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GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma (GINAKIT2)

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ClinicalTrials.gov Identifier: NCT03294954
Recruitment Status : Recruiting
First Posted : September 27, 2017
Last Update Posted : September 11, 2018
Sponsor:
Collaborators:
Center for Cell and Gene Therapy, Baylor College of Medicine
Texas Children's Hospital
Information provided by (Responsible Party):
Andras Heczey, Baylor College of Medicine

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Neuroblastoma Genetic: GINAKIT Cells Drug: Cyclophosphamide Drug: Fludarabine Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: GD2 Specific Chimeric Antigen Receptor (CAR) and Interleukin-15 Expressing Autologous Natural Killer T-cells to Treat Children With Neuroblastoma
Actual Study Start Date : January 18, 2018
Estimated Primary Completion Date : September 10, 2019
Estimated Study Completion Date : August 10, 2034


Arm Intervention/treatment
Experimental: GINAKIT cells + cytoxan + fludara

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

Genetic: GINAKIT Cells

Four 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

Drug: Cyclophosphamide
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.
Other Name: Cytoxan

Drug: Fludarabine
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.
Other Name: Fludara




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. Anti-tumor response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma. [ Time Frame: 15 years ]
    Summarize tumor response by calculating overall response rates and report the Kaplan-Meier curves for the relapse-free survival.


Other Outcome Measures:
  1. Immunologic response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma. [ Time Frame: 15 years ]
    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.



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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Serum creatinine normal for age
  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. Serum creatinine normal for age
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03294954


Contacts
Contact: Andras Heczey, MD 832-824-4233 axheczey@txch.org

Locations
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Andras Heczey, MD    832-824-4233    axheczey@txch.org   
Sponsors and Collaborators
Baylor College of Medicine
Center for Cell and Gene Therapy, Baylor College of Medicine
Texas Children's Hospital
Investigators
Principal Investigator: Andras Heczey, MD Baylor College of Medicine

Responsible Party: Andras Heczey, Assistant Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT03294954     History of Changes
Other Study ID Numbers: GINAKIT2
First Posted: September 27, 2017    Key Record Dates
Last Update Posted: September 11, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Andras Heczey, Baylor College of Medicine:
Neuroblastoma
Natural Killer T-Cells
Chimerical Antigen Receptor

Additional relevant MeSH terms:
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites