<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/NCT02253602</url>
  </required_header>
  <id_info>
    <org_study_id>NL48757.018.14</org_study_id>
    <nct_id>NCT02253602</nct_id>
  </id_info>
  <brief_title>Innovative MRI Techniques to Improve Treatment Stratification of Patients With Esophageal Cancer</brief_title>
  <acronym>IMPROVE</acronym>
  <official_title>Innovative MRI Techniques to Improve Treatment Stratification of Patients With Esophageal Cancer: an Optimization and Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The current standard treatment of resectable esophageal cancer consists of neoadjuvant&#xD;
      chemoradiation followed by resection. However, some patients develop recurrent disease&#xD;
      despite chemoradiation and additional (systemic) treatment might have been indicated. Other&#xD;
      patients show a (nearly) complete response after chemoradiation and could possibly have been&#xD;
      treated with a less extensive treatment regimen. In patients without a threatened&#xD;
      circumferential resection margin (CRM) and lymph node metastases chemoradiotherapy could&#xD;
      possibly be omitted.&#xD;
&#xD;
      Better stratification of patients with esophageal cancer is therefore urgently needed.&#xD;
      Functional magnetic resonance imaging techniques (MRI) can provide in vivo, quantitative&#xD;
      information on tumor biology and may prove to be a useful non-invasive tool for this purpose.&#xD;
      In this project, ultra-small superparamagnetic particles of iron oxide (USPIO) enhanced MRI&#xD;
      using ferumoxytol (Rienso®), diffusion weighted MRI (DWI) and T2* MRI will be developed, both&#xD;
      in terms of improvement of acquisition and data processing techniques.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The outcome of esophageal cancer is poor, with an overall 5-year survival rate of 10%&#xD;
      worldwide. In resectable esophageal cancer, outcome can be improved by multimodality&#xD;
      treatment. The current standard treatment of resectable esophageal cancer consists of&#xD;
      neoadjuvant chemoradiation followed by resection. In the Netherlands, the preferred&#xD;
      chemoradiation regimen consists of carboplatin plus paclitaxel with concurrent radiotherapy&#xD;
      in 23 fractions of 1.8 Gray.1 In a meta-analysis the benefit of chemoradiation over surgery&#xD;
      alone for both adenocarcinoma and squamous cell carcinoma has been shown.2 However, not all&#xD;
      patients benefit from this preoperative treatment regimen. Some patients develop recurrent&#xD;
      disease despite chemoradiation and additional (systemic) treatment might have been indicated.&#xD;
      In contrast, in other patients a (nearly) complete response is observed after chemoradiation&#xD;
      and those patients could possibly have been treated with a less extensive treatment regimen.&#xD;
      Furthermore, in patients without a threatened circumferential resection margin (CRM) and&#xD;
      lymph node metastases chemoradiotherapy could possibly be omitted, reducing patients' risk&#xD;
      for complications and unnecessary, expensive treatment. Thus, stratification of patients with&#xD;
      esophageal cancer is urgently needed. Functional magnetic resonance imaging techniques (MRI)&#xD;
      can provide in vivo, quantitative information on tumor biology and may prove to be a useful&#xD;
      non-invasive tool for this purpose. In this project, ultra-small superparamagnetic particles&#xD;
      of iron oxide (USPIO) enhanced MRI using ferumoxytol (Rienso®), diffusion weighted MRI (DWI)&#xD;
      and T2* MRI will be developed, both in terms of improvement of acquisition and data&#xD;
      processing techniques. For patients with esophageal cancer, the proposed acquisition&#xD;
      techniques and data processing have not been performed before.&#xD;
&#xD;
      Objectives of the study&#xD;
&#xD;
        1. To determine the optimal acquisition technique for USPIO enhanced MRI and DWI and T2*&#xD;
           MRI of esophageal cancer in terms of signal-to-noise ratio, time resolution and spatial&#xD;
           resolution.&#xD;
&#xD;
        2. To determine the optimal data processing approach for USPIO enhanced MRI, DWI and T2*&#xD;
           MRI of esophageal cancer.&#xD;
&#xD;
        3. To explore the correlation between lymph node involvement on USPIO enhanced MRI in&#xD;
           relation to results obtained at pathological examination.&#xD;
&#xD;
        4. To explore the correlation of DWI and T2* MRI of esophageal cancer in relation to&#xD;
           stromal involvement and markers of hypoxia and vasculature obtained at pathological&#xD;
           examination.&#xD;
&#xD;
        5. To explore the accuracy of MRI concerning circumferential tumor delineation compared to&#xD;
           pathological examination.&#xD;
&#xD;
        6. To determine the feasibility to detect lymph node involvement on USPIO enhanced MRI in&#xD;
           initial staging, prior to preoperative chemoradiation therapy.&#xD;
&#xD;
        7. To determine the correlation between lymph node involvement on pre-treatment USPIO MRI&#xD;
           in relation to results obtained at pathology after complete treatment.&#xD;
&#xD;
      The project will be executed in four steps:&#xD;
&#xD;
        1. Optimization of acquisition and data processing techniques of USPIO MRI, DWI and T2* in&#xD;
           five healthy volunteers to optimize field of view, number of slices, slice thickness&#xD;
           (objectives 1 and 2).&#xD;
&#xD;
        2. Assessment of ferumoxytol dose-response with three different dose levels at three&#xD;
           different time points in six healthy volunteers (two per dose-level) (objectives 1 and&#xD;
           2).&#xD;
&#xD;
        3. Using the data of (1) and (2): assessment of USPIO MRI, DWI and T2* MRI in 20 esophageal&#xD;
           cancer patients with clinically suspect lymph nodes directly before surgery (objectives&#xD;
           3, 4 and 5).&#xD;
&#xD;
        4. Using the data of (1) and (2): assessment of USPIO MRI, DWI and T2* MRI in 10 esophageal&#xD;
           cancer patients with clinically suspect lymph nodes, before initial start of the&#xD;
           treatment (objectives 6 and 7).&#xD;
&#xD;
      For step 1 and 2 we aim to include healthy volunteers; for step 3 and 4 we aim to include&#xD;
      patients with esophageal cancer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2014</start_date>
  <completion_date type="Actual">May 2018</completion_date>
  <primary_completion_date type="Actual">May 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>USPIO MRI</measure>
    <time_frame>24, 48 or 72 hours after USPIO administration</time_frame>
    <description>For USPIO enhanced MRI the main endpoint is the change in T2 and T2* at the tumor and lymph nodes on MRI after the administration of USPIO.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>DWI/IVIM MRI</measure>
    <time_frame>1 hour before USPIO administration</time_frame>
    <description>For DWI the main endpoint is the perfusion fraction f and the diffusion coefficient D obtained by IVIM of the primary tumor.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>T2* MRI</measure>
    <time_frame>1 hour before USPIO administration</time_frame>
    <description>For T2* MRI the main endpoint is T2* of the primary tumor</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ferumoxytol dose response</measure>
    <time_frame>24, 48, 72 hours and 12 weeks after the administration of Ferumoxytol</time_frame>
    <description>For Ferumoxytol dose evaluation the main endpoint is the change in T2 and T2* at the tumor and lymph nodes on MRI at 24, 48, 72 hours and 12 weeks after the administration of Ferumoxytol.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Esophageal Neoplasms</condition>
  <arm_group>
    <arm_group_label>Ferumoxytol Dose optimization</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>We will assess three different dose levels of Ferumoxytol (4 mg/kg, 6 mg/kg, 8 mg/kg).&#xD;
Images will be acquired at baseline (before Ferumoxytol administration), during injection of Ferumoxytol and 24, 48 and 72 hours after Ferumoxytol administration to identify the optimal moment of scanning.To assess whether USPIOs are sufficiently cleared within 12 weeks from lymph nodes, the MRI scans will be repeated in all six volunteers at 12 weeks after Ferumoxytol administration. Thus, volunteers will undergo an MRI scan for five times. Ferumoxytol is administered only once</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Before Surgery</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Twenty patients will be measured directly before surgery. Patients will be measured at baseline, during injection of Ferumoxytol and 24, 48 or 72 hours after Ferumoxytol administration, depending on the results of the dose optimization study. MR parameters will be correlated with pathology data.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Before Neoadjucant therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ten patients will be measured before start of neoadjuvant chemoradiation. Patients will be measured at baseline, during injection of Ferumoxytol and 24, 48 or 72 hours after Ferumoxytol administration, based on the dose optimization study. MR parameters will be correlated with pathology data.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ferumoxytol</intervention_name>
    <description>maximum rate of administration 1 ml/sec</description>
    <arm_group_label>Before Neoadjucant therapy</arm_group_label>
    <arm_group_label>Before Surgery</arm_group_label>
    <arm_group_label>Ferumoxytol Dose optimization</arm_group_label>
    <other_name>USPIO</other_name>
    <other_name>Rienso</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with biopsy proven esophageal cancer (squamous cell carcinoma or&#xD;
             adenocarcinoma)&#xD;
&#xD;
          -  Suspected nodal involvement on EUS or CT at diagnosis.&#xD;
&#xD;
          -  WHO-performance score 0-2&#xD;
&#xD;
          -  Scheduled for surgery&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any psychological, familial, sociological or geographical condition potentially&#xD;
             hampering adequate informed consent or compliance with the study protocol&#xD;
&#xD;
          -  Contra-indications for MR scanning, including patients with a pacemaker, cochlear&#xD;
             implant or neurostimulator; patients with non-MR compatible metallic implants in their&#xD;
             eye, spine, thorax or abdomen; or a non-MR compatible aneurysm clip in their brain;&#xD;
             patients with severe claustrophobia&#xD;
&#xD;
          -  Active inflammatory diseases&#xD;
&#xD;
          -  History of anaphylaxis or other hypersensitivity reactions&#xD;
&#xD;
          -  History of iron overload&#xD;
&#xD;
          -  History of abnormal liver function, or elevated liver enzymes (ALAT, ASAT &gt; 3 times&#xD;
             upper limit of normal)&#xD;
&#xD;
          -  Elevated Serum Transferrin Saturation (TSAT) (&gt;50%) or hemoglobin (&gt;10.5mmol/L)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hanneke WM van Laarhoven, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Academic Medical Center</name>
      <address>
        <city>Amsterdam</city>
        <state>Noord Holland</state>
        <zip>1105AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>September 4, 2014</study_first_submitted>
  <study_first_submitted_qc>September 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 1, 2014</study_first_posted>
  <last_update_submitted>January 15, 2019</last_update_submitted>
  <last_update_submitted_qc>January 15, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</investigator_affiliation>
    <investigator_full_name>H.W.M. van Laarhoven</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Esophageal Neoplasms</keyword>
  <keyword>Lymph Nodes</keyword>
  <keyword>USPIO</keyword>
  <keyword>Magnetic Resonance Imaging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Esophageal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ferrosoferric Oxide</mesh_term>
  </intervention_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/NCT02253602
org study id: NL48757.018.14
nct id: NCT02253602
lead sponsor: 
has dmc: No
The current standard treatment of resectable esophageal cancer consists of neoadjuvant
      chemoradiation followed by resection. However, some patients develop recurrent disease
      despite chemoradiation and additional (systemic) treatment might have been indicated. Other
      patients show a (nearly) complete response after chemoradiation and could possibly have been
      treated with a less extensive treatment regimen. In patients without a threatened
      circumferential resection margin (CRM) and lymph node metastases chemoradiotherapy could
      possibly be omitted.

      Better stratification of patients with esophageal cancer is therefore urgently needed.
      Functional magnetic resonance imaging techniques (MRI) can provide in vivo, quantitative
      information on tumor biology and may prove to be a useful non-invasive tool for this purpose.
      In this project, ultra-small superparamagnetic particles of iron oxide (USPIO) enhanced MRI
      using ferumoxytol (Rienso®), diffusion weighted MRI (DWI) and T2* MRI will be developed, both
      in terms of improvement of acquisition and data processing techniques.
The outcome of esophageal cancer is poor, with an overall 5-year survival rate of 10%
      worldwide. In resectable esophageal cancer, outcome can be improved by multimodality
      treatment. The current standard treatment of resectable esophageal cancer consists of
      neoadjuvant chemoradiation followed by resection. In the Netherlands, the preferred
      chemoradiation regimen consists of carboplatin plus paclitaxel with concurrent radiotherapy
      in 23 fractions of 1.8 Gray.1 In a meta-analysis the benefit of chemoradiation over surgery
      alone for both adenocarcinoma and squamous cell carcinoma has been shown.2 However, not all
      patients benefit from this preoperative treatment regimen. Some patients develop recurrent
      disease despite chemoradiation and additional (systemic) treatment might have been indicated.
      In contrast, in other patients a (nearly) complete response is observed after chemoradiation
      and those patients could possibly have been treated with a less extensive treatment regimen.
      Furthermore, in patients without a threatened circumferential resection margin (CRM) and
      lymph node metastases chemoradiotherapy could possibly be omitted, reducing patients' risk
      for complications and unnecessary, expensive treatment. Thus, stratification of patients with
      esophageal cancer is urgently needed. Functional magnetic resonance imaging techniques (MRI)
      can provide in vivo, quantitative information on tumor biology and may prove to be a useful
      non-invasive tool for this purpose. In this project, ultra-small superparamagnetic particles
      of iron oxide (USPIO) enhanced MRI using ferumoxytol (Rienso®), diffusion weighted MRI (DWI)
      and T2* MRI will be developed, both in terms of improvement of acquisition and data
      processing techniques. For patients with esophageal cancer, the proposed acquisition
      techniques and data processing have not been performed before.

      Objectives of the study

        1. To determine the optimal acquisition technique for USPIO enhanced MRI and DWI and T2*
           MRI of esophageal cancer in terms of signal-to-noise ratio, time resolution and spatial
           resolution.

        2. To determine the optimal data processing approach for USPIO enhanced MRI, DWI and T2*
           MRI of esophageal cancer.

        3. To explore the correlation between lymph node involvement on USPIO enhanced MRI in
           relation to results obtained at pathological examination.

        4. To explore the correlation of DWI and T2* MRI of esophageal cancer in relation to
           stromal involvement and markers of hypoxia and vasculature obtained at pathological
           examination.

        5. To explore the accuracy of MRI concerning circumferential tumor delineation compared to
           pathological examination.

        6. To determine the feasibility to detect lymph node involvement on USPIO enhanced MRI in
           initial staging, prior to preoperative chemoradiation therapy.

        7. To determine the correlation between lymph node involvement on pre-treatment USPIO MRI
           in relation to results obtained at pathology after complete treatment.

      The project will be executed in four steps:

        1. Optimization of acquisition and data processing techniques of USPIO MRI, DWI and T2* in
           five healthy volunteers to optimize field of view, number of slices, slice thickness
           (objectives 1 and 2).

        2. Assessment of ferumoxytol dose-response with three different dose levels at three
           different time points in six healthy volunteers (two per dose-level) (objectives 1 and
           2).

        3. Using the data of (1) and (2): assessment of USPIO MRI, DWI and T2* MRI in 20 esophageal
           cancer patients with clinically suspect lymph nodes directly before surgery (objectives
           3, 4 and 5).

        4. Using the data of (1) and (2): assessment of USPIO MRI, DWI and T2* MRI in 10 esophageal
           cancer patients with clinically suspect lymph nodes, before initial start of the
           treatment (objectives 6 and 7).

      For step 1 and 2 we aim to include healthy volunteers; for step 3 and 4 we aim to include
      patients with esophageal cancer.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: USPIO MRI
time frame: 24, 48 or 72 hours after USPIO administration
description: For USPIO enhanced MRI the main endpoint is the change in T2 and T2* at the tumor and lymph nodes on MRI after the administration of USPIO.
measure: DWI/IVIM MRI
time frame: 1 hour before USPIO administration
description: For DWI the main endpoint is the perfusion fraction f and the diffusion coefficient D obtained by IVIM of the primary tumor.
measure: T2* MRI
time frame: 1 hour before USPIO administration
description: For T2* MRI the main endpoint is T2* of the primary tumor
measure: Ferumoxytol dose response
time frame: 24, 48, 72 hours and 12 weeks after the administration of Ferumoxytol
description: For Ferumoxytol dose evaluation the main endpoint is the change in T2 and T2* at the tumor and lymph nodes on MRI at 24, 48, 72 hours and 12 weeks after the administration of Ferumoxytol.
arm group label: Ferumoxytol Dose optimization
arm group type: Experimental
description: We will assess three different dose levels of Ferumoxytol (4 mg/kg, 6 mg/kg, 8 mg/kg).
Images will be acquired at baseline (before Ferumoxytol administration), during injection of Ferumoxytol and 24, 48 and 72 hours after Ferumoxytol administration to identify the optimal moment of scanning.To assess whether USPIOs are sufficiently cleared within 12 weeks from lymph nodes, the MRI scans will be repeated in all six volunteers at 12 weeks after Ferumoxytol administration. Thus, volunteers will undergo an MRI scan for five times. Ferumoxytol is administered only once
arm group label: Before Surgery
arm group type: Experimental
description: Twenty patients will be measured directly before surgery. Patients will be measured at baseline, during injection of Ferumoxytol and 24, 48 or 72 hours after Ferumoxytol administration, depending on the results of the dose optimization study. MR parameters will be correlated with pathology data.
arm group label: Before Neoadjucant therapy
arm group type: Experimental
description: Ten patients will be measured before start of neoadjuvant chemoradiation. Patients will be measured at baseline, during injection of Ferumoxytol and 24, 48 or 72 hours after Ferumoxytol administration, based on the dose optimization study. MR parameters will be correlated with pathology data.
intervention type: Drug
intervention name: Ferumoxytol
description: maximum rate of administration 1 ml/sec
arm group label: Before Neoadjucant therapy
arm group label: Before Surgery
arm group label: Ferumoxytol Dose optimization
other name: USPIO
other name: Rienso
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Hanneke WM van Laarhoven, MD, PhD
role: Principal Investigator
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
investigator full name: H.W.M. van Laarhoven
investigator title: MD, PhD
mesh term: Esophageal Neoplasms
mesh term: Ferrosoferric Oxide