Axi-cel in CNS Lymphoma
Axi-cel in CNS Lymphoma
This research is being done to test the safety and effectiveness of axicabtagene ciloleucel
 (axi-cel), an anti-CD19 directed chimeric antigen receptor (CAR) T-cell therapy in treating
 relapsed/refractory central nervous system (CNS) lymphoma, systemic lymphoma with concurrent
 CNS lymphoma, or systemic lymphoma with a history of treated CNS lymphoma, and to better
 understand what causes neurological toxicity following treatment with axi-cel.

 The names of the study drug(s) involved in this study are:

 -  axicabtagene ciloleucel (axi-cel)

 -  ludarabine will be given with axicel to help axicel work more effectively

 -  cyclophosphamide will be given with axicel to help axicel work more effectively
This research study is a Phase I clinical trial, which tests the safety of an investigational
 drug and also tries to define the appropriate dose of the investigational drug to use for
 further studies. "Investigational" means that the drug is being studied. This study will
 examine the safety and efficacy of axi-cel in participants who either currently or previously
 had had central nervous system involvement of their lymphoma.

 The name of the study drug involved in this study is axi-cel. Axi-cel is a chimeric antigen
 receptor (CAR) T-cell therapy that is manufactured using a person's own white blood cells. A
 virus is used to introduce a gene that creates a protein (called a CAR) on the surface of T
 cells, a type of blood cell that fights infection and can eliminate cancer cells. The CAR on
 the T cells may bind to and kill cells that express CD19, a molecule that is found on B-cell
 lymphomas. CAR-T cells (including axi-cel) designed to target CD19, a protein present on B
 lymphocytes have been used to treat patients with CD19+ tumors. This adoptive cell therapy
 (ACT) approach has shown significant and durable clinical benefits in the treatment of CD19+
 tumors. Axi-cel has been FDA approved for the treatment of relapsed and refractory aggressive
 B cell lymphomas that occur outside the central nervous system and have recurred after two or
 more prior therapies.

 Participants will receive two chemotherapy medicines, fludarabine and cyclophosphamide. These
 drugs are not intended as direct cancer treatment but instead to help axi-cel work with less
 interference from immune system cells.

 The research study procedures include screening for eligibility and study treatment including
 leukapheresis, evaluations and follow up visits.

 Participants in this study will be divided into groups (cohorts) based on the type of disease
 they have and treatment history.

 -  Cohort 1: Participants with relapsed/refractory primary CNSL (PCNSL) and secondary CNSL
 without evidence of lymphoma outside the central nervous system

 -  Cohort 2: Participants with relapsed/refractory lymphoma outside the central nervous
 system, with either active, or previously treated, involvement of the central nervous
 system by the lymphoma

 Participants will receive study treatment once and will be followed for up to 15 years.

 It is expected that about 18 people will take part in this research study.

 Kite Pharma, a pharmaceutical company, is supporting this research study by providing
 axi-cel.
Inclusion Criteria:

 -  Cohort 1:

 -  Patients with relapsed/refractory active primary or secondary CNS lymphoma,
 histologically proven aggressive B cell lymphoma, including DLBCL, HGBL,

 PMBL, or 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.

 -  Measurable CNS disease by MRI of the brain (longest diameter >1cm on gadolinium
 enhanced MRI)

 -  No evidence of active systemic lymphoma (treated systemic lymphoma in remission
 is allowed)

 -  Cohort 2:

 -  Patients with relapsed and/or refractory systemic aggressive B cell lymphoma,
 including DLBCL, HGBL, PMBL or tFL, with active or treated secondary CNS lymphoma

 -  R/R systemic lymphoma with concurrent CNS disease

 -  R/R systemic lymphoma with history of CNS disease

 -  History of treated secondary CNS lymphoma in remission but with R/R systemic
 lymphoma

 -  Systemic lymphomas must be either DLBCL, PMBL, high grade B cell lymphoma,
 or transformed lymphoma and must have relapsed following at least 2 prior
 lines of therapy (which must have included an anti-CD20 monoclonal antibody
 (unless the tumor is CD20 negative) and an anthracycline)

 -  Radiographically evident disease

 -  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

 -  ECOG performance status of 0 or 1 (see Appendix A)

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

 -  Absolute neutrophil count (ANC) ≥1000/μL

 -  Platelet count ≥ 75,000/μL

 -  Absolute lymphocyte count ≥ 100/μL

 -  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 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 GCSF and transfusions are not
 allowed for eligibility determination.+++

 -  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 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 and or CSF protein ≥100 mg/dL

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

 -  History of Richter's transformation of 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 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.

 -  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.

 -  Active tuberculosis

 -  History or presence of non-malignant CNS disorder such as seizure disorder,
 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 idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis
 obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
 pneumonitis per chest computed tomography (CT) scan at screening. History of radiation
 pneumonitis in the radiation field (fibrosis) is allowed.

 -  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.