<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/NCT03816657</url>
  </required_header>
  <id_info>
    <org_study_id>L3P1578</org_study_id>
    <nct_id>NCT03816657</nct_id>
  </id_info>
  <brief_title>The Predictive Role of Programmed Death Ligand 1 (PD-L1) and Neutrophil to Lymphocyte Ratio (NLR) in Non-Small Cell Lung Cancer (NSCLC)</brief_title>
  <acronym>PD-L1</acronym>
  <official_title>Integration of Programmed Cell Death Ligand 1 and Neutrophil to Lymphocyte Ratio to Predict Response to Nivolumab in Non-Small Cell Lung Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione Ricerca Traslazionale</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione Ricerca Traslazionale</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 retrospective study explores the combination of Programmed cell death ligand 1 (PD-L1)&#xD;
      expression and Neutrophil to Lymphocyte Ratio (NLR) as an easy feasible panel to predict&#xD;
      benefit to nivolumab.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      We will retrospectively analyze patients with advanced NSCLC who have received at least one&#xD;
      cycle of nivolumab (3mg/kg intravenously every 2 weeks) within the early access program (EAP)&#xD;
      or after the drug approval. All patients have been treated with immunotherapy, in second or&#xD;
      further line, in two Italian Institution (the S. Maria delle Croci Hospital in Ravenna and&#xD;
      the S. Maria della Misericordia Hospital in Perugia) between February 2015 and May 2017.&#xD;
&#xD;
      Patient data and laboratory values will be recorded in an electronic anonymized database and&#xD;
      personally collected by one of the investigators (C.B.). PD-L1 expression will be assessed by&#xD;
      immunoistochemistry (IHC) on available archival tissue samples with clone E1L3N (monoclonal&#xD;
      rabbit; Cell Signaling technology, Danverd, MA) or SP263 (monoclonal rabbit; Ventana Medical&#xD;
      System, Tucson, AZ), in a Ventana automated stainer according to the manufacturer's protocol&#xD;
      and using proprietary reagents. Since a specific PD-L1 level is not mandatory for prescribing&#xD;
      immunotherapy in second or further lines, except for pembrolizumab, we established the PD-L1&#xD;
      positivity as expression on ≥ 1% of tumor cells. To calculate NLR, the absolute neutrophil&#xD;
      count will be divided by the lymphocytes value measured in peripheral blood within 4 weeks&#xD;
      prior to the first infusion of nivolumab. Patients will be dichotomized according to a&#xD;
      pre-specified cutoff value as high (NLR ≥ 3) or low (NLR &lt; 3), since a ratio greater than 3&#xD;
      has been associated with poor outcome in many types of cancer. Patients will be divided in&#xD;
      two cohorts according to combined PD-L1/NLR value: cohort1 with PD-L1 positive and low NLR&#xD;
      and cohort 2 with PD-L1 negative and high NLR. Primary end point will be ORR, calculated as&#xD;
      the percentage of responses among all treated patients. Response to treatment will be&#xD;
      assessed by computed tomography and classified according to RECIST 1.1 criteria [15 Eisenauer&#xD;
      Cancer 2009]. The influence of the combined PD-L1/NLR on overall response rates (ORR), will&#xD;
      be analyzed with univariable logistic regression. Secondary outcome will be OS and PFS,&#xD;
      calculated from the start of nivolumab treatment to death and radiographic or clinical&#xD;
      progression, respectively, with deterioration of performance status classified as disease&#xD;
      progression. We will also examine whether PD-L1, NRL, or combined PD-L1/NRL contribute to the&#xD;
      prediction of OS or PFS, through multi-variable analyses. Since data collected included many&#xD;
      variables, we will perform multivariable models to examine the dependence of OS and PFS on&#xD;
      known prognostic factors: Eastern Cooperative Oncology Group Performance Status (ECOG PS)&#xD;
      (0-1 vs. ≥2) and brain involvement at time of initiating nivolumab, smoking history [never&#xD;
      (&lt;100 cigarettes per lifetime) vs. former/current smokers], histology (squamous vs.&#xD;
      non-squamous), molecular profiling for epidermal growth factor receptor (EGFR), Kirsten rat&#xD;
      sarcoma viral oncogene homolog (K-RAS) and anaplastic lymphoma kinase (ALK) when available.&#xD;
      Patients with squamous-cell cancers will be counted as wild type for targetable mutation,&#xD;
      which are considered to be infrequent in this population. The study was approved by the local&#xD;
      Research Ethics Committee.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">February 15, 2015</start_date>
  <completion_date type="Anticipated">March 30, 2019</completion_date>
  <primary_completion_date type="Actual">May 15, 2017</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>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>ORR</measure>
    <time_frame>3 months</time_frame>
    <description>Overall Response Rate</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PFS</measure>
    <time_frame>3 months</time_frame>
    <description>Progression Free Survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS</measure>
    <time_frame>3 months</time_frame>
    <description>Overall Survival</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">93</enrollment>
  <condition>To Define an Easy and Feasible Panel Which May be Routinely Applied to Select Patients for Immunotherapy Avoiding More Complex and Expensive Methods</condition>
  <arm_group>
    <arm_group_label>Cohort1</arm_group_label>
    <description>Cohort1 (PD-L1+/low NLR)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort2</arm_group_label>
    <description>Cohort 2 (PD-L1-/High NLR)</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with advanced NSCLC who received at least one cycle of nivolumab (3mg/kg&#xD;
        intravenously every 2 weeks) within the expanded access program (EAP) or in a routine&#xD;
        clinical practice after the drug approval&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with histologic diagnosis of advanced NSCLC who received Nivolumab as second&#xD;
             or further line of therapy&#xD;
&#xD;
          -  Paraffin-embedded tissue sample available for PD-L1 analysis&#xD;
&#xD;
          -  disponibilità di emocromo entro 4 settimane dall'inizio del trattamento con Nivolumab&#xD;
&#xD;
          -  To calculate NLR, the absolute neutrophil count was divided by the lymphocytes value&#xD;
             measured in peripheral blood within 4 weeks prior to the first infusion of nivolumab.&#xD;
&#xD;
        No main Exclusion Criteria&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 22, 2019</study_first_submitted>
  <study_first_submitted_qc>January 22, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>January 22, 2019</last_update_submitted>
  <last_update_submitted_qc>January 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 25, 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>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_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/NCT03816657
org study id: L3P1578
nct id: NCT03816657
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This retrospective study explores the combination of Programmed cell death ligand 1 (PD-L1)
      expression and Neutrophil to Lymphocyte Ratio (NLR) as an easy feasible panel to predict
      benefit to nivolumab.
We will retrospectively analyze patients with advanced NSCLC who have received at least one
      cycle of nivolumab (3mg/kg intravenously every 2 weeks) within the early access program (EAP)
      or after the drug approval. All patients have been treated with immunotherapy, in second or
      further line, in two Italian Institution (the S. Maria delle Croci Hospital in Ravenna and
      the S. Maria della Misericordia Hospital in Perugia) between February 2015 and May 2017.

      Patient data and laboratory values will be recorded in an electronic anonymized database and
      personally collected by one of the investigators (C.B.). PD-L1 expression will be assessed by
      immunoistochemistry (IHC) on available archival tissue samples with clone E1L3N (monoclonal
      rabbit; Cell Signaling technology, Danverd, MA) or SP263 (monoclonal rabbit; Ventana Medical
      System, Tucson, AZ), in a Ventana automated stainer according to the manufacturer's protocol
      and using proprietary reagents. Since a specific PD-L1 level is not mandatory for prescribing
      immunotherapy in second or further lines, except for pembrolizumab, we established the PD-L1
      positivity as expression on ≥ 1% of tumor cells. To calculate NLR, the absolute neutrophil
      count will be divided by the lymphocytes value measured in peripheral blood within 4 weeks
      prior to the first infusion of nivolumab. Patients will be dichotomized according to a
      pre-specified cutoff value as high (NLR ≥ 3) or low (NLR < 3), since a ratio greater than 3
      has been associated with poor outcome in many types of cancer. Patients will be divided in
      two cohorts according to combined PD-L1/NLR value: cohort1 with PD-L1 positive and low NLR
      and cohort 2 with PD-L1 negative and high NLR. Primary end point will be ORR, calculated as
      the percentage of responses among all treated patients. Response to treatment will be
      assessed by computed tomography and classified according to RECIST 1.1 criteria [15 Eisenauer
      Cancer 2009]. The influence of the combined PD-L1/NLR on overall response rates (ORR), will
      be analyzed with univariable logistic regression. Secondary outcome will be OS and PFS,
      calculated from the start of nivolumab treatment to death and radiographic or clinical
      progression, respectively, with deterioration of performance status classified as disease
      progression. We will also examine whether PD-L1, NRL, or combined PD-L1/NRL contribute to the
      prediction of OS or PFS, through multi-variable analyses. Since data collected included many
      variables, we will perform multivariable models to examine the dependence of OS and PFS on
      known prognostic factors: Eastern Cooperative Oncology Group Performance Status (ECOG PS)
      (0-1 vs. ≥2) and brain involvement at time of initiating nivolumab, smoking history [never
      (<100 cigarettes per lifetime) vs. former/current smokers], histology (squamous vs.
      non-squamous), molecular profiling for epidermal growth factor receptor (EGFR), Kirsten rat
      sarcoma viral oncogene homolog (K-RAS) and anaplastic lymphoma kinase (ALK) when available.
      Patients with squamous-cell cancers will be counted as wild type for targetable mutation,
      which are considered to be infrequent in this population. The study was approved by the local
      Research Ethics Committee.
observational model: Cohort
time perspective: Retrospective
measure: ORR
time frame: 3 months
description: Overall Response Rate
measure: PFS
time frame: 3 months
description: Progression Free Survival
measure: OS
time frame: 3 months
description: Overall Survival
arm group label: Cohort1
description: Cohort1 (PD-L1+/low NLR)
arm group label: Cohort2
description: Cohort 2 (PD-L1-/High NLR)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
responsible party type: Sponsor
mesh term: Carcinoma, Non-Small-Cell Lung