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JOURNAL ONKOLOGIE – STUDIE
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

Rekrutierend

NCT-Nummer:
NCT02625480

Studienbeginn:
Februar 2016

Letztes Update:
15.04.2024

Wirkstoff:
Brexucabtagene Autoleucel (KTE-X19), Fludarabine, Cyclophosphamide

Indikation (Clinical Trials):
Lymphoma, Leukemia, Lymphoma, Non-Hodgkin, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphoid, Lymphoma, B-Cell

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Kite, A Gilead Company

Collaborator:
-

Studienleiter

Kite Study Director
Study Director
Kite, A Gilead Company

Kontakt

Studienlocations
(3 von 37)

University Medical Center Hamburg-Eppendorf (UKE)
20246 Hamburg
(Hamburg)
GermanyRekrutierend» Google-Maps
Klinikum Innenstadt der LMU
80337 Munich
(Bayern)
GermanyZurückgezogen» Google-Maps
Children's Hospital Los Angeles
90027 Los Angeles
United StatesRekrutierend» Google-Maps
Children's Hospital of Orange County
92868 Orange
United StatesRekrutierend» Google-Maps
UCSF Benioff Children's Hospital
94158 San Francisco
United StatesRekrutierend» Google-Maps
Children's Hospital Colorado
80045 Aurora
United StatesZurückgezogen» Google-Maps
University of Miami Hospital & Clinics
33136 Miami
United StatesRekrutierend» Google-Maps
Kapi'olani Medical Center for Women and Children
96826 Honolulu
United StatesRekrutierend» Google-Maps
Ann & Robert H. Lurie Children's Hospital
60611 Chicago
United StatesRekrutierend» Google-Maps
University of Chicago
60637 Chicago
United StatesZurückgezogen» Google-Maps
Johns Hopkins University
21287 Baltimore
United StatesAktiv, nicht rekrutierend» Google-Maps
Children's Hospitals and Clinics of Minnesota
55404 Minneapolis
United StatesAbgeschlossen» Google-Maps
Columbia University Irving Medical Center/Morgan Stanley Children's Hospital-NYP
10032 New York
United StatesRekrutierend» Google-Maps
University of Rochester Medical Center
14642 Rochester
United StatesRekrutierend» Google-Maps
Cincinnati Children's Hospital Medical Center
45229 Cincinnati
United StatesZurückgezogen» Google-Maps
The Children's Hospital of Philadelphia
19104 Philadelphia
United StatesRekrutierend» Google-Maps
Monroe-Carell Jr. Children's Hospital at Vanderbilt
37232 Nashville
United StatesRekrutierend» Google-Maps
Texas Children's Hospital
77030 Houston
United StatesRekrutierend» Google-Maps
The University of Texas M.D. Anderson Cancer Center
77030 Houston
United StatesRekrutierend» Google-Maps
University of Virginia Health System, Pediatric Hematology/Oncology Clinic
22908 Charlottesville
United StatesRekrutierend» Google-Maps
Medical College of Wisconsin (Administrative Offices)
53226 Milwaukee
United StatesZurückgezogen» Google-Maps
The Hospital for Sick Children
M5G 1X8 Toronto
CanadaRekrutierend» Google-Maps
Unité d'Oncologie et Hématologie Pédiatriques
33 000 Bordeaux
FranceRekrutierend» Google-Maps
Institut d'Hematologie et Oncologie Pediatrique
69373 Lyon
FranceAbgeschlossen» Google-Maps
Hopital d'Enfants la Timone
13385 Marseille Cedex 5
FranceRekrutierend» Google-Maps
Hopital Robert Debre - Sevice d'Hemato-immunologic
75935 Paris Cedex 19
FranceRekrutierend» Google-Maps
Bambino Gesù Children's Hospital
00165 Rome
ItalyRekrutierend» Google-Maps
Jurasz University Hospital 1; Collegium Medicum
85-094 Bydgoszcz
PolandRekrutierend» Google-Maps
Karolinska University Hospital
SE-141 86 Stockholm
SwedenRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

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.

Ein-/Ausschlusskriterien

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

- 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.

- 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 12 months after the completion of lymphodepleting 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.

Studien-Rationale

Primary outcome:

1. Phase 1: Percentage of Participants Experiencing Adverse Events Defined as Dose-Limiting Toxicities (DLT) (Time Frame - 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.

2. Phase 2: Overall Complete Remission Rate in the ALL Cohort (Time Frame - Up to 24 months):
Overall complete remission rate will be determined per independent review.

3. Phase 2: Objective Response Rate in the NHL Cohorts (Time Frame - Up to 24 months):
Objective Response Rate will be determined per investigator review.

Secondary outcome:

1. Minimum Residual Disease Negative Remission Rate in the ALL Cohort (Time Frame - Up to 3 months):
Minimal residual disease (MRD) response rate is defined as MRD < 10^-4 per the standard assessment.

2. Allogeneic Stem Cell Transplant Rate in the ALL Cohort (Time Frame - Up to 24 months):
The incidence of allogeneic stem cell transplant will be analyzed.

3. Changes Over Time in Patient Reported Outcomes (PRO) Scores in the ALL and NHL Cohorts (Time Frame - 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.

4. Overall Complete Remission Rate in the ALL Cohort (Time Frame - Up to 15 years)

5. Relapse-Free Survival for the ALL Cohort (Time Frame - 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.

6. Progression Free Survival in the NHL Cohort (Time Frame - Up to 15 years)

7. Overall Survival in the ALL and NHL Cohorts (Time Frame - 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.

8. Duration of Remission in the ALL and NHL Cohorts (Time Frame - 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.

9. Percentage of Participants with Anti-Brexucabtagene Autoleucel (KTE-X19) Antibodies in Blood in the ALL and NHL Cohorts (Time Frame - Up to 15 years)

10. 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 (Time Frame - Up to 15 years)

11. CR Rate Within 3 Months Per Independent Review in ALL Cohorts (Time Frame - Up to 15 years)

Geprüfte Regime

  • Brexucabtagene Autoleucel (KTE-X19)
  • Fludarabine:
    Administered intravenously
  • Cyclophosphamide:
    Administered intravenously

Quelle: ClinicalTrials.gov


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"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"

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