<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/NCT04452084</url>
  </required_header>
  <id_info>
    <org_study_id>HA-SIB-WBRT</org_study_id>
    <nct_id>NCT04452084</nct_id>
  </id_info>
  <brief_title>Phase 2 Trial in Multiple Brain Metastases Outcomes With HA-SIB-WBRT</brief_title>
  <official_title>Randomised Prospective Phase 2 Trial in Multiple Brain Metastases Comparing Outcomes Between Hippocampal Avoidance Whole Brain Radiotherapy With or Without Simultaneous Integrated Boost</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Centre, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Singhealth Duke-NUS Oncology Academic Clinical Programme (ONCO ACP)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Singapore General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National Cancer Centre, Singapore</source>
  <oversight_info>
    <has_dmc>No</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>
      Recently, the evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT)&#xD;
      as the recommended treatment option in patients with good prognosis and multiple brain&#xD;
      metastases as it gives better neurocognitive preservation compared to historical whole brain&#xD;
      radiotherapy controls. There is however often poor tumour control with this technique due to&#xD;
      the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is&#xD;
      given to patients who have a limited number of brain metastases, gives a higher radiation&#xD;
      dose to the metastases resulting in better target lesion control. With improvements in&#xD;
      radiation technology, advanced dose-painting techniques now allow a simultaneous integrate&#xD;
      boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve&#xD;
      brain tumour control and preserve cognitive outcomes (HA-SIB-WBRT).&#xD;
&#xD;
      The Investigators believe that the SIB in HA-SIB-WBRT (experimental) will result in better&#xD;
      functional and survival outcomes compared to HA-WBRT (control). Patients who are fit, have&#xD;
      multiple brain metastases (5-25 lesions) and reasonable life expectancy (&gt;6 months) will be&#xD;
      recruited from NCCS over 2 years. Patients will be followed up the over the following year&#xD;
      with imaging, toxicity data, quality of life, activities of daily living and cognitive&#xD;
      measurements at set time points. The results will be compared across the 2 arms.&#xD;
&#xD;
      Patients with brain metastases are living longer. Maintaining functional independence and&#xD;
      brain metastases control is thus increasingly important. Improved radiotherapy treatment&#xD;
      techniques could provide better control and survival outcomes whilst maintain QoL and&#xD;
      functional capacity.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 15, 2020</start_date>
  <completion_date type="Anticipated">June 14, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 14, 2024</primary_completion_date>
  <phase>Phase 2</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>
    <masking_description>Blinding is not feasible in this study and will not be performed.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Target lesion progression</measure>
    <time_frame>From time of randomisation to target lesion progression, up to 6 months after last day of radiotherapy.</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to symptomatic brain metastases</measure>
    <time_frame>From time of randomisation to symptomatic brain progression, up to 12 months after last day of radiotherapy.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidences of treatment-emergent adverse events (AE)</measure>
    <time_frame>From time of randomisation to 12 months after last day of radiotherapy.</time_frame>
    <description>Identified and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>From time of randomisation to death from any cause, up to 12 months after last day of radiotherapy.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>From time of randomisation to overall progression, up to 12 months after last day of radiotherapy.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive function</measure>
    <time_frame>From time of randomisation to 12 months after last day of radiotherapy.</time_frame>
    <description>Assessed using Hopkins Verbal Learning Test</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Brain Metastases</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Experimental Procedure</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>HA-WBRT</intervention_name>
    <description>The accepted standard HA-WBRT doses in the control arm are 30Gy in 10 fractions.</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>HA-SIB-WBRT</intervention_name>
    <description>The doses selected for experimental HA-SIB-WBRT arm are 30Gy in 10 fractions to the whole brain with 40 to 45Gy in 10 fraction SIB doses to tumours.</description>
    <arm_group_label>Experimental Procedure</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  21-80 years old patients with radiological confirmed brain metastases (5-25 lesions)&#xD;
&#xD;
          -  Histologically proven malignancy of primary cancer&#xD;
&#xD;
          -  ECOG performance status ≤ 2&#xD;
&#xD;
          -  Maximum lesion or cavity size ≤ 5cm&#xD;
&#xD;
               -  For patients with large (≥ 3cm) lesions, a neurosurgical consult is recommended&#xD;
                  as the risk of cerebral oedema and hydrocephalus is higher with RT. A&#xD;
                  Ventricular-peritoneal shunt/ surgical excision may be required prior to planning&#xD;
                  of RT&#xD;
&#xD;
               -  If brain surgery or other invasive procedures are performed, the treatment can&#xD;
                  only begin at least 2-weeks post-procedure&#xD;
&#xD;
          -  Life expectancy of at least 6 months&#xD;
&#xD;
          -  Negative serum pregnancy test within 14 days prior to registration for women of&#xD;
             childbearing potential&#xD;
&#xD;
          -  Women of childbearing potential and male participants who are sexually active must&#xD;
             agree to use a medically effective means of birth control throughout protocol&#xD;
             treatment&#xD;
&#xD;
          -  Not recommended or does not want Stereotactic Radiosurgery (SRS)&#xD;
&#xD;
          -  Agrees to be randomised to either HA-WBRT or HA-SIB-WBRT&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior whole brain radiotherapy&#xD;
&#xD;
             o Prior SRS is not an exclusion. Details of treatment must be recorded.&#xD;
&#xD;
          -  Concurrent systemic cytotoxic treatment.&#xD;
&#xD;
             o If patient is on systemic treatment a treatment break of at least 7 days for&#xD;
             immunotherapy or chemotherapy and 3 days for targeted therapy is required before and&#xD;
             after radiotherapy.&#xD;
&#xD;
          -  Leptomeningeal disease&#xD;
&#xD;
          -  Extensive extracranial disease, not controlled by systemic treatment&#xD;
&#xD;
          -  Severe, active co-morbidity, defined as follows:&#xD;
&#xD;
               -  Major medical or psychiatric illness, which in the investigator's opinion would&#xD;
                  interfere with the completion of therapy and follow up or with full understanding&#xD;
                  of the risks and potential complications of the therapy;&#xD;
&#xD;
               -  Unstable angina and/or uncontrolled congestive heart failure;&#xD;
&#xD;
               -  Myocardial infarction within the last 6 months;&#xD;
&#xD;
               -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time&#xD;
                  of registration; note that patients switched from IV antibiotics and currently on&#xD;
                  oral antibiotics whose infection is assessed to be adequately treated or&#xD;
                  controlled are eligible.&#xD;
&#xD;
               -  Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness&#xD;
                  requiring hospitalization or precluding study therapy within 30 days prior to&#xD;
                  registration;&#xD;
&#xD;
               -  Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition;&#xD;
                  note, however, that HIV testing is not required for entry into this protocol. The&#xD;
                  need to exclude patients with AIDS from this protocol is necessary because the&#xD;
                  treatments involved in this protocol may be significantly immunosuppressive.&#xD;
&#xD;
               -  Dementia, ongoing psychotic episodes or moderate-severe depression (PHQ-9).&#xD;
&#xD;
               -  Recent stroke in the past 3 months&#xD;
&#xD;
          -  Pregnancy or women of childbearing potential and men who are sexually active and not&#xD;
             willing/able to use medically acceptable forms of contraception;&#xD;
&#xD;
          -  ECOG performance status &gt;2 despite a duration of high dose steroids&#xD;
&#xD;
          -  Symptomatic brain metastases limiting ADLs&#xD;
&#xD;
          -  Rapid brain progression&#xD;
&#xD;
          -  Patients unable to give informed consent&#xD;
&#xD;
          -  Total tumour planning target volume (PTV) &gt;60cc&#xD;
&#xD;
          -  Radiological evidence of hydrocephalus&#xD;
&#xD;
          -  Contraindication to Gadolinium contrast-enhanced MRI brain&#xD;
&#xD;
          -  Patients who are unable to meet expected follow-up schedule (e.g. non-resident&#xD;
             patients)&#xD;
&#xD;
          -  Patients with diagnoses of small cell carcinoma, lymphoma or primary brain tumour&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Brendan Chia, MB ChB BAO</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Centre, Singapore</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Brendan Chia, MB ChB BAO</last_name>
    <phone>+65 6436 8000</phone>
    <email>brendan.chia.s.h@singhealth.com.sg</email>
  </overall_contact>
  <location>
    <facility>
      <name>National Cancer Center Singapore</name>
      <address>
        <city>Singapore</city>
        <zip>169690</zip>
        <country>Singapore</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>June 25, 2020</study_first_submitted>
  <study_first_submitted_qc>June 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 30, 2020</study_first_posted>
  <last_update_submitted>February 28, 2023</last_update_submitted>
  <last_update_submitted_qc>February 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 2, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Whole Brain Radiotherapy</keyword>
  <keyword>Brain metastases</keyword>
  <keyword>Cognitive outcomes</keyword>
  <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/NCT04452084
org study id: HA-SIB-WBRT
nct id: NCT04452084
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Recently, the evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT)
      as the recommended treatment option in patients with good prognosis and multiple brain
      metastases as it gives better neurocognitive preservation compared to historical whole brain
      radiotherapy controls. There is however often poor tumour control with this technique due to
      the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is
      given to patients who have a limited number of brain metastases, gives a higher radiation
      dose to the metastases resulting in better target lesion control. With improvements in
      radiation technology, advanced dose-painting techniques now allow a simultaneous integrate
      boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve
      brain tumour control and preserve cognitive outcomes (HA-SIB-WBRT).

      The Investigators believe that the SIB in HA-SIB-WBRT (experimental) will result in better
      functional and survival outcomes compared to HA-WBRT (control). Patients who are fit, have
      multiple brain metastases (5-25 lesions) and reasonable life expectancy (>6 months) will be
      recruited from NCCS over 2 years. Patients will be followed up the over the following year
      with imaging, toxicity data, quality of life, activities of daily living and cognitive
      measurements at set time points. The results will be compared across the 2 arms.

      Patients with brain metastases are living longer. Maintaining functional independence and
      brain metastases control is thus increasingly important. Improved radiotherapy treatment
      techniques could provide better control and survival outcomes whilst maintain QoL and
      functional capacity.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
masking description: Blinding is not feasible in this study and will not be performed.
measure: Target lesion progression
time frame: From time of randomisation to target lesion progression, up to 6 months after last day of radiotherapy.
measure: Time to symptomatic brain metastases
time frame: From time of randomisation to symptomatic brain progression, up to 12 months after last day of radiotherapy.
measure: Incidences of treatment-emergent adverse events (AE)
time frame: From time of randomisation to 12 months after last day of radiotherapy.
description: Identified and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria.
measure: Overall Survival
time frame: From time of randomisation to death from any cause, up to 12 months after last day of radiotherapy.
measure: Progression Free Survival
time frame: From time of randomisation to overall progression, up to 12 months after last day of radiotherapy.
measure: Cognitive function
time frame: From time of randomisation to 12 months after last day of radiotherapy.
description: Assessed using Hopkins Verbal Learning Test
arm group label: Control
arm group type: Active Comparator
arm group label: Experimental Procedure
arm group type: Experimental
intervention type: Radiation
intervention name: HA-WBRT
description: The accepted standard HA-WBRT doses in the control arm are 30Gy in 10 fractions.
arm group label: Control
intervention type: Radiation
intervention name: HA-SIB-WBRT
description: The doses selected for experimental HA-SIB-WBRT arm are 30Gy in 10 fractions to the whole brain with 40 to 45Gy in 10 fraction SIB doses to tumours.
arm group label: Experimental Procedure
criteria: 
gender: All
minimum age: 21 Years
maximum age: 80 Years
healthy volunteers: No
last name: Brendan Chia, MB ChB BAO
role: Principal Investigator
affiliation: National Cancer Centre, Singapore
last name: Brendan Chia, MB ChB BAO
phone: +65 6436 8000
email: brendan.chia.s.h@singhealth.com.sg
facility: 
status: Recruiting
country: Singapore
responsible party type: Sponsor
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms