Axicabtagene Ciloleucel for the Treatment of Relapsed/Refractory Primary or Secondary Central Nervous System Lymphoma

Inclusion Criteria

• Patients with relapsed/refractory active primary or secondary CNS lymphoma, histologically proven aggressive B cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), high grade B cell lymphoma (HGBL), primary mediastinal large B cell lymphoma (PMBL), or transformed follicular lymphoma (tFL), and defined by the following categories: * Primary CNS lymphoma, relapsed or refractory following at least one line of CNS-directed therapy. There is no restriction on the number of recurrences * Secondary CNS lymphoma, relapsed or refractory following at least one line of CNS-directed therapy for prophylaxis or treatment of CNS lymphoma * Radiographically event CNS disease by magnetic resonance imaging (MRI) of the brain (ie enhancing lesion on gadolinium enhanced MRI) * For patients with secondary CNSL with concurrent systemic lymphoma, the concurrent systemic lymphoma must be either DLBCL, PMBL, high grade B cell lymphoma, or transformed lymphoma and must have relapsed following at least 1 prior lines of therapy (which must have included an anti-CD20 monoclonal antibody (unless the tumor is CD20 negative) and an anthracycline
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic cancer therapy at the time the subject provides consent
• Age 18 years or older at the time of informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count (ANC) >= 1000/uL * Granulocyte colony stimulating factor (GCSF) and transfusions are not allowed for eligibility determination
• Platelet count >= 75,000/uL * GCSF and transfusions are not allowed for eligibility determination
• Absolute lymphocyte count >= 100/uL * GCSF and transfusions are not allowed for eligibility determination
• Creatinine clearance or glomerular filtration rate (GFR) (by any measure) >= 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 subjects with Gilbert’s syndrome
• Cardiac ejection fraction >= 50%, no clinically significant 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
• Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)

Exclusion Criteria

• Primary vitreoretinal lymphoma and intraocular primary central nervous system lymphoma (PCNSL) without evidence of brain disease. Patients with prior history of intraocular involvement treated only with intraocular methotrexate and no prior systemic therapy are excluded
• PCNSL patients who cannot undergo magnetic resonance imaging assessments
• Patients with brain stem lesions
• Patients with leptomeningeal disease only without brain parenchymal involvement
• Bulky leptomeningeal disease with CSF protein >= 100 mg/dL; for patients without bulky leptomeningeal disease, CSF protein cannot be > 150 mg/dL
• 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
• History of Richter’s transformation of chronic lymphocytic leukemia (CLL)
• History of allogeneic stem cell transplant
• Prior CD19 targeted therapy
• Treatment with systemic immunostimulatory agents (including but not limited to interferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to the first dose of axicabtagene ciloleucel or standard of care (SOC)
• Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy
• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
• If there is a positive history of treated human immunodeficiency virus (HIV) or hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing and for HIV+ patients, CD4 count must be > 200.
• Active tuberculosis
• History or presence of non-malignant CNS disorder such as chronic seizure disorder (seizures as a presenting symptom of CNSL and/or due to reversible causes are allowed), cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
• Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
• 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 disease within 12 months of enrollment
• Requirement for urgent therapy due to tumor mass effects
• History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 12 months
• History of symptomatic deep vein thrombosis or pulmonary embolism requiring ongoing systemic anticoagulation
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
• History of severe immediate hypersensitivity reaction to tocilizumab or any of the agents used in this study
• Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
• Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of chemotherapy on the fetus or infant. Subjects of either sex who are not willing to practice birth control from the time of consent and at least 6 months after the last dose of axicabtagene ciloleucel or SOC chemotherapy
• In the investigators 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