Clinical Trials /

GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma

NCT03294954

Description:

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.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma
  • Official Title: GD2 Specific Chimeric Antigen Receptor (CAR) and Interleukin-15 Expressing Autologous Natural Killer T-cells to Treat Children With Neuroblastoma

Clinical Trial IDs

  • ORG STUDY ID: GINAKIT2
  • NCT ID: NCT03294954

Conditions

  • Neuroblastoma

Interventions

DrugSynonymsArms
CyclophosphamideCytoxanGINAKIT cells + cytoxan + fludara
FludarabineFludaraGINAKIT cells + cytoxan + fludara

Purpose

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.

Detailed Description

      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 4 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 4 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

        -  Measurements of your tumor by routine imaging studies and bone marrow evaluation within
           4 weeks (preferably 2 weeks) before treatment study entry (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.
    

Trial Arms

NameTypeDescriptionInterventions
GINAKIT cells + cytoxan + fludaraExperimentalCyclophosphamide 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
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Procurement Inclusion Criteria:

          1. Relapsed or refractory high risk neuroblastoma

          2. Life expectancy of at least 12 weeks

          3. Age greater than 1 year and less than 21 years old

          4. Karnofsky/Lansky score of 60% or greater

          5. Absence of HAMA prior to enrollment (only in patients that have been previously
             treated with murine antibodies)

          6. Ability to tolerate leukocyte apheresis

          7. Informed consent and assent (as applicable) obtained from parent/guardian and child.

          8. Patients must have an ANC greater than or equal to 500/µl #, platelet count greater
             than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count
             greater than or equal to 20,000/µl.

          9. Pulse Ox greater than or equal to 90% on room air

         10. Serum AST less than 3 times the upper limit of normal

         11. Total Bilirubin less than 1.5 times the upper limit of normal

         12. Creatinine < 1.5 upper limit of normal

         13. Recovered from the acute toxic effects of all prior chemotherapy based on the
             enrolling physician's assessment (if some effects of chemotherapy are expected to last
             long term, patient is eligible if meeting other eligibility criteria).

         14. Weight greater than 12kg

        Procurement Exclusion Criteria:

          1. Rapidly progressive disease

          2. History or hypersensitivity to murine protein-containing products

          3. Tumor causing airway obstruction

          4. Currently receiving immunosuppressive drugs such as corticosteroids$, tacrolimus or
             cyclosporine

          5. Severe previous toxicity from cyclophosphamide or fludarabine based on the enrolling
             physician's assessment

          6. HIV infection

               -  ANC ≥ 500 without the use G-CSF or GM-CSF for at least 48hrs. $: Patients may
                  receive treatment if treated with corticosteroids with dose of less than
                  0.5mg/kg/day of prednisone equivalent.

        Treatment Inclusion Criteria:

          1. Relapsed or refractory high risk neuroblastoma

          2. Life expectancy of at least 12 weeks

          3. Age greater than 1 year and less than 21 years old

          4. Karnofsky/Lansky score of 60% or greater

          5. Patients must have an ANC greater than or equal to 500/µl #, platelet count greater
             than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count
             greater than or equal to 20,000/µl.

          6. Pulse Ox greater than or equal to 90% on room air

          7. Serum AST less than 3 times the upper limit of normal

          8. Pulse Bilirubin less than 1.5 times the upper limit of normal

          9. Creatinine < 1.5 upper limit of normal

         10. Recovered from the acute toxic effects of all prior chemotherapy based on the
             enrolling physician's assessment (if some effects of chemotherapy are expected to last
             long term, patient is eligible if meeting other eligibility criteria and expected to
             tolerate lymphodepletion).

         11. Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who
             have received prior therapy with murine antibodies

         12. Patients must have autologous transduced NKTs with greater than or equal to 20%
             expression of GD2-specific CAR.

         13. Informed consent and assent (as applicable) obtained from parent/guardian and child.

         14. Weight greater than 12kg

        Treatment Exclusion Criteria:

          1. Rapidly progressive disease

          2. Currently receiving any investigational drugs

          3. History or hypersensitivity to murine protein-containing products

          4. Cardiomegaly or bilateral pulmonary infiltrates on chest radiograph or CT. However,
             patients with cardiomegaly on imaging may be enrolled if they have an assessment of
             cardiac function (i.e., ECHO or MUGA) within 3 weeks of starting protocol therapy that
             is within normal limits. Additionally, patients with bilateral pulmonary infiltrates
             on imaging may be enrolled if the lesions are not consistent with active neuroblastoma
             (i.e., negative on functional imaging with PET or MIBG, or by pathologic assessment).

          5. Tumor potentially causing airway obstruction

          6. Pregnancy or lactation or not willing to use birth control

          7. Currently receiving immunosuppressive drugs such as corticosteroids$, tacrolimus or
             cyclosporine

          8. Severe previous toxicity form cyclophosphamide or fludarabine based on the enrolling
             physician's assessment

          9. HIV infection

               -  All labs must be collected within 10 days prior to initiation of study related
                  treatment (except for verification of GD2 transduction) #: ANC ≥ 500/µl without
                  the use G-CSF or GM-CSF for at least 48hrs. $: Patients may receive treatment if
                  treated with corticosteroids with dose of less than 0.5mg/kg/day of prednisone
                  equivalent.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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
Safety Issue:
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.

Secondary Outcome Measures

Measure:Anti-tumor response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma.
Time Frame:15 years
Safety Issue:
Description:Summarize tumor response by calculating overall response rates and report the Kaplan-Meier curves for the relapse-free survival.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Baylor College of Medicine

Trial Keywords

  • Neuroblastoma
  • Natural Killer T-Cells
  • Chimerical Antigen Receptor

Last Updated

July 19, 2019