PRIMARY OBJECTIVE:
I. To assess safety and tolerability of anakinra in reducing incidence of cytokine release
syndrome (CRS) within 30 days after infusion of chimeric antigen receptor (CAR) T cells in
subjects with relapsed or refractory large B-cell lymphoma.
SECONDARY OBJECTIVES:
I. To determine incidence of all grades and duration of both CRS and immune-cell associated
neurotoxicity syndrome (ICANS).
II. To determine the complete response rate (CRR), overall response rate (ORR),
progression-free survival (PFS) and overall survival (OS).
EXPLORATORY OBJECTIVES:
I. To determine the effects of anakinra on the cytokine and chemokine profile in peripheral
blood after CAR-T therapy.
II. To determine the effects of anakinra on the expansion and persistence of CAR T cells.
III. To correlate baseline characteristics with toxicity, response and survival after
anakinra combined with CAR-T therapy.
OUTLINE: This is a dose-escalation study of anakinra.
Patients receive cyclophosphamide intravenously (IV) over 60 minutes and fludarabine IV over
30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity.
Patients then receive axicabtagene ciloleucel IV over 30 minutes or less on day 0 and
anakinra subcutaneously (SC) on days 0-6 in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up at 2 and 4 weeks, and then at
2, 3, 6, 9, 12, 18, and 24 months.
Inclusion Criteria:
- Relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal
B-cell lymphoma (PMBCL), transformed follicular lymphoma (tFL), or high-grade B-cell
lymphoma (HGBCL), at least 2 prior lines of systemic therapy
- Planned to receive standard of care therapy with axicabtagene ciloleucel
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Measurable disease of >= 1.5 cm
- At least two weeks or 5 half-lives, whichever is shorter, must have elapsed since any
prior systemic therapy at the time the subject is planned for axicabtagene ciloleucel
(axi-cel) therapy, except for systemic immune checkpoint inhibitory / immune
stimulatory therapy. At least 3 half-lives must have elapsed from any prior systemic
immune checkpoint inhibitory / immune stimulatory therapy at the time the subject is
planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab,
OX40 agonists, 4-1BB agonists, etc)
- Toxicities due to prior therapy must be stable and recovered to =< grade 1 (except for
clinically non-significant toxicities such as alopecia)
- Absolute neutrophil count of >= 1.0 x 10^9/L
- Platelet count of >= 60 x 10^9/L
- Creatinine clearance (as estimated by Cockcroft Gault) >= 45 mL/minute (min)
- Serum alanine transaminase (ALT) / aspartate transaminase (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% with no evidence of pericardial effusion
- Baseline oxygen saturation > 92% on room air
- No evidence, suspicion, and/or history of lymphoma involving the central nervous
system (CNS)
- 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:
- 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)
- Autologous stem cell transplantation within 6 weeks of planned axi-cel infusion
- History of allogeneic stem cell transplantation
- Prior CD19 targeted therapy
- Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
- Presence 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 principal investigator
- Known history of infection with human immunodeficiency virus (HIV) or hepatitis B
(hepatitis B virus surface antigen [HBsAg] positive) or hepatitis C virus (anti-HCV
positive). A history of hepatitis B or hepatitis C is permitted if the viral load is
undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid
testing
- Known history of tuberculosis. A negative Quantiferon or purified protein derivative
(PPD) up to 2 months before start of anakinra is enough if no specific risk factors
- Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube,
indwelling 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
- Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or
with a history of CNS lymphoma, cerebrospinal fluid malignant cells or brain
metastases
- History or presence of 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, or
other clinically significant cardiac disease within 12 months of enrollment
- Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or
blood vessel compression
- 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
- 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
- History of severe immediate hypersensitivity reaction to any of the agents used in
this study, including E coli-derived proteins
- Live vaccine =< 6 weeks prior to planned start of conditioning regimen
- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant
- Subjects of both genders who are not willing to practice birth control from the time
of consent through 6 months after the completion of anakinra injections
- 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 Trial Treatments
