Modified Immune Cells (GD2 Specific Chimeric Antigen Receptor and IL-15 Expressing Autologous Natural Killer T-Cells) in Treating Children with Relapsed or Refractory Neuroblastoma

Status: Active

Description

This phase I trial studies the best dose and side effects of GD2 specific chimeric antigen receptor (CAR) and interleukin-15 (IL-15) expressing autologous natural killer T-cells (G28z.15 NKTs) in treating children with neuroblastoma that has come back or does not respond to treatment. This trial combines two different ways of fighting cancer: antibodies and natural killer T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. GD2-CAR natural killer T cells are modified immune cells that have been engineered in the laboratory to specifically target GD2 proteins found on neuroblastoma tumor cells and kill them. IL-15 is critical for the development and maintenance of T cells. These new cells may be able to slow the growth of tumor cells in patients with neuroblastoma.

Eligibility Criteria

Inclusion Criteria

  • PROCUREMENT: Relapsed or refractory high risk neuroblastoma.
  • PROCUREMENT: Life expectancy of at least 12 weeks.
  • PROCUREMENT: Karnofsky/Lansky score of 60% or greater.
  • PROCUREMENT: Absence of human anti-mouse antibodies (HAMA) prior to enrollment (only in patients that have been previously treated with murine antibodies).
  • PROCUREMENT: Ability to tolerate leukocyte apheresis.
  • PROCUREMENT: Informed consent and assent (as applicable) obtained from parent/guardian and child.
  • PROCUREMENT: Absolute neutrophil count (ANC) >= 500/ul. * ANC >= 500 without the use granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) for at least 48 hours (hrs).
  • PROCUREMENT: Platelet count >= 20,000/ul. * Patients may be transfused to obtain a platelet count >= 20,000/ul.
  • PROCUREMENT: Pulse oxygen (Ox) >= 90% on room air.
  • PROCUREMENT: Serum aspartate aminotransferase (AST) less than 3 times the upper limit of normal.
  • PROCUREMENT: Total bilirubin less than 1.5 times the upper limit of normal.
  • PROCUREMENT: Creatinine < 1.5 upper limit of normal.
  • PROCUREMENT: 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).
  • PROCUREMENT: Weight greater than 12 kg.
  • TREATMENT: Relapsed or refractory high risk neuroblastoma.
  • TREATMENT: Life expectancy of at least 12 weeks.
  • TREATMENT: Karnofsky/Lansky score of 60% or greater.
  • TREATMENT: Patients must have an ANC >= 500/ul (within 10 days prior to initiation of study related treatment). * ANC >= 500 without the use G-CSF or GM-CSF for at least 48 hrs.
  • TREATMENT: Platelet count >= 20,000/ul (within 10 days prior to initiation of study related treatment). * Patients may be transfused to obtain a platelet count >= 20,000/ul.
  • TREATMENT: Pulse Ox >= 90% on room air (within 10 days prior to initiation of study related treatment).
  • TREATMENT: Serum AST less than 3 times the upper limit of normal (within 10 days prior to initiation of study related treatment).
  • TREATMENT: Total bilirubin less than 1.5 times the upper limit of normal (within 10 days prior to initiation of study related treatment).
  • TREATMENT: Creatinine < 1.5 upper limit of normal (within 10 days prior to initiation of study related treatment).
  • TREATMENT: 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).
  • TREATMENT: Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who have received prior therapy with murine antibodies.
  • TREATMENT: Patients must have autologous transduced NKTs with >= 20% expression of GD2-specific CAR.
  • TREATMENT: Informed consent and assent (as applicable) obtained from parent/guardian and child.
  • TREATMENT: Weight greater than 12 kg.

Exclusion Criteria

  • PROCUREMENT: Rapidly progressive disease.
  • PROCUREMENT: History or hypersensitivity to murine protein-containing products.
  • PROCUREMENT: Tumor causing airway obstruction.
  • PROCUREMENT: Currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine. * Patients may receive treatment if treated with corticosteroids with dose of less than 0.5 mg/kg/day of prednisone equivalent.
  • PROCUREMENT: Severe previous toxicity from cyclophosphamide or fludarabine based on the enrolling physician’s assessment.
  • PROCUREMENT: Human immunodeficiency virus (HIV) infection.
  • TREATMENT: Rapidly progressive disease.
  • TREATMENT: Currently receiving any investigational drugs.
  • TREATMENT: History or hypersensitivity to murine protein-containing products.
  • TREATMENT: 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., echocardiography [ECHO] or multigated acquisition scan [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 positron emission tomography [PET] or MIBG, or by pathologic assessment).
  • TREATMENT: Tumor potentially causing airway obstruction.
  • TREATMENT: Pregnancy or lactation or not willing to use birth control.
  • TREATMENT: Currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine. * Patients may receive treatment if treated with corticosteroids with dose of less than 0.5 mg/kg/day of prednisone equivalent.
  • TREATMENT: Severe previous toxicity form cyclophosphamide or fludarabine based on the enrolling physician’s assessment.
  • TREATMENT: HIV infection.

Locations & Contacts

Texas

Houston
Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center
Status: Active
Contact: Andras Attila Heczey
Phone: 832-824-4233
Texas Children's Hospital
Status: Active
Contact: Andras Attila Heczey
Phone: 832-824-4233

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and safety profile of autologous natural-killer T cells (NKTs) expressing a 2nd generation GD2-specific chimeric antigen receptor that incorporates the co-stimulatory endodomain of CD28 in addition to the CD3 zeta chain as well as interleukin-15 (hereafter referred to as G28z.15 NKTs) administered to patients with relapsed or refractory neuroblastoma.

I a. Assess the MTD of G28z.15 NKTs adoptively transferred to patients with relapsed or refractory neuroblastoma.

I b. Assess the safety profile of G28z.15 NKTs adoptively transferred to patients with relapsed/refractory neuroblastoma.

SECONDARY OBJECTIVES:

I. To evaluate the anti-tumor response of autologous G28z.15 NKT cells in patients with relapsed/refractory neuroblastoma.

I a. Evaluate residual disease sites for change of dimensions of tumor mass by 3-dimensional (3D) imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) after the administration of autologous G28z.15 NKT cells.

I b. Determine the number of detectable metaiodobenzylguanidine (MIBG) avid disease or bone scan positive sites in response to the administration of autologous G28z.15 NKT cells.

I c. Assess bone marrow clearance among children with bone marrow involvement at the time of enrollment after the administration of autologous G28z.15 NKT cells.

ADDITIONAL OBJECTIVES:

I. To evaluate the immunologic response of autologous G28z.15 NKT cells in patients with relapsed/refractory neuroblastoma.

I a. Assess the expansion and functional persistence of G28z.15 NKTs in the peripheral blood of patients using transgene detection by quantitative real-time polymerase chain reaction (PCR) and flow cytometry.

I b. Assess the frequency of NKT target cells: CD1d+CD33+CD14+CD163+/-myelomonocytic cells in blood and in tumor biopsies and bone marrow (BM) aspirates (when available).

I c. Assess the frequency and activation status (CD69) of natural killer (NK) cells (CD3-CD56+).

I d. Assess the sequential changes in patients’ serum cytokine and chemokine levels after G28z.15 NKT infusion.

I e. Assess the changes in CARNKTs and cancer cells post-infusion in tumor biopsies.

OUTLINE: This is a dose-escalation study.

Patients receive cyclophosphamide (IV) on days -4 and -3, fludarabine IV on days -4 to -2, and autologous anti-GD2CAR-CD28-CD3zeta-IL-15-expressing natural killer T-cells IV over 10 minutes on day 0.

After completion of study treatment, patients are followed up at 1, 2, 3, 4, and 8 weeks, 3, 6, 9, and 12 months, every 6 months for 4 years, and annually thereafter for 10 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center

Principal Investigator
Andras Attila Heczey

Trial IDs

Primary ID GINAKIT2 H-41033
Secondary IDs NCI-2019-01956
Clinicaltrials.gov ID NCT03294954