<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/NCT02992210</url>
  </required_header>
  <id_info>
    <org_study_id>GIMI-IRB-16002</org_study_id>
    <nct_id>NCT02992210</nct_id>
  </id_info>
  <brief_title>Study on GD2 Positive Solid Tumors by 4SCAR-GD2</brief_title>
  <official_title>Multicenter Trial of Phase I/II Studies on GD2 Positive Solid Tumors by 4SCAR-GD2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shenzhen Geno-Immune Medical Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Shenzhen Geno-Immune Medical Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </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. The investigators are&#xD;
      attempt to treat these diseases using T cells genetically modified with a 4th generation&#xD;
      lentiviral chimeric antigen receptor (4SCAR fused with an inducible apoptotic caspase 9&#xD;
      domain) targeting GD2 (4SCAR-GD2). The 4SCAR-GD2-modified T cells can recognize and kill&#xD;
      tumor cells through the recognition of GD2, a surface protein expressed at high levels on&#xD;
      many types of tumors but not on normal tissues. This study will evaluate the side effects and&#xD;
      effective doses of 4SCAR-GD2 T cells in treating refractory and/or recurrent tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Patients with refractory and/or recurrent solid tumors have poor prognosis despite complex&#xD;
      multimodal therapy; therefore, novel curative approaches are needed. The investigators are&#xD;
      attempting to use T cells obtained directly from the patient, which can be genetically&#xD;
      modified to express a 4th generation GD2-specific chimeric antigen receptor (4SCAR-GD2). The&#xD;
      chimeric antigen receptor (CAR) molecules enable the T cells to recognize and kill tumor&#xD;
      cells through the recognition of a surface antigen, GD2, which is expressed at high levels on&#xD;
      tumor cells but not at significant levels on normal tissues. This study will evaluate the&#xD;
      side effects and the best dose of a novel 4th generation anti-GD2 CAR T cells to refractory&#xD;
      and/or recurrent solid tumors.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened through physical exam and medical history. Blood and urine&#xD;
      samples will be collected. Imaging studies or bone marrow aspirates may be performed.&#xD;
&#xD;
      Peripheral blood mononuclear cells (PBMC) will be obtained by apheresis, and T cells will be&#xD;
      activated and modified to express the 4SCAR-GD2 gene.&#xD;
&#xD;
      On Day -5 to -7, PBMC will be activated and enriched for T cells, which will be followed by&#xD;
      4SCAR-GD2 lentiviral transduction. The total culture time is approximately 5-7 days.&#xD;
&#xD;
      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 with&#xD;
      standard chemotherapy conditioning regimen.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>May 2016</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">June 2019</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 year</time_frame>
    <description>Determine the toxicity profile the 4SCAR-GD2-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>3 year</time_frame>
    <description>Disease status is defined by the biochemical markers and image scan to get the outcomes such as Complete response/remission (CR) , Very good partial response/remission (VGPR) , etc</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The expansion and persistence of anti-GD2 CAR T cells</measure>
    <time_frame>3 year</time_frame>
    <description>The investigators will monitor the expansion and functional persistence of 4SCAR-GD2 T cells in the peripheral blood of patients and the correlation with antitumor effects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune responses after anti-GD2 infusions</measure>
    <time_frame>1 year</time_frame>
    <description>assessment of lymphocyte phenotypes and anti-tumor activity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune responses after anti-GD2 infusions</measure>
    <time_frame>1 year</time_frame>
    <description>assessment of cytokine profile</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival time of the patients</measure>
    <time_frame>3 year</time_frame>
    <description>Evaluate the survival time of the patients treated with the 4SCAR-GD2 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-GD2 T cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The 4SCAR-GD2-modified T cells can recognize and kill tumor cells through the recognize of GD2 .This study will evaluate the side effects and effective doses of 4SCAR-GD2 T cells in treating refractory and recurrent solid tumors</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>4SCAR-GD2</intervention_name>
    <arm_group_label>effectiveness of 4SCAR-GD2 T cells</arm_group_label>
    <other_name>GD2-specific 4th Generation CART</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with tumors have received standard first-line therapy and been judged to be&#xD;
             non-resectable，metastatic,progressive or recurrent.&#xD;
&#xD;
          -  The GD2 antigen status of the tumor will be determined for eligibility.Positive&#xD;
             expression is defined by GD2 antibody staining results based on immunohistochemistry&#xD;
             or flow cytometry analyses.&#xD;
&#xD;
          -  Body weight greater than or equal to 10 kg.&#xD;
&#xD;
          -  Age: ≥1 year and ≤ 65 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 weeks&#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 for&#xD;
             hematologic toxicity.&#xD;
&#xD;
          -  For all patients enrolled in this study, their parents or legal guardians must sign an&#xD;
             informed consent and assent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.)&#xD;
             or major organ dysfunction, with the exception of grade 3 hematologic toxicity.&#xD;
&#xD;
          -  Untreated central nervous system (CNS) metastasis: Patients with previous CNS tumor&#xD;
             involvement that has been treated and is stable for at least 6 weeks following&#xD;
             completion of therapy are eligible.&#xD;
&#xD;
          -  Previous treatment with other genetically engineered GD2-CAR T cells.&#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>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lung-Ji Chang</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shenzhen Geno-Immune Medical Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lung-Ji Chang, PhD.</last_name>
    <phone>+86-8672-5195</phone>
    <email>c@szgimi.org</email>
  </overall_contact>
  <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>+86-13671121909</phone>
      <email>c@szgimi.org</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>December 3, 2016</study_first_submitted>
  <study_first_submitted_qc>December 13, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 14, 2016</study_first_posted>
  <last_update_submitted>February 14, 2018</last_update_submitted>
  <last_update_submitted_qc>February 14, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 19, 2018</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>Director</investigator_title>
  </responsible_party>
  <keyword>CAR</keyword>
  <keyword>chimeric antigen receptor</keyword>
  <keyword>adoptive T cell transfer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_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/NCT02992210
org study id: GIMI-IRB-16002
nct id: NCT02992210
lead sponsor: 
has dmc: Yes
Patients with refractory and/or recurrent solid tumor have poor prognosis despite complex
      multimodel therapy and therefore, novel approaches are urgently needed. The investigators are
      attempt 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 GD2 (4SCAR-GD2). The 4SCAR-GD2-modified T cells can recognize and kill
      tumor cells through the recognition of GD2, a surface protein expressed at high levels on
      many types of tumors but not on normal tissues. This study will evaluate the side effects and
      effective doses of 4SCAR-GD2 T cells 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 GD2-specific chimeric antigen receptor (4SCAR-GD2). The
      chimeric antigen receptor (CAR) molecules enable the T cells to recognize and kill tumor
      cells through the recognition of a surface antigen, GD2, which is expressed at high levels on
      tumor cells 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-GD2 CAR T cells to refractory
      and/or recurrent solid tumors.

      Design:

      Participants will be screened through physical exam and medical history. Blood and urine
      samples will be collected. Imaging studies or bone marrow aspirates may be performed.

      Peripheral blood mononuclear cells (PBMC) will be obtained by apheresis, and T cells will be
      activated and modified to express the 4SCAR-GD2 gene.

      On Day -5 to -7, PBMC will be activated and enriched for T cells, which will be followed by
      4SCAR-GD2 lentiviral transduction. The total culture time is approximately 5-7 days.

      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.
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 year
description: Determine the toxicity profile the 4SCAR-GD2-modified T cells with Common Toxicity Criteria for Adverse Effects version 4.0
measure: Anti-tumor effects
time frame: 3 year
description: Disease status is defined by the biochemical markers and image scan to get the outcomes such as Complete response/remission (CR) , Very good partial response/remission (VGPR) , etc
measure: The expansion and persistence of anti-GD2 CAR T cells
time frame: 3 year
description: The investigators will monitor the expansion and functional persistence of 4SCAR-GD2 T cells in the peripheral blood of patients and the correlation with antitumor effects
measure: Immune responses after anti-GD2 infusions
time frame: 1 year
description: assessment of lymphocyte phenotypes and anti-tumor activity
measure: Immune responses after anti-GD2 infusions
time frame: 1 year
description: assessment of cytokine profile
measure: Survival time of the patients
time frame: 3 year
description: Evaluate the survival time of the patients treated with the 4SCAR-GD2 T cells, including progression free survival (PFS) and overall survival (OS)
arm group label: effectiveness of 4SCAR-GD2 T cells
arm group type: Experimental
description: The 4SCAR-GD2-modified T cells can recognize and kill tumor cells through the recognize of GD2 .This study will evaluate the side effects and effective doses of 4SCAR-GD2 T cells in treating refractory and recurrent solid tumors
intervention type: Genetic
intervention name: 4SCAR-GD2
arm group label: effectiveness of 4SCAR-GD2 T cells
other name: GD2-specific 4th Generation CART
criteria: 
gender: All
minimum age: 1 Year
maximum age: 65 Years
healthy volunteers: No
last name: Lung-Ji Chang
role: Principal Investigator
affiliation: Shenzhen Geno-Immune Medical Institute
last name: Lung-Ji Chang, PhD.
phone: +86-8672-5195
email: c@szgimi.org
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: Director
mesh term: Neoplasms