<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/NCT03825510</url>
  </required_header>
  <id_info>
    <org_study_id>CKHS 17-009</org_study_id>
    <nct_id>NCT03825510</nct_id>
  </id_info>
  <brief_title>Immunotherapy SBRT Sensitization of the Programmed Death-1 (PD-1) Effect</brief_title>
  <acronym>I-SABR</acronym>
  <official_title>A Prospective Trail of Immunotherapy and Stereotactic Body Radiotherapy (SBRT) for the Treatment of Metastatic Lung Cancer: SBRT Sensitization of the Programmed Death-1 (PD-1) Effect</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Crozer-Keystone Health System</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Saint Peters University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Community Medical Center, Toms River, NJ</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Crozer-Keystone Health System</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine efficacy, safety of Stereotactic Body Radiotherapy&#xD;
      (SBRT) in combination with immunotherapy in participants with metastatic non-small cell lung&#xD;
      cancer (NSCLC) who are eligible for an immunotherapy agent.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Blockade of the PD-1/PD-L1 T-cell checkpoint pathway is an effective and well tolerated&#xD;
      approach to stimulating the immune response which is a critical option in the treatment of&#xD;
      metastatic NSCLC. However, progression free survival (PFS) is increased by only 2-4 months&#xD;
      and median overall survival (OS) by 3-9 months.&#xD;
&#xD;
      There is compelling evidence that PFS is increased up to 3 fold and OS by 2 fold in patients&#xD;
      receiving a course of radiation therapy while on immunotherapy. Radiotherapy is known to&#xD;
      induce immunogenic tumor cell death and upregulation of dendritic cells and antigen&#xD;
      presentation leading to activation of cytotoxic T-Cells. Dramatic T-cell activation has been&#xD;
      demonstrated where tumor regression occurs outside the radiation treatment field in a&#xD;
      phenomenon termed the abscopal effect and is associated with high dose radiation delivered&#xD;
      via SBRT.&#xD;
&#xD;
      As such, SBRT activation of T-cells could be complementary to immunotherapy and enhance&#xD;
      T-cell mediated killing via PD-L1 blockade which could lead to lasting and durable tumor&#xD;
      response with improved progression free survival and overall survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 28, 2017</start_date>
  <completion_date type="Actual">March 8, 2022</completion_date>
  <primary_completion_date type="Actual">March 8, 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>Overall Survival</measure>
    <time_frame>24 months</time_frame>
    <description>Determine overall survival in patients receiving SBRT and immunotherapy as compared to landmark trials of patients receiving immunotherapy alone (Checkmate 057, Keynote 024)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Acute Toxicity: Radiation pnuemonitis measured using NCI CTCAE version 4.0</measure>
    <time_frame>0-15 weeks</time_frame>
    <description>Determine excess/unexpected toxicity that cannot be attributed to routine radiation therapy or immunotherapy side effects.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>3-24 Months</time_frame>
    <description>1. To determine the progression free survival measured from time of enrollment to first evidence of progressive disease and evaluated 3 months after treatment initiation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Local Control</measure>
    <time_frame>0-24 Months</time_frame>
    <description>To determine the local control measured from time of enrollment to first evidence of progressive disease at the treatment site</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Late Toxicity: Pulmonary, Bone or Visceral organ toxicity evaluated 6 months from completion of treatment using NCI CTCAE version 4.</measure>
    <time_frame>6-24 Months</time_frame>
    <description>the incidence of grade ≥ 3 , pneumonitis 6 months after completing SBRT the incidence of any grade pulmonary fibrosis 6 months after completing SBRT the incidence of grade ≥ 3 , bone fracture 6 months after completing SBRT the incidence of grade ≥ 3 visceral organ toxicity at or near a treated site (e.g colitis, nephritis, hepatitis) 6 months after completing SBRT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of Tumor Burden</measure>
    <time_frame>24 Months</time_frame>
    <description>To determine the influence of number of metastatic sites on OS, and PFS. Patients will be stratified based on number of metastatic sites &lt;=3, 4-5, &gt;5</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Metastatic Nonsmall Cell Lung Cancer</condition>
  <condition>Non Small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic Body Radiotherapy</intervention_name>
    <description>All patients in this trial will be treated with fractionated Stereotactic body radiation therapy.&#xD;
SBRT will be delivered to &lt;=3 sites in 3-5 fractions followed by administration of the specified immunotherapy agent (Nivolumab or Pembrolizumab). This approach will take advantage of the transient increase in antigen availability, increased antigen presentation and upregulation of PD-1 by tumor cells following ablative radiation therapy.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
    <other_name>SBRT</other_name>
    <other_name>SRS</other_name>
    <other_name>SABR</other_name>
    <other_name>CyberKnife</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed Stage IV NSCLC according to the 7th AJCC&#xD;
             staging manual.&#xD;
&#xD;
          -  Eligible for an immunotherapy agent. Patients who progress after drug therapy (3&#xD;
             months) for ALK, EGFR or ROS mutation positive lung cancer are eligible.&#xD;
&#xD;
          -  At least 2 lesions that are safely amenable to SBRT. ECOG &lt;=2.&#xD;
&#xD;
          -  At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors&#xD;
             (RECIST) 1.1 criteria for response assessment or at least 1 lesion with FDG avidity&#xD;
             and CT correlate that can be monitored for PET-CT response by SUV Max increase or&#xD;
             decrease.&#xD;
&#xD;
          -  Normal Hepatic and renal function.&#xD;
&#xD;
          -  Bone marrow reserve:&#xD;
&#xD;
               1. ANC ≥ 1.5 x 109/L&#xD;
&#xD;
               2. Hemoglobin ≥9.0 g/dL&#xD;
&#xD;
               3. Platelet count ≥75 x 109/L&#xD;
&#xD;
          -  Ability to comply with follow-up visits and evaluations, treatment planning and&#xD;
             studies and other study related procedures and visits.&#xD;
&#xD;
          -  Ability to sign informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with active CNS metastases&#xD;
&#xD;
          -  Active, known or suspected auto-immune disease.&#xD;
&#xD;
          -  Patients with medical conditions that require systemic immunosuppression.&#xD;
&#xD;
          -  Patients with a history of interstitial lung disease.&#xD;
&#xD;
          -  Prior treatment with immune checkpoint inhibitors/immonotherapy.&#xD;
&#xD;
          -  Other active malignancy requiring intervention.&#xD;
&#xD;
          -  Prior lung radiation, with the only metastatic targets in the lungs.&#xD;
&#xD;
          -  Unresolved toxicity from prior chemotherapy or anti-cancer treatment.&#xD;
&#xD;
          -  Current or prior enrollment in clinical trial with an investigational drug within 4&#xD;
             weeks.&#xD;
&#xD;
          -  Pregnancy or positive pregnancy test.&#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>Philadelphia CyberKnife</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19083</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>August 18, 2017</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>March 3, 2023</last_update_submitted>
  <last_update_submitted_qc>March 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Crozer-Keystone Health System</investigator_affiliation>
    <investigator_full_name>Rachelle Lanciano M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Opdivo, Keytruda, Cyberknife</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 18, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT03825510/Prot_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03825510
org study id: CKHS 17-009
nct id: NCT03825510
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
The purpose of this study is to determine efficacy, safety of Stereotactic Body Radiotherapy
      (SBRT) in combination with immunotherapy in participants with metastatic non-small cell lung
      cancer (NSCLC) who are eligible for an immunotherapy agent.
Blockade of the PD-1/PD-L1 T-cell checkpoint pathway is an effective and well tolerated
      approach to stimulating the immune response which is a critical option in the treatment of
      metastatic NSCLC. However, progression free survival (PFS) is increased by only 2-4 months
      and median overall survival (OS) by 3-9 months.

      There is compelling evidence that PFS is increased up to 3 fold and OS by 2 fold in patients
      receiving a course of radiation therapy while on immunotherapy. Radiotherapy is known to
      induce immunogenic tumor cell death and upregulation of dendritic cells and antigen
      presentation leading to activation of cytotoxic T-Cells. Dramatic T-cell activation has been
      demonstrated where tumor regression occurs outside the radiation treatment field in a
      phenomenon termed the abscopal effect and is associated with high dose radiation delivered
      via SBRT.

      As such, SBRT activation of T-cells could be complementary to immunotherapy and enhance
      T-cell mediated killing via PD-L1 blockade which could lead to lasting and durable tumor
      response with improved progression free survival and overall survival.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Survival
time frame: 24 months
description: Determine overall survival in patients receiving SBRT and immunotherapy as compared to landmark trials of patients receiving immunotherapy alone (Checkmate 057, Keynote 024)
measure: Acute Toxicity: Radiation pnuemonitis measured using NCI CTCAE version 4.0
time frame: 0-15 weeks
description: Determine excess/unexpected toxicity that cannot be attributed to routine radiation therapy or immunotherapy side effects.
measure: Progression Free Survival
time frame: 3-24 Months
description: 1. To determine the progression free survival measured from time of enrollment to first evidence of progressive disease and evaluated 3 months after treatment initiation
measure: Local Control
time frame: 0-24 Months
description: To determine the local control measured from time of enrollment to first evidence of progressive disease at the treatment site
measure: Late Toxicity: Pulmonary, Bone or Visceral organ toxicity evaluated 6 months from completion of treatment using NCI CTCAE version 4.
time frame: 6-24 Months
description: the incidence of grade ≥ 3 , pneumonitis 6 months after completing SBRT the incidence of any grade pulmonary fibrosis 6 months after completing SBRT the incidence of grade ≥ 3 , bone fracture 6 months after completing SBRT the incidence of grade ≥ 3 visceral organ toxicity at or near a treated site (e.g colitis, nephritis, hepatitis) 6 months after completing SBRT
measure: Impact of Tumor Burden
time frame: 24 Months
description: To determine the influence of number of metastatic sites on OS, and PFS. Patients will be stratified based on number of metastatic sites <=3, 4-5, >5
arm group label: Treatment Arm
arm group type: Experimental
intervention type: Radiation
intervention name: Stereotactic Body Radiotherapy
description: All patients in this trial will be treated with fractionated Stereotactic body radiation therapy.
SBRT will be delivered to <=3 sites in 3-5 fractions followed by administration of the specified immunotherapy agent (Nivolumab or Pembrolizumab). This approach will take advantage of the transient increase in antigen availability, increased antigen presentation and upregulation of PD-1 by tumor cells following ablative radiation therapy.
arm group label: Treatment Arm
other name: SBRT
other name: SRS
other name: SABR
other name: CyberKnife
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Crozer-Keystone Health System
investigator full name: Rachelle Lanciano M.D.
investigator title: Principal Investigator
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
sharing ipd: No
provided document: 