapy to the whole brain giving a dose of 20 Gy over a 5 day period. This&#xD;
      study will compare this with volumetric modulated arc therapy (VMAT) which is capable of&#xD;
      delivering 15 Gy in one single session to identified disease within the brain but sparing the&#xD;
      normal surrounding brain tissue. Primarily the study will assess whether it is possible to&#xD;
      recruit sufficient patient numbers to a trial of this type. It will also compare&#xD;
      effectiveness, side effects and quality of life between the two treatment methods.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase II prospective clinical trial. Pre treatment evaluations include estimation&#xD;
      of life expectancy, Creatinine (GFR) and MRI brain with contrast. An assessment of cognitive&#xD;
      function using Montreal Cognitive Assessment questionnaire, assessment of daily living&#xD;
      activities using the Modified Barthel's index and quality of life assessment using EORTC&#xD;
      QLQ-PAL-15 &amp; BN-20 questionnaires will be performed in clinic. Karnofsky Performance Status&#xD;
      will also be assessed by the clinician. If all assessments are within the eligibility&#xD;
      criteria then the patient can be recruited. Before treatment begins a history documenting&#xD;
      baseline symptoms using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version&#xD;
      4.0 and a neurological examination documenting baseline deficits must be obtained.&#xD;
&#xD;
      If patient is randomized to standard treatment of whole brain radiotherapy (WBRT) then&#xD;
      subjects will have a non-contrast CT scan using a slice thickness of 2.5 mm or less to plan&#xD;
      radiotherapy. If patient are randomized to single fraction radiotherapy then a contrast CT&#xD;
      will be used as this aids in identifying metastatic tumours within the brain. Also for the&#xD;
      single fraction arm if a contrast-enhanced diagnostic MRI was obtained ≤ 10 days before the&#xD;
      CT planning scan, with a single-plane high-resolution sequence or low-resolution sequences in&#xD;
      two planes, it can be used for treatment planning. If the contrast-enhanced diagnostic MRI&#xD;
      was obtained &gt; 10 days before the CT planning scan or there is no diagnostic MRI, the subject&#xD;
      requires a gadolinium-enhanced, high-resolution MRI sequence for fusion in the treatment&#xD;
      planning system. During treatment, patients will have daily online cone beam CT scans to&#xD;
      apply setup corrections to ensure treatment accuracy. To ensure minimal movement during&#xD;
      radiotherapy all subjects will be immobilized lying on their back in a plastic headshell with&#xD;
      an integrated bite block.&#xD;
&#xD;
      For subjects in the single-fraction arm that are not requiring steroids before radiotherapy,&#xD;
      dexamethasone 8 mg 1 hour before the radiotherapy and for 5 days afterwards is required. For&#xD;
      subjects in the single-fraction arm that are requiring corticosteroids for symptom management&#xD;
      before radiotherapy, dexamethasone 8 mg before treatment and 8 mg 2 times daily for 2 days is&#xD;
      required. Beginning three days after radiotherapy, a taper back to the pre-radiotherapy dose&#xD;
      can be done swiftly over 4-6 days. However, for subjects who have been on dexamethasone for&#xD;
      more than 2 weeks at this time point, slow tapering from the pre-radiotherapy dose using&#xD;
      decrements of 0.5 - 2 mg every 3-5 days should be used to prevent a hypocortisolemia. For&#xD;
      subjects in the 5-fraction arm, corticosteroids will be prescribed according to the&#xD;
      preference of the treating radiation oncologist. Anti-sickness medication and steroids will&#xD;
      be prescribed are required before each fraction in both arms.&#xD;
&#xD;
      Following therapy completion, all patients will be seen at 6 weeks, 3, 6, 9 and 12 months. At&#xD;
      each visit history and neurological examination will be performed. Cognitive Function,&#xD;
      Karnofsky Performance Status, Quality of life and Adverse Events will all be assessed and&#xD;
      recorded. Activities of Daily Living and steroid use will be assessed by telephone&#xD;
      consultation every 4 weeks (monthly) for 1 year. Steroid use will be confirmed by evaluating&#xD;
      the pharmacy prescription database.&#xD;
&#xD;
      Patients will have contrast-enhanced MRI brain at every time point with a creatinine 1 week&#xD;
      before each MRI to ensure safety of intravenous contrast administration. Steroid use will be&#xD;
      recorded in a patient diary for first 6 weeks post treatment and monthly by telephone&#xD;
      discussion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2014</start_date>
  <completion_date type="Actual">May 18, 2020</completion_date>
  <primary_completion_date type="Actual">May 18, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Accrual</measure>
    <time_frame>8 months</time_frame>
    <description>The time of accrual of 20 subjects will be recorded in months from the official study opening at each cancer centre until the 20th patient is accrued. The rate of accrual will be calculated by dividing the number of patients by the number of months it took to accrue them</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Intracranial disease control</measure>
    <time_frame>3 months</time_frame>
    <description>All subjects who complete radiotherapy and have imaging at 6 weeks will be considered evaluable for response. Those who exhibit objective disease progression on imaging before 6 weeks will also be considered evaluable for response.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Compare the use of corticosteroids</measure>
    <time_frame>Every 4 weeks for 1 year</time_frame>
    <description>The subjects' use of corticosteroids will be recorded in a diary for the first 6 weeks and assessed monthly with phone follow-up. The amount and pattern of corticosteroid use will be compared between the two arms of the study.</description>
  </other_outcome>
  <other_outcome>
    <measure>Compare the incidence of retreatment with cranial radiotherapy</measure>
    <time_frame>3 months</time_frame>
    <description>Subjects with new brain metastases can be treated in a number of ways if their performance status remains good. If 3 months have passed since their initial treatment and there are 1-10 new metastases, subjects can receive the study treatment with 15 Gy in 1 fraction again. However, if the new brain metastases are detected within 3 months or there are more than 10 new brain metastases, subjects must have WBRT, rather than treatment to the metastases alone. Subjects with progression or relapse of a treated brain metastasis can be considered for surgery, retreatment with radiosurgery or retreatment with WBRT. Subjects with poor performance status should be considered for best supportive care.</description>
  </other_outcome>
  <other_outcome>
    <measure>Compare the incidence of acute and late side effects</measure>
    <time_frame>6 weeks, 3 months, 6 months, 9 months, 12 months</time_frame>
    <description>The study will use the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) for grading of acute and late side effects. The incidence of the various side effects will be compared between the two arms.</description>
  </other_outcome>
  <other_outcome>
    <measure>Compare the time to decline in activities of daily living using the Modified Barthel Index</measure>
    <time_frame>Every 4 weeks for 1 year</time_frame>
    <description>The Modified Barthel index will be administered at baseline and at each follow-up visit. The scores will be recorded and analysed. The minimum clinically important difference for this scale is 10 points.</description>
  </other_outcome>
  <other_outcome>
    <measure>Compare the time to decline in Karnofsky Performance Status &lt; 70</measure>
    <time_frame>6 weeks, 3 months, 6 months, 9 months, 12 months</time_frame>
    <description>The KPS will be recorded at each clinic visit. The patient will be regarded as having had a decline in KPS when it falls below 70, at which time subjects are no longer independent.</description>
  </other_outcome>
  <other_outcome>
    <measure>Compare the time to decline in cognition</measure>
    <time_frame>6 weeks, 3 months, 6 months, 9 months, 12 months</time_frame>
    <description>The MoCA questionnaire will be administered at baseline and at each follow-up visit (Appendix II). The score will be recorded and analysed. A decline in MOCA score of 3 is considered to be clinically significant.</description>
  </other_outcome>
  <other_outcome>
    <measure>Time to decline in quality of life</measure>
    <time_frame>6 weeks, 3 months, 6 months, 9 months, 12 months</time_frame>
    <description>The EORTC QLQ-PAL-15 will be administered at baseline and at each follow-up visit. The EORTC BN-20 (brain-specific) quality of life questionnaire will be administered at baseline and at each follow-up visit. The quality of life questionnaire scores will be recorded and analysed.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Brain Metastases</condition>
  <arm_group>
    <arm_group_label>Whole-brain radiotherapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>All subjects will have a non-contrast CT scan using a slice thickness of 2.5mm or less.&#xD;
The Brain contour will be generated using the segmentation wizard and edits as required.&#xD;
PTV_Brain is an expansion of the Brain by 5mm. 99% of PTV_Brain is to be covered by 95% of 20 Gy in 5 fractions using 6-10 MV photons in a parallel-opposed pair lateral beam arrangement.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Single-fraction radiotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Immobilized in the mask, the subject will be imaged for radiotherapy planning with a CT slice thickness of 1.25 mm or less and an axial resolution of &lt; 0.7 mm (CT field of view &lt; 35 cm). Subjects that require contrast with GFR 45-59 will have pre-hydration, contrast dose modification and/or Mucomyst administration to preserve renal function, according to standard practice for radiological imaging at the institution.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Single-fraction radiotherapy</intervention_name>
    <description>Volumetric modulated arc therapy (VMAT) delivering 15 Gy in one fraction to brain metastases</description>
    <arm_group_label>Single-fraction radiotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Whole-brain radiotherapy</intervention_name>
    <description>Whole brain radiotherapy delivering 20 Gy in five fractions to brain metastases</description>
    <arm_group_label>Whole-brain radiotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18&#xD;
&#xD;
          -  Pathologically confirmed solid malignancy&#xD;
&#xD;
          -  1-10 brain or brainstem metastases on MRI with a maximum of 4 cm diameter&#xD;
&#xD;
          -  Documented extracranial disease&#xD;
&#xD;
          -  Anticipated median survival 3-6 months (Graded Prognostic Assessment: Appendix I)&#xD;
&#xD;
          -  Available for regular clinical and imaging follow up (&lt; 1 hour from a cancer centre)&#xD;
&#xD;
          -  Montreal Cognitive Assessment score ≥ 20 (Appendix II)&#xD;
&#xD;
          -  Karnofsky Performance Score (KPS) ≥ 70 (Appendix III)&#xD;
&#xD;
          -  Barthel Activities of Daily Living score ≥ 90 (Appendix IV)&#xD;
&#xD;
          -  Able to complete EORTC quality of life questionnaires (Appendix V)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A metastasis located within 5 mm of the optic nerves or optic chiasm&#xD;
&#xD;
          -  Requiring craniotomy to relieve mass effect&#xD;
&#xD;
          -  Cytotoxic systemic therapy administered within one week before radiotherapy or planned&#xD;
             within one week after radiotherapy&#xD;
&#xD;
          -  Neurological decline since starting corticosteroids&#xD;
&#xD;
          -  Metastatic germinoma, small cell carcinoma, multiple myeloma, lymphoma or leukaemia&#xD;
&#xD;
          -  Systemic lupus erythematosis, scleroderma, or other connective tissue disorders not in&#xD;
             remission&#xD;
&#xD;
          -  Multiple sclerosis&#xD;
&#xD;
          -  Glomerular Filtration Rate &lt; 45 ml/minute&#xD;
&#xD;
          -  Contra-indications to MRI&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  AST, ALT or Bilirubin &gt; 3 times upper limit of normal&#xD;
&#xD;
          -  Haemorrhagic Metastases&#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>Nichol Alan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>British Columbia Cancer Agency</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>British Columbia Cancer Agency</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 4E6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
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  <verification_date>May 2020</verification_date>
  <study_first_submitted>August 15, 2014</study_first_submitted>
  <study_first_submitted_qc>August 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 20, 2014</study_first_posted>
  <last_update_submitted>May 19, 2020</last_update_submitted>
  <last_update_submitted_qc>May 19, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 20, 2020</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>
  <!-- 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/NCT02220491
org study id: H14-02032
nct id: NCT02220491
lead sponsor: 
has dmc: No
Patients with brain metastases with expected life expectancy of 3-6 months are typically
      treated with radiotherapy to the whole brain giving a dose of 20 Gy over a 5 day period. This
      study will compare this with volumetric modulated arc therapy (VMAT) which is capable of
      delivering 15 Gy in one single session to identified disease within the brain but sparing the
      normal surrounding brain tissue. Primarily the study will assess whether it is possible to
      recruit sufficient patient numbers to a trial of this type. It will also compare
      effectiveness, side effects and quality of life between the two treatment methods.
This is a Phase II prospective clinical trial. Pre treatment evaluations include estimation
      of life expectancy, Creatinine (GFR) and MRI brain with contrast. An assessment of cognitive
      function using Montreal Cognitive Assessment questionnaire, assessment of daily living
      activities using the Modified Barthel's index and quality of life assessment using EORTC
      QLQ-PAL-15 & BN-20 questionnaires will be performed in clinic. Karnofsky Performance Status
      will also be assessed by the clinician. If all assessments are within the eligibility
      criteria then the patient can be recruited. Before treatment begins a history documenting
      baseline symptoms using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version
      4.0 and a neurological examination documenting baseline deficits must be obtained.

      If patient is randomized to standard treatment of whole brain radiotherapy (WBRT) then
      subjects will have a non-contrast CT scan using a slice thickness of 2.5 mm or less to plan
      radiotherapy. If patient are randomized to single fraction radiotherapy then a contrast CT
      will be used as this aids in identifying metastatic tumours within the brain. Also for the
      single fraction arm if a contrast-enhanced diagnostic MRI was obtained ≤ 10 days before the
      CT planning scan, with a single-plane high-resolution sequence or low-resolution sequences in
      two planes, it can be used for treatment planning. If the contrast-enhanced diagnostic MRI
      was obtained > 10 days before the CT planning scan or there is no diagnostic MRI, the subject
      requires a gadolinium-enhanced, high-resolution MRI sequence for fusion in the treatment
      planning system. During treatment, patients will have daily online cone beam CT scans to
      apply setup corrections to ensure treatment accuracy. To ensure minimal movement during
      radiotherapy all subjects will be immobilized lying on their back in a plastic headshell with
      an integrated bite block.

      For subjects in the single-fraction arm that are not requiring steroids before radiotherapy,
      dexamethasone 8 mg 1 hour before the radiotherapy and for 5 days afterwards is required. For
      subjects in the single-fraction arm that are requiring corticosteroids for symptom management
      before radiotherapy, dexamethasone 8 mg before treatment and 8 mg 2 times daily for 2 days is
      required. Beginning three days after radiotherapy, a taper back to the pre-radiotherapy dose
      can be done swiftly over 4-6 days. However, for subjects who have been on dexamethasone for
      more than 2 weeks at this time point, slow tapering from the pre-radiotherapy dose using
      decrements of 0.5 - 2 mg every 3-5 days should be used to prevent a hypocortisolemia. For
      subjects in the 5-fraction arm, corticosteroids will be prescribed according to the
      preference of the treating radiation oncologist. Anti-sickness medication and steroids will
      be prescribed are required before each fraction in both arms.

      Following therapy completion, all patients will be seen at 6 weeks, 3, 6, 9 and 12 months. At
      each visit history and neurological examination will be performed. Cognitive Function,
      Karnofsky Performance Status, Quality of life and Adverse Events will all be assessed and
      recorded. Activities of Daily Living and steroid use will be assessed by telephone
      consultation every 4 weeks (monthly) for 1 year. Steroid use will be confirmed by evaluating
      the pharmacy prescription database.

      Patients will have contrast-enhanced MRI brain at every time point with a creatinine 1 week
      before each MRI to ensure safety of intravenous contrast administration. Steroid use will be
      recorded in a patient diary for first 6 weeks post treatment and monthly by telephone
      discussion.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Accrual
time frame: 8 months
description: The time of accrual of 20 subjects will be recorded in months from the official study opening at each cancer centre until the 20th patient is accrued. The rate of accrual will be calculated by dividing the number of patients by the number of months it took to accrue them
measure: Intracranial disease control
time frame: 3 months
description: All subjects who complete radiotherapy and have imaging at 6 weeks will be considered evaluable for response. Those who exhibit objective disease progression on imaging before 6 weeks will also be considered evaluable for response.
measure: Compare the use of corticosteroids
time frame: Every 4 weeks for 1 year
description: The subjects' use of corticosteroids will be recorded in a diary for the first 6 weeks and assessed monthly with phone follow-up. The amount and pattern of corticosteroid use will be compared between the two arms of the study.
measure: Compare the incidence of retreatment with cranial radiotherapy
time frame: 3 months
description: Subjects with new brain metastases can be treated in a number of ways if their performance status remains good. If 3 months have passed since their initial treatment and there are 1-10 new metastases, subjects can receive the study treatment with 15 Gy in 1 fraction again. However, if the new brain metastases are detected within 3 months or there are more than 10 new brain metastases, subjects must have WBRT, rather than treatment to the metastases alone. Subjects with progression or relapse of a treated brain metastasis can be considered for surgery, retreatment with radiosurgery or retreatment with WBRT. Subjects with poor performance status should be considered for best supportive care.
measure: Compare the incidence of acute and late side effects
time frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
description: The study will use the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) for grading of acute and late side effects. The incidence of the various side effects will be compared between the two arms.
measure: Compare the time to decline in activities of daily living using the Modified Barthel Index
time frame: Every 4 weeks for 1 year
description: The Modified Barthel index will be administered at baseline and at each follow-up visit. The scores will be recorded and analysed. The minimum clinically important difference for this scale is 10 points.
measure: Compare the time to decline in Karnofsky Performance Status < 70
time frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
description: The KPS will be recorded at each clinic visit. The patient will be regarded as having had a decline in KPS when it falls below 70, at which time subjects are no longer independent.
measure: Compare the time to decline in cognition
time frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
description: The MoCA questionnaire will be administered at baseline and at each follow-up visit (Appendix II). The score will be recorded and analysed. A decline in MOCA score of 3 is considered to be clinically significant.
measure: Time to decline in quality of life
time frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
description: The EORTC QLQ-PAL-15 will be administered at baseline and at each follow-up visit. The EORTC BN-20 (brain-specific) quality of life questionnaire will be administered at baseline and at each follow-up visit. The quality of life questionnaire scores will be recorded and analysed.
arm group label: Whole-brain radiotherapy
arm group type: Active Comparator
description: All subjects will have a non-contrast CT scan using a slice thickness of 2.5mm or less.
The Brain contour will be generated using the segmentation wizard and edits as required.
PTV_Brain is an expansion of the Brain by 5mm. 99% of PTV_Brain is to be covered by 95% of 20 Gy in 5 fractions using 6-10 MV photons in a parallel-opposed pair lateral beam arrangement.
arm group label: Single-fraction radiotherapy
arm group type: Experimental
description: Immobilized in the mask, the subject will be imaged for radiotherapy planning with a CT slice thickness of 1.25 mm or less and an axial resolution of < 0.7 mm (CT field of view < 35 cm). Subjects that require contrast with GFR 45-59 will have pre-hydration, contrast dose modification and/or Mucomyst administration to preserve renal function, according to standard practice for radiological imaging at the institution.
intervention type: Radiation
intervention name: Single-fraction radiotherapy
description: Volumetric modulated arc therapy (VMAT) delivering 15 Gy in one fraction to brain metastases
arm group label: Single-fraction radiotherapy
intervention type: Radiation
intervention name: Whole-brain radiotherapy
description: Whole brain radiotherapy delivering 20 Gy in five fractions to brain metastases
arm group label: Whole-brain radiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nichol Alan, MD
role: Principal Investigator
affiliation: British Columbia Cancer Agency
facility: 
country: Canada
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responsible party type: Sponsor
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms