A Phase 1/2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-X19 in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL) (ZUMA-3)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 125
- 试验地点
- 33
- 主要终点
- Phase 1: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The primary objectives of this study are to determine the safety and efficacy of brexucabtagene autoleucel (KTE-X19) in adult participants with relapsed/refractory (r/r) B-precursor acute lymphoblastic leukemia (ALL).
详细描述
Bridging therapy could be administered at the discretion of the investigator and is recommended for participants with high disease burden at baseline (M3 marrow [> 25% leukemic blasts] or ≥ 1,000 blasts/mm^3 in the peripheral circulation) to control participant's disease prior to conditioning chemotherapy. Bridging therapy includes:
Attenuated VAD: Vincristine non-liposomal (1-2 mg IV weekly) or liposomal (2.25 mg/m^2 IV weekly), and dexamethasone 20-40 mg IV or oral administration (PO) daily x 3-4 days per week. Optional doxorubicin 50 mg/m^2 IV x 1 (first week only).
Mercaptopurine (6-MP): 50-75 mg/m^2/day by mouth (administer at bedtime on an empty stomach to improve absorption).
Hydroxyurea: Doses titrated between 15-50 mg/kg/day (rounded to the nearest 500 mg capsule and given as a single daily oral dose on a continuous basis).
DOMP: Dexamethasone 6 mg/m^2/day PO (or IV) divided twice daily (BID) Days 1-5, vincristine 1.5 mg/m^2 (maximum dose 2 mg) IV on Day 1, methotrexate 20 mg/m^2 PO weekly, 6-MP 50- 75mg/m^2/day PO daily.
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
- •Relapsed or refractory B-precursor ALL defined as one of the following:
- •Primary refractory disease
- •First relapse if first remission ≤ 12 months
- •Relapsed or refractory disease after 2 or more lines of systemic therapy
- •Relapsed or refractory disease after allogeneic transplant provided individuals is at least 100 days from stem cell transplant at the time of enrollment
- •Morphological disease in the bone marrow (≥ 5% blasts)
- •Individuals with Philadelphia chromosome positive (Ph+) disease are eligible if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have relapsed/refractory disease despite treatment with at least 2 different TKIs
- •Eastern cooperative oncology group (ECOG) performance status of 0 or 1
- •Adequate renal, hepatic, pulmonary and cardiac function defined as:
- •Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 cc/min
- •Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN)
- •Total bilirubin ≤ 1.5 mg/dl, except in individuals with Gilbert's syndrome.
- •Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion, and no clinically significant arrhythmias
- •Baseline oxygen saturation > 92% on room air
- •In individuals previously treated with blinatumomab, cluster of differentiation 19 (CD19) tumor expression in bone marrow or peripheral blood.
排除标准
- •Diagnosis of Burkitt's leukemia/lymphoma according to World Health Organization (WHO) classification or chronic myelogenous leukemia lymphoid blast crisis
- •History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years
- •Isolated extramedullary disease
- •Central nervous system (CNS) abnormalities
- •Presence of CNS-3 disease or CNS-2 disease with neurological changes
- •History or presence of any CNS disorder such as a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
- •History of concomitant genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome or any other known bone marrow failure syndrome
- •History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment
- •History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment.
- •Primary immunodeficiency
- •Known infection with human immunodeficiency virus (HIV), hepatitis B (HBsAg positive) or hepatitis C virus.
- •Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management.
- •Prior medication:
- •Salvage chemotherapy including TKIs for Ph+ ALL within 1 week prior to enrollment
- •Prior CD19 directed therapy other than blinatumomab
- •Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis
- •Donor lymphocyte infusion (DLI) within 28 days prior to enrollment
- •Any drug used for graft-versus-host disease (GVHD) within 4 weeks prior to enrollment
- •At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy prior to enrollment
- •Corticosteroid therapy for 7 days prior to enrollment
- •Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Ommaya reservoirs and dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted
- •Acute GVHD grade II-IV by Glucksberg criteria or severity B-D by International Bone Marrow Transplant Registry (IBMTR) index; acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment
- •Live vaccine ≤ 4 weeks prior to enrollment
- •Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential
- •Individuals of both genders of child-bearing potential who are not willing to practice birth control from the time of consent through 6 months after the completion of brexucabtagene autoleucel (KTE-X19)
- •In the investigators judgment, the individuals is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation
- •History of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Phase 1: 2 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with relapsed or refractory B-precursor acute lymphoblastic leukemia (r/r B-ALL) will receive conditioning chemotherapy (fludarabine 25 mg/m^2 intravenously [IV] over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel (KTE-X19) chimeric antigen receptor (CAR) transduced autologous T cells at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: brexucabtagene autoleucel (Biological)
Phase 1: 2 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with relapsed or refractory B-precursor acute lymphoblastic leukemia (r/r B-ALL) will receive conditioning chemotherapy (fludarabine 25 mg/m^2 intravenously [IV] over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel (KTE-X19) chimeric antigen receptor (CAR) transduced autologous T cells at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: Cyclophosphamide (Drug)
Phase 1: 2 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with relapsed or refractory B-precursor acute lymphoblastic leukemia (r/r B-ALL) will receive conditioning chemotherapy (fludarabine 25 mg/m^2 intravenously [IV] over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel (KTE-X19) chimeric antigen receptor (CAR) transduced autologous T cells at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: Fludarabine (Drug)
Phase 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 1 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 1 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: brexucabtagene autoleucel (Biological)
Phase 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 1 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 1 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: Cyclophosphamide (Drug)
Phase 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 1 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 1 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: Fludarabine (Drug)
Phase 1: 0.5 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 0.5 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 0.5 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: brexucabtagene autoleucel (Biological)
Phase 1: 0.5 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 0.5 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 0.5 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: Cyclophosphamide (Drug)
Phase 1: 0.5 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 0.5 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 0.5 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: Fludarabine (Drug)
Phase 2: 1 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 1 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 1 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: brexucabtagene autoleucel (Biological)
Phase 2: 1 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 1 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 1 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: Cyclophosphamide (Drug)
Phase 2: 1 x 10^6 Anti-CD19 CAR T Cells/kg
Participants with r/r B-ALL will receive conditioning chemotherapy (fludarabine 25 mg/m^2 IV over 30 minutes on Day -4, Day -3, and Day -2 and cyclophosphamide 900 mg/m^2 IV over 60 minutes on Day -2) following a single IV infusion of brexucabtagene autoleucel CAR transduced autologous T cells at a target dose of 1 x 10^6 anti-CD19 CAR T cells/kg of body weight on Day 0. For participants weighing > 100 kg, a maximum flat dose of 1 x 10^8 anti-CD19 CAR T cells/kg of body weight will be administered.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Phase 1: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
时间窗: First infusion date of brexucabtagene autoleucel up to 28 days. Participants were evaluated in specified period but GR4 hematologic toxicity (specified in description) having onset in this period were further observed for 30 days for confirmation
DLT is drug-related events with onset within first 28 days following infusion: * Grade (GR) 4 hematologic toxicity lasting more than 30 days (except lymphopenia) if not attributable to underlying disease * All drug-related GR 3 lasting for \> 7 days or 4 non-hematologic toxicities regardless of duration (except: aphasia/dysphasia or confusion/cognitive disturbance which resolves to at least GR 1/baseline within 2 weeks or baseline within 4 weeks, fever GR 3/ 4, immediate hypersensitivity reactions within 2 hours of drug infusion that are reversible ≤ GR 2 within 24 hours, renal toxicity which requires dialysis for ≤ 7 days, intubation for airway protection if ≤ 7 days, tumor lysis syndrome, GR 3 liver function test elevation, provided there is resolution to ≤ GR 2 within 14 days, GR 4 transient serum hepatic enzyme abnormalities provided there is resolution to ≤ GR 3 within \< 72 hours, hypogammaglobulinemia GR 3/ 4 and GR 3 nausea and/or anorexia).
Phase 2: Overall Complete Remission (OCR) Rate (Complete Remission [CR]+ Complete Remission With Incomplete Hematologic Recovery [CRi]) as Assessed Per Independent Review
时间窗: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years
OCR rate:percentage of participants achieving CR+CRi.CR: ≤5% blasts by morphology in bone marrow(BM);absolute neutrophil count(ANC)≥1000/microliters (μL) and platelets(Plt) ≥100000/μL in peripheral blood(PB);central nervous system extramedullary disease(CNS EMD) of CNS-1(no detectable leukemia in cerebrospinal fluid\[CSF\]);Non-CNS baselineEMD:if present(images shows CR),if no(images not needed),if performed shows negative positron emission tomography(PET) baseline,baseline lesions shows CR as disappearance of measurable and nonmeasurable nodal lesions(Nodal masses \>1.5 cm in greatest transverse diameter\[GTD\] at baseline have regressed to ≤l.5 cm GTD,nodes that were 1.1 to 1.5 cm\[long axis\] and \>1.0 cm\[short axis\] have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size) and no new lesions.CRi:all CR criteria except in PB ANC≥1000/μL and Plt\<100000/μL or ANC\<1000/μL and Plt ≥100000/μL.95% confidence interval (CI) was calculated by Clopper-Pearson method.
次要结局
- Phase 2: Complete Remission (CR) Rate Per Independent Review(First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years)
- Phase 2: Complete Remission With Incomplete Hematologic Recovery (CRi) Rate Per Independent Review(First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years)
- Phase 2: Duration of Remission (DOR) Per Independent Review(From first CR or CRi (Phase 2) up to 3.7 years)
- Phase 2: Minimum Residual Disease (MRD) Negative Remission Rate(First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years)
- Phase 2: OCR Rate (CR + CRi) Per Investigator Review(First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years)
- Phase 2: Percentage of Participants With Allogeneic Stem Cell Transplant (Allo-SCT)(First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years)
- Phase 2: MRD Negative Remission Rate Among Complete Remission (CR) Participants(First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years)
- Phase 2: MRD Negative Remission Rate Among Complete Remission With Incomplete Hematologic Recovery (CRi) Participants(First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years)
- Phase 2: Overall Survival (OS)(First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years)
- Phase 2: Relapse-free Survival (RFS)(First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years)
- Phase 2: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)(Up to 5 years)
- Phase 2: Number of Participants Experiencing Laboratory Toxicity Grade 3 or Higher TEAEs Resulting From Increased Parameter Value(Up to 5 years)
- Phase 2: Number of Participants Experiencing Laboratory Toxicity Grade 3 or Higher TEAEs Resulting From Decreased Parameter Value(Up to 5 years)
- Phase 2: Percentage of Participants With Anti-KTE-X19 Antibodies(First infusion date of brexucabtagene autoleucel (Phase 2) up to 2.7 years)
- Phase 2: Number of Participants With 5-Level European Quality of Life-5 Dimensions (EQ-5D-5L): Health Utility Index Scale(Baseline, Day 28, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, and Month 24)
- Phase 2: EQ-5D Visual Analogue Scale (VAS) Score(Baseline, Day 28, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, and Month 24)