A Phase I Study of Autologous Activated T-cells Targeting the CD19 Antigen and Containing the Inducible Caspase 9 Safety Switch in Subjects With Relapsed/Refractory B-cell Lymphoma
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).
∙ Unless otherwise noted, subjects must meet all of the following criteria to participate in all stages of this study:
• Written informed consent and HIPAA authorization for release of personal health information.
• Adults ≥18 years of age.
• Histologically confirmed B-cell NHL, including the following types defined by WHO 2016:
∙ Aggressive Lymphomas:
• DLBCL not otherwise specified (NOS)
• T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type; EBV-positive DLBCL NOS; DLBCL associated with chronic inflammation; Large B-cell lymphoma with IRF4 rearrangement; Intravascular large B-cell lymphoma; ALK-positive large B-cell lymphoma
• Primary mediastinal (thymic) large B-cell lymphoma
• High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; high grade B-cell lymphoma, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
• Transformation of indolent lymphoma or CLL to DLBCL will also be included
• Burkitt lymphoma
• Primary CNS lymphoma
∙ Indolent Lymphomas:
• Follicular lymphoma
• Splenic marginal zone lymphoma
• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
• Nodal marginal zone lymphoma
• Waldenstrom's macroglobulinemia (Lymphoplasmacytic lymphoma)
• Mantle cell lymphoma
• CLL/SLL by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
• Subjects with CNS involvement of lymphoma are eligible.
⁃ -For aggressive lymphomas, must have relapsed or refractory disease after having received at least 2 prior lines of systemic therapy, including, at a minimum:
⁃ An anti-CD20 monoclonal antibody
⁃ An anthracycline containing chemotherapy regimen (if eligible)
⁃ An autologous stem cell transplant (if eligible)
• Subjects with primary CNS lymphoma must have failed at least 1 prior line of therapy that included high dose methotrexate.
• For indolent lymphomas, subjects must have received at least 2 prior lines of therapy for their lymphoma
• Subjects with specifically relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma must have received at least 2 prior therapy regimens which can include, but not limited to:
‣ A combination of an anti-CD20 monoclonal antibody and an alkylating agent, OR
⁃ A Bruton's Tyrosine Kinase Inhibitor, OR
• A BCL-2 inhibitor in combination with an anti-CD20 monoclonal antibody.
• Subjects with prior or concurrent malignancies of the same or different tumor type whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational drug are eligible for enrollment at the discretion of the clinical investigator.
• Subjects relapsed after allogeneic stem cell transplant will be eligible if they meet other inclusion criteria and have no active graft vs host disease (GVHD)
• Measurable or assessable disease by Lugano criteria, response criteria for primary CNS lymphoma, or WM criteria, or IWCLL criteria. Subjects with bone marrow-only involvement are eligible.
• Karnofsky score of \> 60%
• Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for \> 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. WOCBP subjects will also be instructed to tell their male partners to use a condom.