Ensayos clínicos

Inclusion Criteria:

• Histologically confirmed large B-cell lymphoma.
• Chemotherapy-refractory disease, defined as one or more of the following:
  • No response to first-line therapy (primary refractory disease); 
  • No response to second or greater lines of therapy; OR 
  • Refractory after autologous stem cell transplant (ASCT).
• At least 1 measureable lesion according to the Lugano Classification (Cheson 2014).
• Individuals must have received adequate prior therapy, including at a minimum: 
  • Anti-CD20 monoclonal antibody;
  • An anthracycline-containing chemotherapy regimen.
• No evidence, suspicion, and/or history of central nervous system (CNS) involvement of lymphoma or detectable cerebrospinal fluid (CSF) malignant cells or brain metastases.
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis.
• Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities, such as alopecia).
• Age 18 or older.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Absolute neutrophil count (ANC) ≥ 1,000/μL. Growth factor 7 days prior to screening is not allowed to meet ANC eligibility criteria.
• Platelet count ≥ 75,000/μL. Transfusion 7 days prior to screening is not allowed to meet platelet eligibility criteria.
• Absolute lymphocyte count ≥ 100/μL
• Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function. 
• Females of childbearing potential (FCBP)* must have medically supervised negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL
• Adequate renal, hepatic, pulmonary, and cardiac function defined as:
  • Creatinine clearance (CrCl; 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% and no evidence of pericardial effusion;
  • No clinically significant pleural effusion;
  • Baseline oxygen saturation > 92% on room air.
• Subjects must be able to comply with relevant, equivalent requirements adopted from the REVLIMID REMS® (US) or aRMMs as part of the RMP (EU) as stated in this protocol
• FCBP must agree to practice highly effective forms of birth control until at least 6 months after lymphodepleting chemotherapy, 6 months after axicabtagene ciloleucel, or 12 months after rituximab dosing, whichever is longer, and must also agree to routine pregnancy testing

*A female is considered of childbearing potential (ie, fertile) following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

• FCBP must agree to practice birth control until at least 6 months after completing conditioning chemotherapy or axicabtagene ciloleucel, whichever is longer, and must also agree to routine pregnancy testing as described in the schedule of assessments. 

Exclusion Criteria: 

• Known CD19 negative or CD20 negative tumor.
• History of Richter’s transformation of CLL.
• Prior CAR therapy or other genetically modified T-cell therapy.
• Hypersensitivity to rituximab or any excipients of either drug.
• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the sponsor’s medical monitor.
• History of human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Subjects 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.
• Presence of any in-dwelling line or drain (e.g., percutaneous nephrostomy tube, in-dwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted.
• History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, progressive multifocal leukoencephalopathy, 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, heart failure requiring use of digoxin or other drug for rate control, or other clinically significant cardiac disease within 12 months of enrollment.
• Requirement for urgent therapy due to tumor mass effects (e.g., blood vessel compression, bowel obstruction, or transmural gastric involvement).
• Primary immunodeficiency History of autoimmune disease (e.g., Crohn’s, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and subjects with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
• History of deep vein thrombosis (DVT) or pulmonary embolism within the last 6 months.
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
• Live vaccine ≤ 6 weeks prior to planned start of conditioning chemotherapy.
• Women who are breastfeeding.
• History of malignancy other than nonmelanoma skin cancer in situ (e.g., cervix, bladder, breast) or low-grade (Gleason ≤ 6) prostate cancer or surveillance without any plans for treatment, unless disease-free for at least 3 years
• ASCT within 6 weeks of planned enrollment.
• Prior organ transplantation, including prior allogeneic stem cell transplant (SCT).
• Prior CD19 targeted therapy.
• 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.