Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42316   clinical trials with a EudraCT protocol, of which   6969   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2016-000227-71
    Sponsor's Protocol Code Number:ITCC-059
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-07-12
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2016-000227-71
    A.3Full title of the trial
    A phase I/II study of Inotuzumab Ozogamicin as a single agent and in combination with chemotherapy for pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia
    Estudio de fase I/II de inotuzumab ozogamicina (InO) en monoterapia y en combinación con quimio para el tto de la leucemia linfoblástica aguda positiva para CD22 recidivante o refractaria en sujetos pediátricos.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The safety and efficacy of the medicine Inotuzumab Ozogamicin in children with relapsed/refractory acute lymphatic leukemia (ALL)
    La seguridad y eficacia del medicamento Inotuzumab Ozogamicin en niños con leucemia linfoblástica aguda recidivante o refractaria
    A.3.2Name or abbreviated title of the trial where available
    ITCC-059
    ITCC-059
    A.4.1Sponsor's protocol code numberITCC-059
    A.5.4Other Identifiers
    Name:NTRNumber:NTR5736
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/304/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorErasmus Medical Center
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospital Universitario Infantil Niño Jesús
    B.5.2Functional name of contact pointDr. Lucas Moreno
    B.5.3 Address:
    B.5.3.1Street AddressAvenida Menéndez Pelayo, 65
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28009
    B.5.3.4CountrySpain
    B.5.4Telephone number349150359007351
    B.5.5Fax number34915035902
    B.5.6E-mailensayosclinicos.hnjs@salud.madrid.org
    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/3/13/1127
    D.3 Description of the IMP
    D.3.1Product nameInotuzumab Ozogamicin
    D.3.2Product code PF-05208773
    D.3.4Pharmaceutical form Powder for solution 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 INNInotuzumab Ozogamicin
    D.3.9.1CAS number 635715-01-4
    D.3.9.3Other descriptive nameINOTUZUMAB OZOGAMICIN
    D.3.9.4EV Substance CodeSUB33081
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    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 No
    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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    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
    pediatric CD22-positive relapsed/refractory Acute Lymphoblastic Leukemia
    sujetos pediátricos con leucemia linfoblástica aguda (LLA) positiva para CD22 recidivante o refractaria
    E.1.1.1Medical condition in easily understood language
    Pediatric relapsed Acute Lymphoblastic Leukemia
    Leucemia linfoblástica aguda pediátrica recidivante
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10063625
    E.1.2Term Acute lymphoblastic leukemia recurrent
    E.1.2System Organ Class 100000012975
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective Stratum 1A:
    To establish the maximum tolerated dose of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL.

    Primary objective Phase 2 Cohort:
    To establish the activity (ORR) of single agent InO when administered in children with CD22-positive relapsed/refractory BCP-ALL.

    Primary objective Stratum 2: To explore the safety and tolerability of InO as a single agent in children with relapsed/refractory other CD22 positive B-cell malignancies.
    Objetivos principales Estrato 1A:
    *Saber la dosis máxima tolerada de InO en monoterapia si se administra en niños con LLA precursoras de linfo B CD22+ recidivante o refractaria.

    Objetivos principales Cohorte de la fase 2:
    *Establecer la actividad (respuesta global como RC,RCi y RCp) de InO en monoterapia si se administra en niños con LLA precursoras de linfo B CD22+ recidivante o refractaria.

    Objetivos principales Estrato 2
    *Estudiar la seguridad y tolerabilidad de InO en monoterapia en niños con neoplasias malignas precursoras de linfoB CD22+ recidivante o refractaria
    E.2.2Secondary objectives of the trial
    Stratum 1A and Phase 2 cohort:
    To determine:
    •safety and tolerability of InO as a single agent (during course 1, cumulative toxicity, and after subsequent allo-HSCT).
    •hematological response rate (Stratum 1A only)
    •MRD levels in responding patients, % of patients with complete MRD.
    •durability of response and long-term FUP (relapse-rates, HSCT-nrs, overall survival).
    •serum PK parameters
    •the relationship between CD22 receptor density, WBC-Count at start of treatment, CD22 saturation kinetics, cytogenetics, and in-vitro calicheamicin resistance to clinical response.
    •persistence of B-Cell aplasia and hypogammaglobulinemia in responding patients.
    •nr of patients developing ADAs

    Stratum 2 (Other B-cell malignancies):
    to determine
    •response rates
    •durability of response and long-term FUP (SCT-nrs, relapse, overall survival)
    •serum PK parameters
    •persistence of B-Cell aplasia and hypogammaglobulinemia in responding patients
    •nr of patients developing ADA
    Estrato 1A y cohorte de fase II
    *seguridad y tolerabilidad de InO en monoterapia (ciclo 1,toxicidad,y tras aloTCMH)
    *tasa de respuesta hematopoyética(estrato 1A)
    *grado de EMR,incluido el % con una respuesta de EMR completa
    *duración de la respuesta y seguimiento a largo plazo(SCT-nrs,recidiva,supervivencia global)
    *parámetros PK séricos
    *ratio entre la densidad del receptor CD22,N de leucocitos al inicio del tto,cinética de saturación de CD22,citogenética y la resistencia in vitro de la calicheamicina a la respuesta clínica
    *persistencia de la aplasia de linfB y la hipogammaglobulinemia en sujetos que responden
    *N sujetos con anticuerpos anti InO

    Estrato 2(otras neoplasias malignas de linf B)
    *tasa de respuesta
    *duración de la respuesta y del seguimiento a largo plazo(SCT-nrs,recidiva,supervivencia global)
    *parámetros PK séricos de InO
    *persistencia de la aplasia de linfB y la hipogammaglobulinemia en sujetos que responden
    *Número de sujetos con ACF
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Age:
    Patients must be ≥ 1 and < 18 years of age at the time of enrollment.
    •The first 3 BCP-ALL patients on dose level 1 must be aged 6-18 yrs.
    •Then at least 2 additional patients must be enrolled from age 1-6 yrs at the same dose level.
    •After this: subsequent dose levels may enroll patients aged 1-18 yrs.
    •In case 2 younger patients are not yet recruited, patients aged 6-18yrs may continue to be enrolled at dose level 1 until a maximum of 6 patients are enrolled.

    Stratum 1A: Diagnosis
    Patients must have either first relapsed BCP-ALL after allo-HSCT or second or greater relapsed or refractory BCP-ALL, or refractory disease and must meet the following criteria:
    •M2 or M3 marrow status (≥ 5% blasts by morphology)
    •CD22 surface antigen positive (either BM or PB)
    •The first 6 patients must have M3 marrow status (≥ 25% blasts by morphology).
    •Refractory is defined as newly diagnosed patients who are induction failures after at least 2 previous regimens without attainment of remission, or patients with refractory first relapse after 1 previous reinduction regimen without attainment of remission.

    Phase 2 Cohort: Diagnosis
    Patients must have either first relapsed BCP-ALL after allo-HSCT or second or greater relapsed or refractory BCP-ALL, or refractory disease as defined below, and must meet the following criteria:
    •M2 or M3 marrow status (≥ 5% blasts by morphology)
    •CD22 surface antigen positive (either BM or PB)
    •Refractory is defined as newly diagnosed patients who are induction failures after at least 2 previous regimens without attainment of remission, or patients with refractory first relapse after 1 previous reinduction regimen without attainment of remission.

    Stratum 2: Diagnosis
    Patients must have first relapsed BCP-ALL after allo-HSCT or second or greater relapsed or refractory CD22-positive B-cell malignancy including but not limited to diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), Burkitt lymphoma, Burkitt leukemia or B-cell precursor lymphoblastic lymphoma:
    • histologic verification of disease at original diagnosis or subsequent relapse.
    •Patient must have evaluable or measurable disease documented by radiographic criteria or bone marrow disease present at study entry.
    • CD22 surface antigen positive (in either biopsy material, BM or PB)

    Performance Level and Life Expectancy:
    •Karnofsky > 60% for patients > 16 years of age and Lansky > 60% for patients ≤ 16 years of age.
    •life expectancy of at least 6 weeks.

    Prior Therapy:
    Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy defined as resolution of all such non-hematologic toxicities to ≤ Grade 2 per the CTCAE 4.03.
    •Chemotherapy: At least 7 days wash-out; except for hydroxyurea, 6-mp and steroids (wash-out 48 hrs) and intrathecal therapy (no wash-out). Patients who relapse while receiving maintenance chemotherapy will not be required to have a waiting period.
    •Radiotherapy: At least 28 days must have elapsed since any prior radiation therapy.
    •Hematopoietic Stem Cell Transplant: At least 180 days must have elapsed since previous allo-HSCT. No evidence of active GVHD; not receiving GVHD prophylaxis or treatment.
    •Hematopoietic growth factors: At least 7 days wash-out of therapy with GCSF or other growth factors. At least 14 days wash-out of pegfilgrastim (Neulasta®).
    •Immunotherapy: At least 42 days wash-out of any type of immunotherapy, e.g. tumor vaccines or CART therapy. No prior CD22-targeted therapy permitted.
    •Monoclonal antibodies: wash-out of at least 3 half-lives of the antibody (ie: Rituximab = 66 days, Epratuzumab = 69 days), with the exclusion of blinatumomab. Patients must have been off blinatumomab infusion for at least 14 days and all drug-related toxicity must have resolved to grade 2 or lower.
    •Investigational drugs: At least 7 days or 5 drug half-lives (whichever is longer) must have elapsed since prior treatment with any experimental drug (with the exception of monoclonal antibodies).
    •no prior treatment with a calicheamicin-conjugated antibody (e.g. gemtuzumab ozogamicin).
    Renal and Hepatic Function:
    •serum creatinine ≤ 1.5 x ULN according to age. If the serum creatinine is > than 1.5 xULN, the patient must have a radioisotope GFR ≥ 70mL/min/1.73m2.
    •AST and ALT ≤ 2.5 x ULN.
    •total bilirubin ≤ 1.5 x ULN (unless patient has documented Gilbert syndrome &AST and ALT are <=2.5 x ULN).
    Cardiac Function:
    •shortening fraction ≥ 30% by ECG or an ejection fraction > 50% by MUGA.
    Reproductive Function:
    •If applicable, negative urine or serum pregnancy test confirmed prior to enrollment.
    •If applicable, agree not to breastfeed while on this study.
    •If applicable, agree using effective method of contraception during the study and for 90 days after the last dose of InO.
    Edad
    Los sujetos deben ser entre de 1-18 años en el momento de la inclusión
    *Los primeros 3 sujetos con LLA de precursores de linfo B en el nivel de dosis 1 deben tener entre 6 y 18 años
    *Luego,debe incluirse al menos a 2 sujetos adicionales de 1-6 años en el mismo nivel de dosis
    *Además los posteriores niveles de dosis pueden incluir a sujetos de entre 1 y 18 años
    *En caso de no reclutar 2 sujetos más jóvenes,se podrán incluir sujetos de 6-18 años en el nivel de dosis 1 hasta un máximo de 6 sujetos

    Estrato 1A:Diagnóstico
    Los sujetos deben presentar primera recidiva de LLA de precursores de linfoB tras aloTCMH,o LLA secundaria o posterior de precursores de linfoB recidivante o resistente,o enfermedad refractaria y deben cumplir lo siguiente:
    *Tener un estado de la médula M2 o M3(≥5% de blastos por morfología)
    *El clon maligno debe ser CD22+(en la médula ósea o la sangre periférica) según procedimientos locales
    *Los primeros 6 sujetos deben presentar un estado M3 de la médula(≥25% de blastos por morfología)
    *Enfermedad refractaria:sujetos nuevamene diagnosticados tras fracaso de la inducción después de al menos 2 ttos previos sin lograr la remisión,o sujetos con una primera recidiva refractaria tras un tto de reinducción previo que no ha logrado la remisión

    Cohorte fase II:Diagnóstico
    Los sujetos con primera recidiva de la LLA de precursores de linfoB tras aloTCMH,o LLA secundaria o posterior de precursores de linfoB recidivante o resistente,o enfermedad refractaria y deben cumplir lo siguiente:
    *Tener un estado de la médula M2 o M3(≥5% de blastos por morfología)
    *El clon maligno debe ser CD22+ (en la médula ósea o la sangre periférica) de acuerdo a las normas del centro,según determine el laboratorio local
    *enfermedad refractaria:sujetos nuevamene diagnosticados tras fracaso de la inducción después de al menos 2 ttos previos sin lograr la remisión,o sujetos con una primera recidiva refractaria tras un tto de reinducción previo que no ha logrado la remisión

    Estrato 2:Diagnóstico
    Los sujetos con una neoplasia maligna secundaria o posterior de linfo B CD22+ recidivante o refractaria; esto incluye,entre otros,linfoma difuso de linfo B grandes(LDLBG),linfoma primario mediastínico de linfo B grandes(LPMLB),linfoma de Burkitt,leucemia de Burkitt o linfoma linfoblástico precursor de linfoB
    *Confirmación histológica de la enfermedad en el momento del diagnóstico original o de la recidiva posterior
    *El paciente con enfermedad evaluable o medible documentada mediante criterios radiológicos o de la médula ósea en el momento de su inclusión
    *Las células malignas deben mostrar CD22+ (en muestra biopsiada,médula ósea o sangre periférica) según procedimientos locales

    Grado funcional y esperanza de vida
    *Presentar Karnofsky≥ 60% para sujetos >16 años y Lansky ≥60% para sujetos ≤16 años
    *Tener una esperanza de vida de 6 semanas o más

    Tratamiento previo
    Los sujetos deben estar recuperados totalmente de los efectos tóxicos agudos de la quimio,inmunoterapia o radioterapia previas definidos como la resolución de las reacciones adversas no hematológicas ≤G2 según CTCAE v4.03
    *quimioterapia:al menos 7 días desde el fin de quimio,con la excepción de hidroxiurea,6-mercaptopurina y esteroides,que están permitidos hasta 48h antes de iniciar el tto del protocolo.Está permitido tto intratecal en cualquier momento antes de la inclusión.Los sujetos que experimenten una recidiva mientras reciben quimio de mantenimiento no tendrán que pasar un período de espera antes de la inclusión
    *Radioterapia:al menos 28 días desde cualquier radioterapia previa
    *Trasplante de células madres hematopoyéticas:al menos 180 días desde un aloTCMH previo y no presentar indicios de enfermedad injerto contra huésped (EICH) activa.No deben estar recibiendo profilaxis o tto contra la EICH
    *Factores de crecimiento hematopoyéticos:al menos 7 días desde el fin del tto con FECG u otros factores de crecimiento en el momento de la inclusión y al menos 14 días desde el fin del tto con pegfilgrastim (Neulasta)
    *Inmunoterapia:al menos 42 días desde el fin de cualquier tipo de inmunoterapia,p.ej.,vacunas antitumorales o tto con linfoT con receptores antigénicos quiméricos(CART).Los sujetos no pueden haber recibido ningún tto previo dirigido a CD22(ttos con inmunotoxinas o CART)
    *Anticuerpos monoclonales:al menos tres semividas del anticuerpo tras la última dosis de anticuerpos monoclonales(Rituximab=66 días,epratuzumab=69 días),excepto blinatumomab.Al menos 14 días desde la última perfusión de blinatumomab y se deben haber resuelto todos los AEs relacionadas con el fármaco hasta ≤G2
    *Fármacos en investigación:al menos 7 días o 5 semividas del fármaco (lo que sea mayor) desde el tto previo con cualquier fármaco actualmente en fase de investigación (con la excepción de anticuerpos monoclonales).
    *Exposición previa a calicheamicina:no recibir tto previo con un anticuerpo conjugado con calicheamicina (p.ej.,gemtuzumab ozogamicina)
    E.4Principal exclusion criteria
    Isolated extramedullary relapse:
    •Patients with isolated extramedullary disease are excluded (not applicable to lymphoma patients except for isolated CNS-relapse)

    VOD/SOS:
    •Patients with any history of prior or ongoing VOD/SOS per the modified Seattle criteria are excluded, as specified in appendix 3, or prior liver-failure [defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5)].

    Infection:
    Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient may not have:
    •A requirement for vasopressors;
    •Positive blood culture within 48 hours of study enrollment;
    •Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
    •A positive fungal culture within 30 days of study enrollment.
    •Active fungal, viral, bacterial, or protozoal infection requiring IV or oral treatment. Chronic prophylaxis therapy to prevent infections is allowed.

    Other anti-cancer therapy:
    •Patients will be excluded if there is a plan to administer non-protocol anti-cancer therapy including but not limited to chemotherapy, radiation therapy, or immunotherapy during the study period.

    Allergic reaction:
    •Patients with prior Grade 3/4 allergic reaction to a monoclonal antibody are excluded.

    Concurrent disease:
    •Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with protocol therapy, interfere with consent, study participation, follow up, or interpretation of study results.
    •Patients with Down syndrome are excluded for the phase 1 dose finding part (stratum 1A), but not in the stratum 1 phase 2 cohort.
    Recidiva extramedular aislada
    * Se excluirá del estudio a los sujetos con enfermedad extramedular aislada (no aplicable a los sujetos con linfoma,excepto recidiva en el SNC aislada).
    EVO/SOS
    * Se excluirá del estudio a los sujetos con cualquier antecedente de EVO o SOS previa o en curso según los criterios de Seattle modificados,tal como se especifica en el apéndice 3,o insuficiencia hepática previa (definida como lesión hepática aguda grave con encefalopatía y alteración de la función de síntesis [IIN ≥ 1,5]).
    Infección
    * Se excluirá del estudio a los sujetos que presenten infección sistémica de origen fúngico,bacteriano,vírico o de otro tipo que muestre signos o síntomas en curso relacionados con la infección que no mejoran a pesar de la administración de antibióticos u otro tto apropiado.El paciente no puede presentar:
    - Necesidad de vasopresores.
    - Hemocultivo positivo en las 48 horas posteriores a la inclusión en el estudio
    - Fiebre superior a 38,2 en las 48 horas posteriores a la inclusión en el estudio con signos clínicos de infección.Está permitida la fiebre atribuible a la carga tumoral si los hemocultivos han dado negativo al menos en las 48 horas previas a la inclusión y no hay signos ni síntomas simultáneos de infección activa ni inestabilidad hemodinámica.
    - Cultivo fúngico positivo en los 30 días posteriores a la inclusión en el estudio
    - Infección fúngica,vírica,bacteriana o protozoica activa que requiera tto por vía oral o intravenosa (i.v.).Se permite el tto profiláctico crónico para la prevención de infecciones.
    Otro tto antineoplásico
    * Se excluirá del estudio a los sujetos para los que se haya previsto un plan de administración de algún tto antineoplásico que no se recoge en el protocolo,incluidos entre otros quimio,radioterapia o inmunoterapia,durante el período del estudio.
    Reacción alérgica
    * Se excluirá del estudio a los sujetos con una reacción alérgica previa de grado 3 o 4 a un anticuerpo monoclonal.
    Enfermedad simultánea
    * Se excluirá del estudio a los sujetos que presenten una enfermedad,afección,alteración psiquiátrica o problema social simultáneo importante y que pudiera poner en peligro la seguridad del paciente o el cumplimiento del tto del protocolo o interferir con el consentimiento,la participación en el estudio,el seguimiento o la interpretación de los resultados del estudio.
    * Los niños con síndrome de Down quedan excluidos de la participación en la parte de búsqueda de dosis (estrato 1A),pero no en la cohorte del estrato 1 de la fase II.
    E.5 End points
    E.5.1Primary end point(s)
    Stratum 1A:
    Dose-limiting toxicities (DLTs) during the first course of therapy.

    Phase 2 cohort:
    Overall Response Rate (ORR), defined as CR, CRi, CRp, measured as best response during InO treatment (see Appendix 2 for definitions).

    Stratum 2: Safety and tolerability:
    • AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy, during the first and subsequent courses of therapy.
    • Occurrence of toxic death; i.e., death attributable to InO therapy.
    • Occurrence of hepatic VOD/SOS during or after therapy with InO.
    • Laboratory abnormalities as characterized by type, frequency, severity and timing.
    Estrato 1A
    Toxicidad limitante de la dosis (TLD) durante el C1 de terapia.

    Cohorte de la fase 2
    Tasa de respuesta global (TRG), definida como RC, RCi o RCp, como la mejor respuesta durante el tto con InO (consulte las definiciones en el apéndice 2).

    Estrato 2
    Seguridad y tolerabilidad:
    * AAs caracterizados por tipo, frecuencia, gravedad (según CTCAE v4.03), tiempo, seriedad y relación con el tto del estudio, durante el primer ciclo y los ciclos posteriores de este tto
    * Incidencia de muerte debida a reacciones adversas, es decir, muerte atribuible al tto con InO.
    * Incidencia de EVO hepática o SOS durante o después del tto con InO
    * Alteraciones analíticas caracterizadas por tipo, frecuencia, gravedad y tiempo
    E.5.1.1Timepoint(s) of evaluation of this end point
    After course 1
    Depués del ciclo 1
    E.5.2Secondary end point(s)
    Stratum 1A:
    1. Safety and tolerability:
    • AEs (type, frequency, severity, timing, seriousness, and relation to study therapy.
    • Occurrence of toxic death
    • Occurrence of hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) during or after therapy with InO.
    • Laboratory abnormalities (type, frequency, severity and timing).
    2. Measures of anti-leukemic activity:
    • Overall Response Rate (ORR), defined as CR, CRi, CRp , best response over multiple courses
    • MRD levels, incl. % of patients who become MRD-negative (defined as an MRD-level < 1x10-4), after course 1, as well as the best response (MRD-negativity) over multiple courses.
    • Duration of response (time between achieving response (CR, CRi or CRp) after starting study treatment and documented relapse or death).
    • Number and percentage of patients being transplanted after treatment with Ino.
    • Event-free survival (EFS), defined as the time between start of study treatment and first event including failure to achieve CR/CRp/CRi (calculated as an event on day 0), relapse, death of any cause and second malignancies.
    • Overall survival, defined as time to death following start of study treatment.
    3. Serum pharmacokinetic parameters of InO and unconjugated calicheamicin.
    4. Pharmacodynamic parameters:
    • Relationship between response (ORR) and CD22 expression levels, WBC, CD22 saturation kinetic, calicheamicin sensitivity.
    • Clonal evolution (CD22-negativity) and relation to loss of response.
    5. Other endpoints
    • % of patients responding to InO (ORR) without adequate recovery of CD19-positive B-cells or immunoglobulins following 4 wks, 10 wks, 3, 6 and 12 mnths after treatment (excl. HSCT patients).
    • % of patients with anti-drug antibodies (ADA).

    Phase 2 cohort:
    Safety:
    • AEs (type, frequency, severity, timing, seriousness, and relation to study therapy)
    • Occurrence of toxic death
    • Occurrence of VOD/SOS during or after therapy with InO.
    • Laboratory abnormalities (type, frequency, severity and timing).

    2. Other measures of anti-leukemic activity:
    • Overall Response Rate (ORR) after course 1.
    • Minimal residual disease levels, including the percentage of patients who become MRD-negative , after course 1, as well as the best response (MRD-negativity) over multiple courses.
    • Duration of response (time between achieving response (CR, CRi or CRp) after starting study treatment and documented relapse or death).
    • Number and percentage of patients being transplanted after treatment with Ino.
    • Event-free survival (EFS), defined as the time between start of study treatment and first event including failure to achieve CR/CRp/CRi (calculated as an event on day 0), relapse, death of any cause and second malignancies.
    • Survival, defined as time to death following start of study treatment.
    3. Serum pharmacokinetic parameters of InO and unconjugated calicheamicin.
    4. Pharmacodynamic parameters:
    • Relationship between response (ORR) and CD22 expression levels, WBC, CD22 saturation kinetics and calicheamicin sensitivity.
    • Clonal evolution (CD22-negativity) and relation to loss of response.
    5. Other endpoints
    • The percentage of patients responding to InO (ORR) without adequate recovery of CD19-positive B-cells or immunoglobulins following 4 wks, 10 wks, 3, 6 and 12 months after treatment with InO, (excl. HSCT patients from HSCT date)
    • Percentage of patients who exhibit ADA.

    Stratum 2 secondary endpoints:
    1. Measures of anti-tumor activity:
    • Overall remission rate (CR and PR) both after course 1 as well as overall best response in patients receiving multiple courses of InO therapy (see Appendix 2 for definitions).
    • Duration of response (time between achieving response (CR and PR) after starting study treatment and documented relapse or death).
    • Number and percentage of patients being transplanted after treatment with Ino.
    • Event-free survival (EFS), defined as the time between start of study treatment and first event including failure to achieve CR/PR (calculated as an event on day 0), relapse, death of any cause and second malignancies.
    • Overall survival, defined as time to death following start of study treatment.
    2. Serum pharmacokinetic parameters of InO and unconjugated calicheamicin.
    3. Other endpoints:
    • The percentage of patients responding to InO (ORR) without adequate recovery of CD19-positive B-cells or immunoglobulins following 4 wks, 10 wks, 3, 6 and 12 mths after treatment, (excl HSCT patients from HSCT date).
    • Percentage of patients who exhibit ADA.
    Estrato 1A
    1.Seguridad y tolerabilidad:
    *AAs (tipo,frecuencia,gravedad,tiempo,seriedad y relación con el tto)
    *Incidencia de enfermedad venoclusiva (EVO) hepática o síndrome de obstrucción sinusoidal (SOS) durante o después del tto
    *Alteraciones analíticas (tipo,frecuencia,gravedad y tiempo)
    2.Medidas de actividad antileucémica:
    *Tasa de respuesta global (TRG),definida como RC,RCi o RCp tras el ciclo 1,la mejor respuesta tras varios ciclos de tto
    *Nivel EMR,incluido % de sujetos con EMR negativa (definida nivel EMR < 1x10-4),tras el ciclo 1,así como la mejor respuesta global (negatividad de EMR) durante varios ciclos
    *Duración de la respuesta (tiempo transcurrido desde que se logra la respuesta (RC,RCi o RCp) tras el inicio del tto del estudio y la recidiva o muerte documentadas)
    *Número y % de sujetos que reciben un trasplante tras el tto con InO
    *Supervivencia sin acontecimientos (SSA),definida como el tiempo entre el inicio del tto del estudio y el primer acontecimiento,incluidas la imposibilidad de lograr RC,RCp o RCi (calculada como un acontecimiento en el día 0),la recidiva,la muerte por cualquier causa y las neoplasias malignas secundarias
    *Supervivencia global,definida como el tiempo hasta la muerte tras el inicio del tto del estudio
    3.Parámetros farmacocinéticos séricos de InO y calicheamicina no conjugada
    4.Parámetros farmacodinámicos:
    *Relación entre la respuesta (TRG) y los niveles de expresión de CD22,leucocitos,la cinética de saturación de CD22,la sensibilidad a la calicheamicina.
    *Evolución clonal (negatividad para CD22) y relación con la pérdida de respuesta
    5.Otros criterios de valoración
    *El % de sujetos que responden a InO (TRG) sin la suficiente recuperación de linfocitos B CD19+ o inmunoglobulinas tras 4 y 10 semanas y 3,6 y 12 meses después del tto (excluidos los sujetos con TCMH)
    *% de sujetos que presentan anticuerpos contra el fármaco (ACF)
    Cohorte de la fase 2
    1.Seguridad:
    *AAs por tipo,frecuencia,gravedad,tiempo,seriedad y relación con el tto del estudio
    *Incidencia de muerte debida atribuible al tto con InO
    *Incidencia de EVO o SOS durante o después del tto con InO
    *Alteraciones analíticas (tipo,frecuencia,gravedad y tiempo)
    2.Otras medidas de actividad antileucémica:
    *Tasa de respuesta global (TRG) tras el ciclo 1
    *Nivel EMR,incluido % de sujetos con EMR negativa (definida nivel EMR < 1x10-4),tras el ciclo 1,así como la mejor respuesta global (negatividad de EMR) durante varios ciclos
    *Duración de la respuesta,definida como el tiempo transcurrido desde que se logra la respuesta (RC,RCi o RCp) tras el inicio del tto del estudio y la recidiva o muerte documentadas
    *Número y % de sujetos que reciben un trasplante tras el tto
    *Supervivencia sin acontecimientos (SSA),definida como el tiempo entre el inicio del tto del estudio y el primer acontecimiento,incluidas la imposibilidad de lograr RC,RCp o RCi (calculada como un acontecimiento en el día 0),la recidiva,la muerte por cualquier causa y las neoplasias malignas secundarias
    *Supervivencia,definida como el tiempo hasta la muerte tras el inicio del tto
    3.Parámetros farmacocinéticos séricos de InO y calicheamicina no conjugada.
    4.Parámetros farmacodinámicos
    *Relación entre la respuesta (TRG) y los niveles de expresión de CD22,leucocitos,la cinética de saturación de CD22,la sensibilidad a la calicheamicina.
    *Evolución clonal (negatividad para CD22) y relación con la pérdida de respuesta.
    5.Otros criterios de valoración
    *El % de sujetos que responden a InO (TRG) sin la suficiente recuperación de linfoB CD19+ o inmunoglobulinas tras 4 y 10 semanas y 3,6 y 12 meses después del tto con InO,excluidos sujetos con TCMH que han recibido un TCMH.
    *% de sujetos que presentan ACF.

    Estrato 2
    1.Medidas de actividad antitumoral:
    *Tasa de remisión global (RC y RP) tras el ciclo 1 y como mejor respuesta global en sujetos que reciben varios ciclos de tto InO (consulte las definiciones en el apéndice 2).
    *Duración de la respuesta,definida como el tiempo hasta lograr respuesta (RC o RP) tras el inicio del tto y la recidiva o muerte documentada
    *Número y % de sujetos que reciben un trasplante tras el tto con InO.
    *Supervivencia sin acontecimientos (SSA),definida como el tiempo entre el inicio del tto y el primer acontecimiento,incluidas la imposibilidad de lograr RC o RP (calculada como un acontecimiento en el día 0),la recidiva,la muerte por cualquier causa y las neoplasias malignas secundarias.
    *Supervivencia global,definida como el tiempo hasta la muerte tras el inicio del tto
    2.Parámetros farmacocinéticos séricos de InO y calicheamicina no conjugada.
    3.Otros criterios de valoración:
    *El % de sujetos que responden a InO (TRG) sin la suficiente recuperación de linfoB CD19+ o inmunoglobulinas tras 4 y 10 semanas y 3,6 y 12 meses después del tto con InO,excluidos sujetos con TCMH que han recibido un TCMH.
    * % de sujetos que presentan ACF.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After course 1, after each subsequent course of therapy, and at 4wks, 10wks, 3months, 6 months and 9 months of FUP
    Después del ciclo 1, tras cada ciclo siguiente, y la semana 4 y 10 y meses 3,6 y 9 meses de seguimiento
    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 Yes
    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
    First administration in pediatric population
    Primera administración en población pediátrica
    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 Yes
    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 No
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Czech Republic
    Denmark
    France
    Germany
    Ireland
    Israel
    Italy
    Netherlands
    Spain
    Sweden
    Switzerland
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 96
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 58
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 28
    F.1.2Adults (18-64 years) No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 96
    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
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation ITCC
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-10-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-13
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA