This phase I trial tests the safety, side effects, and best dose of total body irradiation (TBI) in combination with standard of care lymphodepletion with cyclophosphamide and fludarabine before tisagenlecleucel (Tisa-cel) and how well the combination works in patients with large B-cell lymphoma (LBCL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). TBI is a common treatment that sends radiation (for example, through x-rays) to the entire body. Lymphodepleting chemotherapy, such as cyclophosphamide and fludarabine, along with TBI helps kill cancer cells in the body and helps prepare the body for the Tisa-cel infusion. Tisagenlecleucel is made using a patient's T cells (a type of immune system cell). A gene for a special receptor called chimeric antigen receptor (CAR) is added to the T cells in the laboratory. These changed T cells called CAR T cells are grown in large numbers in the laboratory and given to the patient by infusion. Tisa-cel binds to a protein called CD19, which is found on some leukemia and lymphoma cells. This helps the body's immune system kill cancer cells. Tisa-cel is a type of CAR T-cell therapy. Giving low dose TBI in combination with standard of care lymphodepletion therapy and Tisa-cel may be safe, tolerable, and/or effective in treating patients with relapsed or refractory (R/R) LBCL.
Eligible for standard of care anti-CD19 CAR-T treatment with Tisa-cel
Age ≥ 18 years
Biopsy-confirmed relapsed or refractory large B-cell lymphoma after 2 lines of prior therapy
Qualitative CD19 expression by either immunohistochemistry (IHC) or flow cytometry
Active central nervous system (CNS) disease at screening or prior to lymphodepletion
Prior therapy with autologous or allogenic CAR-T or CAR-natural killer (NK) cell therapy
Prior anti-CD19 therapies (such as, but not limited to tafasitamab or loncastuximab)
Prior allogeneic stem cell transplant
Single group
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Computed Tomography
Procedure/SurgeryUndergo PET/CT or CT
Cyclophosphamide
DrugGiven IV
Fludarabine
DrugGiven IV
Leukapheresis
Procedure/SurgeryUndergo leukapheresis
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Tisagenlecleucel
Biological/VaccineGiven IV
Total-Body Irradiation
RadiationUndergo low dose TBI
Dose-limiting toxicities
Adverse events will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Cytokine release syndrome and immune effector cell associated neurotoxicity syndrome are graded using American Society for Transplantation and Cellular Therapy (ASTCT) Consensus grading.
Maximum tolerated dose or recommended phase 2 dose (RP2D)
Will define the dose as the RP2D for which the isotonic estimate of the toxicity rate is closest to the targeted toxicity rate (i.e., 25%). If there is a tie, the higher dose level when the isotonic estimate is lower than the targeted toxicity rate; and will choose the lower dose level when the isotonic estimate is greater than the targeted toxicity rate.
Incidence of adverse events
Frequency and nature of adverse events of different grades, overall and by dose levels will be described.
Complete remission rate
Will be evaluated with descriptive statistics with proportions used to describe response rates (complete and overall).
Objective response rate
Will be estimated with 95% confidence intervals.
Median duration of response
Will be calculated using Kaplan Meier method, comparisons between groups will be done using the log rank test.
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Nathan Denlinger
Lead sponsor
Ohio State University Comprehensive Cancer Center
Sponsor institution
Novartis
Collaborator
