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Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Participants With Refractory Aggressive Non-Hodgkin Lymphoma (ZUMA-1)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02348216
Recruitment Status : Completed
First Posted : January 28, 2015
Results First Posted : November 23, 2021
Last Update Posted : June 4, 2024
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences ( Kite, A Gilead Company )

Brief Summary:

This study will be separated into 3 distinct phases designated as the Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2 safety management study (Cohort 3 and Cohort 4, Cohort 5 and Cohort 6).

The primary objectives of this study are:

  • Phase 1 Study: Evaluate the safety of axicabtagene ciloleucel regimens
  • Phase 2 Pivotal Study; Evaluate the efficacy of axicabtagene ciloleucel
  • Phase 2 Safety Management Study: Assess the impact of prophylactic regimens or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities

Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.


Condition or disease Intervention/treatment Phase
Refractory Diffuse Large B Cell Lymphoma (DLBCL) Relapsed Diffuse Large B-Cell Lymphoma Transformed Follicular Lymphoma (TFL) Primary Mediastinal B-cell Lymphoma (PMBCL) High Grade B-cell Lymphoma (HGBCL) Biological: Axicabtagene Ciloleucel Drug: Fludarabine Drug: Cyclophosphamide Drug: Levetiracetam Drug: Tocilizumab Drug: Dexamethasone Drug: High-dose methylprednisolone Drug: Bendamustine Drug: Rituximab Drug: Doxorubicin Drug: Prednisone Drug: Vincristine Drug: Ifosfamide Drug: Carboplatin Drug: Etoposide Drug: Gemcitabine Drug: Oxaliplatin Drug: Cisplatin Drug: Methylprednisolone Phase 1 Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 307 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma
Actual Study Start Date : April 21, 2015
Actual Primary Completion Date : July 27, 2023
Actual Study Completion Date : July 27, 2023


Arm Intervention/treatment
Experimental: Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy
Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) will receive conditioning chemotherapy (fludarabine 30 mg/m^2 intravenously [IV] over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel chimeric antigen receptor (CAR) transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of body weight (BW) on Day 0.
Biological: Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.
Other Name: Yescarta®

Drug: Fludarabine
Administered according to package insert

Drug: Cyclophosphamide
Administered according to package insert

Experimental: Phase 2 (Pivotal Study): Cohort 1
Participants with refractory DLBCL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.
Biological: Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.
Other Name: Yescarta®

Drug: Fludarabine
Administered according to package insert

Drug: Cyclophosphamide
Administered according to package insert

Experimental: Phase 2 (Pivotal Study): Cohort 2
Participants with refractory PMBCL or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.
Biological: Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.
Other Name: Yescarta®

Drug: Fludarabine
Administered according to package insert

Drug: Cyclophosphamide
Administered according to package insert

Experimental: Phase 2 (Safety Management Study): Cohort 3
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2).
Biological: Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.
Other Name: Yescarta®

Drug: Fludarabine
Administered according to package insert

Drug: Cyclophosphamide
Administered according to package insert

Drug: Levetiracetam
Administered according to package insert

Drug: Tocilizumab
Administered according to package insert

Experimental: Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
Biological: Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.
Other Name: Yescarta®

Drug: Fludarabine
Administered according to package insert

Drug: Cyclophosphamide
Administered according to package insert

Drug: Levetiracetam
Administered according to package insert

Drug: Tocilizumab
Administered according to package insert

Drug: Dexamethasone
Administered according to package insert

Drug: High-dose methylprednisolone
Administered according to package insert

Drug: Bendamustine
Administered according to package insert

Drug: Rituximab
Administered according to package insert

Experimental: Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
Biological: Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.
Other Name: Yescarta®

Drug: Fludarabine
Administered according to package insert

Drug: Cyclophosphamide
Administered according to package insert

Drug: Levetiracetam
Administered according to package insert

Drug: Rituximab
Administered according to package insert

Drug: Doxorubicin
Administered according to package insert

Drug: Prednisone
Administered according to package insert

Drug: Vincristine
Administered according to package insert

Drug: Ifosfamide
Administered according to package insert

Drug: Carboplatin
Administered according to package insert

Drug: Etoposide
Administered according to package insert

Drug: Gemcitabine
Administered according to package insert

Drug: Oxaliplatin
Administered according to package insert

Drug: Cisplatin
Administered according to package insert

Experimental: Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
Biological: Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.
Other Name: Yescarta®

Drug: Fludarabine
Administered according to package insert

Drug: Cyclophosphamide
Administered according to package insert

Drug: Levetiracetam
Administered according to package insert

Drug: Tocilizumab
Administered according to package insert

Drug: Dexamethasone
Administered according to package insert

Drug: High-dose methylprednisolone
Administered according to package insert

Drug: Bendamustine
Administered according to package insert

Drug: Rituximab
Administered according to package insert

Drug: Methylprednisolone
Administered according to package insert




Primary Outcome Measures :
  1. Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) [ Time Frame: First infusion date of axicabtagene ciloleucel up to 30 days ]

    DLT was defined as axicabtagene ciloleucel-related events with onset within first 30 days following infusion:

    • Grade (GR) 4 neutropenia lasting > 21 days and GR 4 thrombocytopenia lasting > 35 days from day of cell transfer;
    • Any axicabtagene ciloleucel-related AE requiring intubation;
    • All other GR 3 toxicities lasting > 3 days and all GR 4 toxicities, with exception of following conditions which were not considered DLTs: aphasia/dysphasia or confusion/cognitive disturbance which resolved to GR ≤ 1 within 2 weeks and to baseline within 4 weeks; fever GR 3; myelosuppression defined as lymphopenia, decreased hemoglobin, neutropenia and thrombocytopenia unless neutropenia and thrombocytopenia met DLT definition described above; immediate hypersensitivity reactions occurring within 2 hours of cell infusion that were reversible to a ≤ GR 2 within 24 hours of cell administration with standard therapy; hypogammaglobulinemia GR 3 or 4.

  2. Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator Per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma [ Time Frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7 years) ]
    ORR was defined as the percentage of participants achieving either a complete response (CR) or a partial response (PR), as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% confidence interval (CI) was calculated by Clopper-Pearson method.

  3. Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades [ Time Frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 6.8 years) ]
    TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or continuous venovenous hemodialysis (CVVHD), and Grade 5: Death. Neurologic toxicities were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.

  4. Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades [ Time Frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 5.4 years) ]
    TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.

  5. Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades [ Time Frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.4 years) ]
    TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.

  6. Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades [ Time Frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.1 years) ]
    TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.


Secondary Outcome Measures :
  1. Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma [ Time Frame: First OR to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively) ]
    Among participants who experience an objective response (OR), DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to disease progression per the revised IWG Response Criteria for Malignant Lymphoma or death regardless of cause. CR and PR as defined in outcome measure 2. Disease progression (PD) was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. Kaplan-Meier (KM) estimates was used for analyses.

  2. Phase 1 Study: ORR as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma [ Time Frame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months) ]
    ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules.

  3. Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC) [ Time Frame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years) ]
    ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma. CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method.

  4. Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma [ Time Frame: First infusion date of axicabtagene ciloleucel to last follow-up visit (maximum duration: 6.8, 5.4, 4.4, 4.1 years for Cohorts 3, 4, 5, and 6 respectively) ]
    ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method.

  5. Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma [ Time Frame: First infusion date of axicabtagene ciloleucel to disease progression or death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively) ]
    PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Disease progression was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. KM estimates was used for analyses.

  6. Phase 2: Overall Survival (OS) [ Time Frame: First infusion date of axicabtagene ciloleucel to the date of death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively) ]
    OS was defined as the time from axicabtagene ciloleucel infusion to the date of death. Participants who did not die by the analysis data cutoff date were censored at their last contact date. KM estimates was used for analyses.

  7. Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007 [ Time Frame: First objective response up to the data cutoff date of 11 August 2018 (maximum: 2.7 years) ]
    Among participants who experience an objective response, DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to PD, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death regardless of cause. CR and PR as defined in outcome measure 2. PD was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. Kaplan-Meier (KM) estimates was used for analyses.

  8. Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 [ Time Frame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years) ]
    The best overall response for each participant was based on the assessments of response (CR, PR, stable disease [SD], PD, and not done [ND]) made by the the IRRC using IWG 2007 criteria (Cheson et al, 2007). CR and PR as defined in outcome measure 2. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentage of participants with best overall response of CR, PR, SD, PD, and ND was reported.

  9. Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007 [ Time Frame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years) ]
    PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. KM estimates was used for analyses.

  10. Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years) ]
    An adverse event was defined as any untoward medical occurrence in a clinical trial participants. The event did not necessarily have a relationship with study treatment. Adverse events included worsening of a pre-existing medical condition. Worsening indicated that the pre-existing medical condition had increased in severity, frequency, and/or duration or had an association with a worse outcome. A pre-existing condition that had not worsened during the study or involved an intervention such as elective cosmetic surgery or a medical procedure while on study, was not considered an adverse event. TEAE was defined as any AE with onset on or after the start of treatment.

  11. Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs [ Time Frame: First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years) ]
    Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening.

  12. Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies [ Time Frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively) ]
  13. Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood [ Time Frame: Baseline up to Month 60 (for Phase 1 and Phase 2 Cohorts 1, 2, and 3); Baseline up to Month 24 (for Phase 2 Cohorts 4, 5, and 6) ]
    Peak was defined as the maximum number of CAR T cells measured post-infusion.

  14. Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Baseline up to Month 3 ]
    Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: interferon-gamma induced protein 10 (IP-10), ferritin, granzyme B, intercellular adhesion molecule (ICAM-1), interferon-gamma (IFN-gamma), interleukin-1 receptor antagonist (IL-1RA), IL-2, interleukin-2 receptor alpha (IL-2 R alpha), IL-6, IL-7, IL-8, IL-10, IL-15, perforin, tumor necrosis factor alpha (TNF alpha), and vascular cell adhesion molecule- 1 (VCAM-1).

  15. Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) [ Time Frame: Baseline up to Month 3 ]
    Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: IP-10, granzyme B, IFN-gamma, IL-1 RA, IL-2, IL-6, IL-7, IL-8, IL-10, IL-15, TNF alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF).

  16. Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) [ Time Frame: Baseline up to Month 3 ]
    Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1.

  17. Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum [ Time Frame: Baseline up to Month 3 ]
    Peak was defined as the maximum post-baseline level of the cytokine.

  18. Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2) [ Time Frame: Baseline up to Month 3 ]
    Peak was defined as the maximum post-baseline level of the cytokine.

  19. Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3) [ Time Frame: Baseline up to Month 3 ]
    Peak was defined as the maximum post-baseline level of the cytokine.

  20. Percentage of Participants With Positive Replication Competent Retrovirus (RCR) [ Time Frame: Day 0 (pre-infusion) up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively) ]
    RCR was analyzed in blood samples by central laboratory. Because axicabtagene ciloleucel comprised retroviral vector transduced T cells, the presence of RCR in the blood of treated participants was reported.

  21. Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score [ Time Frame: Baseline, Week 4, Month 3, and Month 6 ]
    EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant scoring 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was divided into 5 levels of severity: "No problem", "Slight problems", "Moderate problems", "Severe problems", and "Extreme problems (unable to perform)". EQ-5D health states, defined by the EQ-5D descriptive system, are converted into a single summary index by applying a formula that attaches values (also called QOL weights or QOL utilities) to each of the levels in each dimension. EQ-5D Summary Index values range from -0.11 (worst health state) to 1.00 (perfect health state).

  22. Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score [ Time Frame: Baseline, Week 4, Month 3, and Month 6 ]
    EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant. The EQ-5D-VAS records the participant's self-rated health on a vertical visual analogue scale and is asked to make a global assessment of their current state of health with 0 indicating the worst health they can imagine and 100 indicating the best health they can imagine.



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.


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

Key Inclusion Criteria

  1. Histologically confirmed:

    • Diffuse Large B Cell Lymphoma (DLBCL)
    • Primary Mediastinal Large B Cell Lymphoma (PMBCL)
    • Transformation Follicular Lymphoma (TFL)
    • High grade B-cell lymphoma (HGBCL)
  2. Chemotherapy-refractory disease, defined as one of more of the following:

    • No response to last line of therapy i. Progressive disease (PD) as best response to most recent therapy regimen ii. Stable disease (SD) as best response to most recent therapy with duration no longer than 6 month from last dose of therapy OR
    • Refractory post-autologous stem cell transplant (ASCT) i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy
  3. Individuals must have received adequate prior therapy including at a minimum:

    • Anti-cluster of differentiate 20 (CD20) monoclonal antibody unless investigator determines that tumor is CD20-negative and
    • an anthracycline containing chemotherapy regimen
    • for individual with transformed FL must have chemorefractory disease after transformation to DLBCL.
  4. At least one measurable lesion per revised international working group (IWG Response Criteria
  5. Eastern cooperative oncology group (ECOG) performance status of 0 or 1
  6. Absolute neutrophil count (ANC) ≥ 1000/microliters (uL)
  7. Absolute lymphocyte count ≥ 100/uL
  8. Platelet count ≥ 75,000/uL
  9. Adequate renal, hepatic, pulmonary and cardiac function defined as:

    • Creatinine clearance (as estimated by Cockcroft Gault) > 60 mL/min
    • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 upper limit of normal (ULN)
    • Total bilirubin < 1.5 mg/dL, except in individuals with Gilbert's syndrome
    • Cardiac ejection fraction >50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant pleural effusion
    • Baseline oxygen saturation >92% on room air
  10. All individuals or legally appointed representatives/caregivers, must personally sign and date the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved consent form before initiating any study specific procedures or activities.
  11. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy

Key Exclusion Criteria

  1. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years
  2. History of allogeneic stem cell transplantation
  3. Prior chimeric antigen receptor (CAR) therapy or other genetically modified T cell therapy
  4. 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
  5. History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection. Individuals with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines
  6. Individuals with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases
  7. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement

Note: Other protocol defined Inclusion/Exclusion criteria may apply.


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): NCT02348216


Locations
Show Show 36 study locations
Sponsors and Collaborators
Kite, A Gilead Company
Investigators
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Study Director: Kite Study Director Kite, A Gilead Company
  Study Documents (Full-Text)

Documents provided by Gilead Sciences ( Kite, A Gilead Company ):
Study Protocol: Amendment 8  [PDF] February 11, 2019
Study Protocol: Amendment 10  [PDF] June 14, 2022
Statistical Analysis Plan  [PDF] July 8, 2019

Additional Information:
Publications of Results:
Topp MS, van Meerten T, Wermke M et al. Preliminary Results of Earlier Steroid Use with Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Large B Cell Lymphoma. Poster presented at the American Society of Presented at: American Society of Clinical Oncology Annual Meeting. May 31-June 4, 2019; Chicago, Illinois; Abstract 7558.
Topp, M, van Meerten T, Houot R, et al. (2019). Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma. Blood (ASH Annual Meeting Abstracts) 134(Suppl 1): 243. Abstract 626.
Abstract: Oluwole OO, et al. Prophylactic corticosteroid use with axicabtagene ciloleucel in patients with relapsed/refractory large B-cell lymphoma. Transplantation and Cellular Therapy 2021.
Santa Monica, Calif. New Four-Year Data Show Long-Term Survival in Patients With Large B-Cell Lymphoma Treated With Yescarta® in ZUMA-1 Trial. Data presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition. December 5, 2020; Abstract 1187
Max S. Topp, Tom van Meerten, Martin Wermke, Pieternella J. Lugtenburg, Monique C. Minnema, Kevin W. Song, Catherine Thieblemont, Yizhou Jiang, Vicki Plaks, Anne Kerber, Marie José Kersten. Preliminary Results of Earlier Steroid Use With Axicabtagene Ciloleucel in Patients With Relapsed/ Refractory Large B Cell Lymphoma. Poster presented at ASCO 2019 Annual Meeting. June 3, 2019; Abstract 7558
Sattva S. Neelapu, Caron A. Jacobson, Olalekan O. Oluwole, Javier Munoz, Abhinav Deol, David B. Miklos, Nancy L. Bartlett, Ira Braunschweig, Yizhou Jiang, Jenny J. Kim, Lianqing Zheng, John M. Rossi, Frederick L. Locke. Axicabtagene Ciloleucel (Axi-Cel) In Refractory Large B Cell Lymphoma: Outcomes in Patients ≥ or < 65 Years of Age in the Pivotal Phase 1/2 ZUMA-1 Study. Poster presented at EHA 2019. June 15, 2019; Abstract 1066
Max S. Topp, Tom van Meerten, Martin Wermke, Pieternella J. Lugtenburg, Monique C. Minnema, Kevin W. Song, Catherine Thieblemont, Yizhou Jiang, Vicki Plaks, Anne Kerber, Marie José Kersten. Axicabtagene Ciloleucel (Axi-Cel) in Patients With Relapsed/Refractory Large B Cell Lymphoma: Preliminary Results of Earlier Steroid Use. Poster presented at EHA 2019. June 15, 2019; Abstract 1067
Sattva S. Neelapu, John M. Rossi, Caron A. Jacobson, Frederick L. Locke, David B. Miklos, Patrick M. Reagan, Scott Rodig, Lazaros J. Lekakis, Ian W. Flinn, Lianqing Zheng, Francesca Milletti, Edmund Chang, Allen Xue, Vicki Plaks, Jenny J. Kim, Adrian Bot. CD19-Loss With Preservation of Other B Cell Lineage Features in Patients With Large B Cell Lymphoma Who Relapsed Post-Axi-Cel. Blood (ASH Annual Meeting Abstracts) 134(Suppl 1): 203. Abstract 704.
Sattva S. Neelapu, Frederick L. Locke, Nancy L. Bartlett, Lazaros J. Lekakis, Patrick Reagan, David B. Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, Michael Crump, John Kuruvilla, Eric Van Den Neste, Umar Farooq, Lynn Navale, Venita DePuy, Jenny J. Kim, Christian Gisselbrecht. A Comparison of Two-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel) and SCHOLAR-1 in Patients With Refractory Large B Cell Lymphoma. Blood (ASH Annual Meeting Abstracts) 134(Suppl 1): 4095. Abstract 626.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Kite, A Gilead Company
ClinicalTrials.gov Identifier: NCT02348216    
Other Study ID Numbers: KTE-C19-101
2015-005007-86 ( EudraCT Number )
First Posted: January 28, 2015    Key Record Dates
Results First Posted: November 23, 2021
Last Update Posted: June 4, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and transparency
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: 18 months after study completion
Access Criteria: A secured external environment with username, password, and RSA code.
URL: http://www.gilead.com/research/disclosure-and-transparency

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Prednisone
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Cyclophosphamide
Bendamustine Hydrochloride
Ifosfamide
Rituximab
Carboplatin
Gemcitabine
Doxorubicin
Oxaliplatin
Fludarabine
Etoposide
Vincristine
Axicabtagene ciloleucel
Levetiracetam