xml: <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/NCT06000358</url>
    </required_header>
    <id_info>
      <org_study_id>LUCACRIMUNO-001</org_study_id>
      <nct_id>NCT06000358</nct_id>
    </id_info>
    <brief_title>The Effect of Combined Cryotherapy and Immunotherapy on Systemic T Cell Changes and Clinical Outcomes in Metastatic Non-small Cell Lung Cancer</brief_title>
    <acronym>LUCACRIMUNO</acronym>
    <official_title>The Effect of Combined Cryotherapy and Immunotherapy on Systemic T Cell Changes and Clinical Outcomes in Metastatic Non-small Cell Lung Cancer</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Lithuanian University of Health Sciences</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Research Council of Lithuania</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Lithuanian University of Health Sciences</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>
        Lung cancer remains one of the most commonly diagnosed oncological diseases worldwide and the&#xD;
        first in terms of mortality. Although immune checkpoint inhibitors form the backbone of&#xD;
        current metastatic non-small cell lung cancer treatments, there is still no ideal predictive&#xD;
        marker for its efficacy and patients still achieve suboptimal results in overall response and&#xD;
        survival. While immune checkpoint inhibitors are known to shift systemic anti-tumor immune&#xD;
        response from suppression to stimulation in some patients, the investigators hypothesize that&#xD;
        this effect can be further enhanced by cryotherapy, especially in &quot;cold&quot; tumors. If proven&#xD;
        successful, cryotherapy in combination with immunotherapy, could potentiate a more powerful&#xD;
        immune response compared to systemic therapy alone, improve overall response rate, patients'&#xD;
        survival without disease progression, and overall survival. The investigators, therefore, aim&#xD;
        to use combined local tumor cryotherapy, combined with immune checkpoint inhibitor therapy to&#xD;
        induce and evaluate systemic anti-tumor T lymphocyte response and achieve improved non-small&#xD;
        cell lung cancer patient outcomes than with immunotherapy alone.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">April 1, 2023</start_date>
    <completion_date type="Anticipated">March 31, 2026</completion_date>
    <primary_completion_date type="Anticipated">March 31, 2026</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Changes in T Lymphocyte Count and Function in Response to Cryotherapy and Immunotherapy</measure>
      <time_frame>6 weeks</time_frame>
      <description>Changes in T lymphocyte counts and function in peripheral venous blood assessed via flow cytometry</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Necrotic cancer cell death</measure>
      <time_frame>6 weeks</time_frame>
      <description>A change in the concentration of High mobility group box 1 protein (HMGB-1) in venous blood</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The influence of immune cell infiltration in tumor tissue on subsequent cryotherapy and immunotherapy treatment</measure>
      <time_frame>1 day</time_frame>
      <description>Number of tumor-infiltrating CD4 and CD8 lymphocytes in non-small cell lung cancer biopsy material by immunohistochemistry.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Objective response rate</measure>
      <time_frame>1 year</time_frame>
      <description>Assessed according to RECIST and iRECIST criteria</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Progression-free survival</measure>
      <time_frame>1 year</time_frame>
      <description>The time from the first cycle of systemic treatment to radiologically confirmed disease progression</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall survival</measure>
      <time_frame>1 year</time_frame>
      <description>The time from the first cycle of systemic treatment to death from any cause</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Safety of bronchoscopic cryotherapy and immunotherapy</measure>
      <time_frame>1 year</time_frame>
      <description>Documentation and assessment of adverse treatment events according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in T Lymphocyte Function in Response to Cryotherapy and Immunotherapy</measure>
      <time_frame>6 weeks</time_frame>
      <description>Changes in T lymphocyte function in peripheral venous blood assessed via RNA expression</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in T Lymphocyte Effector Function in Response to Cryotherapy and Immunotherapy</measure>
      <time_frame>6 weeks</time_frame>
      <description>Changes in T lymphocyte effector function in peripheral venous blood evaluated via cytokine panels</description>
    </secondary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">120</enrollment>
    <condition>Lung Cancer Stage IV</condition>
    <arm_group>
      <arm_group_label>Cryotherapy and Pembrolizumab monotherapy;</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab monotherapy (PD-L1 expression equal to or greater than 50%, no EGFR mutations or ALK translocations). Bronchoscopic cryotherapy procedure is performed before the start of systemic treatment.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cryotherapy and Pembrolizumab with platinum-based chemotherapy;</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab and platinum-based chemotherapy (PD-L1 expression less than 50%, no EGFR mutations or ALK translocations). Bronchoscopic cryotherapy procedure is performed before the start of systemic treatment.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Pembrolizumab monotherapy;</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab monotherapy (PD-L1 expression equal to or greater than 50%, no EGFR mutations or ALK translocations).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Pembrolizumab with platinum-based chemotherapy;</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab and platinum-based chemotherapy (PD-L1 expression less than 50%, no EGFR mutations or ALK translocations).</description>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Bronchoscopic cryotherapy</intervention_name>
      <description>The cryotherapy procedure is performed before the start of systemic treatment, under visual (for endobronchial cryotherapy) or radial EBUS and fluoroscopy control (for transbronchial cryotherapy), ensuring the correct position of the cryoprobe in the tumor. After being placed in the correct position. After being placed in the correct position, the cryoprobe is cooled using CO2 and allowed to cool passively. The cooling-thawing stages are repeated for a total of 3 cycles.</description>
      <arm_group_label>Cryotherapy and Pembrolizumab monotherapy;</arm_group_label>
      <arm_group_label>Cryotherapy and Pembrolizumab with platinum-based chemotherapy;</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Pembrolizumab</intervention_name>
      <description>As a standard of care, patients will receive pembrolizumab.</description>
      <arm_group_label>Cryotherapy and Pembrolizumab monotherapy;</arm_group_label>
      <arm_group_label>Cryotherapy and Pembrolizumab with platinum-based chemotherapy;</arm_group_label>
      <arm_group_label>Pembrolizumab monotherapy;</arm_group_label>
      <arm_group_label>Pembrolizumab with platinum-based chemotherapy;</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Platinum based chemotherapy</intervention_name>
      <description>As a standard of care, patients will receive platinum-based chemotherapy in addition to pembrolizumab if PD-L1 expression is less than 50%.</description>
      <arm_group_label>Cryotherapy and Pembrolizumab with platinum-based chemotherapy;</arm_group_label>
      <arm_group_label>Pembrolizumab with platinum-based chemotherapy;</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients with Eastern Cooperative Oncology Group (ECOG) performance score 0 - 1;&#xD;
  &#xD;
            -  Patients with histologically confirmed metastatic non-small cell lung cancer and PD-L1&#xD;
               expression on tumor cells was evaluated;&#xD;
  &#xD;
            -  CT examination shows measurable tumor formations according to the RECIST 1.1 criteria;&#xD;
  &#xD;
            -  Primary lung tumor or metastasis accessible to flexible bronchoscopy;&#xD;
  &#xD;
            -  Patients may have received surgery, adjuvant or neoadjuvant chemotherapy prior to the&#xD;
               study if it was completed at least 12 months before relapse;&#xD;
  &#xD;
            -  Patients informed about the purpose and course of the study and provided a written&#xD;
               consent to participate.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients who refused to participate in the clinical trial and did not sign the&#xD;
               informed consent form;&#xD;
  &#xD;
            -  Men and women under the age of 18, pregnant women;&#xD;
  &#xD;
            -  Patients belonging to a vulnerable social group;&#xD;
  &#xD;
            -  High risk of general anesthesia, defined as American Society of Anesthesiologists&#xD;
               (ASA) class 4 - 6;&#xD;
  &#xD;
            -  Documented allergy to medications used during general and local anesthesia, systemic&#xD;
               cancer treatment;&#xD;
  &#xD;
            -  Patients previously treated with immune checkpoint inhibitors;&#xD;
  &#xD;
            -  EGFR mutations or ALK translocations have been identified in patients;&#xD;
  &#xD;
            -  Patients with previously diagnosed autoimmune diseases, active viral hepatitis,&#xD;
               uncontrolled human immunodeficiency virus (HIV) infection or untreated tuberculosis;&#xD;
  &#xD;
            -  Patients treated with immunosuppressive drugs, systemic corticosteroids, with&#xD;
               equivalent doses of prednisolone exceeding 10 mg/day;&#xD;
  &#xD;
            -  Patients with an increased risk of bleeding during an interventional procedure;&#xD;
  &#xD;
            -  Acute untreated conditions that would make it impossible to perform an interventional&#xD;
               lung procedure.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>99 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Marius Zemaitis, PhD, professor</last_name>
      <phone>+37061256473</phone>
      <email>marius.zemaitis@kaunoklinikos.lt</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Gediminas Vasiliauskas, PhD student</last_name>
      <phone>+37060403787</phone>
      <email>gediminas.vasiliauskas@kaunoklinikos.lt</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Lithuanian University of Health Sciences</name>
        <address>
          <city>Kaunas</city>
          <zip>LT 44307</zip>
          <country>Lithuania</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Rimantas Benetis, PhD, professor</last_name>
        <phone>+37037327200</phone>
        <email>rektoratas@lsmuni.lt</email>
      </contact>
    </location>
    <location_countries>
      <country>Lithuania</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 3, 2023</study_first_submitted>
    <study_first_submitted_qc>August 16, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 21, 2023</study_first_posted>
    <last_update_submitted>August 16, 2023</last_update_submitted>
    <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 21, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Lithuanian University of Health Sciences</investigator_affiliation>
      <investigator_full_name>Marius Zemaitis</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <keyword>Pulmonology</keyword>
    <keyword>Oncology</keyword>
    <keyword>Immunotherapy</keyword>
    <keyword>Cryotherapy</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lung Neoplasms</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Pembrolizumab</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06000358
  org study id: LUCACRIMUNO-001
  nct id: NCT06000358
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Lung cancer remains one of the most commonly diagnosed oncological diseases worldwide and the
        first in terms of mortality. Although immune checkpoint inhibitors form the backbone of
        current metastatic non-small cell lung cancer treatments, there is still no ideal predictive
        marker for its efficacy and patients still achieve suboptimal results in overall response and
        survival. While immune checkpoint inhibitors are known to shift systemic anti-tumor immune
        response from suppression to stimulation in some patients, the investigators hypothesize that
        this effect can be further enhanced by cryotherapy, especially in "cold" tumors. If proven
        successful, cryotherapy in combination with immunotherapy, could potentiate a more powerful
        immune response compared to systemic therapy alone, improve overall response rate, patients'
        survival without disease progression, and overall survival. The investigators, therefore, aim
        to use combined local tumor cryotherapy, combined with immune checkpoint inhibitor therapy to
        induce and evaluate systemic anti-tumor T lymphocyte response and achieve improved non-small
        cell lung cancer patient outcomes than with immunotherapy alone.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Changes in T Lymphocyte Count and Function in Response to Cryotherapy and Immunotherapy
  time frame: 6 weeks
  description: Changes in T lymphocyte counts and function in peripheral venous blood assessed via flow cytometry
  measure: Necrotic cancer cell death
  time frame: 6 weeks
  description: A change in the concentration of High mobility group box 1 protein (HMGB-1) in venous blood
  measure: The influence of immune cell infiltration in tumor tissue on subsequent cryotherapy and immunotherapy treatment
  time frame: 1 day
  description: Number of tumor-infiltrating CD4 and CD8 lymphocytes in non-small cell lung cancer biopsy material by immunohistochemistry.
  measure: Objective response rate
  time frame: 1 year
  description: Assessed according to RECIST and iRECIST criteria
  measure: Progression-free survival
  time frame: 1 year
  description: The time from the first cycle of systemic treatment to radiologically confirmed disease progression
  measure: Overall survival
  time frame: 1 year
  description: The time from the first cycle of systemic treatment to death from any cause
  measure: Safety of bronchoscopic cryotherapy and immunotherapy
  time frame: 1 year
  description: Documentation and assessment of adverse treatment events according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.
  measure: Changes in T Lymphocyte Function in Response to Cryotherapy and Immunotherapy
  time frame: 6 weeks
  description: Changes in T lymphocyte function in peripheral venous blood assessed via RNA expression
  measure: Changes in T Lymphocyte Effector Function in Response to Cryotherapy and Immunotherapy
  time frame: 6 weeks
  description: Changes in T lymphocyte effector function in peripheral venous blood evaluated via cytokine panels
  arm group label: Cryotherapy and Pembrolizumab monotherapy;
  arm group type: Active Comparator
  description: Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab monotherapy (PD-L1 expression equal to or greater than 50%, no EGFR mutations or ALK translocations). Bronchoscopic cryotherapy procedure is performed before the start of systemic treatment.
  arm group label: Cryotherapy and Pembrolizumab with platinum-based chemotherapy;
  arm group type: Active Comparator
  description: Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab and platinum-based chemotherapy (PD-L1 expression less than 50%, no EGFR mutations or ALK translocations). Bronchoscopic cryotherapy procedure is performed before the start of systemic treatment.
  arm group label: Pembrolizumab monotherapy;
  arm group type: Active Comparator
  description: Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab monotherapy (PD-L1 expression equal to or greater than 50%, no EGFR mutations or ALK translocations).
  arm group label: Pembrolizumab with platinum-based chemotherapy;
  arm group type: Active Comparator
  description: Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab and platinum-based chemotherapy (PD-L1 expression less than 50%, no EGFR mutations or ALK translocations).
  intervention type: Procedure
  intervention name: Bronchoscopic cryotherapy
  description: The cryotherapy procedure is performed before the start of systemic treatment, under visual (for endobronchial cryotherapy) or radial EBUS and fluoroscopy control (for transbronchial cryotherapy), ensuring the correct position of the cryoprobe in the tumor. After being placed in the correct position. After being placed in the correct position, the cryoprobe is cooled using CO2 and allowed to cool passively. The cooling-thawing stages are repeated for a total of 3 cycles.
  arm group label: Cryotherapy and Pembrolizumab monotherapy;
  arm group label: Cryotherapy and Pembrolizumab with platinum-based chemotherapy;
  intervention type: Drug
  intervention name: Pembrolizumab
  description: As a standard of care, patients will receive pembrolizumab.
  arm group label: Cryotherapy and Pembrolizumab monotherapy;
  arm group label: Cryotherapy and Pembrolizumab with platinum-based chemotherapy;
  arm group label: Pembrolizumab monotherapy;
  arm group label: Pembrolizumab with platinum-based chemotherapy;
  intervention type: Drug
  intervention name: Platinum based chemotherapy
  description: As a standard of care, patients will receive platinum-based chemotherapy in addition to pembrolizumab if PD-L1 expression is less than 50%.
  arm group label: Cryotherapy and Pembrolizumab with platinum-based chemotherapy;
  arm group label: Pembrolizumab with platinum-based chemotherapy;
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 99 Years
  healthy volunteers: No
  last name: Marius Zemaitis, PhD, professor
  phone: +37061256473
  email: marius.zemaitis@kaunoklinikos.lt
  last name: Gediminas Vasiliauskas, PhD student
  phone: +37060403787
  email: gediminas.vasiliauskas@kaunoklinikos.lt
  facility: 
  status: Recruiting
  contact: 
  country: Lithuania
  responsible party type: Principal Investigator
  investigator affiliation: Lithuanian University of Health Sciences
  investigator full name: Marius Zemaitis
  investigator title: Professor
  mesh term: Lung Neoplasms
  mesh term: Pembrolizumab