A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 307
- 试验地点
- 36
- 主要终点
- Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
研究概览
简要总结
This study will be separated into 3 distinct phases designated as the Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2 safety management study (Cohort 3 and Cohort 4, Cohort 5 and Cohort 6).
The primary objectives of this study are:
- Phase 1 Study: Evaluate the safety of axicabtagene ciloleucel regimens
- Phase 2 Pivotal Study; Evaluate the efficacy of axicabtagene ciloleucel
- Phase 2 Safety Management Study: Assess the impact of prophylactic regimens or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities
Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy
Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) will receive conditioning chemotherapy (fludarabine 30 mg/m^2 intravenously [IV] over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel chimeric antigen receptor (CAR) transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of body weight (BW) on Day 0.
干预措施: Cyclophosphamide (Drug)
Phase 2 (Pivotal Study): Cohort 1
Participants with refractory DLBCL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.
干预措施: Axicabtagene Ciloleucel (Biological)
Phase 2 (Pivotal Study): Cohort 1
Participants with refractory DLBCL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.
干预措施: Fludarabine (Drug)
Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy
Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) will receive conditioning chemotherapy (fludarabine 30 mg/m^2 intravenously [IV] over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel chimeric antigen receptor (CAR) transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of body weight (BW) on Day 0.
干预措施: Axicabtagene Ciloleucel (Biological)
Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy
Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) will receive conditioning chemotherapy (fludarabine 30 mg/m^2 intravenously [IV] over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel chimeric antigen receptor (CAR) transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of body weight (BW) on Day 0.
干预措施: Fludarabine (Drug)
Phase 2 (Pivotal Study): Cohort 1
Participants with refractory DLBCL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.
干预措施: Cyclophosphamide (Drug)
Phase 2 (Pivotal Study): Cohort 2
Participants with refractory PMBCL or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.
干预措施: Axicabtagene Ciloleucel (Biological)
Phase 2 (Pivotal Study): Cohort 2
Participants with refractory PMBCL or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.
干预措施: Fludarabine (Drug)
Phase 2 (Pivotal Study): Cohort 2
Participants with refractory PMBCL or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.
干预措施: Cyclophosphamide (Drug)
Phase 2 (Safety Management Study): Cohort 3
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2).
干预措施: Axicabtagene Ciloleucel (Biological)
Phase 2 (Safety Management Study): Cohort 3
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2).
干预措施: Fludarabine (Drug)
Phase 2 (Safety Management Study): Cohort 3
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2).
干预措施: Cyclophosphamide (Drug)
Phase 2 (Safety Management Study): Cohort 3
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2).
干预措施: Levetiracetam (Drug)
Phase 2 (Safety Management Study): Cohort 3
Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2).
干预措施: Tocilizumab (Drug)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Axicabtagene Ciloleucel (Biological)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Fludarabine (Drug)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Cyclophosphamide (Drug)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Levetiracetam (Drug)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Tocilizumab (Drug)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Dexamethasone (Drug)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: High-dose methylprednisolone (Drug)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Bendamustine (Drug)
Phase 2 (Safety Management Study): Cohort 4
Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Rituximab (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Axicabtagene Ciloleucel (Biological)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Fludarabine (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Cyclophosphamide (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Levetiracetam (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Rituximab (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Doxorubicin (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Prednisone (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Vincristine (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Ifosfamide (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Carboplatin (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Etoposide (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Gemcitabine (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Oxaliplatin (Drug)
Phase 2 (Safety Management Study): Cohort 5
Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.
干预措施: Cisplatin (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Axicabtagene Ciloleucel (Biological)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Fludarabine (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Cyclophosphamide (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Levetiracetam (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Tocilizumab (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Dexamethasone (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: High-dose methylprednisolone (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Bendamustine (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Rituximab (Drug)
Phase 2 (Safety Management Study): Cohort 6
Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
干预措施: Methylprednisolone (Drug)
结局指标
主要结局
Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
时间窗: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 5.4 years)
TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.
Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)
时间窗: First infusion date of axicabtagene ciloleucel up to 30 days
DLT was defined as axicabtagene ciloleucel-related events with onset within first 30 days following infusion: * Grade (GR) 4 neutropenia lasting \> 21 days and GR 4 thrombocytopenia lasting \> 35 days from day of cell transfer; * Any axicabtagene ciloleucel-related AE requiring intubation; * All other GR 3 toxicities lasting \> 3 days and all GR 4 toxicities, with exception of following conditions which were not considered DLTs: aphasia/dysphasia or confusion/cognitive disturbance which resolved to GR ≤ 1 within 2 weeks and to baseline within 4 weeks; fever GR 3; myelosuppression defined as lymphopenia, decreased hemoglobin, neutropenia and thrombocytopenia unless neutropenia and thrombocytopenia met DLT definition described above; immediate hypersensitivity reactions occurring within 2 hours of cell infusion that were reversible to a ≤ GR 2 within 24 hours of cell administration with standard therapy; hypogammaglobulinemia GR 3 or 4.
Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades
时间窗: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 6.8 years)
TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or continuous venovenous hemodialysis (CVVHD), and Grade 5: Death. Neurologic toxicities were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.
Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
时间窗: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.1 years)
TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.
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
时间窗: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7 years)
ORR was defined as the percentage of participants achieving either a complete response (CR) or a partial response (PR), as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules. 95% confidence interval (CI) was calculated by Clopper-Pearson method.
Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
时间窗: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.4 years)
TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.
次要结局
- Phase 2: Overall Survival (OS)(First infusion date of axicabtagene ciloleucel to the date of death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively))
- Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma(First OR to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively))
- Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC)(First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years))
- Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007(First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years))
- 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)(Baseline up to Month 3)
- Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6)(Baseline up to Month 3)
- Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2)(Baseline up to Month 3)
- Phase 1 Study: ORR as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma(First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months))
- 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(First infusion date of axicabtagene ciloleucel to last follow-up visit (maximum duration: 6.8, 5.4, 4.4, 4.1 years for Cohorts 3, 4, 5, and 6 respectively))
- Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs(First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years))
- Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3)(Baseline up to Month 3)
- Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3)(Baseline up to Month 3)
- Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score(Baseline, Week 4, Month 3, and Month 6)
- Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma(First infusion date of axicabtagene ciloleucel to disease progression or death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively))
- Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies(First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively))
- Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood(Baseline up to Month 60 (for Phase 1 and Phase 2 Cohorts 1, 2, and 3); Baseline up to Month 24 (for Phase 2 Cohorts 4, 5, and 6))
- Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007(First objective response up to the data cutoff date of 11 August 2018 (maximum: 2.7 years))
- Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007(First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years))
- Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)(First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years))
- Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum(Baseline up to Month 3)
- Percentage of Participants With Positive Replication Competent Retrovirus (RCR)(Day 0 (pre-infusion) up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively))
- Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score(Baseline, Week 4, Month 3, and Month 6)