<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/NCT03265418</url>
  </required_header>
  <id_info>
    <org_study_id>W 16 09 00091</org_study_id>
    <nct_id>NCT03265418</nct_id>
  </id_info>
  <brief_title>BioXmark, Rectal Feasibility Trial</brief_title>
  <official_title>BioXmark Liquid Fiducials to Enable Radiotherapy Tumor Boosting in Rectal Cancer, a Feasibility Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht Radiation Oncology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Maastricht Radiation Oncology</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>
      To test the feasibility and accuracy of BioXmark fiducial markers for image guided&#xD;
      radiotherapy (IGRT) based rectal tumor boosting in 20 patients referred for long course&#xD;
      chemo-radiotherapy of the locally advanced rectal cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a prospective non-randomized open label trial.&#xD;
&#xD;
      A total of 20 patients who will undergo neo-adjuvant chemo-radiotherapy for rectal cancer&#xD;
      will be included in this study upon informed consent.&#xD;
&#xD;
      During an extra sigmoidoscopy after enema preparation, 4 liquid marker spots will be placed 1&#xD;
      cm from the tumor; two in the in the cranial and two in the caudal direction of the tumor (4&#xD;
      markers in total per patient).&#xD;
&#xD;
      Participants will undergo standard treatment for their rectal cancer.&#xD;
&#xD;
      As part of standard patient set-up directly before each radiotherapy treatment, kilovoltage&#xD;
      (KV) cone-beam computed tomography (CBCT) will be acquired. Treatment positioning will be&#xD;
      based on the regular clinical decision protocols for treatment of rectal cancer and not on&#xD;
      the markers. During treatment potential fiducial movement will be assessed using an&#xD;
      externally positioned ultra-sound probe (this probe will be positioned against the abdominal&#xD;
      or perineal skin of the patients depending on de position of the tumor/fiducials in the&#xD;
      rectum). Moreover, for patients in this study 2 orthogonal kV images will be made immediately&#xD;
      after each radiation using the electronic portal imaging (EPI) device.&#xD;
&#xD;
      As part of standard clinical practice an Magnetic resonance imaging (MRI) of the rectum will&#xD;
      be made for response evaluation 6-8 weeks after the end of neo-adjuvant chemo-radiotherapy.&#xD;
&#xD;
      As part of standard clinical practice patients whose tumor has not responded completely will&#xD;
      be operated on 8-12 weeks after the end of neoadjuvant chemo-radiotherapy. Patients with a&#xD;
      complete response will be follow-upped according to the &quot;wait-and-see&quot; protocol.&#xD;
&#xD;
      Cone-beam CT and MR images which are obtained as routine practice during treatment of the&#xD;
      participants will be compared with images of 20 non-participating patients treated at our&#xD;
      institute in the same period.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2, 2018</start_date>
  <completion_date type="Actual">July 25, 2019</completion_date>
  <primary_completion_date type="Actual">July 25, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Positional stability of BioXmark liquid fiducial markers during the treatment course</measure>
    <time_frame>will be determined through the course of radiotherapy, an average of 5 weeks</time_frame>
    <description>Positional stability / potential marker migration will be assessed by calculating marker pair distances.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Visibility/visual stability of BioXmark liquid fiducial markers during the treatment course</measure>
    <time_frame>will be determined for the time interval between placement and the post-treatment MRI, an average of 12 weeks</time_frame>
    <description>Visual stability will be evaluated by scoring visibility of the markers on CT, CBCT, EPI and MRI (T1, T2 and diffusion weighted images) by 2 independent observers using a subjective scoring system: 0 = not visible, 1 = barely visible, 2 = clearly visible.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of markers lost from injection to CT acquisition for RT planning</measure>
    <time_frame>will be determined for the time interval between placement and pretreatment radiotherapy planning CT, an average of 1 week</time_frame>
    <description>(1 - number of markers visible on the last CBCT (cone-beam computed tomography) during treatment / number of visible markers at pCT) * 100</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of markers lost from injection to CT acquisition for RT planning</measure>
    <time_frame>will be determined for the time intervals through the course of radiotherapy, an average of 5 weeks</time_frame>
    <description>(1 - number of markers visible on the last CBCT (cone-beam computed tomography) during treatment / number of visible markers at pCT) * 100</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events (AE) potentially associated with BioXmark</measure>
    <time_frame>until rectal surgery, on average 11 weeks, or in case of omission of surgery, until 3 months after marker placement.</time_frame>
    <description>The safety of bioXmark liquid fiducials placement will be assessed by recording Adverse events (AE) potentially associated with BioXmark until rectal surgery, on average 11 weeks, or in case of omission of surgery, until 3 months after marker placement.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inter-observer variation in gross tumor volume (GTV) localization with and without markers</measure>
    <time_frame>through the course of radiotherapy, an average of 5 weeks</time_frame>
    <description>The concordance index (CI) of gross tumor volume (GTV) localization between observers on kV CBCT will be determined. The CI is the ratio of the intersection and the union of the two volumes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of BioXmark liquid fiducial markers on post-treatment MRI images</measure>
    <time_frame>at the moment of the post-treatment MRI, on average 6-8 weeks after chemo-radiation</time_frame>
    <description>Potential BioXmark induced artefacts will be scored by 2 independent observers using a subjective scoring system:</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Potential BioXmark induced alterations in the surgical specimen</measure>
    <time_frame>on average 10-12 weeks after chemo-radiation</time_frame>
    <description>The surgical specimens will be evaluated for signs of marker-induced alterations.&#xD;
Potential BioXmark induced alteration in the surgical specimen will be scored by 2 independent observers using a subjective scoring system.In case the markers can't be located in the surgical specimen standard clinical evaluation of the specimen will take place. If the marker got lost during tissue processing potential inflammation/perforation will be scored as follows:A) 0 = no signs of extra inflammatory changes possibly related to the fiducials, 1 = limited extra inflammatory changes possibly related to the fiducials, 2 = severe extra inflammatory changes possibly related to the fiducials; B) 0 = no perforation of the rectal possibly related to fiducials, 1 = perforation of the rectal possibly related to the fiducials</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Rectal Cancer</condition>
  <arm_group>
    <arm_group_label>BioXmark liquid fiducial markers</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Placement of 4 BioXmark liquid fiducial markers, standard treatment (chemo-radiotherapy followed by surgery or wait-and-see) with extra imaging to evaluate the behaviour of the markers before, during and after the radiotherapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>BioXmark liquid fiducial markers</intervention_name>
    <description>Before the start of the treatment planning during an extra sigmoidoscopy after enema preparation, 4 liquid marker spots will be placed 1 cm from the tumor; two in the in the cranial and two in the caudal direction of the tumor (4 markers in total per patient).</description>
    <arm_group_label>BioXmark liquid fiducial markers</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Imaging</intervention_name>
    <description>As part of standard patient set-up directly before each radiotherapy treatment, kV cone-beam CTs will be acquired. Treatment positioning will be based on the regular clinical decision protocols for treatment of rectal cancer and not on the markers. During treatment potential fiducial movement will be assessed using an externally positioned ultra-sound probe, positioned against the abdominal or perineal skin of the patients depending on de position of the tumor/fiducials in the rectum. For patients in this study 2 orthogonal kV images will be made immediately after each radiation using the electronic portal imaging (EPI) device.&#xD;
As part of standard clinical practice an MR of the rectum will be made for response evaluation 6-8 weeks after the end of neo-adjuvant chemo-radiotherapy.</description>
    <arm_group_label>BioXmark liquid fiducial markers</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>surgery or wait-and-see</intervention_name>
    <description>As part of standard clinical practice patients whose tumor has not responded completely will be operated on 8-12 weeks after the end of neoadjuvant chemo-radiotherapy. Patients with a complete response will be follow-upped according to the &quot;wait-and-see&quot; protocol.</description>
    <arm_group_label>BioXmark liquid fiducial markers</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with histological or cytological proven adenocarcinoma of the rectum, treated&#xD;
             with long course external beam radiotherapy&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  Have given written informed consent before patient registration&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients using anticoagulants: platelet aggregation inhibitors or coumarines&#xD;
&#xD;
          -  Iodine allergy&#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>Maaike Berbée, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Maastro Clinic, The Netherlands</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>MAASTRO Clinic</name>
      <address>
        <city>Maastricht</city>
        <state>Limburg</state>
        <zip>6202 NA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>April 26, 2017</study_first_submitted>
  <study_first_submitted_qc>August 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 29, 2017</study_first_posted>
  <last_update_submitted>September 3, 2019</last_update_submitted>
  <last_update_submitted_qc>September 3, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 4, 2019</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>Rectal 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/NCT03265418
org study id: W 16 09 00091
nct id: NCT03265418
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To test the feasibility and accuracy of BioXmark fiducial markers for image guided
      radiotherapy (IGRT) based rectal tumor boosting in 20 patients referred for long course
      chemo-radiotherapy of the locally advanced rectal cancer.
This study is a prospective non-randomized open label trial.

      A total of 20 patients who will undergo neo-adjuvant chemo-radiotherapy for rectal cancer
      will be included in this study upon informed consent.

      During an extra sigmoidoscopy after enema preparation, 4 liquid marker spots will be placed 1
      cm from the tumor; two in the in the cranial and two in the caudal direction of the tumor (4
      markers in total per patient).

      Participants will undergo standard treatment for their rectal cancer.

      As part of standard patient set-up directly before each radiotherapy treatment, kilovoltage
      (KV) cone-beam computed tomography (CBCT) will be acquired. Treatment positioning will be
      based on the regular clinical decision protocols for treatment of rectal cancer and not on
      the markers. During treatment potential fiducial movement will be assessed using an
      externally positioned ultra-sound probe (this probe will be positioned against the abdominal
      or perineal skin of the patients depending on de position of the tumor/fiducials in the
      rectum). Moreover, for patients in this study 2 orthogonal kV images will be made immediately
      after each radiation using the electronic portal imaging (EPI) device.

      As part of standard clinical practice an Magnetic resonance imaging (MRI) of the rectum will
      be made for response evaluation 6-8 weeks after the end of neo-adjuvant chemo-radiotherapy.

      As part of standard clinical practice patients whose tumor has not responded completely will
      be operated on 8-12 weeks after the end of neoadjuvant chemo-radiotherapy. Patients with a
      complete response will be follow-upped according to the "wait-and-see" protocol.

      Cone-beam CT and MR images which are obtained as routine practice during treatment of the
      participants will be compared with images of 20 non-participating patients treated at our
      institute in the same period.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Positional stability of BioXmark liquid fiducial markers during the treatment course
time frame: will be determined through the course of radiotherapy, an average of 5 weeks
description: Positional stability / potential marker migration will be assessed by calculating marker pair distances.
measure: Visibility/visual stability of BioXmark liquid fiducial markers during the treatment course
time frame: will be determined for the time interval between placement and the post-treatment MRI, an average of 12 weeks
description: Visual stability will be evaluated by scoring visibility of the markers on CT, CBCT, EPI and MRI (T1, T2 and diffusion weighted images) by 2 independent observers using a subjective scoring system: 0 = not visible, 1 = barely visible, 2 = clearly visible.
measure: Percentage of markers lost from injection to CT acquisition for RT planning
time frame: will be determined for the time interval between placement and pretreatment radiotherapy planning CT, an average of 1 week
description: (1 - number of markers visible on the last CBCT (cone-beam computed tomography) during treatment / number of visible markers at pCT) * 100
measure: Percentage of markers lost from injection to CT acquisition for RT planning
time frame: will be determined for the time intervals through the course of radiotherapy, an average of 5 weeks
description: (1 - number of markers visible on the last CBCT (cone-beam computed tomography) during treatment / number of visible markers at pCT) * 100
measure: Adverse events (AE) potentially associated with BioXmark
time frame: until rectal surgery, on average 11 weeks, or in case of omission of surgery, until 3 months after marker placement.
description: The safety of bioXmark liquid fiducials placement will be assessed by recording Adverse events (AE) potentially associated with BioXmark until rectal surgery, on average 11 weeks, or in case of omission of surgery, until 3 months after marker placement.
measure: Inter-observer variation in gross tumor volume (GTV) localization with and without markers
time frame: through the course of radiotherapy, an average of 5 weeks
description: The concordance index (CI) of gross tumor volume (GTV) localization between observers on kV CBCT will be determined. The CI is the ratio of the intersection and the union of the two volumes.
measure: Effect of BioXmark liquid fiducial markers on post-treatment MRI images
time frame: at the moment of the post-treatment MRI, on average 6-8 weeks after chemo-radiation
description: Potential BioXmark induced artefacts will be scored by 2 independent observers using a subjective scoring system:
measure: Potential BioXmark induced alterations in the surgical specimen
time frame: on average 10-12 weeks after chemo-radiation
description: The surgical specimens will be evaluated for signs of marker-induced alterations.
Potential BioXmark induced alteration in the surgical specimen will be scored by 2 independent observers using a subjective scoring system.In case the markers can't be located in the surgical specimen standard clinical evaluation of the specimen will take place. If the marker got lost during tissue processing potential inflammation/perforation will be scored as follows:A) 0 = no signs of extra inflammatory changes possibly related to the fiducials, 1 = limited extra inflammatory changes possibly related to the fiducials, 2 = severe extra inflammatory changes possibly related to the fiducials; B) 0 = no perforation of the rectal possibly related to fiducials, 1 = perforation of the rectal possibly related to the fiducials
arm group label: BioXmark liquid fiducial markers
arm group type: Experimental
description: Placement of 4 BioXmark liquid fiducial markers, standard treatment (chemo-radiotherapy followed by surgery or wait-and-see) with extra imaging to evaluate the behaviour of the markers before, during and after the radiotherapy
intervention type: Device
intervention name: BioXmark liquid fiducial markers
description: Before the start of the treatment planning during an extra sigmoidoscopy after enema preparation, 4 liquid marker spots will be placed 1 cm from the tumor; two in the in the cranial and two in the caudal direction of the tumor (4 markers in total per patient).
arm group label: BioXmark liquid fiducial markers
intervention type: Other
intervention name: Imaging
description: As part of standard patient set-up directly before each radiotherapy treatment, kV cone-beam CTs will be acquired. Treatment positioning will be based on the regular clinical decision protocols for treatment of rectal cancer and not on the markers. During treatment potential fiducial movement will be assessed using an externally positioned ultra-sound probe, positioned against the abdominal or perineal skin of the patients depending on de position of the tumor/fiducials in the rectum. For patients in this study 2 orthogonal kV images will be made immediately after each radiation using the electronic portal imaging (EPI) device.
As part of standard clinical practice an MR of the rectum will be made for response evaluation 6-8 weeks after the end of neo-adjuvant chemo-radiotherapy.
arm group label: BioXmark liquid fiducial markers
intervention type: Procedure
intervention name: surgery or wait-and-see
description: As part of standard clinical practice patients whose tumor has not responded completely will be operated on 8-12 weeks after the end of neoadjuvant chemo-radiotherapy. Patients with a complete response will be follow-upped according to the "wait-and-see" protocol.
arm group label: BioXmark liquid fiducial markers
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Maaike Berbée, MD,PhD
role: Principal Investigator
affiliation: Maastro Clinic, The Netherlands
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Rectal Neoplasms
sharing ipd: No