Anakinra for the Prevention of Cytokine Release Syndrome and Neurotoxicity in Patients With B-Cell Non-Hodgkin Lymphoma Receiving CD19-Targeted CAR-T Cell Therapy

Phase 2

Completed

Conditions: B-Cell Non-Hodgkin Lymphoma

Interventions: Biological: Anakinra
Procedure: X-Ray Imaging
Procedure: Positron Emission Tomography
Procedure: Computed Tomography
Procedure: Bone Marrow Aspiration
Procedure: Bone Marrow Biopsy
Procedure: Lumbar Puncture
Procedure: Biospecimen Collection

Registration Number: NCT04359784

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: This phase II trial studies how well anakinra works in decreasing the occurrence of cytokine release syndrome (CRS) and damage to the nerves (neurotoxicity) in patients with B-cell non-Hodgkin lymphoma who are receiving CD-19 targeted chimeric antigen receptor T-cell (CAR-T) therapy. CAR-T cell therapy may be complicated by two potentially life-threatening side effects: CRS and neurotoxicity. Anakinra is a drug typically used to treat rheumatoid arthritis, but may also help in preventing CAR-T cell-related cytokine release syndrome and neurotoxicity.

Detailed Description: OUTLINE:

Patients receive anakinra intravenously (IV) \[previously subcutaneously (SC) for some patients\] over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, positron emission tomography/computed tomography (PET/CT) or CT, bone marrow aspirate (BMA) and biopsy (if clinically indicated), and lumbar puncture (if clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.

After completion of lisocabtagene maraleucel infusion, patients are followed up periodically for up to 90 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 27

Inclusion Criteria

Subjects must be 18 years of age or older
Karnofsky performance status of >= 60%
Patients with B-cell non-Hodgkin lymphoma (B-NHL) and eligible for treatment with liso-cel. Patients treated with non-conforming (out-of-specification) liso-cell may remain on study.
Negative serum pregnancy test within 2 weeks of enrollment for women of childbearing potential, defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year
Fertile male and female subjects must be willing to use an effective contraceptive method before, during, and for at least 4 months after the last dose of anakinra
Ability to understand and provide informed consent

Exclusion Criteria

Subjects requiring ongoing daily corticosteroid therapy at a dose of > 15 mg of prednisone per day (or equivalent). Pulsed corticosteroid use for disease control is acceptable
Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the principal investigator (PI)
Known hypersensitivity to Escherichia € coli-derived proteins, anakinra, or to any component of the product
Major organ dysfunction defined as:
- Serum creatinine > 2.5 mg/dL
- Significant hepatic dysfunction (Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 5x upper limit of normal; bilirubin > 3.0 mg/dL) unless due to malignancy or Gilbert's syndrome in the opinion of the PI or designee
- Subjects with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing. Those with a forced expiratory volume in 1 second (FEV1) of < 50% of predicted or diffusion capacity of the lung for carbon monoxide (DLCO) (corrected) < 40% will be excluded
- Significant cardiovascular abnormalities as defined by any one of the following: New York Heart Association (NYHA) class III or IV congestive heart failure, clinically significant hypotension, uncontrolled symptomatic coronary artery disease, or a documented ejection fraction of < 35%
Uncontrolled serious and active infection

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Prevention (anakinra, lisocabtagene maraleucel)	Positron Emission Tomography	Patients receive anakinra IV (previously SC) over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, PET/CT or CT, BMA and biopsy (as clinically indicated), and lumbar puncture (as clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.
Prevention (anakinra, lisocabtagene maraleucel)	Anakinra	Patients receive anakinra IV (previously SC) over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, PET/CT or CT, BMA and biopsy (as clinically indicated), and lumbar puncture (as clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.
Prevention (anakinra, lisocabtagene maraleucel)	X-Ray Imaging	Patients receive anakinra IV (previously SC) over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, PET/CT or CT, BMA and biopsy (as clinically indicated), and lumbar puncture (as clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.
Prevention (anakinra, lisocabtagene maraleucel)	Computed Tomography	Patients receive anakinra IV (previously SC) over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, PET/CT or CT, BMA and biopsy (as clinically indicated), and lumbar puncture (as clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.
Prevention (anakinra, lisocabtagene maraleucel)	Bone Marrow Aspiration	Patients receive anakinra IV (previously SC) over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, PET/CT or CT, BMA and biopsy (as clinically indicated), and lumbar puncture (as clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.
Prevention (anakinra, lisocabtagene maraleucel)	Bone Marrow Biopsy	Patients receive anakinra IV (previously SC) over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, PET/CT or CT, BMA and biopsy (as clinically indicated), and lumbar puncture (as clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.
Prevention (anakinra, lisocabtagene maraleucel)	Lumbar Puncture	Patients receive anakinra IV (previously SC) over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, PET/CT or CT, BMA and biopsy (as clinically indicated), and lumbar puncture (as clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.
Prevention (anakinra, lisocabtagene maraleucel)	Biospecimen Collection	Patients receive anakinra IV (previously SC) over 10-30 minutes daily on days 0-13 and lisocabtagene maraleucel via infusion on day 0. Patients should also undergo at screening an x-ray, PET/CT or CT, BMA and biopsy (as clinically indicated), and lumbar puncture (as clinically indicated), and at follow-up as clinically indicated. Patients also undergo blood sample collection on study.

Primary Outcome Measures

Name	Time	Method
Absence of Any Grade Cytokine Release Syndrome (CRS)	Up to 28 days after lisocabtagene maraleucel (liso-cel) infusion	Will assess the efficacy of anakinra in preventing the occurrence of any grade CRS using the Bayesian optimal phase 2 design. Assessed based on the ASTCT Consensus Grading for CRS and Neurotoxicity Associated with Immune Effector Cell.

Secondary Outcome Measures

Name	Time	Method
CRS Grade	Up to 28 days after liso-cel infusion	CRS severity was graded per American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria (Lee et al, Biol Blood Marrow Transplant, 2019) based on the presence and severity of fever, hypotension, and hypoxia: grade 1, fever ≥38°C without hypotension or hypoxia; grade 2, hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen; grade 3, hypotension requiring a single vasopressor or hypoxia requiring high-flow oxygen; grade 4, life-threatening hypotension requiring multiple vasopressors and/or hypoxia requiring positive-pressure ventilation; grade 5, death.
Disease Response to Liso-cel	Approximately 90 days after liso-cel infusion	Best response within approximately 90 days post liso-cel infusion will be assessed based on institutional standard using physical examination, imaging (CT or PET-CT), and if necessary, bone marrow biopsies, in patients with measurable disease prior to treatment.
ICANS Grade	Up to 28 days after liso-cel infusion	ICANS severity was graded per American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria (Lee et al, Biol Blood Marrow Transplant, 2019): grade 1, immune effector cell-associated encephalopathy (ICE, overall score range 0-10, higher score = better condition) score 7-9, awakens spontaneously; grade 2, ICE score 3-6, awakens to voice; grade 3, ICE score 0-2, awakens only to tactile stimulus, any clinical seizure that resolves rapidly or non-convulsive seizures on EEG that resolve with intervention, focal/local oedema on neuroimaging; grade 4, ICE 0, unarousable and unable to perform ICE, unarousable or requires vigorous or repetitive tactile stimuli to arouse, stupor or coma, life-threatening prolonged seizure (\>5 min); or repetitive clinical or electrical seizures without return to baseline in between, deep focal motor weakness such as hemiparesis or paraparesis, diffuse cerebral oedema on neuroimaging, decerebrate or decorticate posturing, or cranial nerve VI
Rate of Hospitalization After Liso-cel Treatment	Up to 28 days after liso-cel infusion	Number of patients hospitalized after liso-cel treatment.
Duration of Hospitalization After Liso-cel Treatment	Up to 28 days after liso-cel infusion	Duration of hospitalization measured in days following liso-cel administration.
Corticosteroid Usage After Liso-cel Treatment	Up to 28 days after liso-cel infusion	Number of patients who received corticosteroids within 28 days after liso-cel infusion.
Adverse Events (AEs)	Up to 28 days after liso-cel infusion	Grade 3 or greater AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Trial Locations

Locations (1): Fred Hutch/University of Washington Cancer Consortium
🇺🇸
Seattle, Washington, United States
Fred Hutch/University of Washington Cancer Consortium
🇺🇸Seattle, Washington, United States