Clinical trial NCT02625480: 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
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia
Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2015-12-09
Enrollment: 95
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Percentage of Participants Experiencing Adverse Events Defined as Dose-Limiting Toxicities (DLT)
timeFrame: Up to 28 days
measure: Phase 2: Overall Complete Remission Rate in the ALL Cohort
timeFrame: Up to 24 months
measure: Phase 2: Objective Response Rate in the NHL Cohorts
timeFrame: Up to 24 months
Secondary outcomes:
measure: Minimum Residual Disease Negative Remission Rate in the ALL Cohort
timeFrame: Up to 3 months
measure: Allogeneic Stem Cell Transplant Rate in the ALL Cohort
timeFrame: Up to 24 months
measure: Changes Over Time in Patient Reported Outcomes (PRO) Scores in the ALL and NHL Cohorts
timeFrame: Up to 15 years
measure: Overall Complete Remission Rate in the ALL Cohort
timeFrame: Up to 15 years
measure: Relapse-Free Survival for the ALL Cohort
timeFrame: Up to 24 months
measure: Progression Free Survival in the NHL Cohort
timeFrame: Up to 15 years
measure: Overall Survival in the ALL and NHL Cohorts
timeFrame: Up to 15 years
measure: Duration of Remission in the ALL and NHL Cohorts
timeFrame: Up to 24 months
measure: Percentage of Participants with Anti-Brexucabtagene Autoleucel (KTE-X19) Antibodies in Blood in the ALL and NHL Cohorts
timeFrame: Up to 15 years
measure: 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
timeFrame: Up to 15 years
measure: CR Rate Within 3 Months Per Independent Review in ALL Cohorts
timeFrame: Up to 15 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Miami
country: United States
facility: University of Miami Hospital & Clinics
state: Florida
city: Honolulu
country: United States
facility: Kapi'olani Medical Center for Women and Children
state: Hawaii
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota
state: Minnesota
city: New York
country: United States
facility: Columbia University Irving Medical Center/Morgan Stanley Children's Hospital-NYP
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Monroe-Carell Jr. Children's Hospital at Vanderbilt
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System, Pediatric Hematology/Oncology Clinic
state: Virginia
city: Gent
country: Belgium
facility: University Hospital Gent
city: Toronto
country: Canada
facility: The Hospital for Sick Children
city: Brno
country: Czechia
facility: University Hospital Brno
city: Bordeaux
country: France
facility: Unité d'Oncologie et Hématologie Pédiatriques
city: Lyon
country: France
facility: Institut d'Hematologie et Oncologie Pediatrique
city: Marseille Cedex 5
country: France
facility: Hopital d'Enfants la Timone
city: Paris Cedex 19
country: France
facility: Hopital Robert Debre - Sevice d'Hemato-immunologic
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf (UKE)
city: Rome
country: Italy
facility: Bambino Gesù Children's Hospital
city: Utrecht
country: Netherlands
facility: Prinses Maxima Centrum
city: Bydgoszcz
country: Poland
facility: Jurasz University Hospital 1; Collegium Medicum
city: Wroclaw
country: Poland
facility: Wroclaw Medical University
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
affiliation: Kite, A Gilead Company
name: Kite Study Director
role: STUDY_DIRECTOR
References: