Clinical Trials /

Axi-cel in CNS Lymphoma

NCT04608487

Description:

This research is being done to test the safety and effectiveness of axicabtagene ciloleucel (axi-cel), an anti-CD19 directed chimeric antigen receptor (CAR) T-cell therapy in treating relapsed/refractory central nervous system (CNS) lymphoma, systemic lymphoma with concurrent CNS lymphoma, or systemic lymphoma with a history of treated CNS lymphoma, and to better understand what causes neurological toxicity following treatment with axi-cel. The names of the study drug(s) involved in this study are: - axicabtagene ciloleucel (axi-cel) - ludarabine will be given with axicel to help axicel work more effectively - cyclophosphamide will be given with axicel to help axicel work more effectively

Related Conditions:
  • Central Nervous System Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Axi-cel in CNS Lymphoma
  • Official Title: A Phase I Study of Anti-CD19 CAR T-cell Therapy With Axicabtagene Ciloleucel (Axi-cel) in Patients With Relapsed/Refractory Primary and Secondary Central Nervous System (CNS) Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 20-274
  • NCT ID: NCT04608487

Conditions

  • Lymphoma
  • Lymphoma Cns

Interventions

DrugSynonymsArms
FludarabineFludaraFludarabine + Cyclophosphamide + Axicabtagene Ciloleucel
CyclophosphamideCytoxan, NeosarFludarabine + Cyclophosphamide + Axicabtagene Ciloleucel
Axicabtagene CiloleucelYescartaFludarabine + Cyclophosphamide + Axicabtagene Ciloleucel

Purpose

This research is being done to test the safety and effectiveness of axicabtagene ciloleucel (axi-cel), an anti-CD19 directed chimeric antigen receptor (CAR) T-cell therapy in treating relapsed/refractory central nervous system (CNS) lymphoma, systemic lymphoma with concurrent CNS lymphoma, or systemic lymphoma with a history of treated CNS lymphoma, and to better understand what causes neurological toxicity following treatment with axi-cel. The names of the study drug(s) involved in this study are: - axicabtagene ciloleucel (axi-cel) - ludarabine will be given with axicel to help axicel work more effectively - cyclophosphamide will be given with axicel to help axicel work more effectively

Detailed Description

      This research study is a Phase I clinical trial, which tests the safety of an investigational
      drug and also tries to define the appropriate dose of the investigational drug to use for
      further studies. "Investigational" means that the drug is being studied. This study will
      examine the safety and efficacy of axi-cel in participants who either currently or previously
      had had central nervous system involvement of their lymphoma.

      The name of the study drug involved in this study is axi-cel. Axi-cel is a chimeric antigen
      receptor (CAR) T-cell therapy that is manufactured using a person's own white blood cells. A
      virus is used to introduce a gene that creates a protein (called a CAR) on the surface of T
      cells, a type of blood cell that fights infection and can eliminate cancer cells. The CAR on
      the T cells may bind to and kill cells that express CD19, a molecule that is found on B-cell
      lymphomas. CAR-T cells (including axi-cel) designed to target CD19, a protein present on B
      lymphocytes have been used to treat patients with CD19+ tumors. This adoptive cell therapy
      (ACT) approach has shown significant and durable clinical benefits in the treatment of CD19+
      tumors. Axi-cel has been FDA approved for the treatment of relapsed and refractory aggressive
      B cell lymphomas that occur outside the central nervous system and have recurred after two or
      more prior therapies.

      Participants will receive two chemotherapy medicines, fludarabine and cyclophosphamide. These
      drugs are not intended as direct cancer treatment but instead to help axi-cel work with less
      interference from immune system cells.

      The research study procedures include screening for eligibility and study treatment including
      leukapheresis, evaluations and follow up visits.

      Participants in this study will be divided into groups (cohorts) based on the type of disease
      they have and treatment history.

        -  Cohort 1: Participants with relapsed/refractory primary CNSL (PCNSL) and secondary CNSL
           without evidence of lymphoma outside the central nervous system

        -  Cohort 2: Participants with relapsed/refractory lymphoma outside the central nervous
           system, with either active, or previously treated, involvement of the central nervous
           system by the lymphoma

      Participants will receive study treatment once and will be followed for up to 15 years.

      It is expected that about 18 people will take part in this research study.

      Kite Pharma, a pharmaceutical company, is supporting this research study by providing
      axi-cel.
    

Trial Arms

NameTypeDescriptionInterventions
Fludarabine + Cyclophosphamide + Axicabtagene CiloleucelExperimentalTwo (2) cohorts of particpants: Cohort 1: relapsed/refractory primary CNSL (PCNSL) and secondary CNSL without systemic aggressive B cell non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), high grade B cell lymphoma (HGBL), primary mediastinal large B cell lymphoma (PMBL), and transformed follicular lymphoma (tFL). Cohort 2: relapsed/refractory systemic aggressive B cell non-Hodgkin lymphoma, including DLBCL, HGBL, PMBL, and tFL, with either active CNSL or previously treated CNSL Prior to receiving axi-cel, participants will undergo leukapheresis and the need for a Ommaya reservoir placement will be assessed and administered. Day -5 to Day -3 of 28 day study cycle Fludarabine and cyclophosphamide; Day -1 admitted to hospital, receive axi-cel on day 0; Till at least cycle day 7 hospital monitoring; post treatment follow up will occur on day 14 and day 28 of cycle 1, monthly in cycles 2, 3, 6, 9,12,15,18,21,24, then yearly after cycle 24.
  • Fludarabine
  • Cyclophosphamide
  • Axicabtagene Ciloleucel

Eligibility Criteria

        Inclusion Criteria:

          -  Cohort 1:

               -  Patients with relapsed/refractory active primary or secondary CNS lymphoma,
                  histologically proven aggressive B cell lymphoma, including DLBCL, HGBL,

        PMBL, or tFL, and defined by the following categories:

          -  Primary CNS lymphoma, relapsed or refractory following at least one line of
             CNS-directed therapy. There is no restriction on the number of recurrences.

          -  Secondary CNS lymphoma, relapsed or refractory following at least one line of
             CNS-directed therapy for prophylaxis or treatment of CNS lymphoma.

               -  Measurable CNS disease by MRI of the brain (longest diameter >1cm on gadolinium
                  enhanced MRI)

               -  No evidence of active systemic lymphoma (treated systemic lymphoma in remission
                  is allowed)

                    -  Cohort 2:

               -  Patients with relapsed and/or refractory systemic aggressive B cell lymphoma,
                  including DLBCL, HGBL, PMBL or tFL, with active or treated secondary CNS lymphoma

          -  R/R systemic lymphoma with concurrent CNS disease

          -  R/R systemic lymphoma with history of CNS disease

               -  History of treated secondary CNS lymphoma in remission but with R/R systemic
                  lymphoma

                    -  Systemic lymphomas must be either DLBCL, PMBL, high grade B cell lymphoma,
                       or transformed lymphoma and must have relapsed following at least 2 prior
                       lines of therapy (which must have included an anti-CD20 monoclonal antibody
                       (unless the tumor is CD20 negative) and an anthracycline)

                    -  Radiographically evident disease

                         -  At least 2 weeks or 5 half-lives, whichever is shorter, must have
                            elapsed since any prior systemic cancer therapy at the time the subject
                            provides consent

                         -  Age 18 years or older at the time of informed consent

                         -  ECOG performance status of 0 or 1 (see Appendix A)

                         -  Adequate bone marrow, renal, hepatic, pulmonary and cardiac function
                            defined as:

                    -  Absolute neutrophil count (ANC) ≥1000/μL

                    -  Platelet count ≥ 75,000/μL

                    -  Absolute lymphocyte count ≥ 100/μL

                    -  Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min

                    -  Serum alanine aminotransferase/aspartate aminotransferase (ALT/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%, no clinically significant pericardial
                       effusion as determined by an echocardiogram (ECHO), and no clinically
                       significant electrocardiogram (ECG) findings

                    -  No clinically significant pleural effusion

                    -  Baseline oxygen saturation > 92% on room air GCSF and transfusions are not
                       allowed for eligibility determination.+++

                         -  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:

          -  Primary vitreoretinal lymphoma and intraocular PCNSL without evidence of brain
             disease. Patients with prior history of intraocular involvement treated only with
             intraocular methotrexate and no prior systemic therapy are excluded

          -  PCNSL patients who cannot undergo magnetic resonance imaging assessments

          -  Patients with brain stem lesions

          -  Patients with leptomeningeal disease only without brain parenchymal involvement

          -  Bulky leptomeningeal disease and or CSF protein ≥100 mg/dL

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

          -  History of Richter's transformation of CLL

          -  History of allogeneic stem cell transplant

          -  Prior CD19 targeted therapy

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter,
             prior to the first dose of axicabtagene ciloleucel or SOC

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

          -  History of severe, immediate hypersensitivity reaction attributed to aminoglycosides

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

          -  Known history of infection with human immunodeficiency virus (HIV) or hepatitis B
             (HBsAg positive) or hepatitis C virus (anti-HCV positive). If there is a positive
             history of treated hepatitis B or hepatitis C, the viral load must be undetectable per
             quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.

          -  Active tuberculosis

          -  History or presence of non-malignant 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,
             New York Heart Association Class II or greater congestive heart failure, or other
             clinically significant cardiac disease within 12 months of enrollment

          -  Requirement for urgent therapy due to tumor mass effects

          -  History of autoimmune disease, requiring systemic immunosuppression and/or systemic
             disease modifying agents within the last 12 months.

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis per chest computed tomography (CT) scan at screening. History of radiation
             pneumonitis in the radiation field (fibrosis) is allowed.

          -  History of symptomatic deep vein thrombosis or pulmonary embolism requiring ongoing
             systemic anticoagulation

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

          -  History of severe immediate hypersensitivity reaction to tocilizumab or any of the
             agents used in this study

          -  Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine during the course of the study

          -  Women of childbearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of chemotherapy on the fetus or infant. Subjects of
             either sex who are not willing to practice birth control from the time of consent and
             at least 6 months after the last dose of axicabtagene ciloleucel or SOC chemotherapy

          -  In the investigators 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0
Time Frame:Enrollment until 30 days after last dose of study treatment up to 24 Months
Safety Issue:
Description:Measured by the rate of TLTs and the rate of grade 3+ adverse events (AEs) regardless of attribution

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:2 years
Safety Issue:
Description:CNS lymphoma response assessment will be evaluated by International Primary CNS Lymphoma Collaborative Group (IPCG) criteria Systemic lymphoma response assessment will be evaluated by the Lugano 2014 criteria
Measure:Complete response (CR) rate
Time Frame:2 years
Safety Issue:
Description:CNS lymphoma response assessment will be evaluated by International Primary CNS Lymphoma Collaborative Group (IPCG) criteria Systemic lymphoma response assessment will be evaluated by the Lugano 2014 criteria
Measure:Duration of response (DOR)
Time Frame:2 years
Safety Issue:
Description:CNS lymphoma response assessment will be evaluated by International Primary CNS Lymphoma Collaborative Group (IPCG) criteria Systemic lymphoma response assessment will be evaluated by the Lugano 2014 criteria
Measure:Progression-free survival (PFS)
Time Frame:2 years
Safety Issue:
Description:CNS lymphoma response assessment will be evaluated by International Primary CNS Lymphoma Collaborative Group (IPCG) criteria Systemic lymphoma response assessment will be evaluated by the Lugano 2014 criteria
Measure:Overall survival (OS)
Time Frame:2 years
Safety Issue:
Description:CNS lymphoma response assessment will be evaluated by International Primary CNS Lymphoma Collaborative Group (IPCG) criteria Systemic lymphoma response assessment will be evaluated by the Lugano 2014 criteria

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • relapsed/refractory central nervous system (CNS) lymphoma
  • systemic lymphoma with concurrent CNS lymphoma
  • systemic lymphoma with a history of treated CNS lymphoma

Last Updated

October 28, 2020