Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Adults With Refractory Large B-cell Lymphoma
Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Adults With Refractory Large B-cell Lymphoma
The primary objectives of this study are:

 Phase 1: To evaluate the safety of axicabtagene ciloleucel in combination with utomilumab and
 to identify the most appropriate dose and timing of utomilumab to carry forward into Phase 2

 Phase 2: To evaluate the efficacy of axicabtagene ciloleucel and utomilumab in participants
 with refractory large B-cell lymphoma
Key Inclusion Criteria:

 -  Histologically proven large B-cell lymphoma including the following types:

 -  Diffuse large B cell lymphoma (DLBCL) not otherwise specified (ABC/GCB)

 -  High grade B-cell lymphoma (HGBCL) with or without MYC and BCL2 and/or BCL6
 rearrangement

 -  DLBCL arising from follicular lymphoma

 -  T cell/histiocyte rich large B-cell lymphoma

 -  DLBCL associated with chronic inflammation

 -  Primary cutaneous DLBCL, leg type

 -  Epstein-Barr virus (EBV) + DLBCL

 -  Relapsed or chemotherapy-refractory disease, defined as one or more of the following:

 -  No response to first-line therapy (primary refractory disease); subjects who are
 intolerant to first-line systemic chemotherapy 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) with SD duration no longer than 6 months
 from last dose of therapy

 -  No response to second or greater lines of therapy

 -  PD as best response to most recent therapy regimen

 -  SD as best response after at least 2 cycles of last line of therapy with SD
 duration no longer than 6 months from last dose of therapy OR

 -  Refractory post-autologous stem cell transplant (ASCT)

 -  Disease progression or relapsed . 12 months after ASCT (must have biopsy
 proven recurrence in relapsed participant)

 -  if salvage therapy is given post-ASCT, the participant must have had no
 response to or relapsed after the last line of therapy

 -  Relapsed or refractory LBCL including DLBCL, TFL, and HGBCL after 2 or more lines
 of systemic therapy that is defined by and aligns with currently approved
 indication:

 -  Relapsed disease after 2 or more lines of systemic therapy

 -  Best response that is less than a CR to second or greater line of systemic
 therapy

 -  At least 1 measureable lesion according to the Lugano Classification (Cheson et al,
 2014). Lesions that have been previously irradiated will be considered measurable only
 if progression has been documented following completion of radiation therapy.

 -  Participant must have received adequate prior therapy including at a minimum:

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

 -  An anthracycline containing chemotherapy regimen

 -  No radiographic evidence, suspicion and/or history of central nervous system (CNS)
 involvement of lymphoma

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

 -  Absolute neutrophil count (ANC) ≥ 1000/μL

 -  Platelet count ≥ 75,000/μL

 -  Absolute lymphocyte count ≥ 100/μL

 -  Adequate renal, hepatic, pulmonary, and cardiac function defined as:

 -  Creatinine clearance (as estimated by 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, except in individuals with Gilbert's syndrome.

 -  Cardiac ejection fraction ≥ 50% and no evidence of pericardial effusion within
 180 days provided the subject did not receive an anthracycline-based treatment or
 experience a cardiac event or change in performance status

 -  No clinically significant pleural effusion

 -  Baseline oxygen saturation > 92% on room air

 Key Exclusion Criteria:

 -  Histologically proven primary mediastinal B-cell lymphoma (PMBCL)

 -  History of Richter's transformation of chronic lymphocytic lymphoma (CLL)

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

 -  History of severe, immediate hypersensitivity reaction attributed to aminoglycosides

 -  History of HIV infection or acute or chronic active hepatitis B or C infection.
 Individuals with history of hepatitis infection must have cleared their infection as
 determined by standard serological and genetic testing per current Infectious Diseases
 Society of America (IDSA) guidelines or applicable country guidelines

 -  Individuals with detectable cerebrospinal fluid malignant cells, brain metastases, or
 a history of CNS lymphoma

 -  History or presence of CNS disorder, such as seizure disorder, cerebrovascular
 ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS
 involvement

 -  Individuals with cardiac atrial or cardiac ventricular lymphoma involvement

 -  History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or
 other clinically significant cardiac disease within 12 months of enrollment

 -  Requirement for urgent therapy due to tumor mass effects (eg, blood vessel
 compression, bowel obstruction, or transmural gastric involvement

 -  Primary immunodeficiency

 -  History of autoimmune disease (eg, Crohn's, rheumatoid arthritis, systemic lupus)
 resulting in end organ injury or requiring systemic immunosuppression/systemic disease
 modifying agents within the last 2 years. Patients with a history of
 autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and
 patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be
 eligible for this study

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

 -  Any medical condition likely to interfere with assessment of safety or efficacy of
 study treatment

 -  Autologous stem cell transplant within 6 weeks of planned enrollment

 -  Prior organ transplantation including prior allogeneic stem cell transplant (SCT)

 -  Use of any standard or experimental anti-cancer therapy within 2 weeks prior to
 enrollment, including cytoreductive therapy and radiotherapy, immunotherapy, or
 cytokine therapy (except for erythropoietin) Prior treatment with PD-L1 inhibitor,
 PD-1 inhibitor, anti-CTLA4, anti-CD137 (4-1BB), anti-OX40 or other immune checkpoint
 blockade or activator therapy

 -  History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis
 obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
 pneumonitis per chest CT scan at screening. History of radiation pneumonitis in the
 radiation field (fibrosis) is allowed

 -  In the investigator's judgment, the subject is unlikely to complete all
 protocol-required study visits or procedures, including follow-up visits, or comply
 with the study requirements for participation.

 Note: Other protocol defined Inclusion/Exclusion criteria may apply.