A Phase 2 Trial of Anakinra for the Prevention of CAR-T Cell Mediated Neurotoxicity

This research study is studying the combination of anakinra and axicabtagene ciloleucel to reduce the occurrence of the side effects Cytokine Release Syndrome (CRS) and neurologic toxicities with relapsed or refractory Non-Hodgkin lymphoma (NHL).

• Relapsed NHL is the condition of returned Non-Hodgkin lymphoma.
• Refractory NHL is the condition of previous treatment resistant Non-Hodgkin lymphoma.
• Cytokine Release Syndrome (CRS) is a group of side effect symptoms that can include nausea, headache, rapid heartbeat, shortness of breath, kidney damage, and rash.
• Neurologic toxicity is nervous system disorder characterized by confusion

This research study involves two drugs:

• Anakinra
• Axicabtagene Ciloleucel.

Study Overview

• Status: Completed
• Conditions: Non Hodgkin Lymphoma; Neurotoxicity; Neurotoxicity Syndromes; Cytokine Release Syndrome; Refractory Non-Hodgkin Lymphoma; Relapsed Non Hodgkin Lymphoma
• Intervention / Treatment: Drug: Anakinra; Drug: Axicabtagene Ciloleucel

Detailed Description

This Phase 2, single center, open-label research study is studying the combination of Anakinra and Axicabtagene Ciloleucel to reduce the occurrence of the side effects Cytokine Release Syndrome (CRS) and neurologic toxicities in people with relapsed or refractory Non-Hodgkin lymphoma (NHL).

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

• This research study involves two drugs:

  • Anakinra
  • Axicabtagene Ciloleucel
• A total of 20 participants are anticipated to be enrolled to this trial
• The U.S. Food and Drug Administration (FDA) has not approved anakinra for use in treatment of Non-Hodgkin lymphoma (NHL).

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
• At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma 1. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
• 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, except for systemic inhibitory/stimulatory immune checkpoint therapy however steroids only require a 7-day washout. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule 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)
• Age 18 or older
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• ANC ≥1000/uL
• Platelet count ≥75,000/uL
• Absolute lymphocyte count ≥100/uL

• Adequate renal, hepatic, pulmonary and cardiac function defined as:

  • Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
  • Serum ALT/AST ≤2.5 ULN
  • Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's syndrome.
  • Cardiac ejection fraction ≥ 50%, no clinically significant pericardial effusion, and no clinically significant 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) Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years
• History of Richter's transformation of CLL
• Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel infusion
• History of allogeneic stem cell transplantation
• Prior CD19 targeted therapy with the exception of subjects who received axicabtagene ciloleucel in this study and are eligible for re-treatment
• Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
• 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.
• History of HIV infection or acute or chronic active hepatitis B or C 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.
• 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 or primary 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
• Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome)
• Primary immunodeficiency
• 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
• 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. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential
• Subjects of both genders who are not willing to practice birth control from the time of consent through 6 months after the completion of axicabtagene ciloleucel
• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Anakinra and Axicabtagene Ciloleucel; Patients who meet eligibility criteria for the study will subsequently be enrolled for treatment.; Screening; Enrollment/Leukapheresis period; Bridging therapy (if applicable); Lymphodepleting chemotherapy period; Investigational Product (IP) treatment periodAnakinraAxicabtagene Ciloleucel; Post treatment assessment period; Long term follow-up period

Drug: Anakinra; Subcutaneous, dosage per protocol. Day 0 through Day 6.; Other Names: Kineret®; Drug: Axicabtagene Ciloleucel; Once, intravenous infusion, dosage per protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Neurotoxicity as Per CTCAE v4.03 Criteria	The incidence of grade 2+ neurotoxicity is reported below and was assessed using CTCAE (Common Terminology Criteria for Adverse Events) v4.04 criteria. Neurotoxicity is a serious side effect of cancer treatments that can impact the central and peripheral nervous systems. Neurotoxicity manifestations vary and can include confusion, obtundation, seizures, hallucinations, aphasia, ataxia, and more rarely, profound cerebral edema.	30 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	Objective response rate (ORR) is defined as the incidence of either a complete response (CR) or a partial response (PR) by the revised IWG Response Criteria for Malignant Lymphoma. All participants who don't meet the ORR criteria by the analysis data cutoff date will be considered non-responders.; CR = complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy; PET scan negative; lymph nodes/nodal masses regressed to normal size; normal size spleen/liver on CT scan; bone marrow aspirate and biopsy shows no evidence of disease by morphology or negative by IHC.; PR = ≥ 50% decrease in sum of the product of diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no size increase of nodes/liver/spleen; no new sites of disease; post-treatment PET scan positive in ≥ 1 previously involved site.	24 Months
Duration of Response	Among participants who experience an objective response, duration of response (DOR) is defined as the date of their first objective response to disease progression per the revised IWG Response Criteria for Malignant Lymphoma, or death regardless of cause. Participants not meeting the criteria for progressive disease (PD) or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing. * PD = ≥ 50% increase from nadir in the sum of the products of at least two lymph nodes; ≥ 50% increase in product of the diameters of single node; new lesion >1.5 cm; ≥ 50% size increase of splenic/hepatic nodules; ≥ 50% increase in longest diameter of any single previously identified node more than 1 cm in its short axis; PET scan positive	first objective response to disease progression death regardless of cause up 24 Months
Progression-free Survival	Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for progression-free survival time	infusion date to the date of disease progression or death from any cause up 24 Months
Overall Survival	Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for OS.	time from axicabtagene ciloleucel infusion to the date of death or analysis data cutoff date will be censored at last contact date up to 24 months.
Number of Participants With Adverse Events CTCAE Version 4.03 Grade 3 or Higher	Subject incidence rates of adverse events including all, serious, fatal, CTCAE version 4.03 Grade 3 or higher and treatment related AEs reported throughout the conduct of the study will be tabulated by preferred term and system organ class	24 Months
Rate of Cytokine Release Syndrome (CRS) as Per Lee 2014 for CRS	The incidence of max grade 2+ CRS will be assessed	Within 30 days after infusion

Collaborators and Investigators

• Sponsor: Marcela V. Maus, M.D.,Ph.D.
• Collaborators: Kite, A Gilead Company
• Investigators: Principal Investigator: Matt J Frigault, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Frigault MJ, Yao N, Berger TR, Wehrli M, Gallagher KME, Horick N, Graham CE, Jacobson CA, Chen YB, Leick MB, DeFilipp Z, El-Jawahri AR, Johnson PC, Dolaher M, Katsis K, Kim AI, Crombie J, Merryman RW, Cook D, Trailor M, Cho H, Jeffrey R 3rd, Shen R, Filosto S, Nater J, Getz G, Haradhvala NJ, Maus MV. Single-cell dynamics of breakthrough toxicities after anakinra prophylaxis for axicabtagene ciloleucel in lymphoma. Blood Adv. 2025 May 13;9(9):2122-2135. doi: 10.1182/bloodadvances.2024015161.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Actual): October 30, 2023
• Study Completion (Actual): October 31, 2024

Study Registration Dates

• First Submitted: November 1, 2019
• First Submitted That Met QC Criteria: November 1, 2019
• First Posted (Actual): November 5, 2019

Study Record Updates

• Last Update Posted (Estimated): November 25, 2025
• Last Update Submitted That Met QC Criteria: November 12, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Non Hodgkin Lymphoma; Neurotoxicity; Cytokine Release Syndrome; Neurotoxicity Syndromes; Refractory Non-Hodgkin Lymphoma; Relapsed Non Hodgkin Lymphoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Systemic Inflammatory Response Syndrome; Inflammation; Chemically-Induced Disorders; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Poisoning; Shock; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Cytokine Release Syndrome; Lymphoma, Non-Hodgkin; Neurotoxicity Syndromes; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Intercellular Signaling Peptides and Proteins; Cytokines; Interleukin 1 Receptor Antagonist Protein; axicabtagene ciloleucel
• Other Study ID Numbers: 19-348

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: MGH - Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No