Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04205838
Recruitment Status : Recruiting
First Posted : December 20, 2019
Last Update Posted : July 23, 2020
Sponsor:
Information provided by (Responsible Party):
Jonsson Comprehensive Cancer Center

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.

Condition or disease Intervention/treatment Phase
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 Biological: Anakinra Biological: Axicabtagene Ciloleucel Drug: Cyclophosphamide Drug: Fludarabine Drug: Fludarabine Phosphate Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: IL-1 Receptor Antagonist to Prevent Severe Chimeric Antigen Receptor T-Cell Related Encephalopathy Syndrome
Actual Study Start Date : March 4, 2020
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Prevention (anakinra, CAR T-cell therapy)
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.
Biological: Anakinra
Given SC
Other Names:
  • Kinaret
  • Kineret
  • rIL-1ra
  • rIL1RN

Biological: Axicabtagene Ciloleucel
Given via infusion
Other Names:
  • KTE C19
  • KTE-C19
  • KTE-C19 CAR
  • Yescarta

Drug: Cyclophosphamide
Given via infusion
Other Names:
  • (-)-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

Drug: Fludarabine
Given via infusion
Other Name: Fluradosa

Drug: Fludarabine Phosphate
Given via infusion
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586




Primary Outcome Measures :
  1. Number of patients who met the eligibility criteria to receive and did receive anakinra [ Time Frame: Up to 12 months ]
    The study will be considered feasible if 8 study participants are enrolled over 12 months at University of California, Los Angeles.

  2. Rate of severe chimeric antigen receptor T-cell-related encephalopathy syndrome (ICANS) [ Time Frame: Up to 30 days ]
    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 :
  1. Objective response rate (ORR) [ Time Frame: Up to 90 days ]
    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.

  2. Proportion of patients who received anakinra and develop ICAN [ Time Frame: Up to 30 days ]
    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.

  3. Duration of neurotoxicity [ Time Frame: From first day of CRES of any grade to complete resolution of CRES, assessed up to 100 days ]
    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.

  4. Duration of neurotoxicity [ Time Frame: From first day of ICANS of >= grade 3 to improvement of ICANS to < grade 3, assessed up to 100 days ]
    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.

  5. Persistent hepatotoxicity [ Time Frame: Up to 100 days ]
    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.

  6. Incidence of adverse events (AEs) [ Time Frame: Up to 100 days ]
    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.


Other Outcome Measures:
  1. ICANS grade [ Time Frame: up to 30 days ]
    Will evaluate ICANS grade by using the American Society for Blood and Marrow Transplantation 2018 consensus grading for adults.

  2. Cytokine release syndrome (CRS) grade [ Time Frame: Up to 30 days ]
    Will evaluate CRS grade by using the American Society for Blood and Marrow Transplantation 2018 consensus grading for adults.

  3. Changes in inflammatory markers [ Time Frame: Baseline up to 6 days following initiation of anakinra ]
    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.

  4. Changes in Electroencephalogram (EEG) that characterize ICANS: Slowing of EEG activity. [ Time Frame: Baseline up to 100 days ]
    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.

  5. Changes in Electroencephalogram (EEG) that characterize ICANS: focal slowing [ Time Frame: Baseline up to 100 days ]
    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.

  6. Changes in Electroencephalogram (EEG) that characterize ICANS: periodic discharge [ Time Frame: Baseline up to 100 days ]
    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)

  7. Changes in Electroencephalogram (EEG) that characterize ICANS: rhythmic activity [ Time Frame: Baseline up to 100 days ]
    Generalized or lateralized or bilateral independent or multifocal Rhythmic delta activity (</= 4 Hz).

  8. Changes in Electroencephalogram (EEG) that characterize ICANS: Generalized or lateralized or bilateral independent or multifocal spike [ Time Frame: Baseline up to 100 days ]
    Generalized or lateralized or bilateral independent or multifocal spike (duration of the wave <70ms) or sharp (duration of the wave 70-200ms) discharges.

  9. Changes in Electroencephalogram (EEG) that characterize ICANS: seizures [ Time Frame: Baseline up to 100 days ]
    Electrographic seizure occurrence: Percentage of subjects who experience electrographic seizure while undergoing continuous-EEG monitoring.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04205838


Contacts
Layout table for location contacts
Contact: Caspian Oliai, MD 310-206-8477 ext 30870 coliai@mednet.ucla.edu

Locations
Layout table for location information
United States, California
UCLA / Jonsson Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90095
Contact: Caspian Oliai    310-794-4820    COliai@mednet.ucla.edu   
Principal Investigator: John M. Timmerman, M.D.         
Sponsors and Collaborators
Jonsson Comprehensive Cancer Center
Investigators
Layout table for investigator information
Principal Investigator: John M Timmerman, MD UCLA / Jonsson Comprehensive Cancer Center
Layout table for additonal information
Responsible Party: Jonsson Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04205838    
Other Study ID Numbers: 19-000604
NCI-2019-02887 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
19-000604 ( Other Identifier: UCLA / Jonsson Comprehensive Cancer Center )
First Posted: December 20, 2019    Key Record Dates
Last Update Posted: July 23, 2020
Last Verified: May 2020

Layout table for additional information
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Lymphoma, Follicular
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Brain Diseases
Disease Progression
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Central Nervous System Diseases
Nervous System Diseases
Disease Attributes
Pathologic Processes
Vidarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Interleukin 1 Receptor Antagonist Protein
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents