B-Cell Non-Hodgkin Lymphoma
Conditions
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.
Interventions
BIOLOGICALAnakinra
Given IV (previously SC)
PROCEDUREX-Ray Imaging
Undergo x-ray
PROCEDUREPositron Emission Tomography
Undergo PET/CT
PROCEDUREComputed Tomography
Undergo PET/CT or CT
PROCEDUREBone Marrow Aspiration
Undergo BMA
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
PROCEDURELumbar Puncture
Undergo lumbar puncture
PROCEDUREBiospecimen Collection
Undergo blood sample collection
Sponsors
Swedish Orphan Biovitrum
Fred Hutchinson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
Of 27 enrolled participants, 25 met inclusion criteria and started treatment.
Participants by arm
| Arm | Count |
|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) 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.
Anakinra: Given IV (previously SC)
X-Ray Imaging: Undergo x-ray
Positron Emission Tomography: Undergo PET/CT
Computed Tomography: Undergo PET/CT or CT
Bone Marrow Aspiration: Undergo BMA
Bone Marrow Biopsy: Undergo bone marrow biopsy
Lumbar Puncture: Undergo lumbar puncture
Biospecimen Collection: Undergo blood sample collection | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | Prevention (anakinra, lisocabtagene maraleucel) |
|---|---|
| Age, Continuous Age Known | 69 years STANDARD_DEVIATION 7 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 25 |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 15 / 25 |
Outcome results
Primary
Absence of Any Grade Cytokine Release Syndrome (CRS)
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.
Time frame: Up to 28 days after lisocabtagene maraleucel (liso-cel) infusion
Population: Not applicable here (no difference between number of participants analyzed
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) | Absence of Any Grade Cytokine Release Syndrome (CRS) | CRS | 16 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | Absence of Any Grade Cytokine Release Syndrome (CRS) | No CRS | 9 Participants |
Secondary
Adverse Events (AEs)
Grade 3 or greater AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time frame: Up to 28 days after liso-cel infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) | Adverse Events (AEs) | 25 Participants |
Secondary
Corticosteroid Usage After Liso-cel Treatment
Number of patients who received corticosteroids within 28 days after liso-cel infusion.
Time frame: Up to 28 days after liso-cel infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) | Corticosteroid Usage After Liso-cel Treatment | 10 Participants |
Secondary
CRS Grade
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.
Time frame: Up to 28 days after liso-cel infusion
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) | CRS Grade | Peak CRS Grade 0 | 9 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | CRS Grade | Peak CRS Grade 1 | 8 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | CRS Grade | Peak CRS Grade 3 | 1 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | CRS Grade | Peak CRS Grade 2 | 7 Participants |
Secondary
Disease Response to Liso-cel
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.
Time frame: Approximately 90 days after liso-cel infusion
Population: Six patients were not evaluable for this endpoint due to lack of measurable disease prior to treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) | Disease Response to Liso-cel | CR | 8 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | Disease Response to Liso-cel | PR | 5 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | Disease Response to Liso-cel | SD | 2 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | Disease Response to Liso-cel | PD | 4 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | Disease Response to Liso-cel | Not evaluable | 6 Participants |
Secondary
Duration of Hospitalization After Liso-cel Treatment
Duration of hospitalization measured in days following liso-cel administration.
Time frame: Up to 28 days after liso-cel infusion
Population: The number of days in the hospital (hospitalized only) group only included patients who were hospitalized (n=18)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) | Duration of Hospitalization After Liso-cel Treatment | Number of days in the hospital (all pts) | 6 days |
| Prevention (anakinra, lisocabtagene maraleucel) | Duration of Hospitalization After Liso-cel Treatment | Number of days in the hospital (hospitalized only) | 8 days |
Secondary
ICANS Grade
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
Time frame: Up to 28 days after liso-cel infusion
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) | ICANS Grade | Peak ICANS Grade 0 | 16 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | ICANS Grade | Peak ICANS Grade 1 | 4 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | ICANS Grade | Peak ICANS Grade 2 | 2 Participants |
| Prevention (anakinra, lisocabtagene maraleucel) | ICANS Grade | Peak ICANS Grade 3 | 3 Participants |
Secondary
Rate of Hospitalization After Liso-cel Treatment
Number of patients hospitalized after liso-cel treatment.
Time frame: Up to 28 days after liso-cel infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prevention (anakinra, lisocabtagene maraleucel) | Rate of Hospitalization After Liso-cel Treatment | 18 Participants |