Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma
Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma
The purpose of this study is to evaluate whether axicabtagene ciloleucel therapy improves the
 clinical outcome compared with standard of care second-line therapy in patients with
 relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
This is a phase 3 randomized, open-label, multicenter study evaluating the efficacy of
 axicabtagene ciloleucel versus standard of care therapy in subjects with relapsed/refractory
 DLBCL. Adult subjects with relapsed/refractory DLBCL after first-line rituximab and
 anthracycline-based chemotherapy will be randomized in a 1:1 ratio to receive axicabtagene
 ciloleucel or standard of care second-line therapy.

 Standard of care will consist of a protocol-defined, platinum-based salvage combination
 chemotherapy regimen followed by high-dose therapy and autologous stem cell transplant in
 those who respond to salvage chemotherapy.
Key Inclusion Criteria:

 1. Histologically proven large B-cell lymphoma including the following types defined by
 WHO 2016 (Swerdlow et al, 2016)

 -  DLBCL not otherwise specified (ABC/GCB)

 -  HGBL with or without MYC and BCL2 and/or BCL6 rearrangement

 -  DLBCL arising from FL

 -  T-cell/histiocyte rich large B-cell lymphoma

 -  DLBCL associated with chronic inflammation

 -  Primary cutaneous DLBCL, leg type

 -  Epstein-Barr virus (EBV) + DLBCL

 2. Relapsed or refractory disease after first-line chemoimmunotherapy

 -  Refractory disease defined as no complete remission to first-line therapy;
 individuals who are intolerant to first-line therapy are excluded.

 -  Progressive disease (PD) as best response to first-line therapy

 -  Stable disease (SD) as best response after at least 4 cycles of first-line
 therapy (eg, 4 cycles of R-CHOP)

 -  Partial response (PR) as best response after at least 6 cycles and
 biopsy-proven residual disease or disease progression ≤ 12 months of therapy

 -  Relapsed disease defined as complete remission to first-line therapy followed by
 biopsy-proven relapse ≤ 12 months of first-line therapy

 3. Individuals must have received adequate first-line therapy including at a minimum:

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

 -  An anthracycline containing chemotherapy regimen

 4. No known history or suspicion of central nervous system involvement by lymphoma

 5. Eastern cooperative oncology group (ECOG) performance status of 0 or 1

 6. Adequate bone marrow function as evidenced by:

 -  Absolute neutrophil count (ANC) ≥ 1000/uL

 -  Platelet ≥ 75,000/uL

 -  Absolute lymphocyte count ≥ 100/uL

 7. Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:

 -  Creatinine clearance (Cockcroft Gault) ≥ 60 mL/min

 -  Serum Alanine aminotransferase/Aspartate aminotransferase (ALT/AST) ≤ 2.5 Upper
 limit of normal (ULN)

 -  Total bilirubin ≤ 1.5 mg/dl

 -  Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as
 determined by an Echocardiogram (ECHO), and no clinically significant
 Electrocardiogram (ECG) findings

 -  No clinically significant pleural effusion

 -  Baseline oxygen saturation > 92% on room air

 Key Exclusion Criteria:

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

 2. Received more than one line of therapy for DLBCL

 3. History of autologous or allogeneic stem cell transplant

 4. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or
 requiring intravenous antimicrobials for management.

 5. 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 positive
 history of treated hepatitis B or hepatitis C, the viral load must be undetectable per
 quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.

 6. Individuals with detectable cerebrospinal fluid malignant cells or known brain
 metastases, or with a history of cerebrospinal fluid malignant cells or brain
 metastases.

 7. History or presence of non-malignant central nervous system (CNS) disorder such as
 seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease,
 or any autoimmune disease with CNS involvement

 8. Presence of any indwelling line or drain. Dedicated central venous access catheter
 such as a Port-a-Cath or Hickman catheter are permitted.

 9. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina,
 New York Heart Association Class II or greater congestive heart failure, or other
 clinically significant cardiac diseases within 12 months of enrollment

 10. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of
 enrollment

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

 12. History of anti-CD19 or CAR-T therapy or history of prior randomization in ZUMA-7

 Note: Other protocol defined Inclusion/Exclusion criteria may apply