This phase I trial evaluates the best dose, possible benefits and/or side effects of fludarabine and cyclophosphamide with or without rituximab before CD19 chimeric antigen receptor T cells in treating patients with diffuse large B-cell lymphoma that has come back (relapsed) or has not responded to previous treatment (refractory). T-cells are a normal part of the immune system. To make the T-cell medication, T-cells are taken from the blood and altered in a laboratory. They are then returned to the body. The altered T-cells will latch on to a specific part of the cancer cells and hopefully kill them. Once the T-cells have been altered in the laboratory, they are called "CAR T-cells." CAR is short for "chimeric antigen receptors." These are structures on the surface of cells that allow the altered T-Cells to find and destroy the cancer cells. Another part of the T-Cell medication is called "CD19." This part is called a "biomarker." Biomarkers help doctors determine whether a cancer is getting worse and whether medications are working to stop it. The chemotherapy drugs that are given before the T-Cell therapy are cyclophosphamide, fludarabine and rituximab. Rituximab is an immunotherapy drug. These chemotherapy drugs will reduce the number of normal (unaltered) T-Cells in the body to make room for the altered T-cells to kill the cancer cells. Giving fludarabine and cyclophosphamide with or without rituximab before CD19 CAR T cell therapy may help improve response to CD19 CAR T cell therapy in patients with diffuse large B-cell lymphoma.
PRIMARY OBJECTIVES:I. To examine the feasibility to manufacture autologous CD19 CAR T cells at a minimum target dose of 1.0 x 10\^6 cells/kilogram using the CliniMACS automated system.II. To determine the safety of administering high-dose conditioning chemotherapy with cyclophosphamide and fludarabine with rituximab prior to CD19 CAR-T cell therapy in patients with relapsed (R)/refractory (R) diffuse large B cell lymphoma (DLBCL) and to find the recommended regimen after phase II dose for this therapy.III. To determine the safety of infusion of chimeric antigen receptor T cells targeting CD19 in adults with R/R DLBCL. SECONDARY OBJECTIVES:I. To describe the toxicities related to CD19 targeted CAR T cells.II. To describe the overall response rate (ORR) and complete response (CR) rate of relapsed DLBCL treated with CD19 CAR T cells.III. To assess other response variables including overall survival (OS), progression free survival (PFS), and event free survival (EFS). OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 6 dose levels. DOSE LEVEL 1: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes daily and cyclophosphamide IV over 60 minutes daily on days -5 to -3. Patients also receive CD19 CAR T cells IV on day 0. DOSE LEVEL 2: Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -3, and cyclophosphamide IV over 60 minutes on days -5 to -3. Patients also receive CD19 CAR T cells IV on day 0. DOSE LEVEL 3: Patients receive fludarabine phosphate IV over 30 minutes daily on days -3 to -5 and cyclophosphamide IV over 60 minutes daily on day -5. Patients also receive CD19 CAR T cells IV on day 0.DOSE LEVEL 4: Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -3, and cyclophosphamide IV over 60 minutes on day -5. Patients also receive CD19 CAR T cells IV on day 0. DOSE LEVEL 5: Patients receive fludarabine phosphate IV over 30 minutes daily on days -5 to -1 and cyclophosphamide IV over 60 minutes daily on days -5 and -4. Patients also receive CD19 CAR T cells IV on day 0. DOSE LEVEL 6: Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -1, and cyclophosphamide IV over 60 minutes on days -5 and -4. Patients also receive CD19 CAR T cells IV on day 0.After completion of study treatment, patients are followed up at 30, 60, and 90 days, 6 and 12 months, and then annually for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Given CD19 CAR T cells IV
Given IV
Given IV
Given IV
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
RECRUITINGProportion of products successfully manufactured meeting the established release criteria with a goal of at least 1.0 x 10^6 cells/kilogram
Time frame: Up to 15 years
Incidence and severity of adverse events related to lymphodepleting chemotherapy and or CD19 chimeric antigen receptor (CAR) T cells
Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.
Time frame: 2 months
Dose limiting toxicities (DLTs) related to lymphodepleting chemotherapy and or CD19 CAR T cells
Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.
Time frame: 2 months
Maximum tolerated dose
Time frame: 2 months
Incidence and severity of DLT associated with infusion of CD19 CAR T cells (infusion reactions)
Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.
Time frame: 2 months
Incidence of toxicities related to CD19 CAR T cells
Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.
Time frame: Up to 15 years
Overall response rate
Defined as the percentage of patients that achieve partial response or complete response. Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate.
Time frame: At 3 months after completion of CAR-T therapy
Complete response rate
Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate.
Time frame: At 3 months after completion of CAR T therapy
Overall survival
Will be estimated using Kaplan and Meier methods. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.
Time frame: From the start of the conditioning lymphodepletion chemotherapy on day -6 until death, assessed at 1 year
Progression free survival
Will be estimated using Kaplan and Meier methods. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.
Time frame: From the start of the conditioning lymphodepletion chemotherapy regimen until the documentation of disease progression or death due to any cause, whichever occurs first, assessed at 1 year
Event free survival
Will be estimated using Kaplan and Meier methods. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.
Time frame: From the date of day -6 of lymphodepleting conditioning therapy to the date of first documented progression, initiation of new anti-lymphoma treatment, or death, assessed at 1 year
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