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    Summary
    EudraCT Number:2015-005010-30
    Sponsor's Protocol Code Number:KTE-C19-104
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-08-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-005010-30
    A.3Full title of the trial
    A Phase 1/2 Multi-Center Study Evaluating the Safety and Efficacy of KTEX19 in Pediatric and Adolescent Subjects with Relapsed/Refractory Bprecursor Acute Lymphoblastic Leukemia or Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (ZUMA-4)
    Studio multicentrico di fase 1/2 per valutare la sicurezza e l’efficacia di KTE-X19 in soggetti pediatrici e adolescenti con leucemia linfoblastica acuta da precursori delle cellule B recidivata/refrattaria o linfoma non-Hodgkin a cellule B recidivato/refrattario (ZUMA-4)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 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 Non-Hodgkin Lymphoma
    Studio per valutare la sicurezza e l’efficacia di KTE-X19 in soggetti pediatrici e adolescenti con leucemia linfoblastica acuta da precursori delle cellule B recidivata/refrattaria o linfoma non-Hodgkin a cellule B recidivato/refrattario
    A.3.2Name or abbreviated title of the trial where available
    ZUMA-4
    ZUMA-4
    A.4.1Sponsor's protocol code numberKTE-C19-104
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02625480
    A.5.4Other Identifiers
    Name:IND NumberNumber:016675
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/002/2021
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorKITE PHARMA INC.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportKite Pharma, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKite Pharma, Inc.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address2400 Broadway
    B.5.3.2Town/ citySanta Monica
    B.5.3.3Post codeCA 90404
    B.5.3.4CountryUnited States
    B.5.6E-mailregulatory@kitepharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/15/1571; EU/3/15/1553; EU/3/14/1393
    D.3 Description of the IMP
    D.3.1Product nameKTE-X19
    D.3.2Product code [KTE-X19]
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNKTE-X19
    D.3.9.2Current sponsor codeKTE-X19
    D.3.9.3Other descriptive nameautologous peripheral blood T cells CD4 and CD8 selected, and CD3 and CD28 activated transduced with retroviral vector encoding an anti-CD19 CD28/CD3-zeta chimeric antigen receptor and cultured
    D.3.9.4EV Substance CodeSUB193905
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number100000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberGene therapy medicinal product. Doc. Ref. EMA/386920/2019
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tecartus
    D.2.1.1.2Name of the Marketing Authorisation holderKite Pharma EU B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/15/1571; EU/3/15/1553; EU/3/14/1393
    D.3 Description of the IMP
    D.3.1Product nameKTE-X19
    D.3.2Product code [KTE-X19]
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNKTE-X19
    D.3.9.2Current sponsor codeKTE-X19
    D.3.9.3Other descriptive nameautologous peripheral blood T cells CD4 and CD8 selected, and CD3 and CD28 activated transduced with retroviral vector encoding an anti-CD19 CD28/CD3-zeta chimeric antigen receptor and cultured
    D.3.9.4EV Substance CodeSUB193905
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number200000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberGene therapy medicinal product. Doc. Ref. EMA/386920/2019
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/15/1571; EU/3/15/1553; EU/3/14/1393
    D.3 Description of the IMP
    D.3.1Product nameKTE-X19
    D.3.2Product code [KTE-X19]
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNKTE-X19
    D.3.9.2Current sponsor codeKTE-X19
    D.3.9.3Other descriptive nameautologous peripheral blood T cells CD4 and CD8 selected, and CD3 and CD28 activated transduced with retroviral vector encoding an anti-CD19 CD28/CD3-zeta chimeric antigen receptor and cultured
    D.3.9.4EV Substance CodeSUB193905
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number50000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberGene therapy medicinal product. Doc. Ref. EMA/386920/2019
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL)
    Relapsed/Refractory B-cell non-Hodgkin lymphoma (r/r NHL)
    Leucemia Linfoblastica Acuta (LLA) da precursori delle cellule B recidivata o refrattaria (r/r)
    Linfoma non-Hodgkin (LNH) a cellule B recidivato o refrattario (r/r)
    E.1.1.1Medical condition in easily understood language
    Cancers of white blood cells
    Tumori alle cellule dei globuli bianchi
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000844
    E.1.2Term Acute lymphoblastic leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10006595
    E.1.2Term Burkitt's lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10036710
    E.1.2Term Primary mediastinal large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of phase 1 is to evaluate the safety of KTE-X19.

    The primary objective of Phase 2:
    ALL Cohort: The primary objective is to evaluate the efficacy of KTEX19, as measured by the overall complete remission rate defined as complete remission (CR) and complete remission with incomplete hematologic recovery (CRi) in pediatric and adolescent subjects with r/r B-precursor ALL.
    NHL Cohort: The primary objective is to estimate the efficacy as measured by the objective response rate (ORR) defined as a complete response or a partial response (CR+PR) in pediatric subjects with r/r NHL.
    L’obiettivo primario della fase 1 è valutare la sicurezza di KTE-X19.

    Gli obiettivi primari della fase 2 sono i seguenti:
    Coorte LLA: l'obiettio primario è valutare l’efficacia di KTE-X19, misurata dal tasso complessivo di remissione completa, definita come remissione completa (CR) e remissione completa con recupero ematologico incompleto (CRi) in soggetti pediatrici e adolescenti con LLA r/r.
    Coorte LNH: l'obiettio primario è stimare l’efficacia di KTE-X19, misurata dal tasso di risposta obiettiva (ORR), definita come una risposta completa o una risposta parziale (CR+PR) in soggetti pediatrici con LNH r/r.
    E.2.2Secondary objectives of the trial
    Secondary objectives will include assessing the safety and tolerability of KTE-X19, additional efficacy endpoints, and (for Phase 2 only) changes in PRO scores.
    Gli obiettivi secondari comprenderanno la valutazione della sicurezza e della tollerabilità di KTE-X19, degli endpoint di efficacia supplementari e (solo per la fase 2) degli esiti riferiti dal paziente.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ALL Cohort

    101. 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 subject is at least 100 days from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment

    102. Disease burden defined as at least 1 of the following:
    - Morphological disease in the bone marrow (>5% blasts)
    - MRD positive (threshold 10-4 by flow or PCR)

    103. Subjects 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

    104. Age <= 21 years and weight >= 6 kg. Note: Subjects with a weight of >= 6 kg to < 10kg will only be included once a pediatric formulation becomes available.

    111. In subjects previously treated with blinatumomab, CD19 tumor expression on blasts obtained from bone marrow or peripheral blood must be documented after completion of the most recent prior line of therapy and blasts must be >= 90% CD19 positive.


    NHL Cohort
    301. Histologically confirmed aggressive B cell NHL:
    - DLBCL not otherwise specified
    - Primary mediastinal large B-cell lymphoma (including Mediastinal gray zone lymphoma)
    - Burkitt lymphoma, Burkitt-like lymphoma and Unclassified B-cell lymphoma intermediate between DLBCL and Burkitt lymphoma

    302. Relapsed or refractory disease defined as 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 SCT provided subject is at least 100 days from SCT at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment

    303. Subjects 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

    304. At least 1 measurable lesion according to the revised International Pediatric Non-Hodgkin Lymphoma Staging System {Rosolen 2015}. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.

    305. Magnetic resonance imaging (MRI) of the brain showing no evidence of CNS lymphoma

    308. Age <18 years old and weight > or = 6kg. Note: Subjects with a weight of >= 6 kg to < 10kg will only be included
    once a pediatric formulation becomes available.

    Both Cohort
    105. and 309. Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age > or = 16 years at the time of assent/consent) performance status > or = 80 at screening

    106. and 310. ANC > or = 500/uL unless, in the opinion of the PI, cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy

    107. and 311. Platelet count > or = 50,000/uL unless, in the opinion of the PI, cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy

    108. and 312. Absolute lymphocyte count > or = 100/µL

    109. and 313. Adequate renal, hepatic, pulmonary and cardiac function

    110. and 314. Females of childbearing potential must have a negative serum or urine pregnancy test

    For the full list please refer to the Protocol.
    Coorte LLA
    101) LLA da precursori delle cellule B recidivata o refrattaria, definita dalla presenza di almeno una delle seguenti condizioni:
    •Malattia refrattaria primaria
    •Qualsiasi recidiva nei 18 mesi dopo la prima diagnosi
    •Malattia recidivata o refrattaria dopo 2 o più linee di terapia sistemica
    •Malattia recidivata o refrattaria dopo trapianto allogenico, a condizione che siano trascorsi almeno 100 giorni dal trapianto di cellule staminali al momento dell’arruolamento e che il sogg non riceva terapie farmacologiche immunosoppr da almeno 4 sett prima dell’arruolamento
    102) Carico di malattia definito dalla presenza di almeno una delle seguenti condizioni:
    •Malattia morfologica nel midollo osseo (> 5% di blasti)
    •MRD positiva (soglia 10-4 mediante citometria a flusso o PCR)
    103) I sogg con malattia Ph+ sono eleggibili se intolleranti alla terapia con inibitori della tirosin chinasi (TKI) o se presentano malattia r/r nonostante il trattamento con almeno 2 diversi TKI.
    104) Età = 21 anni e peso = 6 kg. Nota: i soggetti di peso tra = 6 kg e < 10 kg saranno arruolati solo quando si renderà disponibile una formulaz pediatrica.
    111) Nei sogg precedentem trattati con blinatumomab, l’espressione tumorale di CD19 sui blasti ottenuti dal midollo osseo o dal sangue periferico deve essere documentata dopo il completamento della più recente linea di terapia precedente, e i blasti devono essere CD19 positivi per = 90%.

    Coorte LNH
    301) LNH a cellule B aggressivo confermato istologicamente:
    •Linfoma diffuso a grandi cellule B (DLBCL) non altrimenti specificato
    •Linfoma a grandi cellule B primitivo del mediastino (incluso linfoma mediastinico della zona grigia)
    •Linfoma di Burkitt, linfoma Burkitt-like e linfoma a cellule B non classificato intermedio tra DLBCL e linfoma di Burkitt
    302) Malattia recidivata o refrattaria definita dalla presenza di una o più delle seguenti condizioni:
    •Malattia refrattaria primaria
    •Malattia recidivata o refrattaria dopo 2 o più linee di terapia sistemica
    •Malattia recidivata o refrattaria dopo SCT autologo/allogenico, a condizione che siano trascorsi almeno 100 giorni dall’SCT al momento dell’arruolamento e che il soggetto non riceva terapie farmacologiche immunosoppressive da almeno 4 settimane prima dell’arruolamento
    303) I sogg devono avere ricevuto una terapia precedente adeguata, comprendente almeno tutti i seguenti:
    •Anticorpo monoclon anti-CD20, a meno che lo sperimentatore non determini che il tumore sia CD20 negativo
    •Un regime chemioterapico contenente antraciclina
    304) Almeno 1 lesione misurab secondo il sistema internazion di stadiazione del linfoma non-Hodgkin pediatrico (International Pediatric Non-Hodgkin Lymphoma Staging System) rivisto {Rosolen 2015}. Le lesioni precedentem irradiate saranno considerate misurabili solo se la progressione è stata documentata dopo il completamento della radioterapia.
    305) RM del cervello che non evidenzia linfoma del SNC.
    308) Età < 18 anni e peso = 6 kg. Nota: i soggetti di peso tra = 6 kg e < 10 kg saranno arruolati solo quando si renderà disponibile una formulaz pediatrica.

    Entrambe le coorti
    105-309) Performance status = 80 alla scala di Lansky (età < 16 anni al momento dell’assenso/del consenso) o di Karnofsky (età = 16 anni al momento dell’assenso/del consenso) (App 4).
    106-310) Conta assoluta dei neutrofili (ANC) = 500/µL, a meno che, a giudizio dello speriment principale, la citopenia sia dovuta alla leucemia di base e sia potenzialm revers con la terapia antileucemica.
    107-311) Conta piastrinica = 50.000/µL, a meno che, a giudizio dello speriment principale, la citopenia sia dovuta alla leucemia di base e sia potenzialm revers con la terapia antileucemica.
    108-312) Conta assoluta dei linfociti = 100/µL.
    109-313) Adeguata funzionalità renale, epatica, polmon e cardiaca
    110-314) Le donne in età fertile devono risultare neg al test di gravidanza sul siero o sulle urine

    Per la lista completa si prega di far riferimento al Protocollo.
    E.4Principal exclusion criteria
    ALL Cohort
    201. Diagnosis of Burkitt's leukemia/lymphoma according to WHO classification or chronic myelogenous leukemia lymphoid blast crisis

    202. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years

    205. History of concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, or Shwachman-Diamond syndrome

    206. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment

    NHL Cohort
    401. History of malignancy other than nonmelanoma skin cancer, carcinoma in situ (eg, cervix, breast), or FL unless disease free for at least 3 years

    402. Autologous SCT within 100 days of planned KTE-X19 infusion

    403. Prior CD19 targeted therapy other than blinatumomab (subjects who received KTE-X19 in this study are eligible for re-treatment)

    404. Prior CAR therapy or other genetically modified T-cell therapy

    409. 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.

    Both Cohort
    204. and 410. CNS involvement and abnormalities:
    a. Any CNS tumor mass by imaging and/or parameningeal mass (cranial and/or spinal).
    b. Presence of CNS-3 disease, defined as WBC =5/µL in CSF with presence of lymphoblasts with or without neurologic symptoms.
    c. 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.
    [Subjects 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].
    d. History or presence of any 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. Patients with seizure disorders requiring active anti-convulsive medication.

    208. and 416. Any medical condition likely to interfere with assessment of the safety or efficacy of study treatment

    209. and 414. Primary immunodeficiency

    210. and 407. History of HIV infection or acute /chronic active hepatitis B or C infection. Subjects 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

    For the full list of the exclusion criteria please refer to the Protocol.
    Coorte LLA
    201) Diagnosi di leucemia/linfoma di Burkitt secondo la classificazione dell’OMS o crisi blastica linfoide di leucemia mieloide cronica.

    202) Anamnesi positiva per neoplasia maligna diversa da tumore cutaneo non-melanoma o carcinoma in situ (ad es. della cervice, della mammella), a meno che il soggetto non sia libero da malattia da almeno 3 anni.

    205) Anamnesi positiva per sindrome genetica concomitante associata a insufficienza midollare, come anemia di Fanconi, sindrome di Kostmann o sindrome di Shwachman-Diamond.

    206) Anamnesi positiva per infarto del miocardio, angioplastica cardiaca o impianto di stent cardiaco, angina instabile o altra cardiopatia clinicamente significativa nei 12 mesi precedenti l’arruolamento.

    Coorte LNH
    401) Anamnesi positiva per neoplasia maligna diversa da tumore cutaneo non-melanoma o carcinoma in situ (ad es. della cervice, della mammella) o linfoma follicolare (FL) a meno che il soggetto non sia libero da malattia da almeno 3 anni.

    402) SCT autologo nei 100 giorni precedenti l’infusione di KTE-X19 programmata.

    403) Precedente terapia mirata a CD19 diversa da blinatumomab (i soggetti che hanno ricevuto KTE-X19 in questo studio sono eleggibili al ritrattamento).

    404) Precedente terapia CAR o altra terapia con cellule T geneticamente modificate.

    409) GvHD acuta di grado II-IV secondo i criteri di Glucksberg o di severità B-D secondo l’indice dell’IBMTR; GvHD acuta o cronica che richiede trattamento sistemico nelle 4 settimane precedenti l’arruolamento.

    Entrambe le coorti
    204) e 410) Interessamento e anomalie a livello di SNC:
    a)Qualsiasi massa tumorale a livello di SNC evidenziata da imaging e/o massa parameningea (cranica e/o spinale).
    b)Presenza di malattia CNS-3, definita come WBC = 5/µL nel LCS con presenza di linfoblasti, con o senza sintomi neurologici.
    c)Presenza di malattia CNS-2, definita come WBC < 5/µL nel LCS con presenza di linfoblasti e con sintomi neurologici (vedere la nota di seguito per ulteriori chiarimenti). Nota: I sintomi neurologici possono comprendere, a titolo esemplificativo, paralisi dei nervi cranici (se non motivata da tumore extracranico) e compressione midollare clinica.
    [I soggetti con CNS-1 (nessun linfoblasto rilevabile nel LCS) e quelli con CNS-2 senza alterazioni neurologiche clinicamente evidenti sono eleggibili alla partecipazione allo studio].
    d)Anamnesi o presenza di patologie del SNC, quali ischemia/emorragia cerebrovascolare, demenza, malattia cerebellare, o qualsiasi malattia autoimmune con interessamento del SNC, sindrome da encefalopatia posteriore reversibile (PRES) o edema cerebrale con difetti strutturali confermati da esami di imaging appropriati. Anamnesi positiva per ictus o attacco ischemico transitorio nei 12 mesi precedenti l’arruolamento. Pazienti con disturbi convulsivi che richiedono terapia farmacologia anticonvulsivante attiva.

    208) e 416) Qualsiasi condizione clinica che potrebbe interferire con la valutazione della sicurezza o dell’efficacia del trattamento in studio.

    209) e 414) Immunodeficienza primaria.

    210) e 407) Anamnesi positiva per infezione da virus dell’immunodeficienza umana (HIV) o infezione da epatite B o C acuta/cronica. I soggetti con anamnesi positiva per infezione da epatite devono essere liberi dall’infezione, come determinato da test sierologici e genetici standard in base alle linee guida attuali dell’Infectious Diseases Society of America o alle linee guida nazionali applicabili.

    Per la lista completa dei criteri di esclusione si prega di far riferimento al Protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1: Incidence of adverse events (AEs) defined as dose-limiting toxicities (DLTs).
    Phase 2:
    ALL Cohort: Overall complete remission rate (CR + CRi) per independent review. All subjects who do not meet the criteria for CR or CRi by the analysis data cutoff date will be considered non-responders for the overall complete remission rate evaluation.
    NHL Cohort: ORR per investigator assessment
    Fase 1: Incidenza di eventi avversi (AE) definiti come tossicità dose limitante (DLT)
    Fase 2:
    Entrambe le Coorti: Tasso complessivo di remissione completa (CR + CRi) secondo revisione indipendente. Tutti i soggetti che non soddisfano i criteri per la CR o la CRi alla data di cut-off dei dati per l’analisi saranno considerati non-responder ai fini della valutazione del tasso complessivo di remissione completa.
    Coorte LNH: ORR secondo revisione dello sperimentatore
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis will occur when the overall study enrollment is complete and all treated subject in the mITT set have had the opportunity to complete the month 6 disease assessment.
    L'analisi primaria avverrà quando l'arruolamento generale dello studio sarà completo e tutti i soggetti trattati nel set mITT avranno avuto l'opportunità di completare la valutazione della malattia del mese 6.
    E.5.2Secondary end point(s)
    - Overall complete remission rate (CR + CRi) per investigator assessment
    - Duration of Remission (DOR) in the ALL and NHL cohort
    - Minimal Residual Disease (MRD) negative rate in ALL cohort
    - Allogeneic SCT rate
    - Overall survival (OS) in the ALL and NHL cohort
    - Relapsed-free Survival (RFS) in ALL cohort
    - Incidence of AEs and Common Terminology Criteria for Adverse Events (CTCAE) grade changes in safety laboratory values in the ALL and NHL cohort
    - Incidence of anti-KTE-X19 antibodies in the ALL and NHL cohort
    - Progression free survival in the NHL cohort
    •Tasso complessivo di remissione completa (CR + CRi) secondo la valutazione dello sperimentatore
    •Durata della remissione (DOR) nelle coorti LLA e LNH
    •Tasso di MRD negativa nella coorte LLA
    •Tasso di SCT allogenico
    •Sopravvivenza complessiva (OS) nelle coorti LLA e LNH
    •Sopravvivenza libera da recidiva (RFS) nelle coorti LLA e LNH
    •Incidenza di AE e variazioni del grado CTCAE dei valori di laboratorio per la sicurezza nelle coorti LLA e LNH
    •Incidenza di anticorpi anti KTE-X19 nel sangue nelle coorti LLA e LNH
    •Sopravvivenza libera da progressione (PFS) nella coorte LNH
    E.5.2.1Timepoint(s) of evaluation of this end point
    All subjects will be followed in the long term follow-up (LTFU) period for survival and disease status if applicable. Subjects will begin the long term follow-up period after they have completed the Month 3 visit of the post treatment assessment period (whether they have responded to treatment or went straight to the month 3 visit due to disease progression)
    - Every 3 months (± 2 weeks) through Month 18
    - Every 6 months (± 1 month) between Month 24 - Month 60
    - Beginning with year 6, Month 72 (± 3 months), subjects will return to the clinic 1 time annually up to 15 years after the last subject receives their KTE X19 infusion.
    All subjects will be followed in the long term follow-up (LTFU) period for survival and disease status if applicable. Subjects will begin the long term follow-up period after they have completed the Month 3 visit of the post treatment assessment period (whether they have responded to treatment or went straight to the month 3 visit due to disease progression)
    - Every 3 months (± 2 weeks) through Month 18
    - Every 6 months (± 1 month) between Month 24 - Month 60
    - Beginning with year 6, Month 72 (± 3 months), subjects will return to the clinic 1 time annually up to 15 years after the last subject receives their KTE X19 infusion.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase I to assess safety, Phase II to assess efficacy of KTE-X19
    Fase I per valutare la sicurezza, Fase II per valutare l'efficacia di KTE-X19
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    in aperto
    open
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    Czechia
    France
    Germany
    Italy
    Netherlands
    Poland
    Spain
    Sweden
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Defined as when the last subject is assessed or received an intervention for evaluation in the study, including survival assessments
    Definito come quando l'ultimo soggetto viene valutato o ha ricevuto un intervento per la valutazione nello studio, comprese le valutazioni di sopravvivenza
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years18
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years23
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 42
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 41
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 33
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children
    Bambini
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 116
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Nessuno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-07-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-15
    P. End of Trial
    P.End of Trial StatusOngoing
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