<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/NCT03283527</url>
  </required_header>
  <id_info>
    <org_study_id>RARESTEM/Organoid</org_study_id>
    <nct_id>NCT03283527</nct_id>
  </id_info>
  <brief_title>Organoid Based Response Prediction in Esophageal Cancer</brief_title>
  <acronym>RARESTEM/Org</acronym>
  <official_title>Chemoradioresistance in Prospectively Isolated Cancer Stem Cells in Esophageal Cancer-Organoid: RARE STEM-Organoid</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Medical Center Groningen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Medical Center Groningen</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>
      Rationale: Current standard treatment of localized esophageal cancer (EC) with neoadjuvant&#xD;
      chemoradiotherapy (nCRT) followed by esophagectomy with curative intent results in 30%&#xD;
      complete, 40-60% partial and 20% no-response at pathologic examination. Clinical response of&#xD;
      nCRT is usually evaluated with PET-CT. However, response measurements are currently still&#xD;
      insufficient in optimizing EC treatment. Proper pre-surgical response prediction may allow&#xD;
      individualized treatment with esophagus-preservation in complete responders or switching to&#xD;
      an alternative treatment in non-responders. Interestingly, in many tumors, a subset of cells&#xD;
      has been found to possess cancer stem cell (CSC) properties with associated signaling as&#xD;
      drivers of tumor (re-)growth and therapy resistance. Response of CSC-derived tissue&#xD;
      resembling in vitro cultured tumor organoids may reflect patient's tumors sensitivity to&#xD;
      therapy.&#xD;
&#xD;
      Objective: To create a patient derived organoid model for EC patients to predict the&#xD;
      pathologic tumor response to nCRT in clinical practice. This will allow a more personalized&#xD;
      approach in future treatment of locally advanced EC.&#xD;
&#xD;
      Study design: Fresh esophageal tumor material will be collected during diagnostic endoscopic&#xD;
      ultrasound (EUS) in participating patients. These biopsies will be used to select cancer stem&#xD;
      cells, which will be cultured to derive organoids (esophageal cancer patient derived&#xD;
      organoids; EC-PDO). When the EC-PDO contain sufficient cells, these cells will be treated&#xD;
      with radiotherapy and/or chemotherapy in order to obtain dose-response curves. The response&#xD;
      of these EC-PDOs will be compared to the actual tumor response to nCRT treatment in these EC&#xD;
      patients, which will be assessed at the definitive pathologic examination of the resection&#xD;
      specimen after esophagectomy with curative intent.&#xD;
&#xD;
      Study population: All patients with curatively treatable and resectable esophageal cancer&#xD;
      (adenocarcinoma or squamous cell carcinoma) can be included in this trial.&#xD;
&#xD;
      Main study parameters/endpoints: The main endpoint is response prediction to&#xD;
      chemoradiotherapy by EC-PDO; the steepness of the dose response survival curve in the&#xD;
      organoids in relation to the pathologic response after resection in the clinical situation.&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness: The patients will be asked to undergo 3 to 6 additional biopsies during&#xD;
      endoscopic ultrasonography (EUS) for the TNM staging of the tumor. The risk of these&#xD;
      additional biopsies is not greater than the biopsies for the diagnosis of EC. The patient&#xD;
      will not benefit from participation in this trial.&#xD;
&#xD;
      For the future approach we can get more insight into the mechanism of (chemo)radiation&#xD;
      response or resistance to nCRT, which might lead to a better patient selection and more&#xD;
      individualized esophageal cancer treatment in the future. This improvement in selection and&#xD;
      treatment can result in less over or under-treatment of these EC patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 1, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Response prediction by EC-PDO</measure>
    <time_frame>january 2020</time_frame>
    <description>The main endpoint is response prediction by EC-PDO; the steepness of the dose response survival curve in relation to the pathologic response after resection.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>EC-PDO growth rate in-vivo</measure>
    <time_frame>December 2018- febr 2019</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stem cell characterization measured by the amount of CD24-/CD44+</measure>
    <time_frame>March 2018</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radio/Chemo-sensitivity/resistance; the effective dose 50% (ED50%) of CSCs enriched subpopulation will be compared with the ED50% esophageal cancer cell lines.</measure>
    <time_frame>december 2019/january 2020</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical response: based on PET-CT (standard): complete, partial or no response</measure>
    <time_frame>December 2019/January 2020</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease free survival (DFS) in months in patients</measure>
    <time_frame>December 2020/January 2021</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS) in months</measure>
    <time_frame>December 2020/January 2021</time_frame>
  </secondary_outcome>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Organoid</condition>
  <condition>Esophageal Cancer</condition>
  <condition>Chemoradiation</condition>
  <eligibility>
    <study_pop>
      <textblock>
        All patients with histologically proven adenocarcinoma or squamous cell carcinoma of the&#xD;
        esophagus, who are candidates for nCRT followed by resection, can be included in this&#xD;
        trial.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically proven adeno- or squamous cell carcinoma of the esophagus&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Candidates for curative treatment; clinical stage T1N+/T2-4aN0-3M0&#xD;
&#xD;
          -  Scheduled for endoscopic ultrasound (EUS) procedure for staging and/or treatment&#xD;
             purposes&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are medically unfit for a curative treatment&#xD;
&#xD;
          -  Signs of distant metastases (M1)&#xD;
&#xD;
          -  Patients who are mentally disabled or incapable to give informed consent&#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>Kristel Muijs, Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radiotherapy</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kristel Muijs, Dr.</last_name>
    <phone>+31652724462</phone>
    <email>c.t.muijs@umcg.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Medical Center Groningen (UMCG)</name>
      <address>
        <city>Groningen</city>
        <zip>9713GZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kristel Muijs, Dr.</last_name>
      <email>c.t.muijs@umcg.nl</email>
    </contact>
    <investigator>
      <last_name>Kristel Muijs, Dr.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Martini Ziekenhuis</name>
      <address>
        <city>Groningen</city>
        <zip>9728NT</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Laurens van der Waaij, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Medisch Centrum Leeuwarden</name>
      <address>
        <city>Leeuwarden</city>
        <zip>8901BR</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Klaas van der Linde, Dr.</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>August 28, 2017</study_first_submitted>
  <study_first_submitted_qc>September 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <last_update_submitted>September 6, 2023</last_update_submitted>
  <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Medical Center Groningen</investigator_affiliation>
    <investigator_full_name>C.T. Muijs</investigator_full_name>
    <investigator_title>Dr.</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Esophageal Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03283527
org study id: RARESTEM/Organoid
nct id: NCT03283527
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Rationale: Current standard treatment of localized esophageal cancer (EC) with neoadjuvant
      chemoradiotherapy (nCRT) followed by esophagectomy with curative intent results in 30%
      complete, 40-60% partial and 20% no-response at pathologic examination. Clinical response of
      nCRT is usually evaluated with PET-CT. However, response measurements are currently still
      insufficient in optimizing EC treatment. Proper pre-surgical response prediction may allow
      individualized treatment with esophagus-preservation in complete responders or switching to
      an alternative treatment in non-responders. Interestingly, in many tumors, a subset of cells
      has been found to possess cancer stem cell (CSC) properties with associated signaling as
      drivers of tumor (re-)growth and therapy resistance. Response of CSC-derived tissue
      resembling in vitro cultured tumor organoids may reflect patient's tumors sensitivity to
      therapy.

      Objective: To create a patient derived organoid model for EC patients to predict the
      pathologic tumor response to nCRT in clinical practice. This will allow a more personalized
      approach in future treatment of locally advanced EC.

      Study design: Fresh esophageal tumor material will be collected during diagnostic endoscopic
      ultrasound (EUS) in participating patients. These biopsies will be used to select cancer stem
      cells, which will be cultured to derive organoids (esophageal cancer patient derived
      organoids; EC-PDO). When the EC-PDO contain sufficient cells, these cells will be treated
      with radiotherapy and/or chemotherapy in order to obtain dose-response curves. The response
      of these EC-PDOs will be compared to the actual tumor response to nCRT treatment in these EC
      patients, which will be assessed at the definitive pathologic examination of the resection
      specimen after esophagectomy with curative intent.

      Study population: All patients with curatively treatable and resectable esophageal cancer
      (adenocarcinoma or squamous cell carcinoma) can be included in this trial.

      Main study parameters/endpoints: The main endpoint is response prediction to
      chemoradiotherapy by EC-PDO; the steepness of the dose response survival curve in the
      organoids in relation to the pathologic response after resection in the clinical situation.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: The patients will be asked to undergo 3 to 6 additional biopsies during
      endoscopic ultrasonography (EUS) for the TNM staging of the tumor. The risk of these
      additional biopsies is not greater than the biopsies for the diagnosis of EC. The patient
      will not benefit from participation in this trial.

      For the future approach we can get more insight into the mechanism of (chemo)radiation
      response or resistance to nCRT, which might lead to a better patient selection and more
      individualized esophageal cancer treatment in the future. This improvement in selection and
      treatment can result in less over or under-treatment of these EC patients.
observational model: Case-Only
time perspective: Prospective
measure: Response prediction by EC-PDO
time frame: january 2020
description: The main endpoint is response prediction by EC-PDO; the steepness of the dose response survival curve in relation to the pathologic response after resection.
measure: EC-PDO growth rate in-vivo
time frame: December 2018- febr 2019
measure: Stem cell characterization measured by the amount of CD24-/CD44+
time frame: March 2018
measure: Radio/Chemo-sensitivity/resistance; the effective dose 50% (ED50%) of CSCs enriched subpopulation will be compared with the ED50% esophageal cancer cell lines.
time frame: december 2019/january 2020
measure: Clinical response: based on PET-CT (standard): complete, partial or no response
time frame: December 2019/January 2020
measure: Disease free survival (DFS) in months in patients
time frame: December 2020/January 2021
measure: Overall survival (OS) in months
time frame: December 2020/January 2021
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kristel Muijs, Dr.
role: Principal Investigator
affiliation: Radiotherapy
last name: Kristel Muijs, Dr.
phone: +31652724462
email: c.t.muijs@umcg.nl
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: University Medical Center Groningen
investigator full name: C.T. Muijs
investigator title: Dr.
mesh term: Esophageal Neoplasms
sharing ipd: Undecided