<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/NCT03294954</url>
  </required_header>
  <id_info>
    <org_study_id>H-41033 GINAKIT2</org_study_id>
    <nct_id>NCT03294954</nct_id>
  </id_info>
  <brief_title>GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma</brief_title>
  <acronym>GINAKIT2</acronym>
  <official_title>GD2 Specific Chimeric Antigen Receptor (CAR) and Interleukin-15 Expressing Autologous Natural Killer T-cells to Treat Children With Neuroblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Center for Cell and Gene Therapy, Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Baylor College of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study combines two different ways of fighting cancer: antibodies and Natural&#xD;
      Killer T cells (NKT). Antibodies are types of proteins that protect the body from infectious&#xD;
      diseases and possibly cancer. T cells, also called T lymphocytes, are special white blood&#xD;
      cells that can kill other cells, including cells infected with viruses and tumor cells. Both&#xD;
      antibodies and T cells have been used to treat patients with cancers. Investigators have&#xD;
      found from previous research that they can put a new gene into T cells that will make them&#xD;
      recognize cancer cells and kill them. In a previous clinical trial, investigators made&#xD;
      artificial genes called a chimeric antigen receptors (CAR), from an antibody called 14g2a&#xD;
      that recognizes GD2, a molecule found on almost all neuroblastoma cells (GD2-CAR).&#xD;
      Investigators put these genes into the patients' own T cells and gave them back to patients&#xD;
      that had neuroblastoma.&#xD;
&#xD;
      NKT cells are another special subgroup of white blood cells that can specifically go into&#xD;
      tumor tissue of neuroblastoma. Inside the tumor, there are other white blood cells called&#xD;
      macrophages which help the cancer cells to grow and recover from injury. NKT cells can&#xD;
      specifically kill these macrophages and slow the tumor growth.&#xD;
&#xD;
      We will expand NKT cells and add GD2-specific chimeric antigen receptors to the cells. We&#xD;
      think these cells might be better able to attack NB since they also work by destroying the&#xD;
      macrophages that allows the tumor to grow. The chimeric antigen receptor will also contain a&#xD;
      gene segment to make the NKT cells last longer. This gene segment is called CD28. In&#xD;
      addition, to further improve the antitumor activity of the GINAKIT cells we added another&#xD;
      gene expressing a molecule called Interleukin -15 (IL-15). The combination of these 3&#xD;
      components showed the most antitumor activity by CAR expressing NKT cells and improved these&#xD;
      cells' survival in animal models.&#xD;
&#xD;
      GD2-CAR expressing NKTs have not been tested in patients so far. The purpose of this study is&#xD;
      to find the largest effective and safe dose of GD2-CAR NKT cells (GINAKIT cells), to evaluate&#xD;
      their effect on the tumor and how long they can be detected in the patient's blood and what&#xD;
      affect they have on the patient's neuroblastoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this study the first step is to collect blood from the patient to make the GINAKIT cells.&#xD;
      Once the GINAKIT cells are made they will be administered to the patient.&#xD;
&#xD;
      This is a dose escalation study. This means that at the beginning, patients will be started&#xD;
      on the lowest dose (1 of 6 different levels) of GINAKIT cells. Once that dose schedule proves&#xD;
      safe, the next group of patients will be started at a higher dose. This process will continue&#xD;
      until all 6 dose levels are studied. If the side effects are too severe, the dose will be&#xD;
      lowered or the infusions will be stopped.&#xD;
&#xD;
      Before getting the GINAKIT cells, the patient will receive cyclophosphamide and fludarabine&#xD;
      intravenously (through a needle inserted into a vein or the patient's port-a-cath) for 2 days&#xD;
      and then fludarabine alone for one more day. The patient will then have one day of rest with&#xD;
      no chemotherapy before receiving the GINAKIT cells.&#xD;
&#xD;
      The patient will be given an injection of GINAKIT cells into the vein through an IV line at&#xD;
      the assigned dose. Before the patient receives the injection, they may be given a dose of&#xD;
      Benadryl (diphenhydramine) and Tylenol (acetaminophen). The injection will take up to 10&#xD;
      minutes. The patient will be monitored in the clinic after the injection for about 4 hours.&#xD;
      The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's&#xD;
      Hospital.&#xD;
&#xD;
      The patient will need to stay in Houston for 4 weeks after the infusion so investigators can&#xD;
      monitor the patient for side effects. The patient will have follow-up visits (at weeks 1, 2,&#xD;
      3, 4 and 8; months 3, 6, 9, and 12; twice a year for 4 years and then once a year for the&#xD;
      next 10 years - for a total of 15 years) and scheduled disease evaluations after the GINAKIT&#xD;
      cell infusion (at week 6 and then as clinically needed).&#xD;
&#xD;
      Before being treated, the patient will receive a series of standard medical tests as follows:&#xD;
&#xD;
        -  Physical exam&#xD;
&#xD;
        -  Blood tests to measure blood cells, kidney and liver function&#xD;
&#xD;
        -  Buccal swabs (cheek scraping)&#xD;
&#xD;
        -  Measurements of your tumor by routine imaging studies and bone marrow evaluation within&#xD;
           4 weeks (preferably 2 weeks) before start of lymphodepletion (no other cancer treatment&#xD;
           should be given after these studies and the GINAKIT cell infusion). Imaging studies that&#xD;
           have been used in the past to best assess your tumor will be used (Computer Tomogram&#xD;
           (CT) or Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET/CT),&#xD;
           and/or MIBG scan). A PET scan is an imaging test that uses radioactive material to look&#xD;
           for disease in the body. A MIBG scan is an imaging test that uses radioactive material&#xD;
           and a special scanner to find or confirm the presence of neuroblastoma.&#xD;
&#xD;
      The patient will receive standard medical tests when they are getting the infusions and&#xD;
      afterwards as follows:&#xD;
&#xD;
        -  Physical exams&#xD;
&#xD;
        -  Blood tests to measure blood cells counts, kidney and liver function.&#xD;
&#xD;
        -  Measurements of the patient's tumor by routine imaging studies 4-6 weeks after the&#xD;
           infusion.&#xD;
&#xD;
        -  Tumor biopsy at 2 weeks and between 4-6 weeks after the infusion and as clinically&#xD;
           indicated thereafter. The evaluation at week 2 after the infusion is for research only&#xD;
           and is done to see whether or not there are GINAKIT cells in the tumor. For all&#xD;
           clinically indicated tumor biopsies a portion of the sample for research will be&#xD;
           requested.&#xD;
&#xD;
        -  If a tumor was in the bone marrow at the time of treatment, the procedure will be&#xD;
           repeated at 2 weeks and between 4-6 weeks after the infusion and as clinically indicated&#xD;
           thereafter. The evaluation at week 2 after the infusion is for research only and is done&#xD;
           to see whether or not there are GINAKIT cells in the bone marrow. For all clinically&#xD;
           indicated bone marrow collections a portion of the sample for research will be&#xD;
           requested.&#xD;
&#xD;
      To learn more about the way the GINAKIT cells are working and how long they last in the body,&#xD;
      an extra amount of blood will be obtained before the chemotherapy, on the day of the GINAKIT&#xD;
      cell infusion (before and at the end of the infusion), 1, 2, 3, 4 and 8 weeks after the&#xD;
      GINAKIT cell infusion, every 3 months for the 1st year, every 6 months for the next 4 years&#xD;
      and then once a year for the next 10 years (for a total of 15 years). The amount of blood&#xD;
      taken will be based on the patient's weight with up to a maximum of 60 ml (12 teaspoons) of&#xD;
      blood to be obtained at any one time. For children, the total amount of blood drawn will not&#xD;
      be more than 3 ml (less than 1 teaspoon) per 1 kg of body weight on any given day. This&#xD;
      volume is considered safe, but may be decreased if the patient is anemic (have a low red&#xD;
      blood cell count).&#xD;
&#xD;
      During the time points listed above, if the GINAKIT cells are found in the patient's blood at&#xD;
      a certain amount, an extra 5ml of blood may need to be collected for additional testing.&#xD;
&#xD;
      If the patient has a procedure where tumor samples are obtained, investigators will request a&#xD;
      sample to be used for research purposes.&#xD;
&#xD;
      If the patient develops a second abnormal growth, significant blood or nervous system&#xD;
      disorder during the trial, a biopsy sample of the tissue will be tested (if a sample can be&#xD;
      obtained).&#xD;
&#xD;
      The patient will receive supportive care for any acute or chronic toxicities, including blood&#xD;
      components or antibiotics, and other intervention as appropriate.&#xD;
&#xD;
      Because the patient will receive cells with a new gene in them they will be followed for a&#xD;
      total of 15 years to see if there are any long term side effects of gene transfer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 18, 2018</start_date>
  <completion_date type="Anticipated">August 10, 2040</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2025</primary_completion_date>
  <phase>Phase 1</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>Maximum tolerated dose of autologous NKTs expressing a 2nd generation GD2-specific chimeric antigen receptor administered to patients with relapsed or refractory neuroblastoma.</measure>
    <time_frame>28 days</time_frame>
    <description>Defined as the highest dose level that will have at most a 33% chance of inducing the following NKT-cell-related dose limiting toxicities (DLTs) within 28 days after infusion of NKTs.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Anti-tumor response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma.</measure>
    <time_frame>15 years</time_frame>
    <description>Summarize tumor response by calculating overall response rates and report the Kaplan-Meier curves for the relapse-free survival.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Immunologic response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma.</measure>
    <time_frame>15 years</time_frame>
    <description>Summarize at pre- and post-infusion time points using descriptive statistics to evaluate their expansion and persistence. Changes in each of these NKTs from pre-infusion to each time point of post-infusion will be assessed and compared.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>Neuroblastoma</condition>
  <arm_group>
    <arm_group_label>GINAKIT cells + cytoxan + fludara</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cyclophosphamide and fludarabine will be administered prior to the GINAKIT cells.&#xD;
Day -4: Cyclophosphamide and Fludarabine&#xD;
Day -3: Cyclophosphamide and Fludarabine&#xD;
Day -2: Fludarabine&#xD;
Day -1: Rest&#xD;
Day 0: GINAKIT cells</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>GINAKIT Cells</intervention_name>
    <description>Six dose levels of GINAKIT cells will be studied. Dosing will be based on the actual number of transduced cells. All doses are per m2.&#xD;
Dose Level 1 = 3 x 10^6&#xD;
Dose Level 2 = 1 x 10^7&#xD;
Dose Level 3 = 3 x 10^7&#xD;
Dose Level 4 = 1 x 10^8&#xD;
Dose Level 5 = 3 x 10^8&#xD;
Dose Level 6 = 1 x 10^9</description>
    <arm_group_label>GINAKIT cells + cytoxan + fludara</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Cyclophosphamide (500 mg/m2/day) will be given for 2 days; given on day -4 and day -3 with GINAKIT cells given on day 0.</description>
    <arm_group_label>GINAKIT cells + cytoxan + fludara</arm_group_label>
    <other_name>Cytoxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>Fludarabine (30 mg/m2/day) will be given for 3 days; given on day -4, day -3 and day -2 with GINAKIT cells given on day 0.</description>
    <arm_group_label>GINAKIT cells + cytoxan + fludara</arm_group_label>
    <other_name>Fludara</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Procurement Inclusion Criteria:&#xD;
&#xD;
          1. Relapsed or refractory high risk neuroblastoma&#xD;
&#xD;
          2. Life expectancy of at least 12 weeks&#xD;
&#xD;
          3. Age greater than 1 year and less than 21 years old&#xD;
&#xD;
          4. Karnofsky/Lansky score of 60% or greater&#xD;
&#xD;
          5. Absence of HAMA prior to enrollment (only in patients that have been previously&#xD;
             treated with murine antibodies)&#xD;
&#xD;
          6. Ability to tolerate leukocyte apheresis&#xD;
&#xD;
          7. Informed consent and assent (as applicable) obtained from parent/guardian and child.&#xD;
&#xD;
          8. Patients must have an ANC greater than or equal to 500/µl$, platelet count greater&#xD;
             than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count&#xD;
             greater than or equal to 20,000/µl.&#xD;
&#xD;
          9. Pulse Ox greater than or equal to 90% on room air&#xD;
&#xD;
         10. Serum AST less than 3 times the upper limit of normal&#xD;
&#xD;
         11. Total Bilirubin less than 1.5 times the upper limit of normal&#xD;
&#xD;
         12. Creatinine &lt; 1.5 times the upper limit of normal&#xD;
&#xD;
         13. Recovered from the acute toxic effects of all prior chemotherapy based on the&#xD;
             enrolling physician's assessment (if some effects of chemotherapy are expected to last&#xD;
             long term, patient is eligible if meeting other eligibility criteria).&#xD;
&#xD;
         14. Weight greater than 12kg&#xD;
&#xD;
        Procurement Exclusion Criteria:&#xD;
&#xD;
          1. Rapidly progressive disease&#xD;
&#xD;
          2. History or hypersensitivity to murine protein-containing products&#xD;
&#xD;
          3. Tumor causing airway obstruction&#xD;
&#xD;
          4. Currently receiving immunosuppressive drugs such as corticosteroids$$, tacrolimus or&#xD;
             cyclosporine&#xD;
&#xD;
          5. Severe previous toxicity from cyclophosphamide or fludarabine based on the enrolling&#xD;
             physician's assessment&#xD;
&#xD;
          6. HIV infection&#xD;
&#xD;
        $ : ANC ≥ 500 without the use G-CSF or GM-CSF for at least 48hrs.&#xD;
&#xD;
        $$ : Patients may receive treatment if treated with corticosteroids with dose of less than&#xD;
        0.5mg/kg/day of prednisone equivalent.&#xD;
&#xD;
        Treatment Inclusion Criteria:&#xD;
&#xD;
          1. Relapsed or refractory high risk neuroblastoma&#xD;
&#xD;
          2. Life expectancy of at least 12 weeks&#xD;
&#xD;
          3. Age greater than 1 year and less than 21 years old&#xD;
&#xD;
          4. Karnofsky/Lansky score of 60% or greater&#xD;
&#xD;
          5. Patients must have an ANC greater than or equal to 500/µl #, platelet count greater&#xD;
             than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count&#xD;
             greater than or equal to 20,000/µl.&#xD;
&#xD;
          6. Pulse Ox greater than or equal to 90% on room air&#xD;
&#xD;
          7. Serum AST less than 3 times the upper limit of normal&#xD;
&#xD;
          8. Total Bilirubin less than 1.5 times the upper limit of normal&#xD;
&#xD;
          9. Creatinine &lt; 1.5 times the upper limit of normal&#xD;
&#xD;
         10. Recovered from the acute toxic effects of all prior chemotherapy based on the&#xD;
             enrolling physician's assessment (if some effects of chemotherapy are expected to last&#xD;
             long term, patient is eligible if meeting other eligibility criteria and expected to&#xD;
             tolerate lymphodepletion).&#xD;
&#xD;
         11. Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who&#xD;
             have received prior therapy with murine antibodies&#xD;
&#xD;
         12. Patients must have autologous transduced NKTs with greater than or equal to 20%&#xD;
             expression of GD2-specific CAR.&#xD;
&#xD;
         13. Informed consent and assent (as applicable) obtained from parent/guardian and child.&#xD;
&#xD;
         14. Weight greater than 12kg&#xD;
&#xD;
        Treatment Exclusion Criteria:&#xD;
&#xD;
          1. Rapidly progressive disease&#xD;
&#xD;
          2. Currently receiving any investigational drugs&#xD;
&#xD;
          3. History or hypersensitivity to murine protein-containing products&#xD;
&#xD;
          4. Cardiomegaly or bilateral pulmonary infiltrates on chest radiograph or CT. However,&#xD;
             patients with cardiomegaly on imaging may be enrolled if they have an assessment of&#xD;
             cardiac function (i.e., ECHO or MUGA) within 3 weeks of starting protocol therapy that&#xD;
             is within normal limits. Additionally, patients with bilateral pulmonary infiltrates&#xD;
             on imaging may be enrolled if the lesions are not consistent with active neuroblastoma&#xD;
             (i.e., negative on functional imaging with PET or MIBG, or by pathologic assessment).&#xD;
&#xD;
          5. Tumor potentially causing airway obstruction&#xD;
&#xD;
          6. Pregnancy or lactation or not willing to use birth control&#xD;
&#xD;
          7. Currently receiving immunosuppressive drugs such as corticosteroids$, tacrolimus or&#xD;
             cyclosporine&#xD;
&#xD;
          8. Severe previous toxicity form cyclophosphamide or fludarabine based on the enrolling&#xD;
             physician's assessment&#xD;
&#xD;
          9. HIV infection&#xD;
&#xD;
               -  All labs must be collected within 10 days prior to initiation of study related&#xD;
                  treatment (except for verification of GD2 transduction) #: ANC ≥ 500/µl without&#xD;
                  the use G-CSF or GM-CSF for at least 48hrs. $: Patients may receive treatment if&#xD;
                  treated with corticosteroids with dose of less than 0.5mg/kg/day of prednisone&#xD;
                  equivalent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andras Heczey, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baylor College of Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Andras Heczey, MD</last_name>
    <phone>832-824-4233</phone>
    <email>axheczey@txch.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ramy Sweidan</last_name>
    <email>rxsweida@texaschildrens.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Texas Children's Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andras Heczey, MD</last_name>
      <phone>832-824-4233</phone>
      <email>axheczey@txch.org</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>September 20, 2017</study_first_submitted>
  <study_first_submitted_qc>September 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <last_update_submitted>July 27, 2023</last_update_submitted>
  <last_update_submitted_qc>July 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Baylor College of Medicine</investigator_affiliation>
    <investigator_full_name>Andras Heczey</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Neuroblastoma</keyword>
  <keyword>Natural Killer T-Cells</keyword>
  <keyword>Chimerical Antigen Receptor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Fludarabine</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/NCT03294954
org study id: H-41033 GINAKIT2
nct id: NCT03294954
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This research study combines two different ways of fighting cancer: antibodies and Natural
      Killer T cells (NKT). Antibodies are types of proteins that protect the body from infectious
      diseases and possibly cancer. T cells, also called T lymphocytes, are special white blood
      cells that can kill other cells, including cells infected with viruses and tumor cells. Both
      antibodies and T cells have been used to treat patients with cancers. Investigators have
      found from previous research that they can put a new gene into T cells that will make them
      recognize cancer cells and kill them. In a previous clinical trial, investigators made
      artificial genes called a chimeric antigen receptors (CAR), from an antibody called 14g2a
      that recognizes GD2, a molecule found on almost all neuroblastoma cells (GD2-CAR).
      Investigators put these genes into the patients' own T cells and gave them back to patients
      that had neuroblastoma.

      NKT cells are another special subgroup of white blood cells that can specifically go into
      tumor tissue of neuroblastoma. Inside the tumor, there are other white blood cells called
      macrophages which help the cancer cells to grow and recover from injury. NKT cells can
      specifically kill these macrophages and slow the tumor growth.

      We will expand NKT cells and add GD2-specific chimeric antigen receptors to the cells. We
      think these cells might be better able to attack NB since they also work by destroying the
      macrophages that allows the tumor to grow. The chimeric antigen receptor will also contain a
      gene segment to make the NKT cells last longer. This gene segment is called CD28. In
      addition, to further improve the antitumor activity of the GINAKIT cells we added another
      gene expressing a molecule called Interleukin -15 (IL-15). The combination of these 3
      components showed the most antitumor activity by CAR expressing NKT cells and improved these
      cells' survival in animal models.

      GD2-CAR expressing NKTs have not been tested in patients so far. The purpose of this study is
      to find the largest effective and safe dose of GD2-CAR NKT cells (GINAKIT cells), to evaluate
      their effect on the tumor and how long they can be detected in the patient's blood and what
      affect they have on the patient's neuroblastoma.
In this study the first step is to collect blood from the patient to make the GINAKIT cells.
      Once the GINAKIT cells are made they will be administered to the patient.

      This is a dose escalation study. This means that at the beginning, patients will be started
      on the lowest dose (1 of 6 different levels) of GINAKIT cells. Once that dose schedule proves
      safe, the next group of patients will be started at a higher dose. This process will continue
      until all 6 dose levels are studied. If the side effects are too severe, the dose will be
      lowered or the infusions will be stopped.

      Before getting the GINAKIT cells, the patient will receive cyclophosphamide and fludarabine
      intravenously (through a needle inserted into a vein or the patient's port-a-cath) for 2 days
      and then fludarabine alone for one more day. The patient will then have one day of rest with
      no chemotherapy before receiving the GINAKIT cells.

      The patient will be given an injection of GINAKIT cells into the vein through an IV line at
      the assigned dose. Before the patient receives the injection, they may be given a dose of
      Benadryl (diphenhydramine) and Tylenol (acetaminophen). The injection will take up to 10
      minutes. The patient will be monitored in the clinic after the injection for about 4 hours.
      The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's
      Hospital.

      The patient will need to stay in Houston for 4 weeks after the infusion so investigators can
      monitor the patient for side effects. The patient will have follow-up visits (at weeks 1, 2,
      3, 4 and 8; months 3, 6, 9, and 12; twice a year for 4 years and then once a year for the
      next 10 years - for a total of 15 years) and scheduled disease evaluations after the GINAKIT
      cell infusion (at week 6 and then as clinically needed).

      Before being treated, the patient will receive a series of standard medical tests as follows:

        -  Physical exam

        -  Blood tests to measure blood cells, kidney and liver function

        -  Buccal swabs (cheek scraping)

        -  Measurements of your tumor by routine imaging studies and bone marrow evaluation within
           4 weeks (preferably 2 weeks) before start of lymphodepletion (no other cancer treatment
           should be given after these studies and the GINAKIT cell infusion). Imaging studies that
           have been used in the past to best assess your tumor will be used (Computer Tomogram
           (CT) or Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET/CT),
           and/or MIBG scan). A PET scan is an imaging test that uses radioactive material to look
           for disease in the body. A MIBG scan is an imaging test that uses radioactive material
           and a special scanner to find or confirm the presence of neuroblastoma.

      The patient will receive standard medical tests when they are getting the infusions and
      afterwards as follows:

        -  Physical exams

        -  Blood tests to measure blood cells counts, kidney and liver function.

        -  Measurements of the patient's tumor by routine imaging studies 4-6 weeks after the
           infusion.

        -  Tumor biopsy at 2 weeks and between 4-6 weeks after the infusion and as clinically
           indicated thereafter. The evaluation at week 2 after the infusion is for research only
           and is done to see whether or not there are GINAKIT cells in the tumor. For all
           clinically indicated tumor biopsies a portion of the sample for research will be
           requested.

        -  If a tumor was in the bone marrow at the time of treatment, the procedure will be
           repeated at 2 weeks and between 4-6 weeks after the infusion and as clinically indicated
           thereafter. The evaluation at week 2 after the infusion is for research only and is done
           to see whether or not there are GINAKIT cells in the bone marrow. For all clinically
           indicated bone marrow collections a portion of the sample for research will be
           requested.

      To learn more about the way the GINAKIT cells are working and how long they last in the body,
      an extra amount of blood will be obtained before the chemotherapy, on the day of the GINAKIT
      cell infusion (before and at the end of the infusion), 1, 2, 3, 4 and 8 weeks after the
      GINAKIT cell infusion, every 3 months for the 1st year, every 6 months for the next 4 years
      and then once a year for the next 10 years (for a total of 15 years). The amount of blood
      taken will be based on the patient's weight with up to a maximum of 60 ml (12 teaspoons) of
      blood to be obtained at any one time. For children, the total amount of blood drawn will not
      be more than 3 ml (less than 1 teaspoon) per 1 kg of body weight on any given day. This
      volume is considered safe, but may be decreased if the patient is anemic (have a low red
      blood cell count).

      During the time points listed above, if the GINAKIT cells are found in the patient's blood at
      a certain amount, an extra 5ml of blood may need to be collected for additional testing.

      If the patient has a procedure where tumor samples are obtained, investigators will request a
      sample to be used for research purposes.

      If the patient develops a second abnormal growth, significant blood or nervous system
      disorder during the trial, a biopsy sample of the tissue will be tested (if a sample can be
      obtained).

      The patient will receive supportive care for any acute or chronic toxicities, including blood
      components or antibiotics, and other intervention as appropriate.

      Because the patient will receive cells with a new gene in them they will be followed for a
      total of 15 years to see if there are any long term side effects of gene transfer.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of autologous NKTs expressing a 2nd generation GD2-specific chimeric antigen receptor administered to patients with relapsed or refractory neuroblastoma.
time frame: 28 days
description: Defined as the highest dose level that will have at most a 33% chance of inducing the following NKT-cell-related dose limiting toxicities (DLTs) within 28 days after infusion of NKTs.
measure: Anti-tumor response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma.
time frame: 15 years
description: Summarize tumor response by calculating overall response rates and report the Kaplan-Meier curves for the relapse-free survival.
measure: Immunologic response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma.
time frame: 15 years
description: Summarize at pre- and post-infusion time points using descriptive statistics to evaluate their expansion and persistence. Changes in each of these NKTs from pre-infusion to each time point of post-infusion will be assessed and compared.
arm group label: GINAKIT cells + cytoxan + fludara
arm group type: Experimental
description: Cyclophosphamide and fludarabine will be administered prior to the GINAKIT cells.
Day -4: Cyclophosphamide and Fludarabine
Day -3: Cyclophosphamide and Fludarabine
Day -2: Fludarabine
Day -1: Rest
Day 0: GINAKIT cells
intervention type: Genetic
intervention name: GINAKIT Cells
description: Six dose levels of GINAKIT cells will be studied. Dosing will be based on the actual number of transduced cells. All doses are per m2.
Dose Level 1 = 3 x 10^6
Dose Level 2 = 1 x 10^7
Dose Level 3 = 3 x 10^7
Dose Level 4 = 1 x 10^8
Dose Level 5 = 3 x 10^8
Dose Level 6 = 1 x 10^9
arm group label: GINAKIT cells + cytoxan + fludara
intervention type: Drug
intervention name: Cyclophosphamide
description: Cyclophosphamide (500 mg/m2/day) will be given for 2 days; given on day -4 and day -3 with GINAKIT cells given on day 0.
arm group label: GINAKIT cells + cytoxan + fludara
other name: Cytoxan
intervention type: Drug
intervention name: Fludarabine
description: Fludarabine (30 mg/m2/day) will be given for 3 days; given on day -4, day -3 and day -2 with GINAKIT cells given on day 0.
arm group label: GINAKIT cells + cytoxan + fludara
other name: Fludara
criteria: 
gender: All
minimum age: 1 Year
maximum age: 21 Years
healthy volunteers: No
last name: Andras Heczey, MD
role: Principal Investigator
affiliation: Baylor College of Medicine
last name: Andras Heczey, MD
phone: 832-824-4233
email: axheczey@txch.org
last name: Ramy Sweidan
email: rxsweida@texaschildrens.org
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Baylor College of Medicine
investigator full name: Andras Heczey
investigator title: Assistant Professor
mesh term: Neuroblastoma
mesh term: Cyclophosphamide
mesh term: Fludarabine