Optimizing lymphoDepletion to Improve Outcomes In Patients Receiving Cell Therapy With Yescarta

Inclusion Criteria:

1. Age ≥ 18 years at the time of informed consent

2. Life expectancy ≥ 12 weeks

3. Biopsy-proven and histologically confirmed R/R large B cell lymphoma, including R/RDLBCL, transformation from FL, and R/R PMBCL.

4. Radiographically documented measurable disease as per Lugano response criteria (i.e.LDi > 1.5 cm that is FDG avid).

5. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since anyprior systemic cancer therapy at the time the subject provides consent

6. Eligible for standard of care CAR T cell therapy, specifically, relapsed orrefractory large B cell lymphoma after two or more lines of systemic therapy, andsubjects must have received adequate first-line therapy including at a minimum:

• Anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20negative, and

• An anthracycline containing chemotherapy regimen

7. Patient does not have active CNS disease

8. Patient is sufficiently stable to facilitate planned CAR T-cell therapy (e.g. notrapidly progressing on temporizing therapy, no significant compromise of vital organfunctions (intubation, dialysis, requiring ICU/vasopressor support)) and has goodperformance status

9. ECOG performance status 0 or 1 at enrollment

10. Patient has not received prior adoptive T-cell immunotherapy

11. Patient is not HIV positive

12. Patient did not receive prior allogeneic stem cell transplant

13. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function

14. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausalfor at least 2 years are not considered to be of childbearing potential)

15. Sexually active males who accept to use a condom during intercourse during treatmentand for 6 months after treatment as they should not father a child in this period. Acondom is required to be used also by vasectomized men (as well as duringintercourse with a male partner) in order to prevent delivery of the drug viaseminal fluid

16. Must have an apheresis product of non-mobilized cells accepted for manufacturing.

Exclusion Criteria:

1. Persisting disease bulk (defined as ≥10 cm) on restaging imaging following bridgingtherapy.

2. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g.cervix, bladder, breast) unless disease free for at least 3 years

3. History of Richter's transformation of CLL

4. History of allogeneic stem cell transplant

5. Received < 2 lines of therapy for large B cell lymphoma

6. Prior CD19 targeted therapy

7. Subject has received or undergone the following: o Therapeutic doses of corticosteroids (defined as >20 mg/day prednisone orequivalent) within 7 days prior to leukapheresis. Physiologic steroid replacement, topical, and inhaled steroids are permitted.

• Cytotoxic chemotherapeutic agents that are not considered lymphotoxic, andintrathecal (IT) chemotherapy must be stopped ≥ 7 days prior to leukapheresis.

• Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide > 300 mg/m2,ifosfamide, bendamustine) 4 weeks prior to leukapheresis.

• Experimental agents within 4 weeks prior to signing the ICF, unless no responseor PD is documented on the experimental therapy and at least 5 half-lives haveelapsed prior to leukapheresis.

• Ibrutinib, lenalidomide and PI3K inhibitor within 5 half-lives prior toleukapheresis

• Immunosuppressive therapies within 4 weeks prior to leukapheresis (eg,calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate,rapamycin thalidomide, immunosuppressive antibodies such as anti-tumor necrosisfactor [TNF], anti-IL6, or anti- IL6R)

• Radiation within 6 weeks of leukapheresis. Subject must have progressivedisease in irradiated lesions or have additional nonirradiated, PET-positivelesions to be eligible. Radiation to a single lesion, if additionalnon-irradiated PET-positive lesions are present, is allowed up to 2 weeks priorto leukapheresis (discuss with sponsor).

• Treatment with systemic immunostimulatory agents (including but not limited tointerferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever isshorter, prior to the infusion of axicabtagene ciloleucel

8. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy

9. Presence of fungal, bacterial, viral, or other infection that is uncontrolled orrequiring intravenous (IV) antimicrobials for management. Simple urinary tractinfection (UTI) and uncomplicated bacterial pharyngitis are permitted if respondingto active treatment.

10. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). If there is a positivehistory of treated hepatitis B or hepatitis C, the viral load must be undetectableper quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.

11. Active tuberculosis

12. Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube,indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardialcatheter). Dedicated central venous access catheters such as a Port-a-Cath orHickman catheter are permitted

13. Subjects with detectable cerebrospinal fluid malignant cells or known CNSinvolvement; a history of prior treated CNS lymphoma which is not active at the timeof relapse is permitted

14. History or presence of significant non-malignant CNS disorder such as seizuredisorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or anyautoimmune disease with CNS involvement

15. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement

16. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina,New York Heart Association Class II or greater congestive heart failure, or otherclinically significant cardiac disease within 12 months of enrollment

17. Requirement for urgent therapy due to tumor mass effects such as bowel obstructionor blood vessel compression

18. History of autoimmune disease, requiring systemic immunosuppression and/or systemicdisease modifying agents within the last 2 years.

19. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of activepneumonitis per chest computed tomography (CT) scan at screening. History ofradiation pneumonitis in the radiation field (fibrosis) is allowed.

20. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months ofenrollment

21. Any medical condition likely to interfere with assessment of safety or efficacy ofstudy treatment

22. History of severe immediate hypersensitivity reaction to tocilizumab or any of theagents used in this study

23. Treatment with a live, attenuated vaccine within 6 weeks prior to initiation ofstudy treatment, or anticipation of need for such a vaccine during the course of thestudy

24. Women of childbearing potential who are pregnant or breastfeeding because of thepotentially dangerous effects of chemotherapy on the fetus or infant.

25. Subjects of either sex who are not willing to practice birth control from the timeof consent and at least 6 months after axicabtagene ciloleucel infusion

26. In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including followup visits, or comply with thestudy requirements for participation.