Non Hodgkin Lymphoma Clinical Trial
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.
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)
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)
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.
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.
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