A Study Evaluating the Safety and Efficacy of Brexucabtagene Autoleucel (KTE-X19) in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ZUMA-3)

Study Overview
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Brief Summary
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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).

Detailed Description
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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. Attenuated FLAG/FLAG-IDA: fludarabine 30 mg/m^2 IV days 1-2, cytarabine 2 g/m^2 IV days 1-2, G-CSF 5 μg/kg subcutaneously (SC) or IV starts on Day 3 and can continue until day before the start of conditioning chemotherapy. With or without idarubicin 6 mg/m^2 IV Days 1-2. Mini-hyper CVAD (courses A and/or B): Course A: Cyclophosphamide 150 mg/m^2 every 12 hours x 3 days, dexamethasone 20 mg/d IV or PO daily Days 1-4 and 11-14, vincristine 2 mg IV x 1 Course B: methotrexate 250 mg/m^2 IV over 24 hours on Day 1,cytarabine 0.5 g/m^2 IV every 12 hours x 4 doses on Days 2 and 3. After completion of the Month 24 visit, subjects who received an infusion of KTE-X19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968

Official Title
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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)

Conditions
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Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: brexucabtagene autoleucel
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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. Key Exclusion Criteria: 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: 2 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* A single infusion of brexucabtagene autoleucel CAR transduced autologous T cells administered intravenously.<br>* Other names: KTE-X19;Drug: Cyclophosphamide<br>* Administered intravenously.<br>Drug: Fludarabine<br>* Administered intravenously.<br>|
| Experimental: Phase 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* A single infusion of brexucabtagene autoleucel CAR transduced autologous T cells administered intravenously.<br>* Other names: KTE-X19;Drug: Cyclophosphamide<br>* Administered intravenously.<br>Drug: Fludarabine<br>* Administered intravenously.<br>|
| Experimental: Phase 1: 0.5 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* A single infusion of brexucabtagene autoleucel CAR transduced autologous T cells administered intravenously.<br>* Other names: KTE-X19;Drug: Cyclophosphamide<br>* Administered intravenously.<br>Drug: Fludarabine<br>* Administered intravenously.<br>|
| Experimental: Phase 2: 1 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* A single infusion of brexucabtagene autoleucel CAR transduced autologous T cells administered intravenously.<br>* Other names: KTE-X19;Drug: Cyclophosphamide<br>* Administered intravenously.<br>Drug: Fludarabine<br>* Administered intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 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). | 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 | 
| Phase 2: Overall Complete Remission (OCR) Rate (Complete Remission [CR]+ Complete Remission With Incomplete Hematologic Recovery [CRi]) as Assessed Per Independent Review | OCR rate: percentage of participants achieving CR+CRi. CR: ≤5% blasts by morphology in bone marrow (BM); absolute neutrophil count (ANC) ≥1000 and platelets (Plt) ≥100000 in peripheral blood (PB); central nervous system extramedullary disease (CNS EMD) of CNS-1 (no detectable leukemia in cerebrospinal fluid [CSF]); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative positron emission tomography (PET) baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses >1.5 cm in greatest transverse diameter [GTD] at baseline must have regressed to ≤l.5 cm GTD, nodes that were 1.1 to 1.5 cm [long axis] and >1.0 cm [short axis] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size, if tested) and no new lesions. CRi: all CR criteria except in PB ANC ≥1000 and Plt <100000 or ANC <1000 and Plt ≥100000. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Minimum Residual Disease (MRD) Negative Remission Rate | MRD was assessed utilizing multicolor flow cytometry to detect residual cancerous cells with a sensitivity of 10^-4. MRD negative remission was defined as MRD < 10^-4 threshold. Percentage of participants with MRD negative remission was reported. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Complete Remission (CR) Rate Per Independent Review | CR: ≤ 5% blasts by morphology in BM; ANC ≥ 1000 and Plt ≥ 100000 in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses > 1.5 cm in GTD at baseline must have regressed to ≤ l.5 cm GTD, nodes that were 1.1 to 1.5 cm [long axis] and > 1.0 cm [short axis] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size, if tested) and no new lesions. Percentage of participants with CR was reported. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Complete Remission With Incomplete Hematologic Recovery (CRi) Rate Per Independent Review | CRi: ≤ 5% blasts by morphology in BM; ANC ≥ 1000 and Plt < 100000 or ANC < 1000 and Plt ≥ 100000 in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses > 1.5 cm in GTD at baseline must have regressed to ≤ l.5 cm GTD, nodes that were 1.1 to 1.5 cm [long axis] and > 1.0 cm [short axis] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size, if tested) and no new lesions. Percentage of participants with CRi was reported. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Duration of Remission (DOR) Per Independent Review | DOR was defined as the time from first CR or CRi to relapse or any death in the absence of documented relapse. CR and CRi are defined in Outcome Measures 4 and 5. Relapse: ≤ 5% blasts by morphology in BM; or circulating leukemia present in PB; or CNS EMD of CNS-2 (detectable CSF blast cells in a sample of CSF with < 5 white blood cells [WBCs] per mm^3 with neurological changes) or CNS-3 (detectable CSF blast cells in a sample of CSF with ≥ 5 WBCs per mm^3 with or without neurological changes); or progressive disease (PD): at least one of the following (≥ 50% increase from nadir in the sum of the products of at least two lymph nodes, or if a single node is involved at least a 50% increase in the product of the diameters of this one node; at least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis; ≥ 50% increase in size of splenic, hepatic or any other non-nodal lesion). Kaplan-Meier (KM) estimates was used for analyses. | From first CR or CRi (Phase 2) to relapse/death or data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: OCR Rate (CR + CRi) Per Investigator Review | OCR rate: percentage of participants achieving CR+CRi. CR: ≤ 5% blasts by morphology in BM; ANC ≥1000 and Plt ≥ 100000 in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses >1.5 cm in GTD at baseline must have regressed to ≤l.5 cm GTD, nodes that were 1.1 to 1.5 cm [long axis] and >1.0 cm [short axis] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size, if tested) and no new lesions. CRi: all CR criteria except in PB ANC ≥1000 and Plt <100000 or ANC <1000 and Plt ≥100000. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Percentage of Participants With Allogeneic Stem Cell Transplant (Allo-SCT) |  | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: MRD Negative Rate Among Complete Remission (CR) Participants | Percentage of participants with MRD negative remission among CR participants was reported. MRD was assessed utilizing multicolor flow cytometry to detect residual cancerous cells with a sensitivity of 10^-4. MRD negative remission was defined as MRD < 10^-4 threshold. CR: ≤5% blasts by morphology in BM; ANC ≥ 1000 and Plt ≥ 100000 in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses > 1.5 cm in GTD at baseline must have regressed to ≤ l.5 cm GTD, nodes that were 1.1 to 1.5 cm [long axis] and > 1.0 cm [short axis] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size, if tested) and no new lesions. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: MRD Negative Rate Among Complete Remission With Incomplete Hematologic Recovery (CRi) Participants | Percentage of participants with MRD negative remission among CRi participants was reported. MRD was assessed utilizing multicolor flow cytometry to detect residual cancerous cells with a sensitivity of 10^-4. MRD negative remission was defined as MRD < 10^-4 threshold. CRi: ≤ 5% blasts by morphology in BM; ANC ≥ 1000 and Plt < 100000 or ANC < 1000 and Plt ≥ 100000 in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses >1.5 cm in GTD at baseline must have regressed to ≤l.5 cm GTD, nodes that were 1.1 to 1.5 cm [long axis] and >1.0 cm [short axis] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size, if tested) and no new lesions. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Overall Survival (OS) | OS was defined as the time from brexucabtagene autoleucel infusion to the date of death from any cause. Participants who had not died by the analysis data cutoff date were censored at their last contact date. KM estimates was used for analyses. | First infusion date of brexucabtagene autoleucel (Phase 2) to death or data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Relapse-free Survival (RFS) | RFS: time from brexucabtagene autoleucel infusion to date of disease relapse or death from any cause. Participants not meeting criteria for relapse by the analysis data cutoff date were censored at their last evaluable disease assessment date. Participants who had not achieved a CR or CRi at analysis data cutoff were evaluated as an RFS event at Day 0. CR and CRi are defined in Outcome Measures 4 and 5. Relapse is defined in Outcome Measure 6. KM estimates was used for analyses. | First infusion date of brexucabtagene autoleucel (Phase 2) to relapse/death or data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | An AE was any untoward medical occurrence in a participant after brexucabtagene autoleucel infusion, which did not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. TEAEs included all AEs with onset on or after initiation of the brexucabtagene autoleucel infusion. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Number of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value | Grading categories are determined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Number of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value | Grading categories are determined by CTCAE version 4.03. | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Percentage of Participants With Anti-KTE-X19 Antibodies |  | First infusion date of brexucabtagene autoleucel (Phase 2) to data cutoff date of 09 September 2020 (Maximum duration: 23 Months) | 
| Phase 2: Number of Participants With 5-Level European Quality of Life-5 Dimensions (EQ-5D-5L): Health Utility Index Scale | EQ-5D-5L is a self-reported questionnaire used for assessing the overall health status of a participant scoring 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was divided into 5 levels of severity: No problem, Slight problems, Moderate problems, Severe problems, and Extreme problems or Unable to. | Baseline, Day 28, Month 3, Month 6, Month 9, Month 12 | 
| Phase 2: Change From Baseline Over Time in EQ-5D: Visual Analogue Scale (VAS) | EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant. The EQ-5D-VAS records the participant's self-rated health on a 20-cm vertical visual analogue scale and is asked to make a global assessment of their current state of health with 0 indicating the worst health they can imagine and 100 indicating the best health they can imagine. | Baseline, Day 28, Month 3, Month 6, Month 9, Month 12 |