<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/NCT03302247</url>
  </required_header>
  <id_info>
    <org_study_id>TH-113</org_study_id>
    <nct_id>NCT03302247</nct_id>
  </id_info>
  <brief_title>Depletion of Myeloid Derived Suppressor Cells to Enhance Anti PD-1 Therapy</brief_title>
  <official_title>Depletion of Myeloid Derived Suppressor Cells to Enhance Anti PD-1 Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fox Chase Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fox Chase Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Metastatic non small cell lung cancer can be treated with cytotoxic chemotherapy or using&#xD;
      recently approved immunotherapy with antibody, Nivolumab. Both the therapies have limitation&#xD;
      due to development of tolerance or immunosuppression. This trial combines one drug from each&#xD;
      category, immunotherapeutic Nivolumab and chemotherapeutic gemcitabine as it was reported&#xD;
      that gemcitabine reduces immunosuppression by killing myeloid derived suppressor cells,&#xD;
      thereby increasing the efficacy of Nivolumab.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objective&#xD;
&#xD;
      • The primary objective of this proposal is to evaluate gemcitabine as a method of MDSC&#xD;
      depletion.&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        -  Evaluate whether these measures result in enhanced T-cell activity and/or NK cell&#xD;
           function and number.&#xD;
&#xD;
        -  Determine the tolerability and clinical activity (including response rate and survival)&#xD;
           of this approach.&#xD;
&#xD;
        -  Correlate MDSC number with tumor PD-L1 expression&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Unable to accrue subjects&#xD;
  </why_stopped>
  <start_date type="Actual">January 15, 2018</start_date>
  <completion_date type="Actual">July 12, 2019</completion_date>
  <primary_completion_date type="Actual">March 21, 2019</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>Nivolumab 240mg, IV on day 1, 15 + Gemcitabine 1000mg/m2, IV on day 1, 8, 15 of 28 days cycle</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Decrease in Macrophage Derived Suppressor Cells (MDSC) Numbers as a Result of Treatment With Gemcitabine.</measure>
    <time_frame>2 years</time_frame>
    <description>Immunosuppression in terms of number of circulating MDSC in the blood by comparing within each arm reduction in the number of MDSCs after each cycle of treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Increase in T-cell Activity</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluate if MDSC elimination by gemcitabine results in increase in T-cell activity</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Non Small Cell Lung Cancer Stage IIIB</condition>
  <arm_group>
    <arm_group_label>Nivolumab+Gemcitabine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Monoclonal antibody against non small cell lung cancer</description>
    <arm_group_label>Nivolumab+Gemcitabine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab+Gemcitabine</intervention_name>
    <description>Gemcitabine is added to the Nivolumab treatment</description>
    <arm_group_label>Nivolumab+Gemcitabine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically confirmed diagnosis of non-small cell lung cancer (NSCLC). Patients&#xD;
             should have stage IV disease (AJCC 7th edition), stage IIIb disease that is not&#xD;
             amenable to potentially curative treatment (e.g. chemoradiotherapy) or unequivocal&#xD;
             progression in a prior irradiated field. Measurable or evaluable disease is required.&#xD;
&#xD;
          2. Fresh/ archived tumor tissue available for molecular marker testing is required for&#xD;
             entry. A tumor block or at least 5 unstained slides must be available. As an&#xD;
             alternative FFPE cell block that is sufficient for histologic analysis is acceptable.&#xD;
             If a patient has had PD-L1 status previously determined with and FDA approved assay,&#xD;
             they have met this requirement. Tissue is still requested (but not required) for&#xD;
             further analysis&#xD;
&#xD;
          3. Age &gt; 18 years.&#xD;
&#xD;
          4. ECOG performance status 0 or 1&#xD;
&#xD;
          5. Patients must have normal organ and marrow functions as defined below:&#xD;
&#xD;
             White blood cells (WBC) &gt;2,000/mcL; Platelets &gt;100,000/mcL; Hb ≥9g/dl; Absolute&#xD;
             neutrophil count (ANC) &gt;1,500/mcL; Serum creatinine ≤1.5 x ULN, or&#xD;
&#xD;
             Creatinine clearance (CrCl) ≥50 ml/min (if using Cockcroft Gault formula below):&#xD;
&#xD;
             Female CrCl= ((140 - age in years)/(72 x serum creatinine in mg/dL)) x weight in kg x&#xD;
             0.85; Male CrCl= ((140 - age in years)/(72 x serum creatinine in mg/dL) x weight in kg&#xD;
             x 1.0; AST/SGOT ≤ 3 x ULN&#xD;
&#xD;
             Total bilirubin:&#xD;
&#xD;
             If no known liver metastasis: total bilirubin ≤ 1.5 x institutional upper limit (ULN)&#xD;
             (except, subjects with Gilbert Syndrome who may have total bilirubin &lt; 3.0 mg/dl; If&#xD;
             known metastasis: total bilirubin ≤ 5 ULN&#xD;
&#xD;
          6. Negative serum pregnancy test result in Women os Child -bearing Potential (WOCBP)&#xD;
&#xD;
          7. Prior therapies:&#xD;
&#xD;
               -  Patients without activating mutations and gene rearrangements should have&#xD;
                  received at least one prior chemotherapy regimen. Any number of prior therapies&#xD;
                  is allowed except for immunotherapy (e.g. anti PD-1, PD-L1, vaccines, CTLA-4&#xD;
                  etc.),&#xD;
&#xD;
               -  Patients with activating mutations with known documented benefit from tyrosine&#xD;
                  kinase inhibitors should have received and demonstrated progression with that&#xD;
                  inhibitor (e.g. EGFR del 19 mutation should have been treated with gefitinib,&#xD;
                  erlotinib or afatanib etc). ALK rearrangements should have been treated with an&#xD;
                  ALK inhibitor. Patients who have progressed on these agents should be assessed,&#xD;
                  if appropriate, for resistance mutations susceptible to approved agents and&#xD;
                  treated with that agent.&#xD;
&#xD;
               -  No prior gemcitabine treatment&#xD;
&#xD;
          8. Ability to understand and willingness to sign a written informed consent and HIPAA&#xD;
             consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with active, known or suspected autoimmune disease. Subjects are permitted to&#xD;
             enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to&#xD;
             autoimmune condition only requiring hormone replacement, psoriasis not requiring&#xD;
             systemic treatment, or conditions not expected to recur in the absence of an external&#xD;
             trigger&#xD;
&#xD;
          2. Patients requiring systemic treatment with either corticosteroids (&gt; 10 mg daily&#xD;
             prednisone equivalents) or other immunosuppressive medications within 14 days of study&#xD;
             drug administration. Inhaled or topical steroids and adrenal replacement doses &gt; 10 mg&#xD;
             daily prednisone equivalents are permitted in the absence of active autoimmune&#xD;
             disease. Subjects are permitted to use topical, ocular, intra-articular, intranasal,&#xD;
             and inhalational corticosteroids (with minimal systemic absorption). Physiologic&#xD;
             replacement doses of systemic corticosteroids are permitted, even if &gt; 10 mg/day&#xD;
             prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg,&#xD;
             contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type&#xD;
             hypersensitivity reaction caused by contact allergen) is permitted.&#xD;
&#xD;
          3. As there is a potential for hepatic toxicity with nivolumab, drugs with predisposition&#xD;
             to hepatotoxicity should be used with caution in patients treated with&#xD;
             nivolumab-containing regimen.&#xD;
&#xD;
          4. Patients are excluded if they have active brain metastases or leptomeningeal&#xD;
             metastases. Subjects with brain metastases are eligible if metastases have been&#xD;
             treated without clinical or radiologic evidence of progression for 14 days prior to&#xD;
             initiation of treatment. An MRI within 14 days of commencing therapy is required for&#xD;
             patients with a history of brain metastases.&#xD;
&#xD;
          5. There must be no requirement for immunosuppressive doses of systemic corticosteroids&#xD;
             (&gt;10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug&#xD;
             administration.&#xD;
&#xD;
          6. History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to nivolumab.&#xD;
&#xD;
          7. Uncontrolled inter-current illness that would increase the risk of toxicity or limit&#xD;
             compliance with study requirements. This includes but is not limited to, uncontrolled&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness or social situations that would limit compliance&#xD;
             with study requirements.&#xD;
&#xD;
          8. Known HIV-positive patients on combination antiretroviral therapy are ineligible&#xD;
             because of the abnormal immune response that results from HIV disease.&#xD;
&#xD;
          9. Patients should be excluded if they are positive test for hepatitis B virus surface&#xD;
             antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating&#xD;
             acute or chronic infection&#xD;
&#xD;
         10. Patients who have had systemic (IV) cytotoxic chemotherapy or any other&#xD;
             investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior&#xD;
             to entering the study or those who have not recovered from adverse events due to&#xD;
             agents administered more than 4 weeks earlier. If a patient received an oral agent,&#xD;
             treatment on study can not commence at least five half-lives of the agent have&#xD;
             elapsed.&#xD;
&#xD;
         11. Subjects with previous malignancies (except non-melanoma skin cancers, and in situ&#xD;
             cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma,&#xD;
             or breast) are excluded unless a complete remission was achieved at least 2 years&#xD;
             prior to study entry and no additional therapy is required or anticipated to be&#xD;
             required during the study period.&#xD;
&#xD;
         12. Other active malignancy requiring concurrent intervention.&#xD;
&#xD;
         13. Subjects with any history of interstitial lung disease.&#xD;
&#xD;
         14. Pregnant or breast feeding.&#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>Fox Chase Cancer Center - Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19111-2497</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>September 27, 2017</study_first_submitted>
  <study_first_submitted_qc>September 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 5, 2017</study_first_posted>
  <results_first_submitted>August 12, 2020</results_first_submitted>
  <results_first_submitted_qc>October 6, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 28, 2020</results_first_posted>
  <last_update_submitted>October 6, 2020</last_update_submitted>
  <last_update_submitted_qc>October 6, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 28, 2020</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 27, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/47/NCT03302247/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 27, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/47/NCT03302247/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Nivolumab+Gemcitabine</title>
          <description>Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle&#xD;
Nivolumab: Monoclonal antibody against non small cell lung cancer&#xD;
Nivolumab+Gemcitabine: Gemcitabine is added to the Nivolumab treatment</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>the study has closed prematurely</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Nivolumab+Gemcitabine</title>
          <description>Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle&#xD;
Nivolumab: Monoclonal antibody against non small cell lung cancer&#xD;
Nivolumab+Gemcitabine: Gemcitabine is added to the Nivolumab treatment</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Decrease in Macrophage Derived Suppressor Cells (MDSC) Numbers as a Result of Treatment With Gemcitabine.</title>
        <description>Immunosuppression in terms of number of circulating MDSC in the blood by comparing within each arm reduction in the number of MDSCs after each cycle of treatment</description>
        <time_frame>2 years</time_frame>
        <population>The study has closed prematurely. Insufficient data for analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab+Gemcitabine</title>
            <description>Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle&#xD;
Nivolumab: Monoclonal antibody against non small cell lung cancer&#xD;
Nivolumab+Gemcitabine: Gemcitabine is added to the Nivolumab treatment</description>
          </group>
        </group_list>
        <measure>
          <title>Decrease in Macrophage Derived Suppressor Cells (MDSC) Numbers as a Result of Treatment With Gemcitabine.</title>
          <description>Immunosuppression in terms of number of circulating MDSC in the blood by comparing within each arm reduction in the number of MDSCs after each cycle of treatment</description>
          <population>The study has closed prematurely. Insufficient data for analysis</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Increase in T-cell Activity</title>
        <description>Evaluate if MDSC elimination by gemcitabine results in increase in T-cell activity</description>
        <time_frame>2 years</time_frame>
        <population>The study has closed prematurely. Data was not collected</population>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab+Gemcitabine</title>
            <description>Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle&#xD;
Nivolumab: Monoclonal antibody against non small cell lung cancer&#xD;
Nivolumab+Gemcitabine: Gemcitabine is added to the Nivolumab treatment</description>
          </group>
        </group_list>
        <measure>
          <title>Increase in T-cell Activity</title>
          <description>Evaluate if MDSC elimination by gemcitabine results in increase in T-cell activity</description>
          <population>The study has closed prematurely. Data was not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 year</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Nivolumab+Gemcitabine</title>
          <description>Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle&#xD;
Nivolumab: Monoclonal antibody against non small cell lung cancer&#xD;
Nivolumab+Gemcitabine: Gemcitabine is added to the Nivolumab treatment</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Intractable leg pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Intractable right hip pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Intractable lower back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Elevated CPK</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rhabdomyolysis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="8" subjects_affected="3" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lip infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="8" subjects_affected="3" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypoantremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal and urinary disorders - other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Martin Edelman</name_or_title>
      <organization>Fox Chase Cancer Center</organization>
      <phone>215-728-5682</phone>
      <email>Martin.Edelman@fccc.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03302247
org study id: TH-113
nct id: NCT03302247
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Metastatic non small cell lung cancer can be treated with cytotoxic chemotherapy or using
      recently approved immunotherapy with antibody, Nivolumab. Both the therapies have limitation
      due to development of tolerance or immunosuppression. This trial combines one drug from each
      category, immunotherapeutic Nivolumab and chemotherapeutic gemcitabine as it was reported
      that gemcitabine reduces immunosuppression by killing myeloid derived suppressor cells,
      thereby increasing the efficacy of Nivolumab.
Primary Objective

      • The primary objective of this proposal is to evaluate gemcitabine as a method of MDSC
      depletion.

      Secondary Objectives

        -  Evaluate whether these measures result in enhanced T-cell activity and/or NK cell
           function and number.

        -  Determine the tolerability and clinical activity (including response rate and survival)
           of this approach.

        -  Correlate MDSC number with tumor PD-L1 expression
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Nivolumab 240mg, IV on day 1, 15 + Gemcitabine 1000mg/m2, IV on day 1, 8, 15 of 28 days cycle
primary purpose: Treatment
masking: None (Open Label)
measure: Decrease in Macrophage Derived Suppressor Cells (MDSC) Numbers as a Result of Treatment With Gemcitabine.
time frame: 2 years
description: Immunosuppression in terms of number of circulating MDSC in the blood by comparing within each arm reduction in the number of MDSCs after each cycle of treatment
measure: Increase in T-cell Activity
time frame: 2 years
description: Evaluate if MDSC elimination by gemcitabine results in increase in T-cell activity
arm group label: Nivolumab+Gemcitabine
arm group type: Experimental
description: Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle
intervention type: Biological
intervention name: Nivolumab
description: Monoclonal antibody against non small cell lung cancer
arm group label: Nivolumab+Gemcitabine
intervention type: Drug
intervention name: Nivolumab+Gemcitabine
description: Gemcitabine is added to the Nivolumab treatment
arm group label: Nivolumab+Gemcitabine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Gemcitabine
mesh term: Nivolumab
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 