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Anakinra in Preventing Severe Chimeric Antigen Receptor T-Cell Related Encephalopathy Syndrome in Patients With Recurrent or Refractory Large B-cell Lymphoma

Primary Purpose

Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, High Grade B-Cell Lymphoma, Progressive Disease

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Anakinra
Axicabtagene Ciloleucel
Cyclophosphamide
Fludarabine
Fludarabine Phosphate
Sponsored by
Jonsson Comprehensive Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Diffuse Large B-Cell Lymphoma, Not Otherwise Specified

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with relapsed or refractory large B-cell lymphoma that has progressed on two prior lines of therapy, who meet the indication for the Food and Drug Administration (FDA)-approved therapy axicabtagene ciloleucel
  • Large B-cell lymphoma includes 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
  • The above includes patients with progressive or stable disease as the best response to the most recent treatment regimen or disease progression within 12 months after autologous hematopoietic stem cell transplantation
  • Patients with central nervous system (CNS) involvement of large B-cell lymphoma that originated outside of the CNS will be included (not primary CNS lymphoma)
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 upper limit of normal
  • Total bilirubin =< 2.0 mg/dL
  • Creatinine clearance > 30 mL/min based on Cockcroft-Gault formula
  • Patients with human immunodeficiency virus (HIV) who have an undetectable viral load will be included
  • Deemed competent to make medical decisions

Exclusion Criteria:

  • Patients who receive CAR T-cell therapy with a product other than axicabtagene ciloleucel
  • Primary CNS lymphoma
  • Transformed DLBCL from chronic lymphocytic leukemia (CLL)
  • Burkitt?s lymphoma
  • Bridging chemotherapy completed < 7 days prior to CAR T-cell lymphodepleting chemotherapy
  • In patients who receive bridging chemotherapy, positron emission tomography (PET)-computed tomography (CT) or CT of chest, abdomen, pelvis was not done after bridging chemotherapy prior lympho-depleting therapy
  • Most recent PET-CT or CT of all known disease is sites done more than 6 weeks prior to CAR T-cell infusion
  • Any individual CNS tumor mass > 2 cm
  • History of autologous hematopoietic stem cell transplantation administered less than 100 days prior to CAR T-cell infusion
  • History of allogeneic hematopoietic stem cell transplantation
  • Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis
  • Less than 3 half-lives elapsed since receiving immune checkpoint inhibitor (pembrolizumab, ipilimumab, nivolumab, atezolizumab, etc.)
  • Presence of uncontrolled fungal, bacterial, or viral infection that require intravenous (IV) antimicrobial treatment
  • History of autoimmune disease resulting in end-organ damage, or autoimmune disease requiring systemic immunosuppressants or disease-modifying antirheumatic drug (DMARDs) within the past 6 months
  • Hypersensitivity to E. Coli-derived proteins
  • Patients with HIV who have a detectable viral load
  • Pregnant or nursing
  • Fertile women who decline use of contraception during the study period

Sites / Locations

  • UCLA / Jonsson Comprehensive Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Prevention (anakinra, CAR T-cell therapy)

Arm Description

Patients receive standard lymphodepleting therapy including fludarabine and cyclophosphamide on days -5 to -3, then receive axicabtagene ciloleucel CAR T-cell infusion. Patients with clinical evidence of ICANS of any grade, or CRS >= grade 3 receive anakinra SC every 6-12 hours for 12-36 doses over 9 days in the absence of unacceptable toxicity.

Outcomes

Primary Outcome Measures

Number of patients who met the eligibility criteria to receive and did receive anakinra
The study will be considered feasible if 8 study participants are enrolled over 12 months at University of California, Los Angeles.
Rate of severe chimeric antigen receptor T-cell-related encephalopathy syndrome (ICANS)
Will be defined as grade >= 3 neurotoxicity by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03. The proportion of patients developing severe ICANS and the corresponding 90% binomial exact confidence interval (CI) will be reported.

Secondary Outcome Measures

Objective response rate (ORR)
Will be defined as a complete response or partial response per the International Working Group criteria malignancy lymphoma based on positron emission tomography (PET)/computed tomography (CT) scan. To account for the adaptive nature of Simon?s two-stage design, final analysis of the objective response rate will report the uniformly minimum variance unbiased estimator and the corresponding p-value and 95% CI for the ORR.
Proportion of patients who received anakinra and develop ICAN
The proportion of patients who received anakinra in the absence of ICANS and then develop ICANS of any grade out of the total number of participants who received anakinra in the absence of ICANS will be evaluated. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate.
Duration of neurotoxicity
Defined as number of days that elapse from first day of ICANS of any grade to complete resolution of ICANS. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate.
Duration of neurotoxicity
Defined as number of days that elapse from first day of ICANS of >= grade 3 to improvement of ICANS to < grade 3 based on CTCAE v4.03. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate.
Persistent hepatotoxicity
Will be defined as grade > 2 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increased for at least 4 weeks duration according to CTCAE v4.03. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate.
Incidence of adverse events (AEs)
Will be based on CTCAE v4.03. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate. All AEs will be listed, documenting the course, outcome, severity, and relationship to the study treatment. Incidence rates of AEs and the proportion of subjects prematurely withdrawn from the study due to AEs will be shown.

Full Information

First Posted
October 2, 2019
Last Updated
June 15, 2023
Sponsor
Jonsson Comprehensive Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04205838
Brief Title
Anakinra in Preventing Severe Chimeric Antigen Receptor T-Cell Related Encephalopathy Syndrome in Patients With Recurrent or Refractory Large B-cell Lymphoma
Official Title
IL-1 Receptor Antagonist to Prevent Severe Chimeric Antigen Receptor T-Cell Related Encephalopathy Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 4, 2020 (Actual)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
June 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Jonsson Comprehensive Cancer Center

4. Oversight

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.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well anakinra works in preventing severe chimeric antigen receptor T-cell-related encephalopathy syndrome after chimeric antigen receptor T-cell therapy in patients with large B-cell lymphoma that has come back or has not responded to treatment. Immunosuppressive therapy, such as anakinra, is used to decrease the body?s immune response, which may prevent severe chimeric antigen receptor T-cell-related encephalopathy syndrome.
Detailed Description
PRIMARY OBJECTIVES: I. To determine if it is feasible to accrue a sufficient number of study participants at one site, in order to justify expanding the trial to three additional sites (pilot study). II. To estimate the efficacy of anakinra in prevention of severe immune effector cell-associated neurotoxicity syndrome. syndrome (ICANS) (full study). SECONDARY OBJECTIVES: I. To estimate the impact that anakinra has on the efficacy of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory lymphoma. II. To estimate the rate of subsequent ICANS development in patients who receive anakinra for grade >= 3 cytokine release syndrome (CRS) in the absence of ICANS. III. To estimate the duration of neurotoxicity in patients who receive anakinra. IV. To estimate the duration of severe neurotoxicity in patients who receive anakinra. V. To determine if anakinra causes persistent hepatotoxicity in patients receiving CAR T-cell for refractory lymphoma. VI. to evaluate the overall toxicity of anakinra in patients receiving CAR T-cell therapy for refractory lymphoma. EXPLORATORY OBJECTIVES: I. To evaluate CRS and ICANS grade by using the American Society for Blood and Marrow Transplantation (ASBMT) 2018 consensus grading for adults. II. To investigate changes in inflammatory markers including IL-1 and IL-6 in the peripheral blood during episodes of ICANS. III. To describe the electroencephalogram (EEG) changes that characterize ICANS. OUTLINE: Patients receive standard lymphodepleting therapy including fludarabine and cyclophosphamide on days -5 to -3, then receive axicabtagene ciloleucel CAR T-cell infusion. Patients with clinical evidence of ICANS of any grade, or CRS >= grade 3 receive anakinra subcutaneously (SC) every 6-12 hours for 12-36 doses over 9 days in the absence of unacceptable toxicity. After completion of study, patients are followed up at 30, 90, and 100 days, then at 6 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, High Grade B-Cell Lymphoma, Progressive Disease, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent High Grade B-Cell Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma, Recurrent Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory High Grade B-Cell Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma, Refractory Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Prevention (anakinra, CAR T-cell therapy)
Arm Type
Experimental
Arm Description
Patients receive standard lymphodepleting therapy including fludarabine and cyclophosphamide on days -5 to -3, then receive axicabtagene ciloleucel CAR T-cell infusion. Patients with clinical evidence of ICANS of any grade, or CRS >= grade 3 receive anakinra SC every 6-12 hours for 12-36 doses over 9 days in the absence of unacceptable toxicity.
Intervention Type
Biological
Intervention Name(s)
Anakinra
Other Intervention Name(s)
Kinaret, Kineret, rIL-1ra, rIL1RN
Intervention Description
Given SC
Intervention Type
Biological
Intervention Name(s)
Axicabtagene Ciloleucel
Other Intervention Name(s)
KTE C19, KTE-C19, KTE-C19 CAR, Yescarta
Intervention Description
Given via infusion
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given via infusion
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fluradosa
Intervention Description
Given via infusion
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given via infusion
Primary Outcome Measure Information:
Title
Number of patients who met the eligibility criteria to receive and did receive anakinra
Description
The study will be considered feasible if 8 study participants are enrolled over 12 months at University of California, Los Angeles.
Time Frame
Up to 12 months
Title
Rate of severe chimeric antigen receptor T-cell-related encephalopathy syndrome (ICANS)
Description
Will be defined as grade >= 3 neurotoxicity by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03. The proportion of patients developing severe ICANS and the corresponding 90% binomial exact confidence interval (CI) will be reported.
Time Frame
Up to 30 days
Secondary Outcome Measure Information:
Title
Objective response rate (ORR)
Description
Will be defined as a complete response or partial response per the International Working Group criteria malignancy lymphoma based on positron emission tomography (PET)/computed tomography (CT) scan. To account for the adaptive nature of Simon?s two-stage design, final analysis of the objective response rate will report the uniformly minimum variance unbiased estimator and the corresponding p-value and 95% CI for the ORR.
Time Frame
Up to 90 days
Title
Proportion of patients who received anakinra and develop ICAN
Description
The proportion of patients who received anakinra in the absence of ICANS and then develop ICANS of any grade out of the total number of participants who received anakinra in the absence of ICANS will be evaluated. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate.
Time Frame
Up to 30 days
Title
Duration of neurotoxicity
Description
Defined as number of days that elapse from first day of ICANS of any grade to complete resolution of ICANS. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate.
Time Frame
From first day of CRES of any grade to complete resolution of CRES, assessed up to 100 days
Title
Duration of neurotoxicity
Description
Defined as number of days that elapse from first day of ICANS of >= grade 3 to improvement of ICANS to < grade 3 based on CTCAE v4.03. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate.
Time Frame
From first day of ICANS of >= grade 3 to improvement of ICANS to < grade 3, assessed up to 100 days
Title
Persistent hepatotoxicity
Description
Will be defined as grade > 2 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increased for at least 4 weeks duration according to CTCAE v4.03. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate.
Time Frame
Up to 100 days
Title
Incidence of adverse events (AEs)
Description
Will be based on CTCAE v4.03. Will be summarized using descriptive statistics such as proportion, mean, standard deviation, median, as appropriate. All AEs will be listed, documenting the course, outcome, severity, and relationship to the study treatment. Incidence rates of AEs and the proportion of subjects prematurely withdrawn from the study due to AEs will be shown.
Time Frame
Up to 100 days
Other Pre-specified Outcome Measures:
Title
ICANS grade
Description
Will evaluate ICANS grade by using the American Society for Blood and Marrow Transplantation 2018 consensus grading for adults.
Time Frame
up to 30 days
Title
Cytokine release syndrome (CRS) grade
Description
Will evaluate CRS grade by using the American Society for Blood and Marrow Transplantation 2018 consensus grading for adults.
Time Frame
Up to 30 days
Title
Changes in inflammatory markers
Description
Peak median serum blood and cerebral spinal fluid (CSF) levels of IL-1 and IL-6 will be summarized using descriptive statistics or contingency tables, as appropriate.
Time Frame
Baseline up to 6 days following initiation of anakinra
Title
Changes in Electroencephalogram (EEG) that characterize ICANS: Slowing of EEG activity.
Description
Slowing of EEG activity including waveform, spectrum, spectrogram, and power in the slow (0.1-1 Hz), delta (1 to 4 Hz), theta (4 to 8 Hz) bands.
Time Frame
Baseline up to 100 days
Title
Changes in Electroencephalogram (EEG) that characterize ICANS: focal slowing
Description
Changes in Electroencephalogram (EEG) that characterize ICANS: Focal regional slowing of the EEG activity within the frontal, temporal, parietal, or occipital region in the delta (<4Hz) and/ or theta (4-8 Hz) band.
Time Frame
Baseline up to 100 days
Title
Changes in Electroencephalogram (EEG) that characterize ICANS: periodic discharge
Description
Generalized or lateralized or bilateral independent or multifocal periodic discharges (repetitive discharges with similar morphology and recurring at regular or near-regular inter-discharge intervals)
Time Frame
Baseline up to 100 days
Title
Changes in Electroencephalogram (EEG) that characterize ICANS: rhythmic activity
Description
Generalized or lateralized or bilateral independent or multifocal Rhythmic delta activity (</= 4 Hz).
Time Frame
Baseline up to 100 days
Title
Changes in Electroencephalogram (EEG) that characterize ICANS: Generalized or lateralized or bilateral independent or multifocal spike
Description
Generalized or lateralized or bilateral independent or multifocal spike (duration of the wave <70ms) or sharp (duration of the wave 70-200ms) discharges.
Time Frame
Baseline up to 100 days
Title
Changes in Electroencephalogram (EEG) that characterize ICANS: seizures
Description
Electrographic seizure occurrence: Percentage of subjects who experience electrographic seizure while undergoing continuous-EEG monitoring.
Time Frame
Baseline up to 100 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with relapsed or refractory large B-cell lymphoma that has progressed on two prior lines of therapy, who meet the indication for the Food and Drug Administration (FDA)-approved therapy axicabtagene ciloleucel Large B-cell lymphoma includes 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 The above includes patients with progressive or stable disease as the best response to the most recent treatment regimen or disease progression within 12 months after autologous hematopoietic stem cell transplantation Patients with central nervous system (CNS) involvement of large B-cell lymphoma that originated outside of the CNS will be included (not primary CNS lymphoma) Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 upper limit of normal Total bilirubin =< 2.0 mg/dL Creatinine clearance > 30 mL/min based on Cockcroft-Gault formula Patients with human immunodeficiency virus (HIV) who have an undetectable viral load will be included Deemed competent to make medical decisions Exclusion Criteria: Patients who receive CAR T-cell therapy with a product other than axicabtagene ciloleucel Primary CNS lymphoma Transformed DLBCL from chronic lymphocytic leukemia (CLL) Burkitt?s lymphoma Bridging chemotherapy completed < 7 days prior to CAR T-cell lymphodepleting chemotherapy In patients who receive bridging chemotherapy, positron emission tomography (PET)-computed tomography (CT) or CT of chest, abdomen, pelvis was not done after bridging chemotherapy prior lympho-depleting therapy Most recent PET-CT or CT of all known disease is sites done more than 6 weeks prior to CAR T-cell infusion Any individual CNS tumor mass > 2 cm History of autologous hematopoietic stem cell transplantation administered less than 100 days prior to CAR T-cell infusion History of allogeneic hematopoietic stem cell transplantation Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis Less than 3 half-lives elapsed since receiving immune checkpoint inhibitor (pembrolizumab, ipilimumab, nivolumab, atezolizumab, etc.) Presence of uncontrolled fungal, bacterial, or viral infection that require intravenous (IV) antimicrobial treatment History of autoimmune disease resulting in end-organ damage, or autoimmune disease requiring systemic immunosuppressants or disease-modifying antirheumatic drug (DMARDs) within the past 6 months Hypersensitivity to E. Coli-derived proteins Patients with HIV who have a detectable viral load Pregnant or nursing Fertile women who decline use of contraception during the study period
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Caspian Oliai, MD
Phone
310-206-8477
Ext
30870
Email
coliai@mednet.ucla.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John M Timmerman, MD
Organizational Affiliation
UCLA / Jonsson Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCLA / Jonsson Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Caspian Oliai
Phone
310-794-4820
Email
COliai@mednet.ucla.edu
First Name & Middle Initial & Last Name & Degree
John M. Timmerman, M.D.

12. IPD Sharing Statement

Learn more about this trial

Anakinra in Preventing Severe Chimeric Antigen Receptor T-Cell Related Encephalopathy Syndrome in Patients With Recurrent or Refractory Large B-cell Lymphoma

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