<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/NCT03808480</url>
  </required_header>
  <id_info>
    <org_study_id>NCC2018-0267</org_study_id>
    <nct_id>NCT03808480</nct_id>
  </id_info>
  <brief_title>Nivolumab After Cyclophosphamide and Doxorubicin Induction Therapy in NSCLC With PD-L1&lt;10%</brief_title>
  <official_title>Nivolumab After Cyclophosphamide and Doxorubicin(CA) Induction Therapy in Previously Treated Advanced Non-squamous Cell Non-small Cell Lung Cancer With PD-L1&lt;10%</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Center, Korea</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Center, Korea</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Nivolumab is now the standard of care for second-line treatment of advanced squamous or&#xD;
      nonsquamous NSCLC regardless of the tumor's expression of PD-1L. CheckMate057 trial results&#xD;
      showed that in unselected patients with advanced or recurrent nonsquamous NSCLC who had&#xD;
      stopped responding to a platinum-based chemotherapy regimen, treatment with nivolumab&#xD;
      produced significantly better overall survival during follow-up as long as 18 months,&#xD;
      compared with a docetaxel-based regimen. But during the first 3 months on randomized&#xD;
      treatment, 15 more patients died in the nivolumab arm than in the docetaxel arm. This quickly&#xD;
      reversed during months 4-6 on treatment, when nine more patients died on docetaxel than on&#xD;
      nivolumab. A post hoc analysis showed a trend to a higher risk for death during the first 3&#xD;
      months of nivolumab treatment among patients with poorer prognostic features, more aggressive&#xD;
      disease, and low or no tumor expression of PD-L1. In addition, only a subgroup of patients&#xD;
      benefits from nivolumab with response rates of 20% in unselected cohorts and 10% in low PD-L1&#xD;
      expression cohort. Strategies to render the tumor micro-environment (TME) more susceptible to&#xD;
      anti-PD1 might include stimulation of anti-cancer immune responses by induction treatment&#xD;
      with low dose chemotherapy.&#xD;
&#xD;
      Given the potent immune-modulating effects and anti-tumor activity of cyclophosphamide and&#xD;
      doxorubicin, Investigator propose a study of combining nivolumab with induction therapy with&#xD;
      cyclophosphamide and doxorubicin for nonsquamous NSCLC with PD-L1 expression less than 10%.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Nivolumab is now the standard of care for second-line treatment of advanced squamous or&#xD;
      nonsquamous non-small cell lung cancer (NSCLC) regardless of the tumor's expression of&#xD;
      programmed death-1 ligand (PD-1L). The 2015 Food and Drug Administration approval cited&#xD;
      results from the Open-Label Randomized Phase III Trial of Nivolumab Versus Docetaxel in&#xD;
      Previously Treated Metastatic nonsquamous-NSCLC (CheckMate057) trial. Those results showed&#xD;
      that in unselected patients with advanced or recurrent nonsquamous NSCLC who had stopped&#xD;
      responding to a platinum-based chemotherapy regimen, treatment with nivolumab produced&#xD;
      significantly better overall survival during follow-up as long as 18 months, compared with a&#xD;
      docetaxel-based regimen. But a more detailed assessment of the survival data showed an&#xD;
      unexpected pattern of an early hazard among the nivolumab patients. During the first 3 months&#xD;
      on randomized treatment, 15 more patients died in the nivolumab arm than in the docetaxel&#xD;
      arm. This quickly reversed during months 4-6 on treatment, when nine more patients died on&#xD;
      docetaxel than on nivolumab. By 12 months after the onset of treatment, overall survival was&#xD;
      51% in the nivolumab group and 39% among those randomized to docetaxel. A post hoc analysis&#xD;
      showed a trend to a higher risk for death during the first 3 months of nivolumab treatment&#xD;
      among patients with poorer prognostic features, more aggressive disease, and low or no tumor&#xD;
      expression of PD-L1. In addition, only a subgroup of patients benefits from nivolumab with&#xD;
      response rates of 20% in unselected cohorts and 10% in low PD-L1 expression cohort.&#xD;
      Strategies to render the tumor micro-environment (TME) more susceptible to anti-PD1 might&#xD;
      include stimulation of anti-cancer immune responses by induction treatment with low dose&#xD;
      chemotherapy.&#xD;
&#xD;
      Cyclophosphamide, an old-school chemotherapeutic agent used across a wide range of&#xD;
      malignancies, was found to be a potent immune modulator that targets suppressive regulatory&#xD;
      immune cells within the tumor microenvironment while enhancing effector cells. However,&#xD;
      cyclophosphamide has a limited effect on TIL from tumors larger than a few mm diameter in&#xD;
      view of an increased percentage of myeloid derived suppressor cells (MDSC). Meanwhile,&#xD;
      doxorubicin is also has a potent immune-modulating activity, which can selectively impair&#xD;
      MDSC-induced immunosuppression. Additionally, both cyclophosphamide and doxorubicin have&#xD;
      anti-tumor activity against NSCLC. Given the potent immune-modulating effects and anti-tumor&#xD;
      activity of cyclophosphamide and doxorubicin, Investigator propose a study of combining&#xD;
      nivolumab with induction therapy with cyclophosphamide and doxorubicin for nonsquamous NSCLC&#xD;
      with PD-L1 expression less than 10%.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 23, 2019</start_date>
  <completion_date type="Anticipated">May 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2022</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>objective response</measure>
    <time_frame>From date of first administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48months</time_frame>
    <description>objective response rate using RECIST v1.1</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">22</enrollment>
  <condition>Non-small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>CA and Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After 1 cycle of cyclophosphamide and doxorubicin (CA) induction therapy, Nivolumab 360mg flat dose will be given on day 1 with CA chemotherapy in a 21-day cycle.&#xD;
After the completion of 4 cycles of CA chemotherapy, Nivolumab will be continued as a single agent at a dose of 480mg flat dose every 4 weeks until loss of clinical benefit</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CA and Nivolumab</intervention_name>
    <description>Cyclophosphamide 500mg/m2 IV on D1 (C1-4), 1cycle=21days) Doxorubicin 50mg/m2 IV on D1 (C1~4, 1cycle=21days) Nivolumab 360 mg/IV C2~4 D1 (1cycle=21days) Nivolumab 400mg/IV on D1 from Cycle 5 every 4 weeks.</description>
    <arm_group_label>CA and Nivolumab</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologic or cytologic diagnosis of nonsquamous NSCLC with SP263 PD-L1 expression&#xD;
             &lt;10%&#xD;
&#xD;
          -  Patients whose tumor is not known to have anaplastic lymphoma kinase(ALK) or epidermal&#xD;
             growth factor receptor(EGFR) mutation and Previously treated with at least one&#xD;
             platinum-based chemotherapy but less than 3 prior chemotherapy&#xD;
&#xD;
          -  Before study entry, a minimum of 21 days must have elapsed since any prior&#xD;
             chemotherapy.&#xD;
&#xD;
          -  Prior radiation therapy is allowed as long as the irradiated area is not the only&#xD;
             source of measurable disease.&#xD;
&#xD;
          -  No other forms of cancer therapy, such as immunotherapy for at least 2 weeks before&#xD;
             the enrollment in study.&#xD;
&#xD;
          -  Performance status of 0-1 on the ECOG criteria.&#xD;
&#xD;
          -  At least one unidimensionally measurable lesion meeting Response Evaluation Criteria&#xD;
             in Solid Tumors (Revised RECIST guideline version 1.1)&#xD;
&#xD;
          -  Estimated life expectancy of at least 8 weeks.&#xD;
&#xD;
          -  Patient compliance that allow adequate follow-up. Adequate hematologic (WBC ≥4,000/mm3&#xD;
             또는 4.0 x 103/㎕ Platelet count ≥130,000mm3 또는 130 x 103/㎕ Bilirubin total ≤1.0 mg/dL&#xD;
             AST/ALT≤ 80 IU/L creatinine concentration 1XULN or creatinine clearance (CrCl) &gt; 50&#xD;
             mL/min (measured using the Cockcroft-Gault formula)&#xD;
&#xD;
          -  Informed consent from patient or patient's relative.&#xD;
&#xD;
          -  Males or females at least 18 years of age.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous therapy with anti-PD-1 or -PD-L1 inhibitors&#xD;
&#xD;
          -  Persistence of clinically relevant therapy related toxicities from previous&#xD;
             chemotherapy and/or radiotherapy&#xD;
&#xD;
          -  Has received prior chemotherapy or tyrosine kinase inhibitor therapy within 3 weeks of&#xD;
             the first dose of trial treatment ; completed palliative radiotherapy(except for brain&#xD;
             and extremities) within 2weeks of the first dose of trial treatment. Prior curative&#xD;
             thoracic radiation therapy(&gt;=60Gy) is permitted if disease progression occured &gt;4weeks&#xD;
             after the completion of therapy.&#xD;
&#xD;
          -  Treatment with other investigational drugs or treatment in another clinical trial&#xD;
             within the past three weeks before start of therapy or concomitantly with this trial&#xD;
&#xD;
          -  Has received a live vaccine(Concomitant yellow fever vaccin) within 4 weeks prior to&#xD;
             the first administration of study medication. Concomitant yellow fever vaccination&#xD;
&#xD;
          -  Active CNS metastases&#xD;
&#xD;
          -  Spinal cord compression not definitively treated with surgery and/or radiation or&#xD;
             previously diagnosed and treated spinal cord compression without evidence that disease&#xD;
             has been clinically stable for 2 weeks prior to randomization&#xD;
&#xD;
          -  Leptomeningeal disease&#xD;
&#xD;
          -  Significant cardiovascular diseases (i.e., hypertension not controlled by medical&#xD;
             therapy, unstable angina, history of myocardial infarction within the past 12 months,&#xD;
             congestive heart failure &gt; NYHA II, serious cardiac arrhythmia, pericardial effusion)&#xD;
&#xD;
          -  Proteinuria CTCAE grade 2 or greater&#xD;
&#xD;
          -  Significant weight loss (&gt; 10 %) within the past 6 weeks prior to treatment in the&#xD;
             present trial&#xD;
&#xD;
          -  Current peripheral neuropathy ≥ CTCAE(version4.0) Grade 2 except due to trauma&#xD;
&#xD;
          -  Major injuries and/or surgery with incomplete wound healing within the past ten days&#xD;
             prior to enrollment&#xD;
&#xD;
          -  Serious infections requiring systemic antibiotic (e.g. antiviral, antimicrobial,&#xD;
             antifungal) therapy&#xD;
&#xD;
          -  Active hepatitis C and/or B infection&#xD;
&#xD;
          -  Known human immunodeficiency virus (HIV) seropositivity&#xD;
&#xD;
          -  Serious illness or concomitant non-oncological disease such as&#xD;
             neurologic-,psychiatric-, infectious disease or active ulcers (gastro-intestinal&#xD;
             tract, skin) or laboratory abnormality that may increase the risk associated with&#xD;
             study participation or study drug administration and in the judgment of the&#xD;
             investigator would make the patient inappropriate for entry into the study&#xD;
&#xD;
          -  Patients who are sexually active and unwilling to use a medically acceptable method of&#xD;
             contraception (e.g. such as implants, injectables, combined oral contraceptives, some&#xD;
             intrauterine devices or vasectomized partner for participating females, condoms for&#xD;
             participating males) during the trial and for at least 7 months after end of active&#xD;
             therapy&#xD;
&#xD;
          -  Pregnancy or breast feeding&#xD;
&#xD;
          -  Psychological, familial, sociological or geographical factors potentially hampering&#xD;
             compliance with the study protocol and follow-up schedule&#xD;
&#xD;
          -  Patients unable to comply with the protocol&#xD;
&#xD;
          -  Active alcohol or drug abuse&#xD;
&#xD;
          -  Other malignancy within the past three years other than basal cell skin cancer or&#xD;
             carcinoma in situ of the cervix&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ji-youn han, Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ji-youn Han, Ph.D</last_name>
    <phone>82-31-920-1210</phone>
    <email>jymama@ncc.re.kr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sehee Oh</last_name>
    <phone>82-31-920-0398</phone>
    <email>oshee97@ncc.re.kr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Cancer Center</name>
      <address>
        <city>Goyang-Si</city>
        <state>Gyeonggi-do</state>
        <zip>10408</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ji-Youn Han, Ph.D</last_name>
      <phone>+82-31-920-1210</phone>
      <email>jymama@ncc.re.kr</email>
    </contact>
    <contact_backup>
      <last_name>Sehee Oh</last_name>
      <phone>+82-31-920-0398</phone>
      <email>oshee97@ncc.re.kr</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>December 26, 2018</study_first_submitted>
  <study_first_submitted_qc>January 15, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 17, 2019</study_first_posted>
  <last_update_submitted>April 4, 2022</last_update_submitted>
  <last_update_submitted_qc>April 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 6, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cancer Center, Korea</investigator_affiliation>
    <investigator_full_name>Ji-youn Han</investigator_full_name>
    <investigator_title>Principle Investigator</investigator_title>
  </responsible_party>
  <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>Nivolumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03808480
org study id: NCC2018-0267
nct id: NCT03808480
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Nivolumab is now the standard of care for second-line treatment of advanced squamous or
      nonsquamous NSCLC regardless of the tumor's expression of PD-1L. CheckMate057 trial results
      showed that in unselected patients with advanced or recurrent nonsquamous NSCLC who had
      stopped responding to a platinum-based chemotherapy regimen, treatment with nivolumab
      produced significantly better overall survival during follow-up as long as 18 months,
      compared with a docetaxel-based regimen. But during the first 3 months on randomized
      treatment, 15 more patients died in the nivolumab arm than in the docetaxel arm. This quickly
      reversed during months 4-6 on treatment, when nine more patients died on docetaxel than on
      nivolumab. A post hoc analysis showed a trend to a higher risk for death during the first 3
      months of nivolumab treatment among patients with poorer prognostic features, more aggressive
      disease, and low or no tumor expression of PD-L1. In addition, only a subgroup of patients
      benefits from nivolumab with response rates of 20% in unselected cohorts and 10% in low PD-L1
      expression cohort. Strategies to render the tumor micro-environment (TME) more susceptible to
      anti-PD1 might include stimulation of anti-cancer immune responses by induction treatment
      with low dose chemotherapy.

      Given the potent immune-modulating effects and anti-tumor activity of cyclophosphamide and
      doxorubicin, Investigator propose a study of combining nivolumab with induction therapy with
      cyclophosphamide and doxorubicin for nonsquamous NSCLC with PD-L1 expression less than 10%.
Nivolumab is now the standard of care for second-line treatment of advanced squamous or
      nonsquamous non-small cell lung cancer (NSCLC) regardless of the tumor's expression of
      programmed death-1 ligand (PD-1L). The 2015 Food and Drug Administration approval cited
      results from the Open-Label Randomized Phase III Trial of Nivolumab Versus Docetaxel in
      Previously Treated Metastatic nonsquamous-NSCLC (CheckMate057) trial. Those results showed
      that in unselected patients with advanced or recurrent nonsquamous NSCLC who had stopped
      responding to a platinum-based chemotherapy regimen, treatment with nivolumab produced
      significantly better overall survival during follow-up as long as 18 months, compared with a
      docetaxel-based regimen. But a more detailed assessment of the survival data showed an
      unexpected pattern of an early hazard among the nivolumab patients. During the first 3 months
      on randomized treatment, 15 more patients died in the nivolumab arm than in the docetaxel
      arm. This quickly reversed during months 4-6 on treatment, when nine more patients died on
      docetaxel than on nivolumab. By 12 months after the onset of treatment, overall survival was
      51% in the nivolumab group and 39% among those randomized to docetaxel. A post hoc analysis
      showed a trend to a higher risk for death during the first 3 months of nivolumab treatment
      among patients with poorer prognostic features, more aggressive disease, and low or no tumor
      expression of PD-L1. In addition, only a subgroup of patients benefits from nivolumab with
      response rates of 20% in unselected cohorts and 10% in low PD-L1 expression cohort.
      Strategies to render the tumor micro-environment (TME) more susceptible to anti-PD1 might
      include stimulation of anti-cancer immune responses by induction treatment with low dose
      chemotherapy.

      Cyclophosphamide, an old-school chemotherapeutic agent used across a wide range of
      malignancies, was found to be a potent immune modulator that targets suppressive regulatory
      immune cells within the tumor microenvironment while enhancing effector cells. However,
      cyclophosphamide has a limited effect on TIL from tumors larger than a few mm diameter in
      view of an increased percentage of myeloid derived suppressor cells (MDSC). Meanwhile,
      doxorubicin is also has a potent immune-modulating activity, which can selectively impair
      MDSC-induced immunosuppression. Additionally, both cyclophosphamide and doxorubicin have
      anti-tumor activity against NSCLC. Given the potent immune-modulating effects and anti-tumor
      activity of cyclophosphamide and doxorubicin, Investigator propose a study of combining
      nivolumab with induction therapy with cyclophosphamide and doxorubicin for nonsquamous NSCLC
      with PD-L1 expression less than 10%.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: objective response
time frame: From date of first administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48months
description: objective response rate using RECIST v1.1
arm group label: CA and Nivolumab
arm group type: Experimental
description: After 1 cycle of cyclophosphamide and doxorubicin (CA) induction therapy, Nivolumab 360mg flat dose will be given on day 1 with CA chemotherapy in a 21-day cycle.
After the completion of 4 cycles of CA chemotherapy, Nivolumab will be continued as a single agent at a dose of 480mg flat dose every 4 weeks until loss of clinical benefit
intervention type: Drug
intervention name: CA and Nivolumab
description: Cyclophosphamide 500mg/m2 IV on D1 (C1-4), 1cycle=21days) Doxorubicin 50mg/m2 IV on D1 (C1~4, 1cycle=21days) Nivolumab 360 mg/IV C2~4 D1 (1cycle=21days) Nivolumab 400mg/IV on D1 from Cycle 5 every 4 weeks.
arm group label: CA and Nivolumab
other name: Opdivo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ji-youn han, Ph.D
role: Principal Investigator
affiliation: National Cancer Center
last name: Ji-youn Han, Ph.D
phone: 82-31-920-1210
email: jymama@ncc.re.kr
last name: Sehee Oh
phone: 82-31-920-0398
email: oshee97@ncc.re.kr
facility: 
status: Recruiting
contact: 
contact backup: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: National Cancer Center, Korea
investigator full name: Ji-youn Han
investigator title: Principle Investigator
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Nivolumab
sharing ipd: No