<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/NCT04432649</url>
  </required_header>
  <id_info>
    <org_study_id>GIMI-IRB-20009</org_study_id>
    <nct_id>NCT04432649</nct_id>
  </id_info>
  <brief_title>Targeting CD276 (B7-H3) Positive Solid Tumors by 4SCAR-276</brief_title>
  <official_title>Multicenter Trial of Phase I/II Studies on CD276 (B7-H3) Positive Solid Tumors Treated With 4SCAR-276</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shenzhen Geno-Immune Medical Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sun Yat-sen University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Shenzhen Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Shenzhen Geno-Immune Medical Institute</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with refractory and/or recurrent solid tumor have poor prognosis despite complex&#xD;
      multimodel therapy and therefore, novel approaches are urgently needed. This study attempts&#xD;
      to treat these diseases using T cells genetically modified with a 4th generation lentiviral&#xD;
      chimeric antigen receptor (4SCAR fused with an inducible apoptotic caspase 9 domain)&#xD;
      targeting CD276 (B7-H3). The 4SCAR-CD276-modified T cells (4SCAR-276) can recognize and kill&#xD;
      tumor cells through the recognition of CD276, a surface protein expressed at high levels on&#xD;
      many types of tumors but at low levels on normal tissues. This study will evaluate the side&#xD;
      effects and effective doses of 4SCAR-276 in treating refractory and/or recurrent tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Patients with refractory and/or recurrent solid tumors have poor prognosis&#xD;
      despite complex multimodal therapy; therefore, novel curative approaches are needed. The&#xD;
      investigators are attempting to use T cells obtained directly from the patient, which can be&#xD;
      genetically modified to express a 4th generation CD276-specific chimeric antigen receptor&#xD;
      (4SCAR-276). The CAR molecules enable the T cells to recognize and kill tumor cells through&#xD;
      the recognition of the surface CD276, which is expressed at high levels on tumor cells&#xD;
      including brain tumors, Ewing's sarcoma (PNET) and many other tumors but not at significant&#xD;
      levels on normal tissues. This study will evaluate the side effects and the best dose of a&#xD;
      novel 4th generation anti-CD276 CAR T cells to target refractory and/or recurrent solid&#xD;
      tumors.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        1. Participants will be screened through physical exam and medical history. Blood and tumor&#xD;
           tissue samples will be collected. Imaging studies will be performed.&#xD;
&#xD;
        2. Peripheral blood mononuclear cells (PBMC) will be obtained by apheresis, and T cells&#xD;
           will be activated and modified to express the 4SCAR-276 gene.&#xD;
&#xD;
        3. On Day -5 to -7, PBMC will be activated and enriched for T cells, which will be followed&#xD;
           by 4SCAR-276 lentiviral transduction. The total culture time is approximately 5-7 days.&#xD;
&#xD;
        4. Participants will receive a preparative conditioning regimen comprising&#xD;
           cyclophosphamide/fludarabine to prepare their immune system to accept the modified CAR T&#xD;
           cells. The preparative regimen will be based on patient immune condition and consistent&#xD;
           with standard chemotherapy conditioning regimen.&#xD;
&#xD;
        5. The patients will receive ~10^6 CART cells/kg body weight per infusion, and may receive&#xD;
           additional booster CART infusions if positive outcome is recorded.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Anticipated">May 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2023</primary_completion_date>
  <phase>Phase 1/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>Number of patients with adverse events</measure>
    <time_frame>3 years</time_frame>
    <description>Determine the toxicity profile the 4SCAR-276-modified T cells with Common Toxicity Criteria for Adverse Effects version 4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Anti-tumor effects</measure>
    <time_frame>1 year</time_frame>
    <description>Defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD) based on imaging analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival time of the patients</measure>
    <time_frame>3 years</time_frame>
    <description>Evaluate the survival time of the patients treated with the 4SCAR-276 T cells, including progression free survival (PFS) and overall survival (OS).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Solid Tumor</condition>
  <arm_group>
    <arm_group_label>Effectiveness of 4SCAR-276 T cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The 4SCAR-276 T cells can recognize and kill tumor cells through the recognition of CD276 .This study will evaluate the side effects and effective doses of 4SCAR-276 T cells in treating refractory and recurrent solid tumors</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>4SCAR-276</intervention_name>
    <description>The 4SCAR-276 T cells can recognize and kill tumor cells through the recognition of CD276 .This study will evaluate the side effects and effective doses of 4SCAR-276 T cells in treating refractory and recurrent solid tumors</description>
    <arm_group_label>Effectiveness of 4SCAR-276 T cells</arm_group_label>
    <other_name>CD276-specific 4th Generation CART</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with tumors have received standard first-line therapy and have been judged to&#xD;
             be non-resectable, metastatic, progressive or recurrent.&#xD;
&#xD;
          -  The CD276 antigen status of the tumor is determined for eligibility. Positive&#xD;
             expression is defined by antibody staining results based on immunohistochemistry or&#xD;
             flow cytometry analysis.&#xD;
&#xD;
          -  Body weight greater than or equal to 10 kg.&#xD;
&#xD;
          -  Age: ≥1 year and ≤ 75 years of age at the time of enrollment.&#xD;
&#xD;
          -  Life expectancy: at least 8 weeks.&#xD;
&#xD;
          -  Prior Therapy: 1) There is no limit to the number of prior treatment regimens. Any&#xD;
             grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to&#xD;
             grade 2 or less. 2) Must not have received hematopoietic growth factors for at least 1&#xD;
             week prior to mononuclear cells collection. 3) At least 7 days must have elapsed since&#xD;
             the completion of therapy with a biologic agent, targeted agent, tyrosine kinase&#xD;
             inhibitor or a metronomic nonmyelosuppressive regimen. 4) At least 4 weeks must have&#xD;
             elapsed since prior therapy that included a monoclonal antibody. 5) At least 1 week&#xD;
             since any radiation therapy at the time of study entry.&#xD;
&#xD;
          -  Karnofsky/jansky score of 60% or greater.&#xD;
&#xD;
          -  Cardiac function: Left ventricular ejection fraction greater than or equal to 40/55&#xD;
             percent .&#xD;
&#xD;
          -  Pulse Ox greater than or equal to 90% on room air.&#xD;
&#xD;
          -  Liver function: defined as alanine transaminase (ALT) &lt;3x upper limit of normal (ULN),&#xD;
             aspartate aminotransferase (AST) &lt;3x ULN; serum bilirubin and alkaline phosphatase &lt;2x&#xD;
             ULN.&#xD;
&#xD;
          -  Renal function: Patients must have serum creatinine less than 3 times upper limit of&#xD;
             normal.&#xD;
&#xD;
          -  Marrow function: White blood cell count ≥1000/ul, Absolute neutrophil count ≥500/ul,&#xD;
             Absolute lymphocyte count ≥500/ul, Platelet count ≥25,000/ul (not achieved by&#xD;
             transfusion).&#xD;
&#xD;
          -  Patients with known bone marrow metastatic disease will be eligible for study as long&#xD;
             as they meet hematologic function criteria, and the marrow disease not evaluable to&#xD;
             have hematologic toxicity.&#xD;
&#xD;
          -  For all patients enrolled in this study, themselves or their parents or legal&#xD;
             guardians must sign an informed consent and assent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.) or&#xD;
        major organ dysfunction, or grade 3 hematologic toxicity.&#xD;
&#xD;
          -  Untreated central nervous system (CNS) metastasis: Patients with CNS tumor involvement&#xD;
             that has been treated and/or is stable for at least 6 weeks following completion of&#xD;
             therapy are eligible.&#xD;
&#xD;
          -  Previous treatment with other genetically engineered CD276-CAR T cells or CD276&#xD;
             antibody therapy.&#xD;
&#xD;
          -  Active HIV, Hepatitis B virus (HBV), Hepatitis C virus (HCV) infection or uncontrolled&#xD;
             infection.&#xD;
&#xD;
          -  Patients who require systemic corticosteroid or other immunosuppressive therapy.&#xD;
&#xD;
          -  Evidence of tumor potentially causing airway obstruction.&#xD;
&#xD;
          -  Inability to comply with protocol requirements.&#xD;
&#xD;
          -  Insufficient CAR T cells availability.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Shenzhen Children's Hospital</name>
      <address>
        <city>Shenzhen</city>
        <state>Guangdong</state>
        <zip>518000</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sixi Liu, MD</last_name>
      <phone>86-189 3869 0206</phone>
      <email>tiger647@126.com</email>
    </contact>
    <contact_backup>
      <last_name>Xiuli Yuan, MD</last_name>
      <phone>86-18938690212</phone>
      <email>18938690212@163.com</email>
    </contact_backup>
    <investigator>
      <last_name>Lichun Xie, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Shenzhen Geno-immune Medical Institute</name>
      <address>
        <city>Shenzhen</city>
        <state>Guangdong</state>
        <zip>518000</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lung-Ji Chang, PhD</last_name>
      <phone>86-075586725195</phone>
      <email>c@szgimi.org</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Sun Yat-Sen University</name>
      <address>
        <city>Shenzhen</city>
        <state>Guangdong</state>
        <zip>518107</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bo Wang, MD</last_name>
      <phone>86-0755-23242570</phone>
      <email>wangb68377@sina.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>June 11, 2020</last_update_submitted>
  <last_update_submitted_qc>June 11, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Shenzhen Geno-Immune Medical Institute</investigator_affiliation>
    <investigator_full_name>Lung-Ji Chang</investigator_full_name>
    <investigator_title>President</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_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/NCT04432649
org study id: GIMI-IRB-20009
nct id: NCT04432649
lead sponsor: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
Patients with refractory and/or recurrent solid tumor have poor prognosis despite complex
      multimodel therapy and therefore, novel approaches are urgently needed. This study attempts
      to treat these diseases using T cells genetically modified with a 4th generation lentiviral
      chimeric antigen receptor (4SCAR fused with an inducible apoptotic caspase 9 domain)
      targeting CD276 (B7-H3). The 4SCAR-CD276-modified T cells (4SCAR-276) can recognize and kill
      tumor cells through the recognition of CD276, a surface protein expressed at high levels on
      many types of tumors but at low levels on normal tissues. This study will evaluate the side
      effects and effective doses of 4SCAR-276 in treating refractory and/or recurrent tumors.
Background: Patients with refractory and/or recurrent solid tumors have poor prognosis
      despite complex multimodal therapy; therefore, novel curative approaches are needed. The
      investigators are attempting to use T cells obtained directly from the patient, which can be
      genetically modified to express a 4th generation CD276-specific chimeric antigen receptor
      (4SCAR-276). The CAR molecules enable the T cells to recognize and kill tumor cells through
      the recognition of the surface CD276, which is expressed at high levels on tumor cells
      including brain tumors, Ewing's sarcoma (PNET) and many other tumors but not at significant
      levels on normal tissues. This study will evaluate the side effects and the best dose of a
      novel 4th generation anti-CD276 CAR T cells to target refractory and/or recurrent solid
      tumors.

      Design:

        1. Participants will be screened through physical exam and medical history. Blood and tumor
           tissue samples will be collected. Imaging studies will be performed.

        2. Peripheral blood mononuclear cells (PBMC) will be obtained by apheresis, and T cells
           will be activated and modified to express the 4SCAR-276 gene.

        3. On Day -5 to -7, PBMC will be activated and enriched for T cells, which will be followed
           by 4SCAR-276 lentiviral transduction. The total culture time is approximately 5-7 days.

        4. Participants will receive a preparative conditioning regimen comprising
           cyclophosphamide/fludarabine to prepare their immune system to accept the modified CAR T
           cells. The preparative regimen will be based on patient immune condition and consistent
           with standard chemotherapy conditioning regimen.

        5. The patients will receive ~10^6 CART cells/kg body weight per infusion, and may receive
           additional booster CART infusions if positive outcome is recorded.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients with adverse events
time frame: 3 years
description: Determine the toxicity profile the 4SCAR-276-modified T cells with Common Toxicity Criteria for Adverse Effects version 4.0
measure: Anti-tumor effects
time frame: 1 year
description: Defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD) based on imaging analysis.
measure: Survival time of the patients
time frame: 3 years
description: Evaluate the survival time of the patients treated with the 4SCAR-276 T cells, including progression free survival (PFS) and overall survival (OS).
arm group label: Effectiveness of 4SCAR-276 T cells
arm group type: Experimental
description: The 4SCAR-276 T cells can recognize and kill tumor cells through the recognition of CD276 .This study will evaluate the side effects and effective doses of 4SCAR-276 T cells in treating refractory and recurrent solid tumors
intervention type: Biological
intervention name: 4SCAR-276
description: The 4SCAR-276 T cells can recognize and kill tumor cells through the recognition of CD276 .This study will evaluate the side effects and effective doses of 4SCAR-276 T cells in treating refractory and recurrent solid tumors
arm group label: Effectiveness of 4SCAR-276 T cells
other name: CD276-specific 4th Generation CART
criteria: 
gender: All
minimum age: 1 Year
maximum age: 75 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Shenzhen Geno-Immune Medical Institute
investigator full name: Lung-Ji Chang
investigator title: President
mesh term: Neoplasms
sharing ipd: No