NCT02625480已完成1 期
A Phase 1/2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-X19 in Pediatric and Adolescent Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia or Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (ZUMA-4)
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 95
- 试验地点
- 60
- 主要终点
- Phase 2: Overall Complete Remission Rate in the ALL Cohort
研究概览
简要总结
The primary objectives of this study are to evaluate the safety and efficacy of brexucabtagene autoleucel (KTE-X19) in pediatric and adolescent participants with relapsed/refractory (r/r) B-precursor acute lymphoblastic leukemia (ALL) or relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (NHL).
As of October 2022, no further patients with acute B-cell Acute Lymphoblastic Leukemia (ALL) will be asked to join the study. The study remains open for recruitment for patients that have B-cell Non Hodgkin Lymphoma (NHL).
详细描述
All participants who received KTE-X19, and have completed at least 24 months of protocol assessments, will be transitioned to a separate long-term follow-up (LTFU) study. The purpose of the LTFU study (KT-US-982-5968.) is to complete the remainder of the 15-year follow-up assessments.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •for the ALL Cohort
- •Relapsed or refractory B-precursor ALL defined as one of the following:
- •Primary refractory disease
- •Any relapse within 18 months after first diagnosis
- •Relapsed or refractory disease after 2 or more lines of systemic therapy
- •Relapsed or refractory disease after allogeneic transplant provided individual is at least 100 days from stem cell transplant at the time of enrollment
- •Disease burden defined as at least 1 of the following:
- •Morphological disease in the bone marrow (> 5% blasts)
- •Minimal/Measurable Residual Disease (MRD) positive (threshold 10^-4 by flow or Polymerase chain reaction (PCR))
- •Individuals with 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
- •Age ≤ 21 years and weight ≥ 6 kg at the time of assent or consent per Institutional Review Board (IRB) guidelines
- •Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age ≥ 16 years at the time of assent/consent) performance status ≥ 80 at screening
- •Adequate renal, hepatic, pulmonary and cardiac function defined as:
- •Creatinine clearance (as estimated by Cockcroft Gault or Schwartz) ≥ 60 mL/min
- •Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN)
- •Total bilirubin ≤ 1.5 x ULN, except in individuals with Gilbert's syndrome
- •Left ventricular shortening fraction (LVSF) ≥ 30% or left ventricular ejection fraction (LVEF) ≥ 50%, as determined by an echocardiogram or multi-gated acquisition scan (MUGA), no evidence of pericardial effusion (except trace or physiological) as determined by an echocardiogram (ECHO) and no clinically significant arrhythmias
- •No clinically significant pleural effusion, pericardial effusion or ascites
- •Baseline oxygen saturation > 92% on room air
排除标准
- •for the ALL Cohort
- •Diagnosis of Burkitt's leukemia/lymphoma according to the 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
- •History of severe hypersensitivity reaction to aminoglycosides or any of the agents used in this study
- •Central nervous system (CNS) involvement and abnormalities:
- •Any CNS tumor mass by imaging and/or parameningeal mass (cranial and/or spinal)
- •Presence of central nervous system (CNS)-3 disease, defined as white blood cell (WBC) ≥ 5/µL in Cerebrospinal Fluid (CSF) with presence of lymphoblasts with or without neurologic symptoms
- •CNS-2 disease, defined as WBC < 5/µL in CSF with presence of lymphoblasts and with neurologic symptoms (see note below for further clarification).
- •Note: Neurologic symptoms may include but are not limited to cranial nerve palsy (if not explained by extracranial tumor) and clinical cord compression.
- •(Individuals with CNS-1 (no detectable lymphoblasts in the CSF) and those with CNS-2 without clinically evident neurological changes are eligible to participate in the study)
- •History or presence of CNS disorder, such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement, posterior reversible encephalopathy syndrome (PRES), or cerebral edema with confirmed structural defects not related to lymphoma by appropriate imaging. History of stroke or transient ischemic attack within 12 months before enrollment. Individuals with seizure disorders requiring active anticonvulsive medication.
- •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
- •History of human immunodeficiency virus (HIV) infection or acute / chronic active hepatitis B or C infection. Individuals with a history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America guidelines or applicable country guidelines.
- •Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management.
- •Prior medication:
- •Prior CD19 directed therapy (other than blinatumomab), including CAR+ T cell, bispecific T cell engager (BiTE), and antibody drug conjugate (ADC), with the exception of individuals who received brexucabtagene autoleucel (KTE-X19) in this study and are eligible for re-treatment
- •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
- •Acute GVHD grade II-IV by Glucksberg criteria or severity B-D by IBMTR index; acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment
- •Live vaccine ≤ 6 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 are not considered to be of childbearing potential
- •Individuals of both genders of child-bearing potential who are not willing to use a birth control method considered to be highly effective per protocol from the time of consent through 6 months after conditioning chemotherapy or brexucabtagene autoleucel (KTE-X19) infusion, whichever is longer.
- •Key Inclusion Criteria for the NHL Cohort
- •Histologically confirmed aggressive B cell NHL
- •Relapsed or refractory histologically confirmed aggressive B-cell NHL per 1 or more of the following:
- •Primary refractory disease
- •Any relapse within 18 months after first diagnosis
- •Relapsed or refractory disease after 1 or more lines of systemic therapy
- •Relapsed or refractory disease after autologous /allogeneic stem cell transplant provided individual is at least 6 weeks from autologous stem cell transplant and at least 3 months from allogeneic stem cell transplant at the time of enrollment
- •Individuals must have received adequate prior therapy including at a minimum all of the following:
- •Anti-CD20 monoclonal antibody, unless the investigator determines that the tumor is CD20 negative
- •An anthracycline-containing chemotherapy regimen
- •Age <18 years old and weight ≥ 6kg
- •Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age ≥ 16 years at the time of assent/consent) performance status ≥ 80 at screening
- •Adequate renal, hepatic, pulmonary, and cardiac function defined as the following:
- •Creatinine clearance (as estimated by Cockcroft Gault or Schwartz) ≥ 60 mL/min
- •Serum ALT/AST ≤ 5 ULN
- •Total bilirubin ≤1.5 x ULN except in individuals with Gilbert's syndrome
- •Left ventricular shortening fraction(LVSF) ≥ 30% or left ventricular ejection fraction (LVEF) ≥ 50%, as determined by ECHO or MUGA, no evidence of pericardial effusion (except trace or physiological) as determined by an ECHO, and no clinically significant arrhythmias
- •Baseline oxygen saturation > 92% on room air
- •Key Exclusion Criteria for the NHL Cohort
- •History of malignancy other than nonmelanoma skin cancer, carcinoma in situ (eg, cervix, breast), or follicular lymphoma (FL) unless disease free for at least 3 years
- •Autologous stem cell transplant within <6 weeks of planned KTE-X19 infusion; allogeneic stem cell transplant within <3 months of planned KTE-X19 infusion
- •Prior CD19 targeted therapy other than blinatumomab and loncastuximab tesirine-lpyl
- •History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
- •Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management.
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研究组 & 干预措施
Single Arm
Experimental
A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by a single infusion of chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR+ T cells/kg or 1 x 10^6 anti-CD19 CAR+ T cells/kg.
干预措施: Brexucabtagene Autoleucel (KTE-X19) (Biological)
Single Arm
Experimental
A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by a single infusion of chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR+ T cells/kg or 1 x 10^6 anti-CD19 CAR+ T cells/kg.
干预措施: Fludarabine (Drug)
Single Arm
Experimental
A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by a single infusion of chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR+ T cells/kg or 1 x 10^6 anti-CD19 CAR+ T cells/kg.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Phase 2: Overall Complete Remission Rate in the ALL Cohort
时间窗: Up to 24 months
Overall complete remission rate will be determined per independent review.
Phase 1: Percentage of Participants Experiencing Adverse Events Defined as Dose-Limiting Toxicities (DLT)
时间窗: Up to 28 days
Dose-limiting toxicity is defined as protocol-defined brexucabtagene autoleucel (KTE-X19)-related events with onset within the first 28 days following brexucabtagene autoleucel (KTE-X19) infusion.
Phase 2: Objective Response Rate in the NHL Cohorts
时间窗: Up to 24 months
Objective Response Rate will be determined per investigator review.
次要结局
- Duration of Remission in the ALL and NHL Cohorts(Up to 24 months)
- Minimum Residual Disease Negative Remission Rate in the ALL Cohort(Up to 3 months)
- Allogeneic Stem Cell Transplant Rate in the ALL Cohort(Up to 24 months)
- Relapse-Free Survival for the ALL Cohort(Up to 24 months)
- Minimum Residual Disease Negative Remission Rate in the ALL Cohort(Up to 3 months)
- Allogeneic Stem Cell Transplant Rate in the ALL Cohort(Up to 24 months)
- Duration of Remission in the ALL and NHL Cohorts(Up to 24 months)
- Percentage of Participants with Anti-Brexucabtagene Autoleucel (KTE-X19) Antibodies in Blood in the ALL and NHL Cohorts(Up to 10 years)
- Percentage of Participants Experiencing Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) Grade Changes in Safety Laboratory Values in ALL and NHL Cohorts(Up to 10 years)
- Changes Over Time in Patient Reported Outcomes (PRO) Scores in the ALL and NHL Cohorts(Up to 10 years)
- Overall Complete Remission Rate in the ALL Cohort(Up to 10 years)
- Relapse-Free Survival for the ALL Cohort(Up to 24 months)
- Progression Free Survival in the NHL Cohort(Up to 10 years)
- Overall Survival in the ALL and NHL Cohorts(Up to 10 years)
- CR Rate Within 3 Months Per Independent Review in ALL Cohorts(Up to 10 years)
研究者
研究点 (60)
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