Anakinra in Preventing Severe Immune Effector Cell-Associated Neurotoxicity Syndrome in Patients with Recurrent or Refractory Large B-cell Lymphoma
This phase Ib/II trial studies how well anakinra works in preventing severe immune effector cell-associated neurotoxicity 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 immune effector cell-associated neurotoxicity syndrome.
Inclusion Criteria
- Patients with relapsed or refractory large B-cell lymphoma that has progressed on two prior lines of therapy, refractory to first-line chemoimmunotherapy, or that relapses within 12 months of first-line chemoimmunotherapy
- 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)
- Participants must have measurable disease prior to leukapheresis, based on the Lugano classification of the initial assessment of measurable disease (Cheson et al. J Clin Oncol 2014)
- 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
- Age ≥ 18 years
- 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
- Most recent positron emission tomography (PET)-computed tomography (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 30 days have 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04205838.
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of Anakinra given via intravenous (IV) push in patients undergoing chimeric antigen receptor (CAR) T-cell therapy.
II. To estimate the efficacy of anakinra in prevention of severe immune effector cell-associated neurotoxicity syndrome (ICANS).
SECONDARY OBJECTIVES:
I. To estimate the impact that anakinra has on the efficacy of CAR T-cell therapy for relapsed/refractory lymphoma.
II. To estimate the rate of subsequent ICANS development in patients who receive anakinra for grade >= 2 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 estimate the rate of protracted cytopenias in participants who receive anakinra.
VI. To determine if anakinra causes persistent hepatotoxicity in patients receiving CAR T-cell for refractory lymphoma.
VII. To evaluate the overall toxicity of anakinra in patients receiving CAR T-cell therapy for refractory lymphoma, including neurotoxicities not included in the definition of ICANS.
X. To evaluate the pharmacokinetics and pharmacodynamics of Anakinra in patients receiving CAR T-cell therapy.
EXPLORATORY OBJECTIVES:
I. To evaluate CRS and ICANS grade by using the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.
II. To investigate changes in inflammatory markers including IL-1 and IL-6 in the peripheral blood during episodes of ICANS.
OUTLINE: This is a dose-escalation study.
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 receive anakinra subcutaneously (SC) every 6 hours for 12-36 doses until ICANS resolves in the absence of unacceptable toxicity. Patients with clinical evidence of CRS >= grade 2 receive anakinra SC every 6 hours for 12 doses in the absence of unacceptable toxicity.
After completion of study, patients are followed up at 30, 90, and 100 days, then at 6 months.
Trial PhasePhase II
Trial Typesupportive care
Lead OrganizationUCLA / Jonsson Comprehensive Cancer Center
Principal InvestigatorJohn Matthew Timmerman
- Primary ID19-000604
- Secondary IDsNCI-2019-02887
- ClinicalTrials.gov IDNCT04205838