Study Evaluating Brexucabtagene Autoleucel (KTE-X19) in Pediatric and Adolescent Participants With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia or Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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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).

Detailed Description
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All subjects 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.

Official Title
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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)

Conditions
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Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia, Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Brexucabtagene Autoleucel (KTE-X19)
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria 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 Key Exclusion Criteria 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 Relapsed or refractory disease after 2 or more lines of systemic therapy Relapsed or refractory disease after autologous /allogeneic transplant provided individual is at least 100 days from 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 Prior CD19 targeted therapy other than blinatumomab 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. History of 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 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. CNS involvement and abnormalities: Any CNS tumor mass and/or parameningeal mass (cranial and/or spinal) by imaging with current or prior history of neurological symptoms within 3 months prior to screening. Note: CNS involvement without neurologic symptoms will be allowed. History or presence of any CNS disorder such as a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, any autoimmune disease with CNS involvement, posterior reversible encephalopathy syndrome (PRES), or cerebral edema with confirmed structural defects by appropriate imaging. History of stroke or transient ischemic attack within 12 months before enrollment. Individuals with seizure disorders requiring active anti-convulsive medication. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment Primary immunodeficiency History of severe immediate hypersensitivity reaction to any of the agents used in this study Live vaccine ≤ 6 weeks prior to planned start of lymphodepleting chemotherapy regimen Individuals of both genders of child-bearing potential who are not willing to use a birth control considered to be highly effective per protocol from the time of consent through 6 months after the completion of conditioning chemotherapy or brexucabtagene autoleucel (KTE-X19) infusion, whichever is longer. Prior medication: Prior CD19 directed therapy (other than blinatumomab), including CAR+ T cell, BiTE, and 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 DLI within 28 days prior to enrollment Any drug used for GVHD within 4 weeks prior to enrollment Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Maximum Age: 21 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>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 | Biological: Brexucabtagene Autoleucel (KTE-X19)<br> <br> Drug: Fludarabine<br>* Administered intravenously<br>Drug: Cyclophosphamide<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 Adverse Events Defined as Dose-Limiting Toxicities (DLT) | 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. | Up to 28 days | 
| Phase 2: Overall Complete Remission Rate in the ALL Cohort | Overall complete remission rate will be determined per independent review. | Up to 24 months | 
| Phase 2: Objective Response Rate in the NHL Cohorts | Objective Response Rate will be determined per investigator review. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Residual Disease Negative Remission Rate in the ALL Cohort | Minimal residual disease (MRD) response rate is defined as MRD < 10^-4 per the standard assessment. | Up to 3 months | 
| Allogeneic Stem Cell Transplant Rate in the ALL Cohort | The incidence of allogeneic stem cell transplant will be analyzed. | Up to 24 months | 
| Changes Over Time in Patient Reported Outcomes (PRO) Scores in the ALL and NHL Cohorts | The PRO scores will be measured by the Pediatric Quality of Life Inventory (PedsQL) for children and adolescents and European Quality-of-Life-5 Dimension (EQ-5D) for all participants. The PedsQL comprises of 23 items in the dimensions of physical, emotional, social, and school functioning. Transformed total, physical health summary, and psychosocial health summary scores range from 0-100 with higher scores indicating better health-related quality of life. The EQ-5D is a generic questionnaire for assessing the participant's overall health status. The EQ-5D consists of a 5 dimension descriptive system including mobility, self-care, usual activities, pain/comfort, and anxiety/depression and a visual analogue scale (EQ-VAS) which allows the respondent to record health. The VAS allows a participant to indicate self-reported health on a vertical scale, ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The PedsQL scores and EQ-5D scores will be reported. | Up to 15 years | 
| Overall Complete Remission Rate in the ALL Cohort |  | Up to 15 years | 
| Relapse-Free Survival for the ALL Cohort | Relapse-Free Survival is defined as the time from the brexucabtagene autoleucel (KTE-X19) infusion date to the date of disease relapse or death from any cause. | Up to 24 months | 
| Progression Free Survival in the NHL Cohort |  | Up to 15 years | 
| Overall Survival in the ALL and NHL Cohorts | Overall survival is defined as the time from brexucabtagene autoleucel (KTE-X19) infusion to the date of death from any cause. | Up to 15 years | 
| Duration of Remission in the ALL and NHL Cohorts | Duration of remission is defined as the time between the participant's first complete response per independent review to relapse or any death in the absence of documented relapse. | Up to 24 months | 
| Percentage of Participants with Anti-Brexucabtagene Autoleucel (KTE-X19) Antibodies in Blood in the ALL and NHL Cohorts |  | Up to 15 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 15 years | 
| CR Rate Within 3 Months Per Independent Review in ALL Cohorts |  | Up to 15 years |