A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy of Axicabtagene Ciloleucel Versus Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma (ZUMA-7)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 359
- 试验地点
- 72
- 主要终点
- Event Free Survival (EFS) Per Blinded Central Assessment
研究概览
简要总结
The goal of this clinical study is to assess whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in participants with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
详细描述
After completing the treatment period, all participants will be followed in the post-treatment follow-up period for up to 5 years. Thereafter, participants who received at least one dose of axicabtagene ciloleucel as protocol therapy will transition to a separate long term follow up (LTFU) study and complete the remainder of the 15-year follow-up assessments within KT-US-982-5968 (NCT05041309).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Histologically proven large B-cell lymphoma (BCL) including the following types defined by World Health Organization (WHO)
- •Diffuse large B-cell lymphoma (DLBCL) not otherwise specified activated B-cell/ germinal center B-cell (ABC/GCB).
- •High-grade B-cell lymphoma (HGBL) with or without myelocytomatosis oncogene (MYC) and BCL 2 and/or BCL 6 rearrangement.
- •DLBCL arising from follicular lymphoma (FL).
- •T-cell/histiocyte rich large B-cell lymphoma.
- •DLBCL associated with chronic inflammation.
- •Primary cutaneous DLBCL, leg type.
- •Epstein-Barr virus (EBV) + DLBCL.
- •Relapsed or refractory disease after first-line chemoimmunotherapy.
- •Refractory disease defined as no complete remission to first-line therapy; individuals who are intolerant to first-line therapy are excluded.
- •Progressive disease (PD) as best response to first-line therapy.
- •Stable disease (SD) as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP).
- •Partial response (PR) as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 12 months of therapy.
- •Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven relapse ≤ 12 months of first-line therapy.
- •Individuals must have received adequate first-line therapy including at a minimum:
- •Anti-Cluster of Differentiation 20 antigen (CD20) monoclonal antibody unless investigator determines that tumor is CD20 negative, and
- •An anthracycline containing chemotherapy regimen.
- •No known history or suspicion of central nervous system involvement by lymphoma.
- •Eastern cooperative oncology group (ECOG) performance status of 0 or
- •Adequate bone marrow function as evidenced by:
- •Absolute neutrophil count (ANC) ≥ 1000/μl
- •Platelet ≥ 75,000/μl
- •Absolute lymphocyte count ≥ 100/μl
- •Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:
- •Creatinine clearance (Cockcroft Gault) ≥ 60 mL/min.
- •Serum Alanine aminotransferase/Aspartate aminotransferase (ALT/AST) ≤ 2.5 Upper limit of normal (ULN).
- •Total bilirubin ≤ 1.5 mg/dl
- •Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an Echocardiogram (ECHO), and no clinically significant Electrocardiogram (ECG) findings.
- •No clinically significant pleural effusion.
- •Baseline oxygen saturation > 92% on room air.
排除标准
- •History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg cervix, bladder, breast) unless disease free for at least 3 years.
- •Received more than one line of therapy for DLBCL.
- •History of autologous or allogeneic stem cell transplant.
- •Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous antimicrobials for management.
- •Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or anti-hepatitis C virus (HCV) positive. If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
- •Individuals with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases.
- •History or presence of non-malignant central nervous system (CNS) disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
- •Presence of any indwelling line or drain. Dedicated central venous access catheter such as a Port-a-Cath or Hickman catheter are permitted.
- •History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac diseases within 12 months of enrollment.
- •History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment.
- •History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years.
- •History of anti-Cluster of Differentiation 19 (CD19) or chimeric antigen receptor (CAR)-T therapy or history of prior randomization in ZUMA-
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply
研究组 & 干预措施
Axicabtagene Ciloleucel Treatment
Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation antigen (CD) 19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0.
Participants who will achieve a partial response or complete response and subsequently experience disease progression may have an option to receive a second course of conditioning chemotherapy and axicabtagene ciloleucel.
干预措施: Axicabtagene Ciloleucel (Biological)
Axicabtagene Ciloleucel Treatment
Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation antigen (CD) 19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0.
Participants who will achieve a partial response or complete response and subsequently experience disease progression may have an option to receive a second course of conditioning chemotherapy and axicabtagene ciloleucel.
干预措施: Cyclophosphamide (Drug)
Axicabtagene Ciloleucel Treatment
Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation antigen (CD) 19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0.
Participants who will achieve a partial response or complete response and subsequently experience disease progression may have an option to receive a second course of conditioning chemotherapy and axicabtagene ciloleucel.
干预措施: Fludarabine (Drug)
Standard of Care Therapy
Participants will receive 2 or 3, 21-day cycles of second-line chemotherapy:
- R-ICE:rituximab 375mg/m^2 before chemotherapy, ifosfamide 5g/m^2 24 hours continuous infusion (CI) on Day 2+mesna, carboplatin area under the curve (AUC)5 Day 2, maximum dose 800mg, etoposide 100mg/m^2/day on Days 1-3;
- R-ESHAP:rituximab 375mg/m^2 Day 1, etoposide 40mg/m^2/day IV on Days 1-4, methylprednisolone 500mg/day IV on Days 1-4 or 5, cisplatin at 25mg/m^2/day CI Days 1-4, cytarabine 2g/m^2 on Day 5;
- R-GDP:rituximab 375mg/m^2 Day 1 (or Day 8), gemcitabine 1g/m^2 on Days 1 and 8, dexamethasone 40mg on Days 1-4, cisplatin 75mg/m^2 Day 1 or carboplatin area under the curve (AUC)=5; or
- R-DHAP:rituximab 375mg/m^2 before chemotherapy, dexamethasone 40mg/day on Days 1-4, high dose cytarabine 2g/m^2 every 12 hours for 2 doses on Day 2 following platinum, cisplatin 100mg/m^2 24 hours CI on Day 1 or oxaliplatin 100mg/m^2.
Responders will receive high-dose therapy and autologous stem cell transplant.
干预措施: Platinum-containing Salvage Chemotherapy (Drug)
结局指标
主要结局
Event Free Survival (EFS) Per Blinded Central Assessment
时间窗: From randomization date up to a median follow-up: 24.9 months
EFS:Time from randomization to disease progression (PD), best response of stable disease (SD) up to Day 150, start of new anti-lymphoma therapy including stem cell transplant, or death from any cause. PD=Score 4 (uptake moderately \> liver) or 5 (uptake markedly \> liver and/or new lesions) with increased uptake from baseline; New fluorodeoxyglucose (FDG)-avid foci consistent with lymphoma rather than another etiology or in bone marrow; Individual node/lesion abnormal with longest diameter \> 1.5 cm, ≥ 50% increase from nadir; Splenic length increase \> 50% of prior increase beyond baseline or ≥ 2 cm increase if no prior splenomegaly; New/recurrent splenomegaly, progression of non-measurable lesions, new lesion, or new/recurrent bone marrow involvement. KM estimates was used for analysis.
次要结局
- Objective Response Rate (ORR) Per Blinded Central Assessment(From randomization date up to a median follow-up: 24.9 months)
- Overall Survival (OS)(Up to 74.9 months)
- Duration of Response (DOR) Per Blinded Central Assessments(From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (Up to 37.8 months))
- Modified Event Free Survival (mEFS) Per Blinded Central Assessment(From randomization date up to a median follow-up: 24.9 months)
- EFS Per Investigator Disease Assessments(From randomization date up to a median follow-up: 47.2 months)
- Progression-Free Survival (PFS) Per Investigator Disease Assessments(From randomization date up to a median follow-up: 47.2 months)
- Modified Event Free Survival (mEFS) Per Investigator Assessment(From randomization date up to a median follow-up: 47.2 months)
- Change From Baseline in Global Health Status Scores(Baseline, Days 50, 100, and 150; Months 9, 12, 15, 18, 21 and 24)
- Change From Baseline in EORTC QLQ-C30 Physical Functioning Score(Baseline, Days 50, 100, 150, Months 9, 12, 15, 18, 21 and 24)
- Changes From Baseline in the European Quality of Life Five Dimensions Five Levels Scale Index Score(Baseline, Days 50, 100, 150; Months 9, 12, 15, 18, 21 and 24)
- Change From Baseline in EQ-5D-5L VAS Scale Score(Baseline, Days 50, 100, 150; Months 9, 12, 15, 18, 21 and 24)
- Number of Participants With Post-dose Anti-Axicabtagene Ciloleucel Antibodies(Up to 74.9 months)
- Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)(From first dose up to 61.8 months)
- Percentage of Participants With Increase in Laboratory Values Reported as Grade 3 or Higher(From first dose up to 61.8 months)
- Percentage of Participants With Decrease in Laboratory Values Reported as Grade 3 or Higher(From first dose up to 61.8 months)