Clinical Trials /

Anakinra for the Reduction of CAR-T Toxicity in Patients With Relapsed or Refractory Large B-cell Lymphoma

NCT04432506

Description:

This phase II trial studies the side effects and best dose of anakinra and to see how well it works in reducing side effects (toxicity) associated with a CAR-T cell treatment called axicabtagene ciloleucel in patients with large B-cell lymphoma that has come back (relapsed) or has not responded to treatment (refractory). Anakinra is a drug typically used to treat rheumatoid arthritis but may also help in reducing CAR-T cell therapy toxicity. Giving anakinra in combination with axicabtagene ciloleucel may help control relapsed or refractory large B-cell lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Primary Mediastinal B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Anakinra for the Reduction of CAR-T Toxicity in Patients With Relapsed or Refractory Large B-cell Lymphoma
  • Official Title: Pilot Study of Anakinra to Mitigate CAR-T Toxicity in Subjects With Relapsed or Refractory Large B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2019-1051
  • SECONDARY ID: NCI-2020-04369
  • SECONDARY ID: 2019-1051
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04432506

Conditions

  • Hematopoietic and Lymphoid Cell Neoplasm
  • 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

Interventions

DrugSynonymsArms
AnakinraKinaret, Kineret, rIL-1ra, rIL1RNTreatment (cyclophosphamide, fludarabine, axi-cel, anakinra)
Axicabtagene CiloleucelKTE C19, KTE-C19, KTE-C19 CAR, YescartaTreatment (cyclophosphamide, fludarabine, axi-cel, anakinra)
Cyclophosphamide(-)-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- 138719Treatment (cyclophosphamide, fludarabine, axi-cel, anakinra)
FludarabineFluradosaTreatment (cyclophosphamide, fludarabine, axi-cel, anakinra)

Purpose

This phase II trial studies the side effects and best dose of anakinra and to see how well it works in reducing side effects (toxicity) associated with a CAR-T cell treatment called axicabtagene ciloleucel in patients with large B-cell lymphoma that has come back (relapsed) or has not responded to treatment (refractory). Anakinra is a drug typically used to treat rheumatoid arthritis but may also help in reducing CAR-T cell therapy toxicity. Giving anakinra in combination with axicabtagene ciloleucel may help control relapsed or refractory large B-cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess safety and tolerability of anakinra in reducing incidence of cytokine release
      syndrome (CRS) within 30 days after infusion of chimeric antigen receptor (CAR) T cells in
      subjects with relapsed or refractory large B-cell lymphoma.

      SECONDARY OBJECTIVES:

      I. To determine incidence of all grades and duration of both CRS and immune-cell associated
      neurotoxicity syndrome (ICANS).

      II. To determine the complete response rate (CRR), overall response rate (ORR),
      progression-free survival (PFS) and overall survival (OS).

      EXPLORATORY OBJECTIVES:

      I. To determine the effects of anakinra on the cytokine and chemokine profile in peripheral
      blood after CAR-T therapy.

      II. To determine the effects of anakinra on the expansion and persistence of CAR T cells.

      III. To correlate baseline characteristics with toxicity, response and survival after
      anakinra combined with CAR-T therapy.

      OUTLINE: This is a dose-escalation study of anakinra.

      Patients receive cyclophosphamide intravenously (IV) over 60 minutes and fludarabine IV over
      30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity.
      Patients then receive axicabtagene ciloleucel IV over 30 minutes or less on day 0 and
      anakinra subcutaneously (SC) on days 0-6 in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 2 and 4 weeks, and then at
      2, 3, 6, 9, 12, 18, and 24 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cyclophosphamide, fludarabine, axi-cel, anakinra)ExperimentalPatients receive cyclophosphamide IV over 60 minutes and fludarabine IV over 30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive axicabtagene ciloleucel IV over 30 minutes or less on day 0 and anakinra SC on days 0-6 in the absence of disease progression or unacceptable toxicity.
  • Anakinra
  • Axicabtagene Ciloleucel
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal
             B-cell lymphoma (PMBCL), transformed follicular lymphoma (tFL), or high-grade B-cell
             lymphoma (HGBCL), at least 2 prior lines of systemic therapy

          -  Planned to receive standard of care therapy with axicabtagene ciloleucel

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Measurable disease of >= 1.5 cm

          -  At least two weeks or 5 half-lives, whichever is shorter, must have elapsed since any
             prior systemic therapy at the time the subject is planned for axicabtagene ciloleucel
             (axi-cel) therapy, except for systemic immune checkpoint inhibitory / immune
             stimulatory therapy. At least 3 half-lives must have elapsed from any prior systemic
             immune checkpoint inhibitory / immune stimulatory therapy at the time the subject is
             planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab,
             OX40 agonists, 4-1BB agonists, etc)

          -  Toxicities due to prior therapy must be stable and recovered to =< grade 1 (except for
             clinically non-significant toxicities such as alopecia)

          -  Absolute neutrophil count of >= 1.0 x 10^9/L

          -  Platelet count of >= 75 x 10^9/L

          -  Creatinine clearance (as estimated by Cockcroft Gault) >= 60 mL/minute (min)

          -  Serum alanine transaminase (ALT) / aspartate transaminase (AST) =< 2.5 upper limit of
             normal (ULN)

          -  Total bilirubin =< 1.5 mg/dL, except in subjects with Gilbert's syndrome

          -  Cardiac ejection fraction >= 50% with no evidence of pericardial effusion

          -  Baseline oxygen saturation > 92% on room air

          -  No evidence, suspicion, and/or history of lymphoma involving the central nervous
             system (CNS)

          -  Females of childbearing potential must have a negative serum or urine pregnancy test
             (females who have undergone surgical sterilization or who have been postmenopausal for
             at least 2 years are not considered to be of childbearing potential)

        Exclusion Criteria:

          -  History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g.
             cervix, bladder, breast) unless disease free for at least 3 years

          -  History of Richter's transformation of chronic lymphocytic leukemia (CLL)

          -  Autologous stem cell transplantation within 6 weeks of planned axi-cel infusion

          -  History of allogeneic stem cell transplantation

          -  Prior CD19 targeted therapy

          -  Prior chimeric antigen receptor therapy or other genetically modified T cell therapy

          -  Presence of fungal, bacterial, viral, or other infection that is uncontrolled or
             requiring IV antimicrobials for management. Simple urinary tract infection (UTI) and
             uncomplicated bacterial pharyngitis are permitted if responding to active treatment
             and after consultation with the principal investigator

          -  Known history of infection with human immunodeficiency virus (HIV) or hepatitis B
             (hepatitis B virus surface antigen [HBsAg] positive) or hepatitis C virus (anti-HCV
             positive). A history of hepatitis B or hepatitis C is permitted if the viral load is
             undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid
             testing

          -  Known history of tuberculosis. A negative Quantiferon or purified protein derivative
             (PPD) up to 2 months before start of anakinra is enough if no specific risk factors

          -  Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube,
             indwelling foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter).
             Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter
             are permitted

          -  Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or
             with a history of CNS lymphoma, cerebrospinal fluid malignant cells or brain
             metastases

          -  History or presence of CNS disorder such as seizure disorder, cerebrovascular
             ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS
             involvement

          -  Subjects with cardiac atrial or cardiac ventricular lymphoma involvement

          -  History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or
             other clinically significant cardiac disease within 12 months of enrollment

          -  Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or
             blood vessel compression

          -  Primary immunodeficiency

          -  History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus)
             resulting in end organ injury or requiring systemic immunosuppression/systemic disease
             modifying agents within the last 2 years

          -  History of deep vein thrombosis or pulmonary embolism within 6 months of enrollment

          -  Any medical condition likely to interfere with assessment of safety or efficacy of
             study treatment

          -  History of severe immediate hypersensitivity reaction to any of the agents used in
             this study, including E coli-derived proteins

          -  Live vaccine =< 6 weeks prior to planned start of conditioning regimen

          -  Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the preparative chemotherapy on the fetus or infant

          -  Subjects of both genders who are not willing to practice birth control from the time
             of consent through 6 months after the completion of anakinra injections

          -  In the investigator's judgment, the subject is unlikely to complete all
             protocol-required study visits or procedures, including follow-up visits, or comply
             with the study requirements for participation Trial Treatments
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of any grade cytokine release syndrome (CRS)
Time Frame:Within 30 days after infusion of CAR T cells
Safety Issue:
Description:Will be tabulated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version (v)5.0. CRS will be assessed by both Lee 2014 criteria as well as American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading system.

Secondary Outcome Measures

Measure:Incidence of different grade
Time Frame:Up to 1 year
Safety Issue:
Description:CRS cytokine release syndrome /ICANS immune-cell associated neurotoxicity syndrome grade (0, 1, 2, 3, 4, 5) Will be tabulated according to the NCI CTCAE v5.0. CRS will be assessed by both Lee 2014 criteria as well as ASTCT Consensus Grading system. ICANS will be assessed by both CTCAE v5.0 as well as ASTCT Consensus Grading system.
Measure:Incidence of duration of both (CRS) cytokine release syndrome
Time Frame:Up to 1 year
Safety Issue:
Description:(CRS) cytokine release syndrome /(ICANS) immune-cell associated neurotoxicity syndrome (days) Will be tabulated according to the NCI CTCAE v5.0. CRS will be assessed by both Lee 2014 criteria as well as ASTCT Consensus Grading system. ICANS will be assessed by both CTCAE v5.0 as well as ASTCT Consensus Grading system.
Measure:Overall response rate
Time Frame:Up to 24 months
Safety Issue:
Description:Will be assessed using the Cheson 2014 Lugano Classification response criteria for malignant lymphoma.
Measure:Complete response rate
Time Frame:Up to 24 months
Safety Issue:
Description:Will be assessed using the Cheson 2014 Lugano Classification response criteria for malignant lymphoma.
Measure:Progression free survival
Time Frame:From the start of treatment to disease progression or death due to any cause whichever happened first, assessed up to 24 months
Safety Issue:
Description:Will be assessed using the Cheson 2014 Lugano Classification response criteria for malignant lymphoma. Will be estimated using the method of Kaplan and Meier.
Measure:Overall survival
Time Frame:From the start of treatment to death due to any cause, assessed up to 24 months
Safety Issue:
Description:Will be assessed using the Cheson 2014 Lugano Classification response criteria for malignant lymphoma. Will be estimated using the method of Kaplan and Meier.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

June 12, 2020