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

Lymphoma Clinical Trial

Official title: 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

Status Recruiting

Clinical Trial 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).

Clinical Trial Description

This study is a phase I dose finding trial to determine if chimeric antigen receptor T (CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9 safety switch can be safely administered to adult subjects with relapsed or refractory B-cell Lymphoma, primary central nervous system lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The safety of iC9-CAR19 cells will be investigated using the 3+3 design. The starting dose of 1 x 106 transduced cells/kg (dose level 1) will enroll at least 3 subjects in the initial cohort. If there are no dose limiting toxicities (DLTs) within 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 2 x 106 transduced cells/kg. If there is toxicity in 1/3 subjects in the initial cohort, the cohort will be expanded to enroll up to 6 subjects. During iC9-CAR19 T cell dose exploration, rimiducid (0.4 mg/kg), a dimerizing agent that is designed to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop grade 4 cytokine release syndrome (CRS) or grade ≥3 CRS that is unresponsive to standard of care interventions, and to 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. After the tolerable cell dose (TCD) of iC9-CAR19 T cells has been determined, up to 18 additional adult subjects may be enrolled in an expansion cohort at the TCD. Rimiducid will be given to subjects in the expansion cohort 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 initial standard of care treatment (tocilizumab for CRS or steroids for ICANS) may be part of the rimiducid sub-study. These subjects will receive one of two assigned dose levels of rimiducid with their second standard of care treatment. The percent reduction in CAR T cells will be measured in these subjects. If the subjects' CRS or ICANS is unresponsive to standard treatment and the assigned dose level of rimiducid, subjects with ≥grade3 CRS or ICANS will then be given a full dose (0.4 mg/kg) of rimiducid. If the subject's CRS or ICANS is at grade 2 48 hours after the first dose of rimiducid, they will receive another dose of rimiducid at the assigned dose level.

Cell Procurement Peripheral blood, up to 300 mL (in up to 3 collections) will be obtained from subjects for cell procurement. In subjects with inadequate lymphocyte count in the peripheral blood, a leukapheresis may be performed to isolate sufficient T cells. The parameters for apheresis will be up to 2 blood volumes.

Lymphodepleting Regimen Subjects will receive a "pre-conditioning" cytoreductive regimen of bendamustine 70 mg/m2/day administered IV followed by an IV dose of fludarabine 30 mg/m2/day administered over 3 consecutive days. These agents will be administered per institutional guidelines. Prophylaxis (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine chemotherapy will be provided per institutional guidelines. At the discretion of the clinical investigator, subjects with a known history of intolerance to bendamustine may be considered for lymphodepletion with cyclophosphamide 500 mg/m2/day administered by IV followed by an IV dose of fludarabine 30 mg/m2/day administered over 3 consecutive days. These agents will be administered per institutional guidelines.

Administration of iC9-CAR19 T cells Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9-CAR19 T cells within 2 - 14 days after completing the lymphodepleting chemotherapy regimen. Post lymphodepletion iC9-CAR19 will be administered at dose levels specified in the protocol. A recently published trial in refractory DLBCL established that a dose of 2 x 10 6 CAR19+ T cells/kg was safe and associated with significant in vivo expansion and we anticipate similar results with iC9-CAR19+ T cells.

Duration of Therapy Therapy in this study involves 1 infusion of iC9-CAR19 cells.

Duration of Follow-up Subjects who receive a cell infusion will be followed for up to 15 years for replication-competent retrovirus evaluation or until death, whichever occurs first. Subjects who are removed from study and do not receive the cellular therapy product due to unacceptable adverse events will be followed until resolution or stabilization of the adverse event. ;

Related Conditions & MeSH terms

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

• NCT number: NCT03696784
• Study type: Interventional
• Source: UNC Lineberger Comprehensive Cancer Center
• Contact: Catherine Cheng
• Phone: 919-445-4208
• Email: UNCImmunotherapy@med.unc.edu
• Status: Recruiting
• Phase: Phase 1
• Start date: March 12, 2019
• Completion date: March 22, 2043