<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/NCT03262454</url>
  </required_header>
  <id_info>
    <org_study_id>NCC2017-0229</org_study_id>
    <secondary_id>ML39728</secondary_id>
    <nct_id>NCT03262454</nct_id>
  </id_info>
  <brief_title>Sequential Hypofractionated Radiotherapy Followed by Anti-PD-L1 Atezolizumab for SCLC</brief_title>
  <acronym>Atezolizumab</acronym>
  <official_title>Sequential Hypofractionated Radiotherapy Followed by Anti-PD-L1 Atezolizumab for Recurrent or Refractory Small Cell Lung Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Center, Korea</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Roche Korea co.,Ltd.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National Cancer Center, Korea</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>
      The investigators hypothesized that local radiation therapy can enhance the effect of&#xD;
      anti-PD-L1 monoclonal antibody through priming T-cell effector function against cancer cells.&#xD;
      Described as above, The investigators concluded that modest dose of radiation to local site&#xD;
      prior to immunotherapy is the best to enhance T-cell-mediated immunity. Accordingly, The&#xD;
      investigators will investigate the combining effect of hypofractionated-sublethal dose of&#xD;
      radiation therapy followed by anti-PD-L1 monoclonal antibody, atezolizumab, for SCLC patients&#xD;
      who are recurrent or refractory for initial platinum-based chemotherapy&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Small cell lung cancer (SCLC), accounting for 10% of all lung cancers (Torre et al., 2015),&#xD;
      shows poor outcomes with 7-10 months of median survival in advanced cases (Jett et al.,&#xD;
      2013). Despite novel treatment strategies including targeted therapy and immunotherapy for&#xD;
      non-small cell lung cancer (NSCLC) have been introduced, the treatment options for SCLC still&#xD;
      remain limited. Many clinical trials, which tested the efficacy of molecular targeted agents&#xD;
      for SCLC, failed to show clinical benefit compared with conventional platinum-based&#xD;
      chemotherapy (Koinis et al., 2016). Nevertheless, recent studies demonstrated that&#xD;
      immunotherapy using anti-CTLA-4 or anti-PD1 monoclonal antibody can be novel therapeutic&#xD;
      strategies for SCLC (Ott et al., 2015; Reck et al., 2013; SJ et al., 2015).&#xD;
&#xD;
      In recent years, many studies have shown that radiation therapy can be a useful treatment as&#xD;
      a combining treatment with immunotherapy. The abscopal effect refers to the ability of&#xD;
      radiation delivered radiation delivered to a local site to treat the other diseases outside&#xD;
      radiation field (Tang et al., 2014). A recent study described that abscopal effect was&#xD;
      observed in a malignant melanoma patient treated with CTLA4 antagonist and radiotherapy&#xD;
      (Postow et al., 2012). Moreover, an animal study presented that blockade of PD-L1 and&#xD;
      ionizing radiation showed synergism (Deng et al., 2014). Based on these emerging evidences,&#xD;
      the investigators hypothesized that local radiation therapy can enhance the effect of&#xD;
      anti-PD-L1 monoclonal antibody through increasing T-cell effector function against tumors.&#xD;
      Atezolizumab, which is a humanized anti-PD-L1 monoclonal antibody, act as an inhibitor the&#xD;
      interaction between PD-L1 and PD-1, and eventually restore suppressed T-cell immunity leading&#xD;
      elimination of cancer cells. In this study, the investigators will investigate the combining&#xD;
      effect of hypofractionated-sublethal dose of radiation therapy followed by anti-PD-L1&#xD;
      monoclonal antibody, atezolizumab, for SCLC patients who are recurrent or refractory for&#xD;
      initial platinum-based chemotherapy.&#xD;
&#xD;
      Based on these emerging evidences, the investigators hypothesized that local radiation&#xD;
      therapy can enhance the effect of anti-PD-L1 monoclonal antibody through priming T-cell&#xD;
      effector function against cancer cells. Described as above, the investigators concluded that&#xD;
      modest dose of radiation to local site prior to immunotherapy is the best to enhance&#xD;
      T-cell-mediated immunity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 22, 2018</start_date>
  <completion_date type="Anticipated">July 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">February 23, 2023</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>ORR</measure>
    <time_frame>through study completion, and average of 1 years</time_frame>
    <description>Objective Response rate using RECIST v1.1</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PFS</measure>
    <time_frame>From date of enroll until the date of first documented progression or date of death from any cause, whichever came first, assessed up to at least 12 months</time_frame>
    <description>Progression Free Survival</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">35</enrollment>
  <condition>Small Cell Lung Cancer Recurrent</condition>
  <arm_group>
    <arm_group_label>Interventions</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Atezolizumab</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab</intervention_name>
    <description>Patients undergo hypofractionated radiation therapy with 24 Gy over 4 fractions in days 1-4 of 1st cycle of atezolimumab and receive Atezolizumab 1200 mg fixed dose via intravenous on day 1 of each 3-week cycle until disease progression or unacceptable toxicity occurs.</description>
    <arm_group_label>Interventions</arm_group_label>
    <other_name>Tecentriq</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female patient aged 18 years or older&#xD;
&#xD;
          2. Histologically confirmed SCLC and available tumor tissues for PD-L1 staining&#xD;
&#xD;
          3. Progression during or after platinum-based chemotherapy.&#xD;
&#xD;
          4. At least one target tumor lesion that has not been irradiated within the past three&#xD;
             months and that can accurately be measured in at least one dimension with longest&#xD;
             diameter&#xD;
&#xD;
          5. Life expectancy of at least three months&#xD;
&#xD;
          6. Performance status of 0, 1, 2 on the ECOG criteria&#xD;
&#xD;
          7. Adequate hematologic and end-organ function, Patients may be transfused or receive&#xD;
             erythropoietic treatment to meet this criterion.&#xD;
&#xD;
          8. Patient has given written informed consent which must be consistent with the&#xD;
             International Conference on Harmonization - Good Clinical Practice (ICH-GCP) and local&#xD;
             legislation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous therapy with anti-PD-1 or -PD-L1 inhibitors&#xD;
&#xD;
          2. Persistence of clinically relevant therapy related toxicities from previous&#xD;
             chemotherapy and/or radiotherapy&#xD;
&#xD;
          3. Chemotherapy, treatment with tyrosine kinase inhibitors, or radiotherapy (except for&#xD;
             brain and extremities) within the past 3 weeks prior to treatment with the trial drug&#xD;
             i.e., the minimum time elapsed since the last anticancer therapy and the first&#xD;
             radiotherapy must be 3 weeks&#xD;
&#xD;
          4. 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;
          5. Concomitant yellow fever vaccination&#xD;
&#xD;
          6. Active or untreated CNS metastases as determined by CT or MRI evaluation during&#xD;
             screening and prior radiographic assessments&#xD;
&#xD;
          7. 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;
          8. Leptomeningeal disease&#xD;
&#xD;
          9. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent&#xD;
             drainage procedures&#xD;
&#xD;
         10. Uncontrolled tumor-related pain&#xD;
&#xD;
         11. Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of&#xD;
             bisphosphonate therapy or denosumab&#xD;
&#xD;
         12. 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;
         13. Proteinuria CTCAE grade 2 or greater&#xD;
&#xD;
         14. Significant weight loss (&gt; 10 %) within the past 6 weeks prior to treatment in the&#xD;
             present trial&#xD;
&#xD;
         15. Current peripheral neuropathy ≥ CTCAE(version4.0) Grade 2 except due to trauma&#xD;
&#xD;
         16. Major injuries and/or surgery with incomplete wound healing within the past ten days&#xD;
             prior to enrollment&#xD;
&#xD;
         17. Serious infections requiring systemic antibiotic (e.g. antiviral, antimicrobial,&#xD;
             antifungal) therapy&#xD;
&#xD;
         18. Active hepatitis C and/or B infection&#xD;
&#xD;
         19. Known human immunodeficiency virus (HIV) seropositivity&#xD;
&#xD;
         20. 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;
         21. 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 5 months after end of active&#xD;
             therapy&#xD;
&#xD;
         22. Pregnancy or breast feeding&#xD;
&#xD;
         23. Psychological, familial, sociological or geographical factors potentially hampering&#xD;
             compliance with the study protocol and follow-up schedule&#xD;
&#xD;
         24. Patients unable to comply with the protocol&#xD;
&#xD;
         25. Active alcohol or drug abuse&#xD;
&#xD;
         26. 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>+82-31-920-1154</phone>
    <email>jymama@ncc.re.kr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sung Jin Yoon</last_name>
    <phone>+82-31-920-0399</phone>
    <email>sjyoon@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>
    </contact>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>August 23, 2017</study_first_submitted>
  <study_first_submitted_qc>August 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</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>Principal 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>Small Cell Lung Carcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atezolizumab</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03262454
org study id: NCC2017-0229
secondary id: ML39728
nct id: NCT03262454
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The investigators hypothesized that local radiation therapy can enhance the effect of
      anti-PD-L1 monoclonal antibody through priming T-cell effector function against cancer cells.
      Described as above, The investigators concluded that modest dose of radiation to local site
      prior to immunotherapy is the best to enhance T-cell-mediated immunity. Accordingly, The
      investigators will investigate the combining effect of hypofractionated-sublethal dose of
      radiation therapy followed by anti-PD-L1 monoclonal antibody, atezolizumab, for SCLC patients
      who are recurrent or refractory for initial platinum-based chemotherapy
Small cell lung cancer (SCLC), accounting for 10% of all lung cancers (Torre et al., 2015),
      shows poor outcomes with 7-10 months of median survival in advanced cases (Jett et al.,
      2013). Despite novel treatment strategies including targeted therapy and immunotherapy for
      non-small cell lung cancer (NSCLC) have been introduced, the treatment options for SCLC still
      remain limited. Many clinical trials, which tested the efficacy of molecular targeted agents
      for SCLC, failed to show clinical benefit compared with conventional platinum-based
      chemotherapy (Koinis et al., 2016). Nevertheless, recent studies demonstrated that
      immunotherapy using anti-CTLA-4 or anti-PD1 monoclonal antibody can be novel therapeutic
      strategies for SCLC (Ott et al., 2015; Reck et al., 2013; SJ et al., 2015).

      In recent years, many studies have shown that radiation therapy can be a useful treatment as
      a combining treatment with immunotherapy. The abscopal effect refers to the ability of
      radiation delivered radiation delivered to a local site to treat the other diseases outside
      radiation field (Tang et al., 2014). A recent study described that abscopal effect was
      observed in a malignant melanoma patient treated with CTLA4 antagonist and radiotherapy
      (Postow et al., 2012). Moreover, an animal study presented that blockade of PD-L1 and
      ionizing radiation showed synergism (Deng et al., 2014). Based on these emerging evidences,
      the investigators hypothesized that local radiation therapy can enhance the effect of
      anti-PD-L1 monoclonal antibody through increasing T-cell effector function against tumors.
      Atezolizumab, which is a humanized anti-PD-L1 monoclonal antibody, act as an inhibitor the
      interaction between PD-L1 and PD-1, and eventually restore suppressed T-cell immunity leading
      elimination of cancer cells. In this study, the investigators will investigate the combining
      effect of hypofractionated-sublethal dose of radiation therapy followed by anti-PD-L1
      monoclonal antibody, atezolizumab, for SCLC patients who are recurrent or refractory for
      initial platinum-based chemotherapy.

      Based on these emerging evidences, the investigators hypothesized that local radiation
      therapy can enhance the effect of anti-PD-L1 monoclonal antibody through priming T-cell
      effector function against cancer cells. Described as above, the investigators concluded that
      modest dose of radiation to local site prior to immunotherapy is the best to enhance
      T-cell-mediated immunity.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: ORR
time frame: through study completion, and average of 1 years
description: Objective Response rate using RECIST v1.1
measure: PFS
time frame: From date of enroll until the date of first documented progression or date of death from any cause, whichever came first, assessed up to at least 12 months
description: Progression Free Survival
arm group label: Interventions
arm group type: Experimental
description: Atezolizumab
intervention type: Drug
intervention name: Atezolizumab
description: Patients undergo hypofractionated radiation therapy with 24 Gy over 4 fractions in days 1-4 of 1st cycle of atezolimumab and receive Atezolizumab 1200 mg fixed dose via intravenous on day 1 of each 3-week cycle until disease progression or unacceptable toxicity occurs.
arm group label: Interventions
other name: Tecentriq
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: +82-31-920-1154
email: jymama@ncc.re.kr
last name: Sung Jin Yoon
phone: +82-31-920-0399
email: sjyoon@ncc.re.kr
facility: 
status: Recruiting
contact: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: National Cancer Center, Korea
investigator full name: Ji-youn Han
investigator title: Principal Investigator
mesh term: Lung Neoplasms
mesh term: Small Cell Lung Carcinoma
mesh term: Atezolizumab