A Phase I Study to Evaluate the Safety of Escalating Doses of Lymphodepleting Conditioning Chemotherapy Prior to CD19 Chimeric Antigen Receptor T Cells in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma
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.
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Commercial CD19 CAR T cell product not available for the patient
• Male or female, aged \>= 18
• In good general health as evidenced by medical history or as determined by the principal investigator (PI)
• Ability to swallow oral medication and willingness to adhere to the study intervention and any required medications
• For females of reproductive potential: use of highly effective contraception (oral contraceptives, intrauterine device) during screening confirmed with serum pregnancy test, and agreement to use such a method during study participation and for an additional 4 weeks after the end of CD19 CAR T cell infusion
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner
• Agreement to adhere to lifestyle considerations throughout study duration including abstaining from tobacco and drug use
• Subjects must have relapsed or refractory diffuse large B cell lymphoma treated with at least two lines of therapy Subjects must have failed to have a complete response, or have recurrent disease after the last treatment regimen. Subjects must have previously been treated with a regimen that includes an anthracycline and an anti-CD20 monoclonal antibody. Autologous transplant will be counted as one line of therapy
• The patient's disease must be CD19 positive, either by immunohistochemistry or flow cytometry analysis on the last biopsy available
• Age \>= 18 years
• Performance status: Adult Subjects: Eastern Cooperative Oncology Group (ECOG) \>= 1; Subjects \> 10 years of age: Karnofsky \>= 80%
• Absolute neutrophil count (ANC) \>= 1000
• Platelets \>= 100/mm\^3
• Hemoglobin \> 8 g/dL
• ANC \>= 500 is acceptable if documented bone marrow involvement by disease
• Creatinine clearance (estimated by Cockcroft Gault) or using 24 hour (hr) urine collection \>= 50 cc/min
• Total bilirubin =\< 2 mg/dL except in subjects with Gilbert's Syndrome in whom total bilirubin must be =\< 3.0
• Alanine transaminase (alanine aminotransferase \[ALT\]/serum glutamic pyruvic transaminase \[SGPT\]) and aspartate aminotransferase (aspartate aminotransferase \[AST\]/serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 3 x the upper limit of normal or =\< 5 x the upper limit of normal if documented liver involvement by disease
• Cardiac left ventricular ejection fraction \>= 45% as determined by an echocardiogram and no clinically significant electrocardiogram (ECG) findings
• Baseline oxygen saturation \> 92% on room air
• Prior cancer directed therapy wash-out: at least 2 weeks or 5 half-lives, whichever is shorter must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for radiotherapy within 10 days of apheresis, systemic corticosteroid use within 7 days of apheresis (with the exception of single dose for an allergic reaction), or any other immunosuppressive therapies within 7 days
• No use of lymphodepleting agents including alemtuzumab and antithymocyte globulin for 7 days prior to peripheral blood collection, 5 days prior to CD19 CAR T cell infusion and for 90 days after infusion