A Phase 2, Open-Label, Multicenter, Basket Study Evaluating the Efficacy of Brexucabtagene Autoleucel in Adults With Rare B-cell Malignancies (ZUMA-25)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 19
- 试验地点
- 26
- 主要终点
- Substudy A: Combined Rate of Complete Response (CR) and Very Good Partial Response (VGPR) Determined by Central Assessment Per the Sixth International Workshop in Waldenstrom Macroglobulinemia (WM)
研究概览
简要总结
Master protocol: The goal of this master clinical study is to test how well the study drug, brexucabtagene autoleucel, works in participants with rare B-cell malignancies: relapsed/refractory Waldenstrom macroglobulinemia (r/r WM) (Substudy A), r/r Richter transformation (RT) (Substudy B), r/r Burkitt lymphoma (BL) (Substudy C) and r/r hairy cell leukemia (HCL) (Substudy D).
详细描述
This study will use a basket study design with separate, indication-specific substudies, to investigate r/r RT and r/r BL.
After completing the treatment period, all participants will be followed in the post-treatment follow-up period. Thereafter, participants will transition to a separate long-term follow-up study (KT-US-982-5968) to continue follow-up out to 15 years.
All substudies have been early terminated by the sponsor. Below is summary of enrollment in each Substudy:
- Substudy-A This substudy was withdrawn. Therefore no participants were enrolled.
- Substudy-B enrollment closed, actual enrollment is 6.
- Substudy-C enrollment closed, actual enrollment is 12.
- Substudy-D enrollment closed, actual enrollment is 1.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •All Substudies:
- •Presence of toxicities due to prior therapy must be stable and recovered to Grade 1 or lower.
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- •Adequate hematologic and end-organ function.
- •Individuals of childbearing potential who engage in heterosexual intercourse must agree to use specified method(s) of contraception.
- •Substudy B:
- •Confirmed diagnosis of chronic lymphocytic leukemia (CLL) based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria with histologically confirmed Richter transformation (RT) to a diffuse large B-cell lymphoma (DLBCL) subtype.
- •Relapsed or refractory disease after 1 line of therapy, defined as at least 1 of the following:
- •Refractory disease, defined as progressive disease or stable disease as best response to first-line therapy.
- •Relapsed disease, defined as complete remission to first-line therapy followed by biopsy-proven disease relapse.
- •At least 1 measurable lesion based on the Lugano Classification. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
- •Substudy C:
- •Histologically confirmed mature B-cell non-Hodgkin lymphoma (NHL) Burkitt lymphoma/leukemia.
- •Relapsed or refractory disease after first-line chemoimmunotherapy, defined as 1 of the following:
- •Refractory disease, defined as progressive disease or stable disease as best response to first-line therapy; individuals who are intolerant to first-line therapy are excluded.
- •Relapsed disease, defined as complete remission to first-line therapy followed by biopsy-proven disease relapse.
- •At least 1 measurable lesion based on the Lugano Classification. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
排除标准
- •All Substudies:
- •Prior chimeric antigen receptor (CAR) therapy or treatment with any anti-Cluster of Differentiation 19 (CD19) therapy.
- •human immunodeficiency virus (HIV)-positive patients, unless taking appropriate anti-HIV medications, having an undetectable viral load by quantitative polymerase chain reaction (qPCR) and a CD4 count > 200 cells/μL.
- •Presence of detectable cerebrospinal fluid malignant cells or brain metastases.
- •History of autoimmune disease (eg, Crohn's disease, rheumatoid arthritis, systemic lupus).
- •Substudy B:
- •Diagnosis of RT not of DLBCL subtype (including, but not limited to, Hodgkin lymphoma (HL) and prolymphocytic leukemia).
- •Prior allogeneic or autologous stem cell transplant < 3 months prior to screening and/or < 4 months prior to planned infusion of brexucabtagene autoleucel.
- •Presence of active graft-versus-host disease following prior stem cell transplant.
- •Substudy C:
- •Burkitt-like lymphoma with 11q aberration, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, or high-grade B-cell lymphoma not otherwise specified.
- •Prior allogeneic stem cell transplant < 3 months prior to screening and/or < 4 months prior to planned infusion of brexucabtagene autoleucel.
- •Presence of active graft-versus-host disease following prior allogeneic stem cell transplant.
- •Presence of central nervous system (CNS) involvement. Individuals with a prior history of CNS involvement are eligible if they show a negative cerebrospinal fluid (CSF) and no involvement by imaging.
- •Substudies A and D have been early terminated by the sponsor.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Substudy A (Relapsed/Refractory Waldenstrom Macroglobulinemia): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Waldenstrom Macroglobulinemia will receive the following treatment during the study:Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day intravenously (IV) and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3). A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T cells/kg on Day 0.
干预措施: Brexucabtagene Autoleucel (Biological)
Substudy A (Relapsed/Refractory Waldenstrom Macroglobulinemia): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Waldenstrom Macroglobulinemia will receive the following treatment during the study:Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day intravenously (IV) and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3). A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T cells/kg on Day 0.
干预措施: Cyclophosphamide (Drug)
Substudy A (Relapsed/Refractory Waldenstrom Macroglobulinemia): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Waldenstrom Macroglobulinemia will receive the following treatment during the study:Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day intravenously (IV) and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3). A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T cells/kg on Day 0.
干预措施: Fludarabine (Drug)
Substudy B (Relapsed/Refractory Richter Transformation): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Richter Transformation will receive the following treatment during the study: Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3).A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Brexucabtagene Autoleucel (Biological)
Substudy B (Relapsed/Refractory Richter Transformation): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Richter Transformation will receive the following treatment during the study: Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3).A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Cyclophosphamide (Drug)
Substudy B (Relapsed/Refractory Richter Transformation): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Richter Transformation will receive the following treatment during the study: Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3).A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Fludarabine (Drug)
Substudy C (Relapsed/Refractory Burkitt Lymphoma): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Burkitt Lymphoma will receive the following treatment during the study:Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3).A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Brexucabtagene Autoleucel (Biological)
Substudy C (Relapsed/Refractory Burkitt Lymphoma): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Burkitt Lymphoma will receive the following treatment during the study:Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3).A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Cyclophosphamide (Drug)
Substudy C (Relapsed/Refractory Burkitt Lymphoma): Brexucabtagene Autoleucel
Participants with Relapsed/Refractory Burkitt Lymphoma will receive the following treatment during the study:Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3).A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Fludarabine (Drug)
Substudy D (Relapsed/Refractory hairy cell leukemia): Brexucabtagene Autoleucel
Participant with Relapsed/Refractory Hairy Cell Leukemia will receive the following treatment during the study: Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3). A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Brexucabtagene Autoleucel (Biological)
Substudy D (Relapsed/Refractory hairy cell leukemia): Brexucabtagene Autoleucel
Participant with Relapsed/Refractory Hairy Cell Leukemia will receive the following treatment during the study: Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3). A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Cyclophosphamide (Drug)
Substudy D (Relapsed/Refractory hairy cell leukemia): Brexucabtagene Autoleucel
Participant with Relapsed/Refractory Hairy Cell Leukemia will receive the following treatment during the study: Lymphodepletion chemotherapy regimen of fludarabine 30 mg/m^2/day IV and cyclophosphamide 500 mg/m^2/day IV for 3 days (Day -5 to Day -3). A single IV infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 CAR T cells/kg on Day 0.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Substudy A: Combined Rate of Complete Response (CR) and Very Good Partial Response (VGPR) Determined by Central Assessment Per the Sixth International Workshop in Waldenstrom Macroglobulinemia (WM)
时间窗: Up to 2 years
The combined rate of CR and VGPR was defined as the percentage of participants who achieved a best response of either CR or VGPR per the Sixth International Workshop in WM.
Substudy B: Objective Response Rate (ORR) Determined by Central Assessment Per the Lugano Classification
时间窗: Up to 2 years
ORR was defined as the percentage of participants who achieved a best response of either CR or PR per the Lugano Classification.
Substudy C: ORR Determined by Central Assessment Per the Lugano Classification
时间窗: Up to 2 years
ORR was defined as the percentage of participants who achieved a best response of either CR or PR per the Lugano Classification.
Substudy D: ORR Determined by Central Assessment Per the Response Criteria Described by Grever and Colleagues
时间窗: Up to 2 years
ORR was defined as the percentage of participants who achieved a best response of either CR or PR per Grever and colleagues. CR: Near normalization of peripheral blood counts: hemoglobin \>11 g/dL (without transfusion); platelets \>100 000/μL; absolute neutrophil count \>1500/μL. Regression of splenomegaly on physical examination. Absence of morphologic evidence of HCL on both the peripheral blood smear and the bone marrow examination. PR: PR required near normalization of the peripheral blood count (as in CR) with a minimum of 50% improvement in organomegaly and bone marrow biopsy infiltration with HCL.
次要结局
- All Substudies (Substudies A, B, C and D): Complete Response (CR) Rate Determined by Central Assessment(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Duration of Response (DOR)(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Overall Survival (OS)(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Progression Free Survival (PFS)(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Time to Next Treatment (TTNT)(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Time to First Objective Response(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Time to Best Objective Response(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)(First infusion date of brexucabtagene autoleucel up to 2 years)
- All Substudies (Substudies A, B, C and D): Number of Participants With Deterioration Scores From Screening in the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire-30 (EORTC QLQ-C30)(Day -5, Day 0, Day 28, Month 3, Month 6, Month 9 and Month 12)
- All Substudies (Substudies A, B, C and D): Number of Participants With Deterioration Scores From Screening in the European Quality of Life Five Dimensions Five Levels Questionnaire (EQ-5D-5L)(Day -5, Day 0, Day 28, Month 3, Month 6, Month 9 and Month 12)
- All Substudies (Substudies A, B, C and D): Number of Participants With Increase in Laboratory Values Reported as Grade 3 or Higher(First infusion date of brexucabtagene autoleucel up to 2 years)
- All Substudies (Substudies A, B, C and D): Number of Participants With Decrease in Laboratory Values Reported as Grade 3 or Higher(First dose date up to 2 years)
- All Substudies (Substudies A, B, C and D): Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)(First infusion date of brexucabtagene autoleucel up to 28 days)
- All Substudies (Substudies A, B, C and D): Number of Participants With Positive Anti-brexucabtagene Autoleucel Antibodies(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Number of Participants With Replication-competent Retrovirus (RCR) in Peripheral Blood Mononuclear Cells (PBMCs)(Up to 2 years)
- All Substudies (Substudies A, B, C and D): Change From Screening in the EQ-ED-5L Visual Analogue Scale (EQ-VAS) Score(Screening, Day -5, Day 0, Day 28, Month 3, Month 6, Month 9 and Month 12)
- Substudy A: ORR (CR, VGPR, or PR) Determined by Central Assessment Per the Sixth International Workshop in WM(Up to 2 years)
- Substudy A: Percentage of Participants With Combined CR and VGPR Determined by Investigator Assessment Per the Sixth International Workshop in WM(Up to 2 years)
- Substudy A: PR Rate Determined by Central Assessment Per the Sixth International Workshop in WM(Up to 2 years)
- Substudy A: VGPR Rate Determined by Central Assessment Per the Sixth International Workshop in WM(Up to 2 years)
- Substudy B: Number of Participants With OR Determined by Investigator Assessment Per the Lugano Classification(Up to 2 years)
- Substudy B: Number of Participants With OR Based on Clonal Relationship to the Underlying CLL by Central Assessment Per the Lugano Classification(Up to 2 years)
- Substudy B: Number of Participants With OR (CR, CRi, or PR) Determined by Investigator Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 Criteria(Up to 2 years)
- Substudy C: Number of Participants With OR Determined by Investigator Assessment Per the Lugano Classification(Up to 2 years)
- Substudy D: Number of Participants With OR Determined by Investigator Assessment Per Grever and Colleagues(Up to 2 years)