<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/NCT04455282</url>
  </required_header>
  <id_info>
    <org_study_id>2020-06-BS</org_study_id>
    <nct_id>NCT04455282</nct_id>
  </id_info>
  <brief_title>CIRCULATing Biomarkers for Individualized Surgical Therapy in gastroEsophageal Cancer - Phase 1</brief_title>
  <acronym>CIRCULATE1</acronym>
  <official_title>CIRCULATing Biomarkers for Individualized Surgical Therapy in gastroEsophageal Cancer - Phase 1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Heinrich-Heine University, Duesseldorf</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital of Cologne</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Heinrich-Heine University, Duesseldorf</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>
      This is an exploratory observational biomarker study in approximately 100 eligible patients&#xD;
      with resectable adenocarcinomas of the esophagus and gastro- esophageal junction (GEJ) type&#xD;
      I-II (GEAC) to investigate the difference deletion frequency of circulating tumor cells&#xD;
      (CTCs) between peripheral veins and tumor-draining veins (primary endpoint), prognostic&#xD;
      value, relevance of a set of two additional blood-based biomarkers analyzed from a single&#xD;
      blood sampling tube (secondary endpoints). The underlying hypothesis is that the biomarker&#xD;
      alone or in combination improve preoperative staging and help to identify patients at risk&#xD;
      for metastasis. This should enable a better stratification of GEAC patients to neo-adjuvant&#xD;
      treatment, (intensified) peri-operative treatment, or even surgery alone, in selected cases.&#xD;
      The data of the CIRCULATE study shall be used design subsequent studies testing the&#xD;
      predictive role of these biomarkers for surgical management. Patients will provide blood&#xD;
      samples and lymphatic fluid during the operation and annual blood samples during clinical&#xD;
      follow up of 5 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an exploratory observational biomarker study. Around 20 mL of blood will be collected&#xD;
      from a peripheral vein and additional 40 mL from tumor draining veins. In addition, around 5&#xD;
      mL of lymphatic fluid will be collected from the thoracic duct, when exposed and opened&#xD;
      during the surgical resection. Annual blood draws (20 mL) will be performed during routine&#xD;
      clinical follow-up or at the time point when the patients develops a (metastatic) relapse. A&#xD;
      one tube protocol will be performed from each blood sample to assess CTCs and tumor derived&#xD;
      extracellular Vesicles (tdEVs) using CELLSEARCH® and ACCEPT&#xD;
      (https://github.com/LeonieZ/ACCEPT/blob/master/ACCEPT.m). In addition, tumor cells will be&#xD;
      enumerated by CELLSEARCH® in the lymphatic fluid. ctDNA will be extracted from plasma of each&#xD;
      blood collection tube and analyzed by mFAST-SeqS. If the mutational status of the primary&#xD;
      tumor is known, deep sequencing of ctDNA will be applied for mutation tracking at a later&#xD;
      time point. Tissue resected during the surgical procedure and not required for routine&#xD;
      pathology will be collected into a biobank (cry-conserved and formalin fixed and paraffin&#xD;
      embedded (FFPE).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 1, 2021</start_date>
  <completion_date type="Anticipated">January 30, 2028</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Difference in CTC detection rate between peripheral and tumor draining veins.</measure>
    <time_frame>24 months</time_frame>
    <description>The difference between the CTC positivity rate (≥1 CTC / 7.5 mL) in blood samples of tumor-draining veins compared to the CTC positivity rate in peripheral blood. The positivity fraction and CTC number per 7.5 mL in tumor draining veins and peripheral blood samples will be determined by CellSearch.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>tdEVs</measure>
    <time_frame>24 months</time_frame>
    <description>1. The tdEV number per 7.5 mL determined from CellSearch images using the ACCEPT software tool and the fraction of tdEVs positive patients (a cut-off threshold will be applied)(de Wit, 2019). 2. The difference between tdEV measurement in the tumor-draining veins and the peripheral blood will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ctDNA</measure>
    <time_frame>24 months</time_frame>
    <description>1. The tumor allele frequency measured by the genome-wide mFAST-SeqS assay (Belic, 2015) and the fraction of patients with high tumor allele frequency will be determined. For this, a threshold of 10% tumour allele frequency will be applied to discriminate high allele frequency (&gt;10%) from low allele frequency (≤10%) cases (Belic, 2015; de Wit, 2019). 2. The difference between ctDNA measurement in the tumor-draining veins and the peripheral blood will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical correlation</measure>
    <time_frame>84 months</time_frame>
    <description>Correlation of any of the biomarker or in combination with clinical parameters and with patient clinical outcome (OS and RFS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dynamic Biobank</measure>
    <time_frame>24 months</time_frame>
    <description>The number of tumor tissues (primary tumor, lymph node metastasis, biopsy material), isolated CELLSEARCH® CTCs and plasma/ctDNA samples generated from CIRCULATE1 and stored in the respective biobanks from the University Hospital of Cologne and from University Hospital Düsseldorf.</description>
  </secondary_outcome>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Cancer of Esophagus</condition>
  <condition>Esophagogastric Junction Disorder</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      blood, tumor material&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The targeted study population of CIRCULATE1 are 100 patients (see 2.3) with resectable GEAC&#xD;
        (GEJ type I-II) undergoing surgery with curative intention. The patients will be recruited&#xD;
        and screened consecutively by trained surgeons involved into the CIRCULATE study. Patients&#xD;
        are recruited to participate in this study at the outpatient clinic&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  histologically proven adenocarcinoma of the GEJ type I and II, resectable,&#xD;
             non-metastatic tumor&#xD;
&#xD;
          -  age ≥18&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2,&#xD;
&#xD;
          -  American Society of Anesthesiologists (ASA) &lt; 4.&#xD;
&#xD;
          -  pre-treatment stage cT1N+ M0 or cT2-4a N0/N+, M0 GEJ type I and II adenocarcinomas can&#xD;
             be included. In case of stage cT4a, curative resectability has to be explicitly&#xD;
             verified by the local surgical investigator prior inclusion.&#xD;
&#xD;
          -  Written informed consent and the ability to understand the nature of the study and the&#xD;
             study-related procedures and to comply with them has to be ensured.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  tumors of squamous, adenosquamous or other non-adenocarcinoma histology&#xD;
&#xD;
          -  patients with inoperable or metastatic GEJ type I and II adenocarcinoma, GEJ type I&#xD;
             and II adenocarcinoma staged cT1N0 and cT4b, GEJ type I and II cT4a evaluated as not&#xD;
             curatively resectable by the local surgical investigator&#xD;
&#xD;
          -  unsigned 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>Nikolas Stoecklein, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Surgery, University Hospital Düsseldorf Germany</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Christiane Bruns, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Surgery, University Hospital Cologne</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Nikolas H Stoecklein, MD</last_name>
    <phone>004921181</phone>
    <phone_ext>16399</phone_ext>
    <email>Nikolas.Stoecklein@med.uni-duesseldorf.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Christiane Bruns, MD</last_name>
    <email>christiane.bruns@uk-koeln.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Hospital Cologne</name>
      <address>
        <city>Cologne</city>
        <state>NRW</state>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christiane Bruns, MD</last_name>
      <phone>+49 221 47</phone>
      <phone_ext>84801</phone_ext>
      <email>christiane.bruns@uk-koeln.de</email>
    </contact>
    <contact_backup>
      <last_name>Raphael Stier, MD</last_name>
      <phone>+49 221 47</phone>
      <phone_ext>84801</phone_ext>
      <email>raphael.stier@uk-koeln.de</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <reference>
    <citation>de Wit S, Rossi E, Weber S, Tamminga M, Manicone M, Swennenhuis JF, Groothuis-Oudshoorn CGM, Vidotto R, Facchinetti A, Zeune LL, Schuuring E, Zamarchi R, Hiltermann TJN, Speicher MR, Heitzer E, Terstappen LWMM, Groen HJM. Single tube liquid biopsy for advanced non-small cell lung cancer. Int J Cancer. 2019 Jun 15;144(12):3127-3137. doi: 10.1002/ijc.32056. Epub 2019 Jan 28.</citation>
    <PMID>30536653</PMID>
  </reference>
  <reference>
    <citation>Belic J, Koch M, Ulz P, Auer M, Gerhalter T, Mohan S, Fischereder K, Petru E, Bauernhofer T, Geigl JB, Speicher MR, Heitzer E. Rapid Identification of Plasma DNA Samples with Increased ctDNA Levels by a Modified FAST-SeqS Approach. Clin Chem. 2015 Jun;61(6):838-49. doi: 10.1373/clinchem.2014.234286. Epub 2015 Apr 20.</citation>
    <PMID>25896989</PMID>
  </reference>
  <reference>
    <citation>Reeh M, Effenberger KE, Koenig AM, Riethdorf S, Eichstadt D, Vettorazzi E, Uzunoglu FG, Vashist YK, Izbicki JR, Pantel K, Bockhorn M. Circulating Tumor Cells as a Biomarker for Preoperative Prognostic Staging in Patients With Esophageal Cancer. Ann Surg. 2015 Jun;261(6):1124-30. doi: 10.1097/SLA.0000000000001130.</citation>
    <PMID>25607767</PMID>
  </reference>
  <reference>
    <citation>Pernot S, Badoual C, Terme M, Castan F, Cazes A, Bouche O, Bennouna J, Francois E, Ghiringhelli F, De La Fouchardiere C, Samalin E, Bachet JB, Borg C, Ducreux M, Marcheteau E, Stanbury T, Gourgou S, Malka D, Taieb J. Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects. Eur J Cancer. 2017 Jul;79:15-22. doi: 10.1016/j.ejca.2017.03.036. Epub 2017 Apr 26.</citation>
    <PMID>28456090</PMID>
  </reference>
  <reference>
    <citation>Buscail E, Chiche L, Laurent C, Vendrely V, Denost Q, Denis J, Thumerel M, Lacorte JM, Bedel A, Moreau-Gaudry F, Dabernat S, Alix-Panabieres C. Tumor-proximal liquid biopsy to improve diagnostic and prognostic performances of circulating tumor cells. Mol Oncol. 2019 Sep;13(9):1811-1826. doi: 10.1002/1878-0261.12534. Epub 2019 Jul 25.</citation>
    <PMID>31216108</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>June 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 2, 2020</study_first_posted>
  <last_update_submitted>March 14, 2023</last_update_submitted>
  <last_update_submitted_qc>March 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Heinrich-Heine University, Duesseldorf</investigator_affiliation>
    <investigator_full_name>Univ.-Prof. Dr. med. Nikolas H. Stoecklein</investigator_full_name>
    <investigator_title>Head of Experimental Surgical Oncology</investigator_title>
  </responsible_party>
  <keyword>Circulating Biomarkers</keyword>
  <keyword>CTC</keyword>
  <keyword>tdEVs</keyword>
  <keyword>ctDNA</keyword>
  <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/NCT04455282
org study id: 2020-06-BS
nct id: NCT04455282
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is an exploratory observational biomarker study in approximately 100 eligible patients
      with resectable adenocarcinomas of the esophagus and gastro- esophageal junction (GEJ) type
      I-II (GEAC) to investigate the difference deletion frequency of circulating tumor cells
      (CTCs) between peripheral veins and tumor-draining veins (primary endpoint), prognostic
      value, relevance of a set of two additional blood-based biomarkers analyzed from a single
      blood sampling tube (secondary endpoints). The underlying hypothesis is that the biomarker
      alone or in combination improve preoperative staging and help to identify patients at risk
      for metastasis. This should enable a better stratification of GEAC patients to neo-adjuvant
      treatment, (intensified) peri-operative treatment, or even surgery alone, in selected cases.
      The data of the CIRCULATE study shall be used design subsequent studies testing the
      predictive role of these biomarkers for surgical management. Patients will provide blood
      samples and lymphatic fluid during the operation and annual blood samples during clinical
      follow up of 5 years.
This is an exploratory observational biomarker study. Around 20 mL of blood will be collected
      from a peripheral vein and additional 40 mL from tumor draining veins. In addition, around 5
      mL of lymphatic fluid will be collected from the thoracic duct, when exposed and opened
      during the surgical resection. Annual blood draws (20 mL) will be performed during routine
      clinical follow-up or at the time point when the patients develops a (metastatic) relapse. A
      one tube protocol will be performed from each blood sample to assess CTCs and tumor derived
      extracellular Vesicles (tdEVs) using CELLSEARCH® and ACCEPT
      (https://github.com/LeonieZ/ACCEPT/blob/master/ACCEPT.m). In addition, tumor cells will be
      enumerated by CELLSEARCH® in the lymphatic fluid. ctDNA will be extracted from plasma of each
      blood collection tube and analyzed by mFAST-SeqS. If the mutational status of the primary
      tumor is known, deep sequencing of ctDNA will be applied for mutation tracking at a later
      time point. Tissue resected during the surgical procedure and not required for routine
      pathology will be collected into a biobank (cry-conserved and formalin fixed and paraffin
      embedded (FFPE).
observational model: Cohort
time perspective: Prospective
measure: Difference in CTC detection rate between peripheral and tumor draining veins.
time frame: 24 months
description: The difference between the CTC positivity rate (≥1 CTC / 7.5 mL) in blood samples of tumor-draining veins compared to the CTC positivity rate in peripheral blood. The positivity fraction and CTC number per 7.5 mL in tumor draining veins and peripheral blood samples will be determined by CellSearch.
measure: tdEVs
time frame: 24 months
description: 1. The tdEV number per 7.5 mL determined from CellSearch images using the ACCEPT software tool and the fraction of tdEVs positive patients (a cut-off threshold will be applied)(de Wit, 2019). 2. The difference between tdEV measurement in the tumor-draining veins and the peripheral blood will be assessed.
measure: ctDNA
time frame: 24 months
description: 1. The tumor allele frequency measured by the genome-wide mFAST-SeqS assay (Belic, 2015) and the fraction of patients with high tumor allele frequency will be determined. For this, a threshold of 10% tumour allele frequency will be applied to discriminate high allele frequency (>10%) from low allele frequency (≤10%) cases (Belic, 2015; de Wit, 2019). 2. The difference between ctDNA measurement in the tumor-draining veins and the peripheral blood will be assessed.
measure: Clinical correlation
time frame: 84 months
description: Correlation of any of the biomarker or in combination with clinical parameters and with patient clinical outcome (OS and RFS)
measure: Dynamic Biobank
time frame: 24 months
description: The number of tumor tissues (primary tumor, lymph node metastasis, biopsy material), isolated CELLSEARCH® CTCs and plasma/ctDNA samples generated from CIRCULATE1 and stored in the respective biobanks from the University Hospital of Cologne and from University Hospital Düsseldorf.
blood, tumor material
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nikolas Stoecklein, MD
role: Principal Investigator
affiliation: Surgery, University Hospital Düsseldorf Germany
last name: Christiane Bruns, MD
role: Principal Investigator
affiliation: Surgery, University Hospital Cologne
last name: Nikolas H Stoecklein, MD
phone: 004921181
phone ext: 16399
email: Nikolas.Stoecklein@med.uni-duesseldorf.de
last name: Christiane Bruns, MD
email: christiane.bruns@uk-koeln.de
facility: 
status: Recruiting
contact: 
contact backup: 
country: Germany
citation: de Wit S, Rossi E, Weber S, Tamminga M, Manicone M, Swennenhuis JF, Groothuis-Oudshoorn CGM, Vidotto R, Facchinetti A, Zeune LL, Schuuring E, Zamarchi R, Hiltermann TJN, Speicher MR, Heitzer E, Terstappen LWMM, Groen HJM. Single tube liquid biopsy for advanced non-small cell lung cancer. Int J Cancer. 2019 Jun 15;144(12):3127-3137. doi: 10.1002/ijc.32056. Epub 2019 Jan 28.
PMID: 30536653
citation: Belic J, Koch M, Ulz P, Auer M, Gerhalter T, Mohan S, Fischereder K, Petru E, Bauernhofer T, Geigl JB, Speicher MR, Heitzer E. Rapid Identification of Plasma DNA Samples with Increased ctDNA Levels by a Modified FAST-SeqS Approach. Clin Chem. 2015 Jun;61(6):838-49. doi: 10.1373/clinchem.2014.234286. Epub 2015 Apr 20.
PMID: 25896989
citation: Reeh M, Effenberger KE, Koenig AM, Riethdorf S, Eichstadt D, Vettorazzi E, Uzunoglu FG, Vashist YK, Izbicki JR, Pantel K, Bockhorn M. Circulating Tumor Cells as a Biomarker for Preoperative Prognostic Staging in Patients With Esophageal Cancer. Ann Surg. 2015 Jun;261(6):1124-30. doi: 10.1097/SLA.0000000000001130.
PMID: 25607767
citation: Pernot S, Badoual C, Terme M, Castan F, Cazes A, Bouche O, Bennouna J, Francois E, Ghiringhelli F, De La Fouchardiere C, Samalin E, Bachet JB, Borg C, Ducreux M, Marcheteau E, Stanbury T, Gourgou S, Malka D, Taieb J. Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects. Eur J Cancer. 2017 Jul;79:15-22. doi: 10.1016/j.ejca.2017.03.036. Epub 2017 Apr 26.
PMID: 28456090
citation: Buscail E, Chiche L, Laurent C, Vendrely V, Denost Q, Denis J, Thumerel M, Lacorte JM, Bedel A, Moreau-Gaudry F, Dabernat S, Alix-Panabieres C. Tumor-proximal liquid biopsy to improve diagnostic and prognostic performances of circulating tumor cells. Mol Oncol. 2019 Sep;13(9):1811-1826. doi: 10.1002/1878-0261.12534. Epub 2019 Jul 25.
PMID: 31216108
responsible party type: Principal Investigator
investigator affiliation: Heinrich-Heine University, Duesseldorf
investigator full name: Univ.-Prof. Dr. med. Nikolas H. Stoecklein
investigator title: Head of Experimental Surgical Oncology
mesh term: Esophageal Neoplasms
sharing ipd: Undecided