ZUMA-4: 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

Sponsor

Kite, A Gilead Company (Industry)

Overall Status

Recruiting

CT.gov ID

NCT02625480

Collaborator

(none)

116

Enrollment

Locations

Arm

270

Anticipated Duration (Months)

3.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma	Biological: Brexucabtagene Autoleucel (KTE-X19) Drug: Fludarabine Drug: Cyclophosphamide	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

116 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Feb 1, 2016

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Aug 1, 2038

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Arm 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) Drug: Fludarabine Administered intravenously Drug: Cyclophosphamide Administered intravenously

Arm

Intervention/Treatment

Experimental: Single Arm

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)

Drug: Fludarabine

Administered intravenously

Drug: Cyclophosphamide

Administered intravenously

Outcome Measures

Primary Outcome Measures

Phase 1: Percentage of Participants Experiencing Adverse Events Defined as Dose-Limiting Toxicities (DLT) [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: Overall Complete Remission Rate in the ALL Cohort [Up to 24 months]
Overall complete remission rate will be determined per independent review.
Phase 2: Objective Response Rate in the NHL Cohorts [Up to 24 months]
Objective Response Rate will be determined per investigator review.

Secondary Outcome Measures

Minimum Residual Disease Negative Remission Rate in the ALL Cohort [Up to 3 months]
Minimal residual disease (MRD) response rate is defined as MRD < 10^-4 per the standard assessment.
Allogeneic Stem Cell Transplant Rate in the ALL Cohort [Up to 24 months]
The incidence of allogeneic stem cell transplant will be analyzed.
Changes Over Time in Patient Reported Outcomes (PRO) Scores in the ALL and NHL Cohorts [Up to 15 years]
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.
Overall Complete Remission Rate in the ALL Cohort [Up to 15 years]
Relapse-Free Survival for the ALL Cohort [Up to 24 months]
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.
Progression Free Survival in the NHL Cohort [Up to 15 years]
Overall Survival in the ALL and NHL Cohorts [Up to 15 years]
Overall survival is defined as the time from brexucabtagene autoleucel (KTE-X19) infusion to the date of death from any cause.
Duration of Remission in the ALL and NHL Cohorts [Up to 24 months]
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.
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
Note: Individuals with a weight of ≥ 6 kg to < 10kg will only be included once a pediatric formulation becomes available.
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
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 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
Note: Individuals with a weight of ≥ 6 kg to < 10kg will only be included once a pediatric formulation becomes available.
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 by imaging and/or parameningeal mass (cranial and/or spinal)
Presence of CNS-3 disease, defined as WBC ≥ 5/µL in CSF with presence of lymphoblasts with or without neurologic symptoms.
Presence of 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 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 conditioning 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
3	Children's Hospital of Orange County	Orange	California	United States	92868
4	UCSF Benioff Children's Hospital	San Francisco	California	United States	94158
5	Children's Hospital Colorado	Aurora	Colorado	United States	80045
6	University of Miami Hospital & Clinics	Miami	Florida	United States	33136
7	Kapi'olani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
8	Ann & Robert H. Lurie Children's Hospital	Chicago	Illinois	United States	60611
9	University of Chicago	Chicago	Illinois	United States	60637
10	Johns Hopkins University	Baltimore	Maryland	United States	21287
11	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota	United States	55404
12	Mayo Clinic	Rochester	Minnesota	United States	55902
13	Columbia University Irving Medical Center/Morgan Stanley Children's Hospital-NYP	New York	New York	United States	10032
14	University of Rochester Medical Center	Rochester	New York	United States	14642
15	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
16	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
17	Monroe-Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee	United States	37232
18	Texas Children's Hospital	Houston	Texas	United States	77030
19	The University of Texas M.D. Anderson Cancer Center	Houston	Texas	United States	77030
20	University of Virginia Health System, Pediatric Hematology/Oncology Clinic	Charlottesville	Virginia	United States	22908
21	Medical College of Wisconsin (Administrative Offices)	Milwaukee	Wisconsin	United States	53226
22	University Hospital Gent	Gent		Belgium	9000
23	The Hospital for Sick Children	Toronto		Canada	M5G 1X8
24	University Hospital Brno	Brno		Czechia	625 00
25	Unité d'Oncologie et Hématologie Pédiatriques	Bordeaux		France	33 000
26	Institut d'Hematologie et Oncologie Pediatrique	Lyon		France	69373
27	Hopital d'Enfants la Timone	Marseille Cedex 5		France	13385
28	Hopital Robert Debre - Sevice d'Hemato-immunologic	Paris Cedex 19		France	75935
29	University Medical Center Hamburg-Eppendorf (UKE)	Hamburg		Germany	20246
30	Klinikum Innenstadt der LMU	Munich		Germany	80337
31	Bambino Gesù Children's Hospital	Rome		Italy	00165
32	Prinses Maxima Centrum	Utrecht		Netherlands	3508
33	Jurasz University Hospital 1; Collegium Medicum	Bydgoszcz		Poland	85-094
34	Wroclaw Medical University	Wroclaw		Poland	50-556
35	Hospital Sant Joan de Déu	Barcelona		Spain	08950
36	Hospital Universitario La Paz	Madrid		Spain	28046
37	Karolinska University Hospital	Stockholm		Sweden	SE-141 86