<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/NCT03820921</url>
  </required_header>
  <id_info>
    <org_study_id>SUCCESS</org_study_id>
    <nct_id>NCT03820921</nct_id>
  </id_info>
  <brief_title>Evaluation of MMR Status and PD-L1 Expression Using Specimens Obtained by EUS-FNB in Patients With Pancreatic Cancer</brief_title>
  <acronym>SUCCESS</acronym>
  <official_title>PD-L1 and MMR Status Provided by Endoscopic Ultrasound-Guided Fine-Needle Biopsies as a Predictor of PrognosiS in Patients With Pancreatic Ductal Adenocarcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ponderas Academic Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Medicine and Pharmacy Craiova</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Ponderas Academic Hospital</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>
      Pancreatic ductal adenocarcinoma (PDAC) has a suboptimal response to standard therapies that&#xD;
      modestly impact survival due to its ability to evade host immune surveillance. Emerging&#xD;
      evidence has shown that the co-inhibitory receptors, such as programmed death 1 (PD-1), play&#xD;
      a critical role in cancer immune-editing. Programmed death-ligand 1 (PD-L1) is an immune&#xD;
      checkpoint that is often activated in cancer and plays a pivotal role in the initiation and&#xD;
      progression of cancer. The advent of immunotherapy, with checkpoint inhibitors, which block&#xD;
      PD-L1 interaction between tumor cells and activated T cells, has significantly altered the&#xD;
      treatment algorithm for several solid tumors.&#xD;
&#xD;
      However, the clinicopathologic significance and prognostic value of PD-L1 in PDAC remains&#xD;
      controversial. The main technical ground may be that PDAC PD-L1 expression quantification is&#xD;
      limited to surgical resection specimens and dependent on specific immunohistochemistry (IHC)&#xD;
      tests. In addition, PD-L1 expression has not been extensively assessed before surgery in&#xD;
      treatment-naive PDAC patients, due to the current IHC test requirement for a histologic&#xD;
      rather than a cytologic evaluation. However, a recent study showed that EUS-fine needle&#xD;
      biopsy (FNB) can successfully determine primary pancreas malignancy PD-L1 status.&#xD;
&#xD;
      One recently identified subtype within the genomic landscape of PDAC is the mismatch&#xD;
      repair-deficient (dMMR) tumor. Evaluation of dMMR status is particularly important following&#xD;
      the FDA approval of the PD-1 inhibitor, pembrolizumab, for the treatment of unresectable or&#xD;
      metastatic, microsatellite instability-high (MSI-H) or dMMR PDAC that have progressed&#xD;
      following prior treatment, and have no satisfactory alternative treatment options.&#xD;
&#xD;
      The objectives of the project will include the assessment of tumor PD-L1/dMMR expression in&#xD;
      patients with PDAC using EUS-FNB samples and the prospective correlation of MMR status and&#xD;
      PD-L1 expression with overall survival and progression-free survival of PDAC patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">February 1, 2019</start_date>
  <completion_date type="Anticipated">January 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2021</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>Feasibility of PD-L1 expression analysis on EUS-FNB pancreatic specimens</measure>
    <time_frame>1 year</time_frame>
    <description>the percentage of cases where EUS-FNB material was adequate to determine PDL-1 expression</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Feasibility of MMR status analysis on EUS-FNB pancreatic specimens</measure>
    <time_frame>1 year</time_frame>
    <description>the percentage of cases where EUS-FNB material was adequate to determine MMR status</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tumor response</measure>
    <time_frame>3 months</time_frame>
    <description>Tumor response will be assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). According to RECIST guidelines,complete response (CR) is defined as the complete disappearance of the tumor, partial response (PR) as ≥30% decrease in longest diameter (LD), progressive disease (PD) as ≥20% increase in LD, and stable disease (SD) as a decrease or increase less than PR or PD based on anatomic assessment. Patients with CR or PR will be defined as responders, whereas those with PD or SD are defined as non-responders.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>up to 12 months</time_frame>
    <description>The overall survival will be measured from the day of diagnosis to the date of death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>up to 12 months</time_frame>
    <description>The progression-free survival (PFS) will be measured from the day of diagnosis to the date of progressive disease.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Pancreatic Cancer</condition>
  <arm_group>
    <arm_group_label>PATIENTS WITH PANCREATIC CANCER</arm_group_label>
    <description>All patients with a suspicion of pancreatic masses will undergo EUS (including EUS-FNB for confirmation of diagnosis). A positive cytological diagnosis will be taken as a final proof of malignancy of the pancreas mass. The diagnoses obtained by EUS-FNB will be further verified during a clinical follow-up of at least 6 months.&#xD;
Immunochemistry will be performed on the EUS-FNB specimens to determine PD-L1 expression and MMR status</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>EUS-FNB</intervention_name>
    <description>EUS WITH EUS-FNB will be performed for confirmation of diagnosis and analysis of MMR status and PD-L1 expression&#xD;
Protocol of EUS with EUS-FNB should include linear EUS instruments with complete examinations of the pancreas. Tumor characteristics (echogenicity, echostructure, size) will be described as well as presence/absence of power Doppler signals.&#xD;
EUS-FNB will be performed in all pancreatic masses with at least three passes in the absence of an onsite cytopathologist using a fanning technique with a 22-gauge needle (SharkCore FNB needle Medtronic Corp. or Acquire FNB needle Boston, MA).</description>
    <arm_group_label>PATIENTS WITH PANCREATIC CANCER</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Immunohistochemistry</intervention_name>
    <description>IHC will be performed on treatment-naïve formalin-fixed paraffin-embedded EUS-FNB pancreatic specimens. Briefly, 4-μm-thick tissue sections will be stained using the Ventana BenchMark XT automated slide-staining system using the following antibodies: Anti-PD-L1 (clone SP263, VENTANA, Tucson, AZ), MLH1 (clone G168-728, Cell Marque, Rocklin, California, United States), MSH2 (clone FE11, Biocare Medical, Concord, Massachusetts, United States), MSH6 (clone BC/44, Biocare Medical, Concord, Massachusetts, United States), and PMS2 (clone A16-4, Biocare Medical, Concord, M Massachusetts, United States). Antigen-antibody reactions will be visualized using UltraView detection with diaminobenzidine as the chromogen. The specimen will be considered to have PD-L1 expression if PD-L1 is expressed in ≥ 1 % of tumor cells and a high level of expression if ≥ 50 %. Tumors will be classified as dMMR if they exhibit absent nuclear staining of DNA mismatch repair proteins (MLH1, MSH2, MSH6, or PMS2).</description>
    <arm_group_label>PATIENTS WITH PANCREATIC CANCER</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with a confirmed diagnosis of pancreatic ductal adenocarcinoma&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          -  Age 18 to 90 years old&#xD;
&#xD;
          -  men or women&#xD;
&#xD;
          -  signed informed consent for EUS and EUS -FNB&#xD;
&#xD;
          -  the diagnosis of adenocarcinoma histologically confirmed by FNB&#xD;
&#xD;
          -  resectable, Unresectable, locally advanced and/or metastatic disease&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        -previous chemotherapy or radiotherapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Alina L Constantin, MD</last_name>
    <phone>+40722468415</phone>
    <email>drconstantinalina@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>ADRIAN SAFTOIU, MD PHD</last_name>
    <email>adriansaftoiu@gmail.com</email>
  </overall_contact_backup>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>December 30, 2018</study_first_submitted>
  <study_first_submitted_qc>January 27, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 29, 2019</study_first_posted>
  <last_update_submitted>January 27, 2019</last_update_submitted>
  <last_update_submitted_qc>January 27, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 29, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Ponderas Academic Hospital</investigator_affiliation>
    <investigator_full_name>alina constantin</investigator_full_name>
    <investigator_title>principal investigator</investigator_title>
  </responsible_party>
  <keyword>EUS-FNB, PDL1, MMR</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pancreatic 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/NCT03820921
org study id: SUCCESS
nct id: NCT03820921
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Pancreatic ductal adenocarcinoma (PDAC) has a suboptimal response to standard therapies that
      modestly impact survival due to its ability to evade host immune surveillance. Emerging
      evidence has shown that the co-inhibitory receptors, such as programmed death 1 (PD-1), play
      a critical role in cancer immune-editing. Programmed death-ligand 1 (PD-L1) is an immune
      checkpoint that is often activated in cancer and plays a pivotal role in the initiation and
      progression of cancer. The advent of immunotherapy, with checkpoint inhibitors, which block
      PD-L1 interaction between tumor cells and activated T cells, has significantly altered the
      treatment algorithm for several solid tumors.

      However, the clinicopathologic significance and prognostic value of PD-L1 in PDAC remains
      controversial. The main technical ground may be that PDAC PD-L1 expression quantification is
      limited to surgical resection specimens and dependent on specific immunohistochemistry (IHC)
      tests. In addition, PD-L1 expression has not been extensively assessed before surgery in
      treatment-naive PDAC patients, due to the current IHC test requirement for a histologic
      rather than a cytologic evaluation. However, a recent study showed that EUS-fine needle
      biopsy (FNB) can successfully determine primary pancreas malignancy PD-L1 status.

      One recently identified subtype within the genomic landscape of PDAC is the mismatch
      repair-deficient (dMMR) tumor. Evaluation of dMMR status is particularly important following
      the FDA approval of the PD-1 inhibitor, pembrolizumab, for the treatment of unresectable or
      metastatic, microsatellite instability-high (MSI-H) or dMMR PDAC that have progressed
      following prior treatment, and have no satisfactory alternative treatment options.

      The objectives of the project will include the assessment of tumor PD-L1/dMMR expression in
      patients with PDAC using EUS-FNB samples and the prospective correlation of MMR status and
      PD-L1 expression with overall survival and progression-free survival of PDAC patients.
observational model: Cohort
time perspective: Prospective
measure: Feasibility of PD-L1 expression analysis on EUS-FNB pancreatic specimens
time frame: 1 year
description: the percentage of cases where EUS-FNB material was adequate to determine PDL-1 expression
measure: Feasibility of MMR status analysis on EUS-FNB pancreatic specimens
time frame: 1 year
description: the percentage of cases where EUS-FNB material was adequate to determine MMR status
measure: Tumor response
time frame: 3 months
description: Tumor response will be assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). According to RECIST guidelines,complete response (CR) is defined as the complete disappearance of the tumor, partial response (PR) as ≥30% decrease in longest diameter (LD), progressive disease (PD) as ≥20% increase in LD, and stable disease (SD) as a decrease or increase less than PR or PD based on anatomic assessment. Patients with CR or PR will be defined as responders, whereas those with PD or SD are defined as non-responders.
measure: Overall survival
time frame: up to 12 months
description: The overall survival will be measured from the day of diagnosis to the date of death
measure: Progression-free survival
time frame: up to 12 months
description: The progression-free survival (PFS) will be measured from the day of diagnosis to the date of progressive disease.
arm group label: PATIENTS WITH PANCREATIC CANCER
description: All patients with a suspicion of pancreatic masses will undergo EUS (including EUS-FNB for confirmation of diagnosis). A positive cytological diagnosis will be taken as a final proof of malignancy of the pancreas mass. The diagnoses obtained by EUS-FNB will be further verified during a clinical follow-up of at least 6 months.
Immunochemistry will be performed on the EUS-FNB specimens to determine PD-L1 expression and MMR status
intervention type: Diagnostic Test
intervention name: EUS-FNB
description: EUS WITH EUS-FNB will be performed for confirmation of diagnosis and analysis of MMR status and PD-L1 expression
Protocol of EUS with EUS-FNB should include linear EUS instruments with complete examinations of the pancreas. Tumor characteristics (echogenicity, echostructure, size) will be described as well as presence/absence of power Doppler signals.
EUS-FNB will be performed in all pancreatic masses with at least three passes in the absence of an onsite cytopathologist using a fanning technique with a 22-gauge needle (SharkCore FNB needle Medtronic Corp. or Acquire FNB needle Boston, MA).
arm group label: PATIENTS WITH PANCREATIC CANCER
intervention type: Other
intervention name: Immunohistochemistry
description: IHC will be performed on treatment-naïve formalin-fixed paraffin-embedded EUS-FNB pancreatic specimens. Briefly, 4-μm-thick tissue sections will be stained using the Ventana BenchMark XT automated slide-staining system using the following antibodies: Anti-PD-L1 (clone SP263, VENTANA, Tucson, AZ), MLH1 (clone G168-728, Cell Marque, Rocklin, California, United States), MSH2 (clone FE11, Biocare Medical, Concord, Massachusetts, United States), MSH6 (clone BC/44, Biocare Medical, Concord, Massachusetts, United States), and PMS2 (clone A16-4, Biocare Medical, Concord, M Massachusetts, United States). Antigen-antibody reactions will be visualized using UltraView detection with diaminobenzidine as the chromogen. The specimen will be considered to have PD-L1 expression if PD-L1 is expressed in ≥ 1 % of tumor cells and a high level of expression if ≥ 50 %. Tumors will be classified as dMMR if they exhibit absent nuclear staining of DNA mismatch repair proteins (MLH1, MSH2, MSH6, or PMS2).
arm group label: PATIENTS WITH PANCREATIC CANCER
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Alina L Constantin, MD
phone: +40722468415
email: drconstantinalina@gmail.com
last name: ADRIAN SAFTOIU, MD PHD
email: adriansaftoiu@gmail.com
responsible party type: Principal Investigator
investigator affiliation: Ponderas Academic Hospital
investigator full name: alina constantin
investigator title: principal investigator
mesh term: Pancreatic Neoplasms
sharing ipd: No