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

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ClinicalTrials.gov Identifier: NCT02348216
Recruitment Status : Completed
First Posted : January 28, 2015
Results First Posted : November 23, 2021
Last Update Posted : September 6, 2023
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences ( Kite, A Gilead Company )

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions 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)
Interventions Biological: Axicabtagene Ciloleucel
Drug: Fludarabine
Drug: Cyclophosphamide
Enrollment 307
Recruitment Details Participants were enrolled at study sites in Canada, France, Germany, Israel, Netherlands, and United States. The first participant was screened on 15 April 2015. Data submitted represent interim analysis performed on data collected by the data cut off date 27 January 2017 for Phase 1 and Phase 2 Cohort 1 and 2, 26 April 2018 for Cohort 3, 6 May 2019 for Cohort 4, 10 September 2020 for Cohort 5, and 16 June 2020 for Cohort 6.
Pre-assignment Details 390 participants were screened. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) received 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) (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised 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. Participants with relapsed or refractory DLBCL, PMBCL, TFL, or high-grade B-cell lymphoma (HGBCL) after 2 systemic lines of therapy received 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 IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing > 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of investigator and could include: dexamethasone 20 mg to 40 mg or equivalent, either oral administration (PO) or IV daily for 1 to 4 days; or 1 g/m^2 of high-dose methylprednisolone (HDMP) for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2) and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0). Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy. Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Period Title: Overall Study
Started 8 81 30 42 46 58 42
Completed 0 0 0 0 0 0 0
Not Completed 8 81 30 42 46 58 42
Reason Not Completed
Death             4             27             3             18             9             23             6
Full consent withdrawal             0             0             0             1             0             0             1
Lost to Follow-up             0             0             0             0             0             0             1
Still on study             3             50             21             19             32             27             32
Enrolled but did not initiate axicabtagene ciloleucel             1             4             6             4             5             8             2
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6 Total
Hide Arm/Group Description Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2. Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0). Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 Tcells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy. Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0). Total of all reporting groups
Overall Number of Baseline Participants 7 77 24 38 41 50 40 277
Hide Baseline Analysis Population Description
The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 77 participants 24 participants 38 participants 41 participants 50 participants 40 participants 277 participants
<65 years 4 60 17 30 28 35 20 194
≥65 years 3 17 7 8 13 15 20 83
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 77 participants 24 participants 38 participants 41 participants 50 participants 40 participants 277 participants
Female 2 27 6 17 13 14 17 96
Male 5 50 18 21 28 36 23 181
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 77 participants 24 participants 38 participants 41 participants 50 participants 40 participants 277 participants
Hispanic or Latino 1 16 2 5 0 1 2 27
Not Hispanic or Latino 6 61 22 33 40 49 38 249
Unknown or Not Reported 0 0 0 0 1 0 0 1
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 7 participants 77 participants 24 participants 38 participants 41 participants 50 participants 40 participants 277 participants
Asian 0 1 3 1 0 5 0 10
Black or African American 1 3 1 3 0 2 1 11
White 6 71 19 31 33 33 34 227
Others 0 2 1 3 7 10 5 28
Unknown or Not Reported 0 0 0 0 1 0 0 1
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 7 participants 77 participants 24 participants 38 participants 41 participants 50 participants 40 participants 277 participants
Canada 0 0 0 1 7 15 0 23
France 0 0 0 0 9 13 8 30
Germany 0 0 0 0 12 9 0 21
Israel 0 0 1 2 2 0 1 6
Netherlands 0 0 0 5 11 13 6 35
United States 7 77 23 30 0 0 25 162
1.Primary Outcome
Title Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)
Hide Description

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.
Time Frame First infusion date of axicabtagene ciloleucel up to 30 days
Hide Outcome Measure Data
Hide Analysis Population Description
DLT-Evaluable Analysis Set included participants treated in Phase 1 dosing cohort who received the target dose and were followed for at least 30 days after the axicabtagene ciloleucel infusion; or dose of anti-CD19 CAR T cells (axicabtagene ciloleucel) lower than the target for that cohort and experienced a DLT during the 30 day post-infusion period.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy
Hide Arm/Group Description:
Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Overall Number of Participants Analyzed 8
Measure Type: Count of Participants
Unit of Measure: Participants
1
2.Primary Outcome
Title 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
Hide Description 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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The Modified Intent-to-Treat (mITT) analysis set included all participants treated with at least 1.0 x 10^6 anti-CD19 CAR T cells/kg.
Arm/Group Title Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2
Hide Arm/Group Description:
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Overall Number of Participants Analyzed 77 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
82
(71 to 90)
83
(63 to 95)
3.Primary Outcome
Title Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades
Hide Description 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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff of 26 April 2018 (maximum: 35 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 3
Hide Arm/Group Description:
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Overall Number of Participants Analyzed 38
Measure Type: Number
Unit of Measure: percentage of participants
Worst Grade 1 CRS 34
Worst Grade 2 CRS 55
Worst Grade 3 CRS 0
Worst Grade 4 CRS 3
Worst Grade 5 CRS 0
Worst Grade ≥ 3 CRS 3
Worst Grade 1 Neurologic Toxicities 24
Worst Grade 2 Neurologic Toxicities 24
Worst Grade 3 Neurologic Toxicities 34
Worst Grade 4 Neurologic Toxicities 3
Worst Grade 5 Neurologic Toxicities 3
Worst Grade ≥ 3 Neurologic Toxicities 39
4.Primary Outcome
Title Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
Hide Description 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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff of 06 May 2019 (maximum: 47.5 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 4
Hide Arm/Group Description:
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 41
Measure Type: Number
Unit of Measure: percentage of participants
Worst Grade 1 CRS 32
Worst Grade 2 CRS 59
Worst Grade 3 CRS 2
Worst Grade 4 CRS 0
Worst Grade 5 CRS 0
Worst Grade ≥ 3 CRS 2
Worst Grade 1 Neurologic Toxicities 34
Worst Grade 2 Neurologic Toxicities 10
Worst Grade 3 Neurologic Toxicities 17
Worst Grade 4 Neurologic Toxicities 0
Worst Grade 5 Neurologic Toxicities 0
Worst Grade ≥ 3 Neurologic Toxicities 17
5.Primary Outcome
Title Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
Hide Description 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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff of 10 September 2020 (maximum: 64 months)
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Hide Analysis Population Description
The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 5
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Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Overall Number of Participants Analyzed 50
Measure Type: Number
Unit of Measure: percentage of participants
Worst Grade 1 CRS 38
Worst Grade 2 CRS 46
Worst Grade 3 CRS 0
Worst Grade 4 CRS 2
Worst Grade 5 CRS 0
Worst Grade ≥ 3 CRS 2
Worst Grade 1 Neurologic Toxicities 26
Worst Grade 2 Neurologic Toxicities 18
Worst Grade 3 Neurologic Toxicities 10
Worst Grade 4 Neurologic Toxicities 2
Worst Grade 5 Neurologic Toxicities 0
Worst Grade ≥ 3 Neurologic Toxicities 12
6.Primary Outcome
Title Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
Hide Description 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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff of 16 June 2020 (maximum: 61 months)
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Hide Analysis Population Description
The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 6
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Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 40
Measure Type: Number
Unit of Measure: percentage of participants
Worst Grade 1 CRS 35
Worst Grade 2 CRS 45
Worst Grade 3 CRS 0
Worst Grade 4 CRS 0
Worst Grade 5 CRS 0
Worst Grade ≥ 3 CRS 0
Worst Grade 1 Neurologic Toxicities 25
Worst Grade 2 Neurologic Toxicities 18
Worst Grade 3 Neurologic Toxicities 8
Worst Grade 4 Neurologic Toxicities 5
Worst Grade 5 Neurologic Toxicities 3
Worst Grade ≥ 3 Neurologic Toxicities 15
7.Secondary Outcome
Title Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
Hide Description 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.
Time Frame First OR to data cutoff date of 27 Jan 2017, 26 Apr 2018, 6 May 2019, 10 Sep 2010, and 16 Jun 2020 for Cohorts 1 and 2, 3, 4, 5, and 6 respectively (median duration: 5.3, 4.9, 11.1, 5.2, 11.4, and 5.8 months for Cohorts 1, 2, 3, 4, 5, and 6 respectively)
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Participants in the mITT Analysis Set with objective response were analyzed.
Arm/Group Title Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
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Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 63 20 24 30 36 38
Median (95% Confidence Interval)
Unit of Measure: months
4.2 [1] 
(2.1 to NA)
NA [2] 
(NA to NA)
NA [3] 
(5.0 to NA)
NA [4] 
(NA to NA)
NA [3] 
(2.2 to NA)
NA [4] 
(7.8 to NA)
[1]
Upper limit of 95% CI was not estimable because almost 50% of participants were censored.
[2]
Data was not estimable because almost 50% of participants were censored.
[3]
Median and upper limit of 95% CI was not estimable because almost 50% of participants were censored.
[4]
Median and upper and lower limit of 95% CI was not estimable because almost 50% of participants were censored.
8.Secondary Outcome
Title Phase 1 Study: ORR as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
Hide Description 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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
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Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy
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Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Overall Number of Participants Analyzed 7
Measure Type: Number
Unit of Measure: percentage of participants
71
9.Secondary Outcome
Title Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC)
Hide Description 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 (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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
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Hide Analysis Population Description
Participants in the mITT Analysis Set were analyzed.
Arm/Group Title Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2
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Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Overall Number of Participants Analyzed 77 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
69
(57 to 79)
79
(58 to 93)
10.Secondary Outcome
Title 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
Hide Description 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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff date of 26 Apr 2018, 06 May 2019, 10 Sep 2020, and 16 Jun 2020 for Cohorts 3, 4, 5, and 6 respectively (maximum: 35, 47.5, 64, and 61 months for Cohorts 3, 4, 5, and 6 respectively)
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Hide Analysis Population Description
Participants in the mITT Analysis Set were analyzed.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
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Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 38 41 50 40
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
63
(46 to 78)
73
(57 to 86)
72
(58 to 84)
95
(83 to 99)
11.Secondary Outcome
Title Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
Hide Description 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.
Time Frame First infusion date to PD or death or data cutoff date 27 Jan 2017, 26 Apr 2018, 06 May 2019, 10 Sep 2020, and 16 Jun 2020 for Cohorts 1 and 2, 3, 4, 5, 6 respectively (maximum: 20, 35, 47.5, 64, and 61 months for Cohorts 1 and 2, 3, 4, 5, 6 respectively)
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Hide Analysis Population Description
Participants in the mITT Analysis Set were analyzed.
Arm/Group Title Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 77 24 38 41 50 40
Median (95% Confidence Interval)
Unit of Measure: months
5.1
(3.0 to 7.3)
NA [1] 
(6.1 to NA)
6.2 [2] 
(2.4 to NA)
NA [1] 
(3.0 to NA)
3.1 [2] 
(2.9 to NA)
NA [1] 
(8.7 to NA)
[1]
Median and upper limit of 95% CI was not estimable because almost 50% of participants were censored.
[2]
Upper limit of 95% CI was not estimable because almost 50% of participants were censored.
12.Secondary Outcome
Title Phase 2: Overall Survival (OS)
Hide Description 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.
Time Frame First infusion date to the death or data cutoff date of 27 Jan 2017, 26 Apr 2018, 6 May 2019, 10 Sep 2020, and 16 Jun 2020 for Cohorts 1 and 2, 3, 4, 5, 6 respectively (maximum: 20, 35, 47.5, 64, and 61 months for Cohorts 1 and 2, 3, 4, 5, 6 respectively)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the mITT Analysis Set were analyzed.
Arm/Group Title Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 77 24 38 41 50 40
Median (95% Confidence Interval)
Unit of Measure: months
11.5 [1] 
(8.6 to NA)
NA [2] 
(9.8 to NA)
15.4 [1] 
(5.4 to NA)
NA [2] 
(15.8 to NA)
14.6 [1] 
(12.5 to NA)
NA [3] 
(NA to NA)
[1]
Upper limit of 95% CI was not estimable because almost 50% of participants were censored.
[2]
Median and upper limit of 95% CI was not estimable because almost 50% of participants were censored.
[3]
Data was not estimable because almost 50% of participants were censored.
13.Secondary Outcome
Title Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007
Hide Description 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 per the revised IWG Response Criteria for Malignant Lymphoma 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.
Time Frame First objective response to the data cutoff date of 27 January 2017 (maximum: 20 months)
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Hide Analysis Population Description
Participants in the mITT Analysis Set with objective response were analyzed.
Arm/Group Title Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2
Hide Arm/Group Description:
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Overall Number of Participants Analyzed 53 19
Median (95% Confidence Interval)
Unit of Measure: months
5.4
(2.5 to 8.1)
NA [1] 
(2.2 to NA)
[1]
Median and upper limit of 95% CI was not estimable because almost 50% of participants were censored.
14.Secondary Outcome
Title Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007
Hide Description 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.
Time Frame First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the mITT Analysis Set were analyzed.
Arm/Group Title Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2
Hide Arm/Group Description:
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Overall Number of Participants Analyzed 77 24
Measure Type: Number
Unit of Measure: percentage of participants
CR 49 58
PR 19 21
SD 21 4
PD 8 4
ND 3 13
15.Secondary Outcome
Title Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007
Hide Description 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. 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.
Time Frame First infusion date of axicabtagene ciloleucel to the date of disease progression or death from any cause or the data cutoff date of 27 January 2017 (maximum: 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the mITT Analysis Set with available data were analyzed.
Arm/Group Title Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2
Hide Arm/Group Description:
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Overall Number of Participants Analyzed 76 24
Median (95% Confidence Interval)
Unit of Measure: months
5.0
(3.0 to 7.0)
NA [1] 
(3.1 to NA)
[1]
Median and upper limit of 95% CI was not estimable because almost 50% of participants were censored.
16.Secondary Outcome
Title Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
Hide Description 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.
Time Frame First infusion date to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum: 20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
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Hide Analysis Population Description
Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 7 77 24 38 41 50 40
Measure Type: Number
Unit of Measure: percentage of participants
100 100 100 100 100 100 100
17.Secondary Outcome
Title Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 4 and Grade 3 or Higher Resulting From Increased Parameter Value
Hide Description Grading categories were determined by CTCAE version 4.03. Shifts to Grade 3 or higher has been reported for Phase 2 Cohort 3. For Phase 1 and all other cohorts of Phase 2, shifts to Grade 4 has been reported.
Time Frame First infusion date to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum: 20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
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Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
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Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 7 77 24 38 41 50 40
Measure Type: Number
Unit of Measure: percentage of participants
Hemoglobin 0 0 0 0 0 0 0
Neutrophils 0 0 0 0 0 0 0
Platelets 0 0 0 0 0 0 0
Potassium 0 0 0 3 2 0 0
Calcium 0 1 0 3 2 0 0
Magnesium 0 0 0 8 0 0 5
Sodium 0 0 0 0 0 0 0
Alanine Aminotransferase 14 1 0 21 0 0 0
Aspartate Aminotransferase 0 0 0 16 2 0 0
Bilirubin 0 1 0 5 0 0 0
Creatinine 0 1 4 5 0 0 3
Urate 0 0 0 13 2 0 3
Albumin 0 0 0 0 0 0 0
Leukocytes 0 0 0 0 0 0 0
Direct Bilirubin 0 0 0 18 0 0 0
Glucose 0 0 0 8 2 0 0
Lymphocytes 0 0 0 0 0 0 0
Phosphate 0 0 0 0 0 0 0
Alkaline Phosphatase 0 0 0 5 0 0 0
18.Secondary Outcome
Title Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 4 and Grade 3 or Higher Resulting From Decreased Parameter Value
Hide Description Grading categories were determined by CTCAE version 4.03. Shifts to Grade 3 or higher has been reported for Phase 2 Cohort 3. For Phase 1 and all other cohorts of Phase 2, shifts to Grade 4 has been reported.
Time Frame First infusion date to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum: 20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
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Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
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Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 7 77 24 38 41 50 40
Measure Type: Number
Unit of Measure: percentage of participants
Hemoglobin 0 0 0 47 0 0 0
Neutrophils 100 82 79 97 90 86 78
Platelets 57 35 17 68 17 38 23
Potassium 0 0 0 13 2 2 0
Calcium 0 4 13 24 7 2 3
Magnesium 0 0 0 0 0 0 0
Sodium 0 0 0 16 0 2 0
Alanine Aminotransferase 0 0 0 0 0 0 0
Aspartate Aminotransferase 0 0 0 0 0 0 0
Bilirubin 0 0 0 0 0 0 0
Creatinine 0 0 0 0 0 0 0
Urate 0 0 0 0 0 0 0
Albumin 0 0 0 13 0 0 0
Leukocytes 100 84 75 97 93 88 85
Direct Bilirubin 0 0 0 0 0 0 0
Glucose 0 0 0 3 0 0 0
Lymphocytes 100 100 100 100 71 46 95
Phosphate 0 0 0 42 2 4 0
Alkaline Phosphatase 0 0 0 0 0 0 0
19.Secondary Outcome
Title Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies
Hide Description [Not Specified]
Time Frame First infusion date to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum: 20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
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Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
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Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 7 77 24 38 41 50 40
Measure Type: Number
Unit of Measure: percentage of participants
0 4 0 5 0 8 8
20.Secondary Outcome
Title Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood
Hide Description Peak was defined as the maximum number of CAR T cells measured post-infusion.
Time Frame Enrollment up to Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Safety Analysis Set with available data were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 6 76 22 36 39 49 40
Median (Inter-Quartile Range)
Unit of Measure: cells/µL
58.512
(18.028 to 147.732)
31.512
(12.445 to 74.746)
58.633
(27.884 to 103.190)
53.670
(22.813 to 146.075)
52.91
(27.25 to 92.78)
26.63
(12.52 to 117.53)
64.38
(6.27 to 131.24)
21.Secondary Outcome
Title Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3)
Hide Description 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).
Time Frame Enrollment up to Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3
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Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Overall Number of Participants Analyzed 7 77 24 38
Median (Full Range)
Unit of Measure: pg/mL
IP-10
2000.0
(147.0 to 2000.0)
2000.0
(628.1 to 2000.0)
2000.0
(434.2 to 2000.0)
2000.0
(541.0 to 2000.0)
Granzyme B
33.1
(0.6 to 463.8)
31.1
(1.0 to 3306.0)
17.3
(1.0 to 406.8)
44.1
(1.0 to 534.6)
ICAM-1
792754.3
(537796.8 to 2424877.7)
1322829.3
(557025.0 to 7495123.2)
989188.4
(544589.3 to 4588974.8)
1009966.4
(256768.6 to 4879749.7)
IFN-gamma
792.0
(81.1 to 1876.0)
493.8
(32.4 to 1876.0)
364.9
(7.5 to 1876.0)
1857.2
(65.0 to 1876.0)
IL-1 RA
2173.3
(544.3 to 4000.0)
2371.2
(510.8 to 4000.0)
1999.9
(649.9 to 4000.0)
2160.5
(653.7 to 4000.0)
IL-2
18.4
(3.1 to 91.0)
25.0
(0.9 to 123.1)
13.4
(0.9 to 63.7)
20.0
(0.9 to 189.4)
IL-2 R alpha
16872.7
(2189.0 to 34044.5)
14383.7
(78.0 to 100000.0)
7817.3
(78.0 to 66024.6)
12386.4
(3002.6 to 100000.0)
IL-6
305.3
(2.4 to 976.0)
89.4
(3.5 to 976.0)
44.6
(3.6 to 976.0)
921.8
(13.3 to 976.0)
IL-7
51.5
(31.2 to 71.5)
38.9
(13.8 to 153.5)
44.1
(27.9 to 98.8)
38.8
(19.1 to 83.8)
IL-8
86.4
(17.1 to 750.0)
118.4
(14.2 to 750.0)
77.2
(9.8 to 750.0)
120.9
(10.3 to 750.0)
IL-10
52.5
(3.8 to 614.0)
43.9
(0.7 to 466.0)
18.8
(0.7 to 263.6)
48.2
(1.8 to 466.0)
IL-15
57.1
(18.7 to 271.3)
56.5
(13.1 to 226.6)
47.6
(11.3 to 195.2)
50.3
(21.9 to 537.3)
Perforin
5389.0
(2582.7 to 20724.3)
11309.5
(2282.3 to 39818.9)
8278.7
(2332.6 to 31857.7)
15411.9
(4327.4 to 30575.9)
TNF alpha
10.5
(1.8 to 443.1)
8.6
(2.6 to 166.9)
6.8
(2.2 to 44.9)
10.9
(3.3 to 52.1)
VCAM-1
1387033.6
(609223.2 to 8424222.9)
1478356.8
(642372.6 to 3859375.8)
1058453.9
(634769.7 to 2864040.2)
1367940.7
(721050.0 to 5184238.4)
22.Secondary Outcome
Title 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)
Hide Description 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).
Time Frame Enrollment up to Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Safety Analysis Set with available data were analyzed.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 41 50 40
Median (Full Range)
Unit of Measure: pg/mL
IP-10 Number Analyzed 41 participants 50 participants 40 participants
1549.70
(469.20 to 2000.00)
1746.15
(349.80 to 2000.00)
1560.03
(347.00 to 2000.000)
Granzyme B Number Analyzed 41 participants 50 participants 40 participants
23.10
(1.00 to 322.60)
27.90
(1.00 to 375.76)
18.40
(1.00 to 162.30)
IFN-gamma Number Analyzed 41 participants 50 participants 40 participants
334.50
(24.90 to 1876.00)
314.90
(7.50 to 1876.00)
207.95
(18.80 to 1876.00)
IL-1 RA Number Analyzed 31 participants 50 participants 40 participants
1093.70
(193.30 to 4493.10)
908.00
(229.00 to 9000.00)
1279.50
(227.00 to 9000.00)
IL-2 Number Analyzed 41 participants 50 participants 40 participants
11.20
(0.90 to 79.40)
11.85
(0.90 to 142.70)
8.40
(0.90 to 277.60)
IL-6 Number Analyzed 41 participants 50 participants 40 participants
136.70
(1.60 to 976.00)
97.95
(1.60 to 976.00)
47.25
(1.60 to 976.00)
IL-7 Number Analyzed 41 participants 50 participants 40 participants
33.10
(18.00 to 67.50)
29.80
(1.40 to 65.20)
28.25
(13.20 to 74.30)
IL-8 Number Analyzed 41 participants 50 participants 40 participants
67.40
(8.50 to 750.00)
75.10
(5.80 to 750.00)
52.55
(10.00 to 750.00)
IL-10 Number Analyzed 41 participants 50 participants 40 participants
19.60
(1.40 to 466.00)
14.45
(0.70 to 300.90)
13.30
(0.70 to 171.20)
IL-15 Number Analyzed 41 participants 50 participants 40 participants
45.80
(22.30 to 272.70)
34.15
(1.40 to 140.00)
37.20
(9.50 to 86.30)
TNF alpha Number Analyzed 41 participants 50 participants 40 participants
5.70
(2.00 to 54.60)
5.25
(1.40 to 33.30)
4.80
(2.10 to 20.20)
GM-CSF Number Analyzed 41 participants 50 participants 40 participants
4.40
(1.90 to 47.00)
2.90
(1.90 to 35.60)
1.90
(1.90 to 47.40)
23.Secondary Outcome
Title Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6)
Hide Description 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.
Time Frame Enrollment up to Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
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Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 41 50 40
Median (Full Range)
Unit of Measure: ng/mL
Ferritin
1086.36
(95.55 to 23900)
1516.11
(89.29 to 31600)
903.50
(171.61 to 6555.10)
ICAM-1
907.97
(359.51 to 5141.64)
636.74
(361.38 to 4835.93)
654.81
(355.15 to 4419.09)
IL-2 R
10.78
(2.81 to 94.59)
7.82
(1.36 to 83.60)
6.43
(1.70 to 33.31)
Perforin
17.22
(3.88 to 44.42)
10.85
(2.53 to 100.00)
10.12
(1.97 to 39.62)
VCAM-1
1255.32
(594.51 to 3932.61)
854.63
(476.60 to 6501.14)
836.04
(411.93 to 5079.25)
24.Secondary Outcome
Title Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum
Hide Description Peak was defined as the maximum post-baseline level of the cytokine.
Time Frame Enrollment up to Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 7 77 24 38 41 50 40
Median (Full Range)
Unit of Measure: mg/mL
112.6
(14.6 to 655.0)
215.7
(31.0 to 496.0)
186.6
(18.5 to 496.0)
137.8
(2.1 to 496.0)
126.53
(18.19 to 496.00)
74.84
(1.81 to 496.00)
76.11
(7.31 to 496.00)
25.Secondary Outcome
Title Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2)
Hide Description Peak was defined as the maximum post-baseline level of the cytokine.
Time Frame Enrollment up to Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2
Hide Arm/Group Description:
Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Overall Number of Participants Analyzed 7 77 24
Median (Full Range)
Unit of Measure: pg/mL
1973400.0
(1201900.0 to 32984400.0)
3681400.0
(780.0 to 25000000.0)
1979360.0
(780.0 to 25000000.0)
26.Secondary Outcome
Title Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3)
Hide Description Peak was defined as the maximum post-baseline level of the cytokine.
Time Frame Enrollment up to Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 3
Hide Arm/Group Description:
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Overall Number of Participants Analyzed 38
Median (Full Range)
Unit of Measure: ng/mL
2440.2
(0.8 to 25000.0)
27.Secondary Outcome
Title Percentage of Participants With Positive Replication Competent Retrovirus (RCR)
Hide Description 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.
Time Frame Day 0 (pre-infusion) to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum:20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Safety Analysis Set were analyzed.
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered.
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 7 77 24 38 41 50 40
Measure Type: Number
Unit of Measure: percentage of participants
0 0 0 0 0 0 0
28.Secondary Outcome
Title Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score
Hide Description 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).
Time Frame Baseline, Week 4, Month 3, and Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in Safety Analysis Set with available data were analyzed.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 38 39 47 34
Measure Type: Count of Participants
Unit of Measure: Participants
Baseline: Mobility Number Analyzed 38 participants 39 participants 47 participants 34 participants
No problem 30 25 33 26
Slight problem 7 9 5 4
Moderate problem 1 5 7 3
Severe problem 0 0 1 1
Unable to perform 0 0 1 0
Week 4: Mobility Number Analyzed 32 participants 37 participants 38 participants 29 participants
No problem 16 21 23 20
Slight problem 11 7 9 5
Moderate problem 4 5 4 4
Severe problem 0 3 1 0
Unable to perform 1 1 1 0
Month 3: Mobility Number Analyzed 23 participants 31 participants 33 participants 29 participants
No problem 14 20 21 22
Slight problem 6 8 6 3
Moderate problem 2 2 6 3
Severe problem 1 1 0 1
Unable to perform 0 0 0 0
Month 6: Mobility Number Analyzed 18 participants 25 participants 17 participants 27 participants
No problem 10 19 11 15
Slight problem 6 4 2 8
Moderate problem 2 2 4 3
Severe problem 0 0 0 1
Unable to perform 0 0 0 0
Baseline: Self-care Number Analyzed 38 participants 39 participants 47 participants 34 participants
No problem 37 38 44 32
Slight problem 1 1 3 1
Moderate problem 0 0 0 1
Severe problem 0 0 0 0
Unable to perform 0 0 0 0
Week 4: Self-care Number Analyzed 32 participants 37 participants 38 participants 29 participants
No problem 25 33 31 24
Slight problem 5 3 6 3
Moderate problem 1 0 1 1
Severe problem 0 1 0 1
Unable to perform 1 0 0 0
Month 3: Self-care Number Analyzed 23 participants 31 participants 33 participants 29 participants
No problem 19 29 32 25
Slight problem 4 2 1 4
Moderate problem 0 0 0 0
Severe problem 0 0 0 0
Unable to perform 0 0 0 0
Month 6: Self-care Number Analyzed 18 participants 25 participants 17 participants 27 participants
No problem 17 25 16 20
Slight problem 1 0 1 7
Moderate problem 0 0 0 0
Severe problem 0 0 0 0
Unable to perform 0 0 0 0
Baseline: Usual activities Number Analyzed 38 participants 39 participants 47 participants 34 participants
No problem 22 22 24 16
Slight problem 10 6 13 14
Moderate problem 4 8 8 2
Severe problem 2 1 1 2
Unable to perform 0 2 1 0
Week 4: Usual activities Number Analyzed 32 participants 37 participants 37 participants 29 participants
No problem 6 12 12 12
Slight problem 13 11 13 11
Moderate problem 11 8 8 4
Severe problem 0 3 2 1
Unable to perform 2 3 2 1
Month 3: Usual activities Number Analyzed 23 participants 31 participants 33 participants 29 participants
No problem 8 16 19 12
Slight problem 9 9 10 14
Moderate problem 5 5 2 2
Severe problem 1 1 1 1
Unable to perform 0 0 1 0
Month 6: Usual activities Number Analyzed 18 participants 25 participants 17 participants 27 participants
No problem 9 15 10 11
Slight problem 5 7 4 12
Moderate problem 3 3 2 3
Severe problem 1 0 1 0
Unable to perform 0 0 0 1
Baseline: Pain/Discomfort Number Analyzed 38 participants 39 participants 47 participants 34 participants
No problem 18 17 16 15
Slight problem 9 17 18 14
Moderate problem 8 5 7 4
Severe problem 1 0 5 1
Unable to perform 2 0 1 0
Week 4: Pain/Discomfort Number Analyzed 32 participants 37 participants 37 participants 29 participants
No problem 12 19 20 17
Slight problem 12 13 10 9
Moderate problem 7 2 5 3
Severe problem 1 3 2 0
Unable to perform 0 0 0 0
Month 3: Pain/Discomfort Number Analyzed 23 participants 31 participants 33 participants 29 participants
No problem 9 10 18 16
Slight problem 5 14 9 5
Moderate problem 9 6 6 5
Severe problem 0 1 0 3
Unable to perform 0 0 0 0
Month 6: Pain/Discomfort Number Analyzed 17 participants 25 participants 17 participants 27 participants
No problem 8 9 6 12
Slight problem 4 14 8 8
Moderate problem 5 1 3 4
Severe problem 0 1 0 3
Unable to perform 0 0 0 0
Baseline: Anxiety/Depression Number Analyzed 38 participants 39 participants 47 participants 34 participants
No problem 16 23 18 21
Slight problem 16 13 17 9
Moderate problem 3 3 10 3
Severe problem 1 0 1 1
Unable to perform 2 0 1 0
Week 4: Anxiety/Depression Number Analyzed 32 participants 37 participants 38 participants 29 participants
No problem 9 25 21 23
Slight problem 15 8 12 3
Moderate problem 7 3 5 3
Severe problem 1 1 0 0
Unable to perform 0 0 0 0
Month 3: Anxiety/Depression Number Analyzed 23 participants 31 participants 33 participants 29 participants
No problem 11 19 16 19
Slight problem 5 8 12 7
Moderate problem 6 4 4 2
Severe problem 1 0 1 1
Unable to perform 0 0 0 0
Month 6: Anxiety/Depression Number Analyzed 18 participants 25 participants 17 participants 26 participants
No problem 9 14 7 18
Slight problem 5 10 8 5
Moderate problem 3 0 1 3
Severe problem 0 1 1 0
Unable to perform 1 0 0 0
29.Secondary Outcome
Title Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score
Hide Description 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.
Time Frame Baseline, Week 4, Month 3, and Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in Safety Analysis Set with available data were analyzed.
Arm/Group Title Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6
Hide Arm/Group Description:
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy.
Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0).
Overall Number of Participants Analyzed 38 38 47 34
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline Number Analyzed 38 participants 38 participants 47 participants 34 participants
71.2  (21.3) 69.5  (18.8) 66.7  (20.7) 70.9  (17.0)
Week 4 Number Analyzed 32 participants 36 participants 38 participants 29 participants
67.8  (15.6) 67.2  (20.9) 70.8  (14.8) 76.1  (13.2)
Month 3 Number Analyzed 23 participants 31 participants 33 participants 29 participants
74.9  (16.6) 78.8  (14.7) 73.3  (19.9) 76.5  (15.0)
Month 6 Number Analyzed 18 participants 25 participants 17 participants 27 participants
77.1  (21.4) 85.1  (12.1) 77.1  (14.7) 79.8  (14.0)
Time Frame Adverse event: First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 Jan 2017 (Phase 1 and Cohorts 1, 2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, and 16 Jun 2020 for Cohorts 3, 4, 5, and 6 respectively (maximum: 20 months for Phase 1 and Cohorts 1, 2; and 35, 47.5, 64, and 61 months for Cohorts 3, 4, 5, and 6 respectively); All-cause mortality: From enrollment to the date of data cutoff (maximum: Month 6)
Adverse Event Reporting Description

Adverse events: The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.

All-cause mortality: For Cohort 1 to 6 - All Enrolled Analysis Set included all enrolled participants in the study; and for retreatment groups, the participants were included from Safety Analysis Set.
 
Arm/Group Title Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6 Retreatment Axicabtagene Ciloleucel: Phase 1 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 1 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 2 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 3 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 4 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 5 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 6
Hide Arm/Group Description Participants with DLBCL, primary PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with refractory DLBCL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with refractory PMBCL or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Participants also received a prophylactic regimen of tocilizumab and levetiracetam. The prophylactic regimen comprised levetiracetam (750 mg orally or IV BID) starting on Day 0 and tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2. Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received earlier interventions with corticosteroids (dexamethasone, methylprednisolone) and/or tocilizumab (8 mg/kg IV over 1 hour [not to exceed 800 mg] at lower grades of toxicity), in addition to prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0). Participants with relapsed/refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing >100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Debulking therapy was administered to reduce a participant's disease prior to conditioning chemotherapy. Participants received a prophylactic regimen of levetiracetam (750 mg orally or IV BID) starting on Day 0. Debulking therapy regimen was chosen at investigator's discretion and could include: R-CHOP (rituximab 375 mg/m^2 Day 1, doxorubicin 50 mg/m^2 Day 1, prednisone 100 mg Days 1 to 5, cyclophosphamide 750 mg/m^2 Day 1, vincristine 1.4 mg/m^2 Day 1); R-ICE (rituximab 375 mg/m^2 Day 1, ifosfamide 5 g/m^2 24h-CI Day 2, carboplatin AUC5 Day 2 maximum dose 800 mg, etoposide 100 mg/m^2/day Days 1 to 3); R-GEMOX (rituximab 375 mg/m^2 Day 1, gemcitabine 1000 mg/m^2 Day 2, oxaliplatin 100 mg/m^2 Day 2); R-GDP (rituximab 375 mg/m^2 Day 1 or 8, gemcitabine 1 g/m^2 on Day 1 and 8, dexamethasone 40 mg on Days 1 to Day 4, cisplatin 75 mg/m^2 on Day 1 [or carboplatin AUC5 on Day 1]); or radiotherapy per local standard up to 20 to 30 Gy. Participants with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy received 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 (a minimum infusion of at least 1 × 10^6 cell/kg of BW) on Day 0. For participants weighing greater than 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells was administered. Bridging therapy was administered to control a participant's disease prior to conditioning chemotherapy. Bridging therapy regimen was chosen at the discretion of the investigator and could include: dexamethasone at a dose of 20 mg to 40 mg or equivalent, either PO or IV daily for 1 to 4 days; or 1 g/m^2 of HDMP for 3 days in combination with rituximab at 375 mg/m^2 weekly for 3 weeks; or combination chemotherapy bendamustine (90 mg/m^2, Days 1 and 2 and rituximab (375 mg/m^2, Day 1). Participants also received interventions with corticosteroids (dexamethasone) and/or tocilizumab at lower grades of toxicity, prophylactic corticosteroids (given prior to axicabtagene ciloleucel infusion on Day 0, Day 1 and Day 2), and prophylactic levetiracetam (750 mg orally or IV BID starting on Day 0). Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the axicabtagene ciloleucel regimen selected for Phase 2. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose.
All-Cause Mortality
Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6 Retreatment Axicabtagene Ciloleucel: Phase 1 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 1 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 2 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 3 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 4 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 5 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 6
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/8 (62.50%)   31/81 (38.27%)   7/30 (23.33%)   22/42 (52.38%)   14/46 (30.43%)   28/58 (48.28%)   8/42 (19.05%)   0/1 (0.00%)   0/8 (0.00%)   0/1 (0.00%)   0/2 (0.00%)   0/1 (0.00%)   0/2 (0.00%)   0/0 
Hide Serious Adverse Events
Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6 Retreatment Axicabtagene Ciloleucel: Phase 1 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 1 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 2 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 3 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 4 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 5 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 6
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/7 (71.43%)   41/77 (53.25%)   11/24 (45.83%)   24/38 (63.16%)   20/41 (48.78%)   26/50 (52.00%)   19/40 (47.50%)   1/1 (100.00%)   4/8 (50.00%)   0/1 (0.00%)   1/2 (50.00%)   0/1 (0.00%)   1/2 (50.00%)   0/0 
Blood and lymphatic system disorders                             
Anaemia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Bone marrow failure † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Febrile bone marrow aplasia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Febrile neutropenia † 1  1/7 (14.29%)  5/77 (6.49%)  0/24 (0.00%)  2/38 (5.26%)  1/41 (2.44%)  1/50 (2.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Histiocytosis haematophagic † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Neutropenia † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  1/38 (2.63%)  2/41 (4.88%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pancytopenia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  2/50 (4.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Thrombocytopenia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cardiac disorders                             
Acute left ventricular failure † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Arrhythmia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Atrial fibrillation † 1  0/7 (0.00%)  3/77 (3.90%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Atrial flutter † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cardiac arrest † 1  0/7 (0.00%)  2/77 (2.60%)  1/24 (4.17%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cardiac failure † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cardiomyopathy † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pericarditis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Sinus tachycardia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Supraventricular tachycardia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tachycardia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Eye disorders                             
Visual impairment † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Gastrointestinal disorders                             
Abdominal pain † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  3/38 (7.89%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Ascites † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dysphagia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Enteritis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Gastritis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Nausea † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pancreatitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tongue ulceration † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Vomiting † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
General disorders                             
Asthenia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Fatigue † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Gait disturbance † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
General physical health deterioration † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Oedema peripheral † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pain † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pyrexia † 1  1/7 (14.29%)  7/77 (9.09%)  1/24 (4.17%)  6/38 (15.79%)  2/41 (4.88%)  4/50 (8.00%)  3/40 (7.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Immune system disorders                             
Haemophagocytic lymphohistiocytosis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypogammaglobulinaemia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Infections and infestations                             
Adenovirus infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Anal abscess † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Atypical pneumonia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Bacteraemia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Bacterial sepsis † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cellulitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Clostridium difficile colitis † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Clostridium difficile infection † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Covid-19 † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Covid-19 pneumonia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cytomegalovirus enteritis † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Device related infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Device related sepsis † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Encephalitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Enterococcal bacteraemia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Escherichia bacteraemia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Escherichia sepsis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Herpes zoster † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Human herpesvirus 6 encephalitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Klebsiella infection † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Lung infection † 1  2/7 (28.57%)  4/77 (5.19%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Meningitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Myelitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Oral herpes † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Peritonitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pneumococcal sepsis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pneumocystis jirovecii infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pneumonia † 1  0/7 (0.00%)  2/77 (2.60%)  1/24 (4.17%)  0/38 (0.00%)  2/41 (4.88%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Pneumonia influenzal † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pneumonia necrotising † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pneumonia staphylococcal † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Respiratory tract infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Rhinitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Rhinovirus infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Sepsis † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  1/41 (2.44%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Septic shock † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  3/50 (6.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Sinusitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Soft tissue infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Urinary tract infection † 1  0/7 (0.00%)  3/77 (3.90%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Urosepsis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Injury, poisoning and procedural complications                             
Brain herniation † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hip fracture † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Radius fracture † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Seroma † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Investigations                             
Alanine aminotransferase increased † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Ejection fraction decreased † 1  0/7 (0.00%)  4/77 (5.19%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Gamma-glutamyltransferase increased † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Neutrophil count decreased † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Platelet count decreased † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Troponin T increased † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Metabolism and nutrition disorders                             
Acidosis † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dehydration † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypercalcaemia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypoglycaemia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hyponatraemia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypophosphataemia † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Lactic acidosis † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Musculoskeletal and connective tissue disorders                             
Amyotrophy † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Arthralgia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Back pain † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Bone pain † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Muscular weakness † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Musculoskeletal pain † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pain in extremity † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                             
Acute myeloid leukaemia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
B-cell lymphoma † 1  1/7 (14.29%)  4/77 (5.19%)  0/24 (0.00%)  3/38 (7.89%)  3/41 (7.32%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cancer pain † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Carcinoma in situ † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Central nervous system lymphoma † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Diffuse large B-cell lymphoma † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Lung neoplasm malignant † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Myelodysplastic syndrome † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  1/1 (100.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Squamous cell carcinoma † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tumour pain † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Nervous system disorders                             
Aphasia † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  3/50 (6.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Apraxia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Ataxia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Brain injury † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Brain oedema † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Car t-cell-related encephalopathy syndrome † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cerebellar infarction † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cognitive disorder † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Depressed level of consciousness † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Disturbance in attention † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dysarthria † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dysgraphia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dyspraxia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Encephalopathy † 1  1/7 (14.29%)  15/77 (19.48%)  3/24 (12.50%)  7/38 (18.42%)  2/41 (4.88%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Haemorrhage intracranial † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Headache † 1  0/7 (0.00%)  0/77 (0.00%)  2/24 (8.33%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Immune effector cell-associated neurotoxicity syndrome † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Intracranial venous sinus thrombosis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Lethargy † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Leukoencephalopathy † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Memory impairment † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Presyncope † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Quadriplegia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Seizure † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Somnolence † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  0/38 (0.00%)  3/41 (7.32%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Syncope † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Toxic encephalopathy † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tremor † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  4/50 (8.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Psychiatric disorders                             
Agitation † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Anxiety † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Confusional state † 1  0/7 (0.00%)  4/77 (5.19%)  2/24 (8.33%)  2/38 (5.26%)  1/41 (2.44%)  5/50 (10.00%)  5/40 (12.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Delirium † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Depression † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Disorientation † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hallucination † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Mental status changes † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Restlessness † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Renal and urinary disorders                             
Acute kidney injury † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Anuria † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cystitis haemorrhagic † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Haematuria † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Renal failure † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Respiratory, thoracic and mediastinal disorders                             
Acute respiratory failure † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Aspiration † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dyspnoea † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Haemoptysis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypoxia † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pleural effusion † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pulmonary embolism † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pulmonary oedema † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Reexpansion pulmonary oedema † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Respiratory failure † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  2/41 (4.88%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Skin and subcutaneous tissue disorders                             
Toxic skin eruption † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Vascular disorders                             
Embolism † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypertension † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypotension † 1  0/7 (0.00%)  2/77 (2.60%)  1/24 (4.17%)  4/38 (10.53%)  2/41 (4.88%)  3/50 (6.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Shock † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
1
Term from vocabulary, MedDRA 23.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Phase 2 (Pivotal Study): Cohort 1 Phase 2 (Pivotal Study): Cohort 2 Phase 2 (Safety Management Study): Cohort 3 Phase 2 (Safety Management Study): Cohort 4 Phase 2 (Safety Management Study): Cohort 5 Phase 2 (Safety Management Study): Cohort 6 Retreatment Axicabtagene Ciloleucel: Phase 1 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 1 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 2 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 3 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 4 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 5 Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 6
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/7 (100.00%)   77/77 (100.00%)   23/24 (95.83%)   38/38 (100.00%)   41/41 (100.00%)   50/50 (100.00%)   40/40 (100.00%)   1/1 (100.00%)   8/8 (100.00%)   1/1 (100.00%)   2/2 (100.00%)   1/1 (100.00%)   2/2 (100.00%)   0/0 
Blood and lymphatic system disorders                             
Anaemia † 1  4/7 (57.14%)  54/77 (70.13%)  13/24 (54.17%)  22/38 (57.89%)  19/41 (46.34%)  22/50 (44.00%)  17/40 (42.50%)  1/1 (100.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Febrile neutropenia † 1  4/7 (57.14%)  24/77 (31.17%)  8/24 (33.33%)  11/38 (28.95%)  3/41 (7.32%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Leukopenia † 1  0/7 (0.00%)  16/77 (20.78%)  2/24 (8.33%)  4/38 (10.53%)  8/41 (19.51%)  8/50 (16.00%)  7/40 (17.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Lymphadenopathy † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  2/41 (4.88%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Lymphopenia † 1  0/7 (0.00%)  7/77 (9.09%)  2/24 (8.33%)  0/38 (0.00%)  3/41 (7.32%)  2/50 (4.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Neutropenia † 1  3/7 (42.86%)  32/77 (41.56%)  11/24 (45.83%)  18/38 (47.37%)  17/41 (41.46%)  16/50 (32.00%)  20/40 (50.00%)  0/1 (0.00%)  1/8 (12.50%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pancytopenia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  4/41 (9.76%)  2/50 (4.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Thrombocytopenia † 1  2/7 (28.57%)  27/77 (35.06%)  6/24 (25.00%)  12/38 (31.58%)  9/41 (21.95%)  9/50 (18.00%)  10/40 (25.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cardiac disorders                             
Acute left ventricular failure † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Atrial fibrillation † 1  0/7 (0.00%)  4/77 (5.19%)  1/24 (4.17%)  1/38 (2.63%)  2/41 (4.88%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Atrial flutter † 1  0/7 (0.00%)  4/77 (5.19%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Bradycardia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Sinus bradycardia † 1  0/7 (0.00%)  5/77 (6.49%)  2/24 (8.33%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Sinus tachycardia † 1  0/7 (0.00%)  20/77 (25.97%)  2/24 (8.33%)  6/38 (15.79%)  3/41 (7.32%)  3/50 (6.00%)  5/40 (12.50%)  0/1 (0.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tachycardia † 1  3/7 (42.86%)  31/77 (40.26%)  8/24 (33.33%)  6/38 (15.79%)  9/41 (21.95%)  7/50 (14.00%)  7/40 (17.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Ventricular arrhythmia † 1  1/7 (14.29%)  3/77 (3.90%)  2/24 (8.33%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Ventricular tachycardia † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Ear and labyrinth disorders                             
Ear pain † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Tinnitus † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  1/40 (2.50%)  1/1 (100.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Eye disorders                             
Eyelid function disorder † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Photophobia † 1  0/7 (0.00%)  0/77 (0.00%)  2/24 (8.33%)  0/38 (0.00%)  1/41 (2.44%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Vision blurred † 1  1/7 (14.29%)  2/77 (2.60%)  2/24 (8.33%)  3/38 (7.89%)  1/41 (2.44%)  1/50 (2.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Vitreous floaters † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Gastrointestinal disorders                             
Abdominal distension † 1  0/7 (0.00%)  5/77 (6.49%)  2/24 (8.33%)  2/38 (5.26%)  1/41 (2.44%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Abdominal pain † 1  1/7 (14.29%)  11/77 (14.29%)  3/24 (12.50%)  5/38 (13.16%)  3/41 (7.32%)  6/50 (12.00%)  5/40 (12.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Abdominal pain upper † 1  0/7 (0.00%)  2/77 (2.60%)  1/24 (4.17%)  5/38 (13.16%)  1/41 (2.44%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Anal incontinence † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  0/38 (0.00%)  2/41 (4.88%)  1/50 (2.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Ascites † 1  1/7 (14.29%)  2/77 (2.60%)  0/24 (0.00%)  2/38 (5.26%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Constipation † 1  2/7 (28.57%)  23/77 (29.87%)  8/24 (33.33%)  11/38 (28.95%)  11/41 (26.83%)  10/50 (20.00%)  22/40 (55.00%)  1/1 (100.00%)  2/8 (25.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Diarrhoea † 1  5/7 (71.43%)  33/77 (42.86%)  10/24 (41.67%)  18/38 (47.37%)  25/41 (60.98%)  15/50 (30.00%)  16/40 (40.00%)  0/1 (0.00%)  1/8 (12.50%)  1/1 (100.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Dry mouth † 1  2/7 (28.57%)  8/77 (10.39%)  3/24 (12.50%)  3/38 (7.89%)  2/41 (4.88%)  0/50 (0.00%)  4/40 (10.00%)  0/1 (0.00%)  2/8 (25.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dyspepsia † 1  0/7 (0.00%)  2/77 (2.60%)  2/24 (8.33%)  0/38 (0.00%)  2/41 (4.88%)  5/50 (10.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dysphagia † 1  0/7 (0.00%)  4/77 (5.19%)  1/24 (4.17%)  5/38 (13.16%)  3/41 (7.32%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Gastrooesophageal reflux disease † 1  1/7 (14.29%)  2/77 (2.60%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  1/1 (100.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Nausea † 1  3/7 (42.86%)  43/77 (55.84%)  16/24 (66.67%)  22/38 (57.89%)  19/41 (46.34%)  18/50 (36.00%)  23/40 (57.50%)  1/1 (100.00%)  3/8 (37.50%)  0/1 (0.00%)  1/2 (50.00%)  1/1 (100.00%)  2/2 (100.00%)  0/0 
Odynophagia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Oesophageal pain † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Rectal haemorrhage † 1  0/7 (0.00%)  1/77 (1.30%)  2/24 (8.33%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Stomatitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  4/50 (8.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tooth disorder † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Toothache † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Vomiting † 1  3/7 (42.86%)  22/77 (28.57%)  12/24 (50.00%)  11/38 (28.95%)  9/41 (21.95%)  10/50 (20.00%)  8/40 (20.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  1/2 (50.00%)  0/0 
General disorders                             
Asthenia † 1  0/7 (0.00%)  7/77 (9.09%)  2/24 (8.33%)  4/38 (10.53%)  2/41 (4.88%)  4/50 (8.00%)  4/40 (10.00%)  0/1 (0.00%)  1/8 (12.50%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Catheter site pain † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  1/41 (2.44%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Chest pain † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  1/38 (2.63%)  4/41 (9.76%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Chills † 1  1/7 (14.29%)  32/77 (41.56%)  7/24 (29.17%)  10/38 (26.32%)  11/41 (26.83%)  14/50 (28.00%)  8/40 (20.00%)  1/1 (100.00%)  2/8 (25.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cyst † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Fatigue † 1  4/7 (57.14%)  40/77 (51.95%)  12/24 (50.00%)  21/38 (55.26%)  19/41 (46.34%)  17/50 (34.00%)  18/40 (45.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  1/2 (50.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Feeling cold † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Gait disturbance † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  4/38 (10.53%)  0/41 (0.00%)  3/50 (6.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hernia † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Influenza like illness † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  2/38 (5.26%)  2/41 (4.88%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Local swelling † 1  1/7 (14.29%)  1/77 (1.30%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Malaise † 1  0/7 (0.00%)  4/77 (5.19%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  2/50 (4.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Non-cardiac chest pain † 1  0/7 (0.00%)  6/77 (7.79%)  1/24 (4.17%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Oedema † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  2/41 (4.88%)  3/50 (6.00%)  1/40 (2.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Oedema peripheral † 1  2/7 (28.57%)  14/77 (18.18%)  2/24 (8.33%)  9/38 (23.68%)  3/41 (7.32%)  4/50 (8.00%)  3/40 (7.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pain † 1  0/7 (0.00%)  7/77 (9.09%)  2/24 (8.33%)  5/38 (13.16%)  0/41 (0.00%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Peripheral swelling † 1  0/7 (0.00%)  5/77 (6.49%)  0/24 (0.00%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pyrexia † 1  7/7 (100.00%)  63/77 (81.82%)  21/24 (87.50%)  36/38 (94.74%)  41/41 (100.00%)  42/50 (84.00%)  33/40 (82.50%)  1/1 (100.00%)  6/8 (75.00%)  1/1 (100.00%)  1/2 (50.00%)  1/1 (100.00%)  2/2 (100.00%)  0/0 
Immune system disorders                             
Graft versus host disease † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypogammaglobulinaemia † 1  2/7 (28.57%)  7/77 (9.09%)  3/24 (12.50%)  2/38 (5.26%)  4/41 (9.76%)  1/50 (2.00%)  7/40 (17.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Infections and infestations                             
Candida infection † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  4/38 (10.53%)  0/41 (0.00%)  2/50 (4.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Clostridium difficile colitis † 1  0/7 (0.00%)  2/77 (2.60%)  1/24 (4.17%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Clostridium difficile infection † 1  0/7 (0.00%)  5/77 (6.49%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Folliculitis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Herpes zoster † 1  2/7 (28.57%)  2/77 (2.60%)  2/24 (8.33%)  1/38 (2.63%)  2/41 (4.88%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Lung infection † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  2/41 (4.88%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Nasopharyngitis † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  3/41 (7.32%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Oral candidiasis † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  2/41 (4.88%)  1/50 (2.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Oral herpes † 1  1/7 (14.29%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pneumonia † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  0/38 (0.00%)  5/41 (12.20%)  3/50 (6.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Respiratory syncytial virus infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  1/50 (2.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Rhinitis † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Sinusitis † 1  1/7 (14.29%)  2/77 (2.60%)  2/24 (8.33%)  2/38 (5.26%)  2/41 (4.88%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Staphylococcal infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  3/50 (6.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tinea versicolour † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tooth infection † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Upper respiratory tract infection † 1  1/7 (14.29%)  2/77 (2.60%)  2/24 (8.33%)  5/38 (13.16%)  2/41 (4.88%)  1/50 (2.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Urinary tract infection † 1  1/7 (14.29%)  3/77 (3.90%)  1/24 (4.17%)  1/38 (2.63%)  0/41 (0.00%)  2/50 (4.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Wound infection † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Injury, poisoning and procedural complications                             
Excoriation † 1  1/7 (14.29%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Fall † 1  0/7 (0.00%)  5/77 (6.49%)  2/24 (8.33%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Head injury † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Infusion related reaction † 1  2/7 (28.57%)  1/77 (1.30%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Procedural pain † 1  1/7 (14.29%)  1/77 (1.30%)  1/24 (4.17%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Wound † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Investigations                             
Alanine aminotransferase increased † 1  3/7 (42.86%)  12/77 (15.58%)  5/24 (20.83%)  8/38 (21.05%)  5/41 (12.20%)  8/50 (16.00%)  1/40 (2.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  1/2 (50.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Aspartate aminotransferase increased † 1  3/7 (42.86%)  11/77 (14.29%)  5/24 (20.83%)  7/38 (18.42%)  5/41 (12.20%)  7/50 (14.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood albumin decreased † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood alkaline phosphatase increased † 1  1/7 (14.29%)  2/77 (2.60%)  1/24 (4.17%)  4/38 (10.53%)  1/41 (2.44%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood bilirubin increased † 1  0/7 (0.00%)  4/77 (5.19%)  1/24 (4.17%)  2/38 (5.26%)  0/41 (0.00%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood creatinine increased † 1  0/7 (0.00%)  4/77 (5.19%)  2/24 (8.33%)  1/38 (2.63%)  3/41 (7.32%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood fibrinogen decreased † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood immunoglobulin G decreased † 1  1/7 (14.29%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  3/50 (6.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood lactate dehydrogenase increased † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood magnesium decreased † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Blood potassium decreased † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  4/50 (8.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
C-reactive protein increased † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  2/38 (5.26%)  7/41 (17.07%)  7/50 (14.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Electrocardiogram QT prolonged † 1  0/7 (0.00%)  1/77 (1.30%)  2/24 (8.33%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Gamma-glutamyltransferase increased † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  3/41 (7.32%)  4/50 (8.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Immunoglobulins decreased † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  3/41 (7.32%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Lymphocyte count decreased † 1  2/7 (28.57%)  14/77 (18.18%)  6/24 (25.00%)  6/38 (15.79%)  5/41 (12.20%)  10/50 (20.00%)  5/40 (12.50%)  1/1 (100.00%)  3/8 (37.50%)  1/1 (100.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Neutrophil count decreased † 1  2/7 (28.57%)  25/77 (32.47%)  7/24 (29.17%)  11/38 (28.95%)  12/41 (29.27%)  25/50 (50.00%)  13/40 (32.50%)  0/1 (0.00%)  3/8 (37.50%)  1/1 (100.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Oxygen saturation decreased † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  3/50 (6.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Platelet count decreased † 1  2/7 (28.57%)  22/77 (28.57%)  5/24 (20.83%)  9/38 (23.68%)  9/41 (21.95%)  18/50 (36.00%)  6/40 (15.00%)  1/1 (100.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  1/2 (50.00%)  0/0 
Serum ferritin increased † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  2/38 (5.26%)  3/41 (7.32%)  5/50 (10.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Urine output decreased † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  1/38 (2.63%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Weight decreased † 1  1/7 (14.29%)  12/77 (15.58%)  4/24 (16.67%)  2/38 (5.26%)  0/41 (0.00%)  4/50 (8.00%)  3/40 (7.50%)  0/1 (0.00%)  2/8 (25.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Weight increased † 1  0/7 (0.00%)  6/77 (7.79%)  0/24 (0.00%)  2/38 (5.26%)  4/41 (9.76%)  6/50 (12.00%)  1/40 (2.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
White blood cell count decreased † 1  2/7 (28.57%)  23/77 (29.87%)  8/24 (33.33%)  11/38 (28.95%)  6/41 (14.63%)  14/50 (28.00%)  8/40 (20.00%)  1/1 (100.00%)  3/8 (37.50%)  1/1 (100.00%)  0/2 (0.00%)  1/1 (100.00%)  1/2 (50.00%)  0/0 
Metabolism and nutrition disorders                             
Decreased appetite † 1  5/7 (71.43%)  37/77 (48.05%)  13/24 (54.17%)  13/38 (34.21%)  6/41 (14.63%)  9/50 (18.00%)  13/40 (32.50%)  0/1 (0.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dehydration † 1  3/7 (42.86%)  5/77 (6.49%)  4/24 (16.67%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  2/40 (5.00%)  1/1 (100.00%)  2/8 (25.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Fluid overload † 1  1/7 (14.29%)  2/77 (2.60%)  0/24 (0.00%)  1/38 (2.63%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hyperglycaemia † 1  0/7 (0.00%)  14/77 (18.18%)  6/24 (25.00%)  2/38 (5.26%)  1/41 (2.44%)  0/50 (0.00%)  4/40 (10.00%)  0/1 (0.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hyperkalaemia † 1  0/7 (0.00%)  6/77 (7.79%)  1/24 (4.17%)  1/38 (2.63%)  0/41 (0.00%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypermagnesaemia † 1  0/7 (0.00%)  1/77 (1.30%)  2/24 (8.33%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypernatraemia † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypoalbuminaemia † 1  2/7 (28.57%)  31/77 (40.26%)  10/24 (41.67%)  5/38 (13.16%)  2/41 (4.88%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  3/8 (37.50%)  0/1 (0.00%)  1/2 (50.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypocalcaemia † 1  2/7 (28.57%)  29/77 (37.66%)  11/24 (45.83%)  4/38 (10.53%)  1/41 (2.44%)  1/50 (2.00%)  4/40 (10.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypokalaemia † 1  2/7 (28.57%)  25/77 (32.47%)  8/24 (33.33%)  7/38 (18.42%)  6/41 (14.63%)  10/50 (20.00%)  11/40 (27.50%)  0/1 (0.00%)  2/8 (25.00%)  0/1 (0.00%)  0/2 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/0 
Hypomagnesaemia † 1  2/7 (28.57%)  13/77 (16.88%)  5/24 (20.83%)  6/38 (15.79%)  2/41 (4.88%)  5/50 (10.00%)  6/40 (15.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Hyponatraemia † 1  4/7 (57.14%)  23/77 (29.87%)  10/24 (41.67%)  2/38 (5.26%)  2/41 (4.88%)  1/50 (2.00%)  6/40 (15.00%)  1/1 (100.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypophosphataemia † 1  3/7 (42.86%)  22/77 (28.57%)  5/24 (20.83%)  6/38 (15.79%)  6/41 (14.63%)  5/50 (10.00%)  11/40 (27.50%)  1/1 (100.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Malnutrition † 1  0/7 (0.00%)  4/77 (5.19%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Metabolic acidosis † 1  1/7 (14.29%)  4/77 (5.19%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Musculoskeletal and connective tissue disorders                             
Arthralgia † 1  0/7 (0.00%)  10/77 (12.99%)  1/24 (4.17%)  1/38 (2.63%)  3/41 (7.32%)  4/50 (8.00%)  7/40 (17.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Back pain † 1  1/7 (14.29%)  12/77 (15.58%)  2/24 (8.33%)  3/38 (7.89%)  6/41 (14.63%)  5/50 (10.00%)  2/40 (5.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Bone pain † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  3/38 (7.89%)  1/41 (2.44%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Flank pain † 1  0/7 (0.00%)  2/77 (2.60%)  1/24 (4.17%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Groin pain † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Muscle spasms † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  2/38 (5.26%)  2/41 (4.88%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Muscular weakness † 1  3/7 (42.86%)  11/77 (14.29%)  3/24 (12.50%)  4/38 (10.53%)  1/41 (2.44%)  3/50 (6.00%)  6/40 (15.00%)  0/1 (0.00%)  2/8 (25.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Myalgia † 1  3/7 (42.86%)  10/77 (12.99%)  3/24 (12.50%)  5/38 (13.16%)  2/41 (4.88%)  1/50 (2.00%)  3/40 (7.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Neck pain † 1  3/7 (42.86%)  4/77 (5.19%)  1/24 (4.17%)  2/38 (5.26%)  2/41 (4.88%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Pain in extremity † 1  1/7 (14.29%)  7/77 (9.09%)  4/24 (16.67%)  3/38 (7.89%)  4/41 (9.76%)  1/50 (2.00%)  4/40 (10.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tenosynovitis stenosans † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                             
Lymphoma † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Nervous system disorders                             
Aphasia † 1  1/7 (14.29%)  12/77 (15.58%)  4/24 (16.67%)  8/38 (21.05%)  4/41 (9.76%)  9/50 (18.00%)  4/40 (10.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Apraxia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  1/50 (2.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Disturbance in attention † 1  0/7 (0.00%)  1/77 (1.30%)  2/24 (8.33%)  0/38 (0.00%)  1/41 (2.44%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dizziness † 1  1/7 (14.29%)  11/77 (14.29%)  10/24 (41.67%)  6/38 (15.79%)  7/41 (17.07%)  9/50 (18.00%)  6/40 (15.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Dysarthria † 1  0/7 (0.00%)  3/77 (3.90%)  1/24 (4.17%)  3/38 (7.89%)  2/41 (4.88%)  1/50 (2.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dysgeusia † 1  0/7 (0.00%)  5/77 (6.49%)  2/24 (8.33%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dysgraphia † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  3/50 (6.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dyskinesia † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Encephalopathy † 1  4/7 (57.14%)  20/77 (25.97%)  6/24 (25.00%)  8/38 (21.05%)  6/41 (14.63%)  5/50 (10.00%)  3/40 (7.50%)  0/1 (0.00%)  2/8 (25.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Grimacing † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Head discomfort † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Headache † 1  3/7 (42.86%)  35/77 (45.45%)  12/24 (50.00%)  19/38 (50.00%)  18/41 (43.90%)  20/50 (40.00%)  17/40 (42.50%)  0/1 (0.00%)  3/8 (37.50%)  1/1 (100.00%)  0/2 (0.00%)  1/1 (100.00%)  1/2 (50.00%)  0/0 
Memory impairment † 1  0/7 (0.00%)  6/77 (7.79%)  1/24 (4.17%)  0/38 (0.00%)  1/41 (2.44%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Muscle contractions involuntary † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Paraesthesia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  4/38 (10.53%)  2/41 (4.88%)  2/50 (4.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Poor sucking reflex † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Post herpetic neuralgia † 1  1/7 (14.29%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Presyncope † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Seizure † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Sensory loss † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Somnolence † 1  3/7 (42.86%)  10/77 (12.99%)  4/24 (16.67%)  4/38 (10.53%)  5/41 (12.20%)  4/50 (8.00%)  5/40 (12.50%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Speech disorder † 1  0/7 (0.00%)  3/77 (3.90%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tremor † 1  4/7 (57.14%)  23/77 (29.87%)  6/24 (25.00%)  16/38 (42.11%)  5/41 (12.20%)  11/50 (22.00%)  9/40 (22.50%)  0/1 (0.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Psychiatric disorders                             
Agitation † 1  1/7 (14.29%)  5/77 (6.49%)  3/24 (12.50%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Anxiety † 1  0/7 (0.00%)  10/77 (12.99%)  3/24 (12.50%)  4/38 (10.53%)  2/41 (4.88%)  2/50 (4.00%)  4/40 (10.00%)  0/1 (0.00%)  2/8 (25.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Bradyphrenia † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Confusional state † 1  1/7 (14.29%)  19/77 (24.68%)  7/24 (29.17%)  17/38 (44.74%)  5/41 (12.20%)  6/50 (12.00%)  12/40 (30.00%)  0/1 (0.00%)  1/8 (12.50%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Delirium † 1  1/7 (14.29%)  1/77 (1.30%)  1/24 (4.17%)  2/38 (5.26%)  0/41 (0.00%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Depression † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Disorientation † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  1/38 (2.63%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hallucination † 1  1/7 (14.29%)  4/77 (5.19%)  0/24 (0.00%)  1/38 (2.63%)  2/41 (4.88%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Insomnia † 1  1/7 (14.29%)  9/77 (11.69%)  3/24 (12.50%)  6/38 (15.79%)  2/41 (4.88%)  0/50 (0.00%)  7/40 (17.50%)  1/1 (100.00%)  3/8 (37.50%)  1/1 (100.00%)  1/2 (50.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Mental status changes † 1  0/7 (0.00%)  4/77 (5.19%)  1/24 (4.17%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Mood altered † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Restlessness † 1  1/7 (14.29%)  2/77 (2.60%)  1/24 (4.17%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Renal and urinary disorders                             
Acute kidney injury † 1  1/7 (14.29%)  5/77 (6.49%)  0/24 (0.00%)  2/38 (5.26%)  2/41 (4.88%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Bladder spasm † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dysuria † 1  0/7 (0.00%)  4/77 (5.19%)  2/24 (8.33%)  3/38 (7.89%)  2/41 (4.88%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Haematuria † 1  0/7 (0.00%)  4/77 (5.19%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pollakiuria † 1  0/7 (0.00%)  2/77 (2.60%)  1/24 (4.17%)  2/38 (5.26%)  2/41 (4.88%)  1/50 (2.00%)  5/40 (12.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Urinary incontinence † 1  0/7 (0.00%)  6/77 (7.79%)  1/24 (4.17%)  4/38 (10.53%)  1/41 (2.44%)  3/50 (6.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Urinary retention † 1  0/7 (0.00%)  4/77 (5.19%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Urinary tract obstruction † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Reproductive system and breast disorders                             
Perineal pain † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Scrotal oedema † 1  0/7 (0.00%)  1/77 (1.30%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Respiratory, thoracic and mediastinal disorders                             
Atelectasis † 1  1/7 (14.29%)  2/77 (2.60%)  1/24 (4.17%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Cough † 1  3/7 (42.86%)  19/77 (24.68%)  7/24 (29.17%)  10/38 (26.32%)  9/41 (21.95%)  7/50 (14.00%)  8/40 (20.00%)  0/1 (0.00%)  3/8 (37.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dyspnoea † 1  3/7 (42.86%)  14/77 (18.18%)  5/24 (20.83%)  5/38 (13.16%)  3/41 (7.32%)  5/50 (10.00%)  7/40 (17.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hiccups † 1  0/7 (0.00%)  6/77 (7.79%)  1/24 (4.17%)  1/38 (2.63%)  1/41 (2.44%)  1/50 (2.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypoxia † 1  4/7 (57.14%)  22/77 (28.57%)  5/24 (20.83%)  10/38 (26.32%)  6/41 (14.63%)  5/50 (10.00%)  8/40 (20.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Laryngeal haemorrhage † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Nasal congestion † 1  1/7 (14.29%)  4/77 (5.19%)  1/24 (4.17%)  2/38 (5.26%)  1/41 (2.44%)  0/50 (0.00%)  4/40 (10.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Nasal dryness † 1  1/7 (14.29%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Oropharyngeal pain † 1  2/7 (28.57%)  4/77 (5.19%)  2/24 (8.33%)  2/38 (5.26%)  1/41 (2.44%)  2/50 (4.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pleural effusion † 1  3/7 (42.86%)  11/77 (14.29%)  2/24 (8.33%)  6/38 (15.79%)  2/41 (4.88%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pulmonary oedema † 1  2/7 (28.57%)  5/77 (6.49%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Rhinitis allergic † 1  1/7 (14.29%)  1/77 (1.30%)  1/24 (4.17%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Rhinorrhoea † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Tachypnoea † 1  0/7 (0.00%)  2/77 (2.60%)  1/24 (4.17%)  3/38 (7.89%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Upper-airway cough syndrome † 1  1/7 (14.29%)  5/77 (6.49%)  1/24 (4.17%)  1/38 (2.63%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Skin and subcutaneous tissue disorders                             
Alopecia † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  2/50 (4.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Dry skin † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  2/38 (5.26%)  2/41 (4.88%)  0/50 (0.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Erythema † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hyperhidrosis † 1  0/7 (0.00%)  1/77 (1.30%)  1/24 (4.17%)  2/38 (5.26%)  2/41 (4.88%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Night sweats † 1  0/7 (0.00%)  0/77 (0.00%)  1/24 (4.17%)  1/38 (2.63%)  0/41 (0.00%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Pruritus † 1  0/7 (0.00%)  4/77 (5.19%)  3/24 (12.50%)  1/38 (2.63%)  1/41 (2.44%)  3/50 (6.00%)  2/40 (5.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Rash † 1  0/7 (0.00%)  3/77 (3.90%)  2/24 (8.33%)  2/38 (5.26%)  2/41 (4.88%)  2/50 (4.00%)  1/40 (2.50%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Rash maculo-papular † 1  0/7 (0.00%)  4/77 (5.19%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  1/50 (2.00%)  1/40 (2.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Vascular disorders                             
Capillary leak syndrome † 1  1/7 (14.29%)  2/77 (2.60%)  0/24 (0.00%)  0/38 (0.00%)  1/41 (2.44%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Deep vein thrombosis † 1  0/7 (0.00%)  2/77 (2.60%)  0/24 (0.00%)  2/38 (5.26%)  0/41 (0.00%)  0/50 (0.00%)  3/40 (7.50%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Embolism † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  2/40 (5.00%)  0/1 (0.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hot flush † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Hypertension † 1  1/7 (14.29%)  11/77 (14.29%)  4/24 (16.67%)  2/38 (5.26%)  2/41 (4.88%)  3/50 (6.00%)  4/40 (10.00%)  0/1 (0.00%)  0/8 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
Hypotension † 1  3/7 (42.86%)  45/77 (58.44%)  14/24 (58.33%)  23/38 (60.53%)  24/41 (58.54%)  26/50 (52.00%)  23/40 (57.50%)  1/1 (100.00%)  1/8 (12.50%)  0/1 (0.00%)  0/2 (0.00%)  0/1 (0.00%)  1/2 (50.00%)  0/0 
Subclavian vein thrombosis † 1  0/7 (0.00%)  0/77 (0.00%)  0/24 (0.00%)  0/38 (0.00%)  0/41 (0.00%)  0/50 (0.00%)  0/40 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/1 (100.00%)  0/2 (0.00%)  0/1 (0.00%)  0/2 (0.00%)  0/0 
1
Term from vocabulary, MedDRA 23.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met:

  • The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or
  • The study has been completed at all study sites for at least 2 years
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Information
Organization: Kite, A Gilead Company
Phone: 844-454-5483 (1-844-454-KITE)
EMail: medinfo@kitepharma.com
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.
Oluwole OO, Bouabdallah K, Munoz J, De Guibert S, Vose JM, Bartlett NL, Lin Y, Deol A, McSweeney PA, Goy AH, Kersten MJ, Jacobson CA, Farooq U, Minnema MC, Thieblemont C, Timmerman JM, Stiff P, Avivi I, Tzachanis D, Kim JJ, Bashir Z, McLeroy J, Zheng Y, Rossi JM, Johnson L, Goyal L, van Meerten T. Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma. Br J Haematol. 2021 Aug;194(4):690-700. doi: 10.1111/bjh.17527. Epub 2021 Jul 22.
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):
Layout table for additonal information
Responsible Party: Gilead Sciences ( Kite, A Gilead Company )
ClinicalTrials.gov Identifier: NCT02348216    
Other Study ID Numbers: KTE-C19-101
2015-005007-86 ( EudraCT Number )
First Submitted: January 22, 2015
First Posted: January 28, 2015
Results First Submitted: September 6, 2021
Results First Posted: November 23, 2021
Last Update Posted: September 6, 2023