<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/NCT03801304</url>
  </required_header>
  <id_info>
    <org_study_id>29BRC18-0005 (VinMetAtezo)</org_study_id>
    <nct_id>NCT03801304</nct_id>
  </id_info>
  <brief_title>Trial to Evaluate Safety and Efficacy of Vinorelbine With Metronomic Administration in Combination With Atezolizumab as Second-line Treatment for Patients With Stage IV Non-small Cell Lung Cancer</brief_title>
  <acronym>VinMetAtezo</acronym>
  <official_title>Open Label Phase II Trial to Evaluate Safety and Efficacy of Vinorelbine With Metronomic Administration in Combination With Atezolizumab as Second-line Treatment for Patients With Stage IV Non-small Cell Lung Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Brest</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Groupe Français de Pneumo-Cancérologie</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Roche Farma, S.A</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pierre Fabre Medicament</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Brest</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>
      The majority of patients diagnosed with advanced NSCLC are treated with platinum-doublet&#xD;
      chemotherapy regimens, except those harboring specific oncogenic drivers such as epidermal&#xD;
      growth-factor-receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.&#xD;
      In the second-line setting, response rates remain low and median survival rarely exceeds 10&#xD;
      months.&#xD;
&#xD;
      Over the past few years, several checkpoint inhibitors targeting programmed cell death&#xD;
      protein-1 (PD1) or its ligand (PDL1) used as second-line therapies generated evidence of&#xD;
      improving survival and, more recently, as first-line NSCLC treatment.&#xD;
&#xD;
      Although pembrolizumab (anti-PD1) was recently approved as first-line treatment for patients&#xD;
      with at least 50% of their NSCLC cells expressing PDL1, many patients are still not&#xD;
      benefiting from this first-line agent.&#xD;
&#xD;
      For patients with relapsed NSCLC, atezolizumab (anti-PDL1) prolonged survival compared to&#xD;
      docetaxel in the phase II POPLAR and phase III OAK trials. Novel concepts of synergic action&#xD;
      between immunotherapy and chemotherapy have emerged recently. However, those types of&#xD;
      treatments are given for different durations: chemotherapy is allowed for only a short period&#xD;
      (rarely exceeding 6 cycles), while anti-PDL1 can be continued for several months until loss&#xD;
      of its clinical benefit.&#xD;
&#xD;
      Metronomic chemotherapy is defined as low-dose and frequent chemotherapy administration,&#xD;
      without prolonged drug-free breaks. Metronomic administration of oral vinorelbine has been&#xD;
      tested against breast cancer and advanced refractory NSCLC. The combination could have&#xD;
      immunostimulatory effects: induction of immunogenic cancer-cell death, enhancement of antigen&#xD;
      presentation through dendritic cell modulation, increased cancer-cell immunogenicity,&#xD;
      preferential depletion of regulatory T cells, modulation of myeloid-derived suppressor cells,&#xD;
      enhancement of the cytotoxic activity of immune-effector cells.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 24, 2019</start_date>
  <completion_date type="Actual">February 23, 2022</completion_date>
  <primary_completion_date type="Actual">January 4, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Atezolizumab will be administered of 1200 mg on day 1 of each 21-day cycle with IV infusions .&#xD;
Vinorelbine at the dose of 40 mg per days will be administered on days 1, 3 and 5 of each week of the 21-day cycle.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of death or progression of the disease</measure>
    <time_frame>4 months</time_frame>
    <description>To evaluate the occurrence of death or progression of the disease</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Emergence of adverse events (Safety and tolerability)</measure>
    <time_frame>12 months</time_frame>
    <description>To evaluate the safety outcomes, tolerability, adverse events frequency</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of death</measure>
    <time_frame>12 months</time_frame>
    <description>To evaluate the occurrence of death over 12 months of follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>4 months</time_frame>
    <description>To evaluate the objective Response Rate and Disease Control Rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Following of the quality of life</measure>
    <time_frame>12 months</time_frame>
    <description>The scale EuroQol 5 dimensions (EDQ5) is used to evaluate the quality of life. The EQ-5D scale is a standardised measure of health status to provide a simple, generic measure of health for clinical and economic appraisal, whih is divided by the EQ-5D descriptive system (mobility, self care, usual activities, pain/discomfort, anxiety/depression) and the EQ Visual Analogue scale (EQ VAS). Each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Following of the quality of life</measure>
    <time_frame>12 months</time_frame>
    <description>The EORTC QLQ-C30 is a questionnaire with 30 questions developed to assess the quality of life of cancer patients. An essential aspect of the &quot;modular&quot; approach to QOL assessment adopted by the EORTC Quality of Life Group is the development of modules specific to tumour site, treatment modality, or a QOL dimension, to be administered in addition to the core questionnaire (EORTC QLQ-C30).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">80</enrollment>
  <condition>Non-small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Atezolizumab associated with vinorelbine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Atezolizumab will be administered with IV infusions. The first one will be a 60-min IV infusion; the subsequent infusions will last 30 minutes when well-tolerated at the dose of 1200 mg on day 1 of each 21-day cycle.&#xD;
Vinorelbine capsules are taken orally on days 1, 3 and 5 of each week of the 21-day cycle. Vinorelbine will be administered at the dose of 40 mg per day on days 1, 3 and 5 of each week of the 21-day cycle. In case of toxicity, the dose will be decreased to 30 mg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab</intervention_name>
    <description>Atezolizumab in IV infusions</description>
    <arm_group_label>Atezolizumab associated with vinorelbine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vinorelbine</intervention_name>
    <description>Vinorelbine capsules</description>
    <arm_group_label>Atezolizumab associated with vinorelbine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed NSCLC;&#xD;
&#xD;
          -  Locally advanced and/or metastatic stage IV NSCLC (according to American Joint&#xD;
             Committee on Cancers) or recurrent NSCLC);&#xD;
&#xD;
          -  Patients without activating EGFR mutation or ALK rearrangement and ROS1 fusions.&#xD;
&#xD;
          -  Subject has provided a formalin-fixed tumor-tissue sample of a tumor-lesion biopsy,&#xD;
             either at the time of or after metastatic disease was diagnosed AND from a site not&#xD;
             previously irradiated to assess for PDL1 status. Archived tissue may be acceptable or&#xD;
             PDL1 status known;&#xD;
&#xD;
          -  Progressive disease after first-line platinum-doublet-based chemotherapy according to&#xD;
             RECIST V.1.1 with measurable lesion (RECIST V1.1);&#xD;
&#xD;
          -  Age ≥18 years, either sex;&#xD;
&#xD;
          -  Eastern Collaborative Oncology Group Performance status (ECOG PS) 0, 1 or 2;&#xD;
&#xD;
          -  Life expectancy exceeds 12 weeks;&#xD;
&#xD;
          -  No history of other malignancy within the last 5 years, except for adequately treated&#xD;
             carcinoma in situ of the cervix or basal cell or spinocellular carcinoma of the skin;&#xD;
&#xD;
          -  Adequate organ function, demonstrated by the following laboratory results within 3&#xD;
             weeks prior to teatment: Normal hepatic function: bilirubin &lt;1.5 × normal (N), Alanine&#xD;
             aminotransferase and Aspartate aminotransferase &lt;2.5 × N or &lt;5 × N if liver metastasis&#xD;
             is present;&#xD;
&#xD;
          -  Normal renal function (calculated creatinine clearance ≥45 mL/min);&#xD;
&#xD;
          -  Normal calcemia;&#xD;
&#xD;
          -  Normal hematological function (polynuclear neutrophils &gt;1.5 G/L, platelets &gt;100 G/L&#xD;
             and hemoglobin&gt;8g/dl);&#xD;
&#xD;
          -  Women of child-bearing potential must use effective contraception;&#xD;
&#xD;
          -  Men might be surgically sterile or accept to use an effective contraceptive procedure&#xD;
             during and until 6 months after the treatment;&#xD;
&#xD;
          -  Written informed consent to participate in the study&#xD;
&#xD;
          -  Patient with social insurance&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  ECOG PS &gt;2;&#xD;
&#xD;
          -  Known hypersensitivity to immunotherapy;&#xD;
&#xD;
          -  Small-cell lung cancer, bronchioloalveolar cancer, neuroendocrine cancer;&#xD;
&#xD;
          -  Tumor harbors EGFR-sensitizing (activating) mutations or ALK translocations or ROS1&#xD;
             fusions and that justify treatment with targeted therapy ;&#xD;
&#xD;
          -  Chemotherapy, hormonotherapy, immunotherapy or tyrosine-kinase inhibitors within the&#xD;
             past 4 weeks prior to treatment with the trial drug;&#xD;
&#xD;
          -  Radiotherapy (except bone or brain) within the past 3 months prior to baseline&#xD;
             imaging;&#xD;
&#xD;
          -  Medical contraindication to oral vinorelbine;&#xD;
&#xD;
          -  Persistence of clinical adverse events with a grade &gt; 2 related to prior treatment;&#xD;
&#xD;
          -  Active brain metastases (e.g. stable for &lt;4 weeks, no adequate previous radiotherapy,&#xD;
             symptomatic, requiring anticonvulsants or corticosteroids)&#xD;
&#xD;
          -  Concurrent radiotherapy, except for palliative bone irradiation.&#xD;
&#xD;
          -  Other concurrent severe illnesses (congestive heart failure, unstable angina,&#xD;
             significant arrhythmia or myocardial infarction &lt;12 months before study entry);&#xD;
&#xD;
          -  Active or prior documented autoimmune or inflammatory disorders;&#xD;
&#xD;
          -  Active B hepatitis, HIV infection …;&#xD;
&#xD;
          -  Psychiatric or neurological disorders preventing the patient from understanding the&#xD;
             nature of the trial;&#xD;
&#xD;
          -  Grade-3 peripheral neuropathy;&#xD;
&#xD;
          -  Uncontrolled infection;&#xD;
&#xD;
          -  Interstitial lung disease or pneumonitis requiring steroid management;&#xD;
&#xD;
          -  Corticosteroid therapy exceeding 10 mg/day;&#xD;
&#xD;
          -  Other severe organic disorders not allowing inclusion in the trial;&#xD;
&#xD;
          -  Malabsorption syndrome;&#xD;
&#xD;
          -  Pregnancy or breast-feeding;&#xD;
&#xD;
          -  Follow-up not possible; and incarcerated or institutionalized patients.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>CH Aix en Provence</name>
      <address>
        <city>Aix-en-Provence</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU de Brest - Hôpital Morvan</name>
      <address>
        <city>Brest</city>
        <zip>29609</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CLCC Caen</name>
      <address>
        <city>Caen</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH de Créteil</name>
      <address>
        <city>Créteil</city>
        <zip>94010</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ch La Roche Sur Yon</name>
      <address>
        <city>La Roche Sur Yon</city>
        <zip>85000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Limoges - Hôpital DUPUYTREN</name>
      <address>
        <city>Limoges</city>
        <zip>87042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH MEAUX</name>
      <address>
        <city>Meaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Pringy</name>
      <address>
        <city>Pringy</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Quimper</name>
      <address>
        <city>Quimper</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Rennes</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Rouen</name>
      <address>
        <city>Rouen</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Saint-Brieuc</name>
      <address>
        <city>Saint-Brieuc</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hia Saint Anne</name>
      <address>
        <city>Toulon</city>
        <zip>83041</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>January 7, 2019</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>May 11, 2022</last_update_submitted>
  <last_update_submitted_qc>May 11, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>immunotherapy</keyword>
  <keyword>second line of chemotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atezolizumab</mesh_term>
    <mesh_term>Vinorelbine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All collected data that underlie results in a publication</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>Data will be available beginning three years and ending fifteen years following the final study report completion</ipd_time_frame>
    <ipd_access_criteria>Data access requests will be reviewed by the internal committee of Brest UH. Requestors will be required to sign and complete a data access agreement.</ipd_access_criteria>
  </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/NCT03801304
org study id: 29BRC18-0005 (VinMetAtezo)
nct id: NCT03801304
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The majority of patients diagnosed with advanced NSCLC are treated with platinum-doublet
      chemotherapy regimens, except those harboring specific oncogenic drivers such as epidermal
      growth-factor-receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.
      In the second-line setting, response rates remain low and median survival rarely exceeds 10
      months.

      Over the past few years, several checkpoint inhibitors targeting programmed cell death
      protein-1 (PD1) or its ligand (PDL1) used as second-line therapies generated evidence of
      improving survival and, more recently, as first-line NSCLC treatment.

      Although pembrolizumab (anti-PD1) was recently approved as first-line treatment for patients
      with at least 50% of their NSCLC cells expressing PDL1, many patients are still not
      benefiting from this first-line agent.

      For patients with relapsed NSCLC, atezolizumab (anti-PDL1) prolonged survival compared to
      docetaxel in the phase II POPLAR and phase III OAK trials. Novel concepts of synergic action
      between immunotherapy and chemotherapy have emerged recently. However, those types of
      treatments are given for different durations: chemotherapy is allowed for only a short period
      (rarely exceeding 6 cycles), while anti-PDL1 can be continued for several months until loss
      of its clinical benefit.

      Metronomic chemotherapy is defined as low-dose and frequent chemotherapy administration,
      without prolonged drug-free breaks. Metronomic administration of oral vinorelbine has been
      tested against breast cancer and advanced refractory NSCLC. The combination could have
      immunostimulatory effects: induction of immunogenic cancer-cell death, enhancement of antigen
      presentation through dendritic cell modulation, increased cancer-cell immunogenicity,
      preferential depletion of regulatory T cells, modulation of myeloid-derived suppressor cells,
      enhancement of the cytotoxic activity of immune-effector cells.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Atezolizumab will be administered of 1200 mg on day 1 of each 21-day cycle with IV infusions .
Vinorelbine at the dose of 40 mg per days will be administered on days 1, 3 and 5 of each week of the 21-day cycle.
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of death or progression of the disease
time frame: 4 months
description: To evaluate the occurrence of death or progression of the disease
measure: Emergence of adverse events (Safety and tolerability)
time frame: 12 months
description: To evaluate the safety outcomes, tolerability, adverse events frequency
measure: Occurrence of death
time frame: 12 months
description: To evaluate the occurrence of death over 12 months of follow-up
measure: Objective Response Rate
time frame: 4 months
description: To evaluate the objective Response Rate and Disease Control Rate
measure: Following of the quality of life
time frame: 12 months
description: The scale EuroQol 5 dimensions (EDQ5) is used to evaluate the quality of life. The EQ-5D scale is a standardised measure of health status to provide a simple, generic measure of health for clinical and economic appraisal, whih is divided by the EQ-5D descriptive system (mobility, self care, usual activities, pain/discomfort, anxiety/depression) and the EQ Visual Analogue scale (EQ VAS). Each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems).
measure: Following of the quality of life
time frame: 12 months
description: The EORTC QLQ-C30 is a questionnaire with 30 questions developed to assess the quality of life of cancer patients. An essential aspect of the "modular" approach to QOL assessment adopted by the EORTC Quality of Life Group is the development of modules specific to tumour site, treatment modality, or a QOL dimension, to be administered in addition to the core questionnaire (EORTC QLQ-C30).
arm group label: Atezolizumab associated with vinorelbine
arm group type: Experimental
description: Atezolizumab will be administered with IV infusions. The first one will be a 60-min IV infusion; the subsequent infusions will last 30 minutes when well-tolerated at the dose of 1200 mg on day 1 of each 21-day cycle.
Vinorelbine capsules are taken orally on days 1, 3 and 5 of each week of the 21-day cycle. Vinorelbine will be administered at the dose of 40 mg per day on days 1, 3 and 5 of each week of the 21-day cycle. In case of toxicity, the dose will be decreased to 30 mg.
intervention type: Drug
intervention name: Atezolizumab
description: Atezolizumab in IV infusions
arm group label: Atezolizumab associated with vinorelbine
intervention type: Drug
intervention name: Vinorelbine
description: Vinorelbine capsules
arm group label: Atezolizumab associated with vinorelbine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Atezolizumab
mesh term: Vinorelbine
sharing ipd: Yes
ipd description: All collected data that underlie results in a publication
ipd info type: Study Protocol
ipd time frame: Data will be available beginning three years and ending fifteen years following the final study report completion
ipd access criteria: Data access requests will be reviewed by the internal committee of Brest UH. Requestors will be required to sign and complete a data access agreement.