Clinical trial NCT04205838: 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
Overall status: RECRUITING
Phase: PHASE2
Conditions: 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
Lead sponsor: Jonsson Comprehensive Cancer Center
Sponsor class: OTHER
First posted: 2019-12-20
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Number of patients who met the eligibility criteria to receive and did receive anakinra
timeFrame: Up to 12 months
measure: Rate of severe chimeric antigen receptor T-cell-related encephalopathy syndrome (ICANS)
timeFrame: Up to 30 days
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: Up to 90 days
measure: Proportion of patients who received anakinra and develop ICAN
timeFrame: Up to 30 days
measure: Duration of neurotoxicity
timeFrame: From first day of CRES of any grade to complete resolution of CRES, assessed up to 100 days
measure: Duration of neurotoxicity
timeFrame: From first day of ICANS of >= grade 3 to improvement of ICANS to < grade 3, assessed up to 100 days
measure: Persistent hepatotoxicity
timeFrame: Up to 100 days
measure: Incidence of adverse events (AEs)
timeFrame: Up to 100 days
Other outcomes:
measure: ICANS grade
timeFrame: up to 30 days
measure: Cytokine release syndrome (CRS) grade
timeFrame: Up to 30 days
measure: Changes in inflammatory markers
timeFrame: Baseline up to 6 days following initiation of anakinra
measure: Changes in Electroencephalogram (EEG) that characterize ICANS: Slowing of EEG activity.
timeFrame: Baseline up to 100 days
measure: Changes in Electroencephalogram (EEG) that characterize ICANS: focal slowing
timeFrame: Baseline up to 100 days
measure: Changes in Electroencephalogram (EEG) that characterize ICANS: periodic discharge
timeFrame: Baseline up to 100 days
measure: Changes in Electroencephalogram (EEG) that characterize ICANS: rhythmic activity
timeFrame: Baseline up to 100 days
measure: Changes in Electroencephalogram (EEG) that characterize ICANS: Generalized or lateralized or bilateral independent or multifocal spike
timeFrame: Baseline up to 100 days
measure: Changes in Electroencephalogram (EEG) that characterize ICANS: seizures
timeFrame: Baseline up to 100 days
Locations:
city: Davis
country: United States
facility: UC Davis Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA / Jonsson Comprehensive Cancer Center
state: California
Study officials:
affiliation: UCLA / Jonsson Comprehensive Cancer Center
name: John M Timmerman, MD
role: PRINCIPAL_INVESTIGATOR
References: