Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma

Summary

This research study combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to create a more effective treatment. The treatment being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration.

Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown.

Preliminary results have shown that subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome and neurotoxicity. In this study, to help reduce cytokine release syndrome and/or neurotoxicity symptoms, the ATLCAR.CD19 cells have a safety switch that, when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject experiences moderate to severe cytokine release syndrome and or neurotoxicity as a result of being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome and/or neurotoxicity. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be given that reduces the severity of the cytokine release syndrome and/or neurotoxicity, but still allows the remaining iC9-CAR19 cells to effectively fight the lymphoma.

The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable in patients with relapsed/refractory B-cell lymphoma, primary central nervous system lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Conditions

• Lymphoma
• Lymphoma, B-Cell
• Immune System Diseases
• Immunoproliferative Disorders
• Lymphatic Diseases

Interventions

BIOLOGICAL

iC9-CAR19 T cells

iC9-CAR19 T cells will be given by a licensed healthcare provider via intravenous injection over 5-10 minutes through either a peripheral or a central line.

DRUG

Bendamustine

70mg/m2 IV given as a daily infusion for 3 days per institutional guidelines 2 - 14 days prior to the T cell infusion.

DRUG

Fludarabine

30 mg/m2 given as a daily infusion for 3 days per institutional guidelines 2 - 14 days prior to the T cell infusion

DRUG

AP1903

0.4 mg/kg of AP1903 as an IV infusion over 2 hrs for subjects who develop Grade 4 cytokine release syndrome (CRS) or grade ≥3 CRS that is unresponsive to standard of care interventions , subjects who develop grade ≥3 Immune effector cell-associated neurotoxicity syndrome (ICANS) that does not improve to grade ≤1 within 72 hours with standard of care interventions, and subjects with grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus. Subjects in the expansion cohort who experience ≥ grade 2 CRS or ICANS that remains ≥ grade 2, twenty-four hours after an initial dose of the standard of care treatment may be part of the sub-study of rimiducid. These subjects will receive one of two assigned dose levels. DL1 and DL2 doses are 0.05 mg/kg and 0.01 mg/kg for subjects and DL1: 0.1 mg/kg and DL2: 0.01 mg/kg for subjects with ICANS.

DRUG

Cyclophosphamide

500 mg/m2/day administered by IV over 3 consecutive days

Sponsors & Collaborators

• UNC Chapel Hill University Cancer Research Fund

  collaborator UNKNOWN

• The V Foundation

  collaborator OTHER

• M.D. Anderson Cancer Center

  collaborator OTHER

• National Cancer Institute (NCI)

  collaborator NIH

• UNC Lineberger Comprehensive Cancer Center

  lead OTHER

Principal Investigators

• Natalie Grover, MD · UNC Lineberger Comprehensive Cancer Center

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2019-03-12

Primary Completion

2025-08-31

Completion

2040-07-31

FDA Drug

Yes

Countries

• United States

Study Locations