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    EudraCT Number:2016-004877-42
    Sponsor's Protocol Code Number:PETHEMA-BLIN-01
    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:2018-02-28
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2016-004877-42
    A.3Full title of the trial
    A phase II, open-label study to evaluate the effect of blinatumomab administered during consolidation to reduce the level of minimal residual disease (MRD) assessed through flow cytometry in adult patients up to 55 years of age with high-risk Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukaemia (ALL) with good response (MRD < 0.1%) after induction therapy
    Estudio de fase II, abierto, para evaluar el efecto del blinatumomab administrado durante la consolidación para reducir el nivel de enfermedad residual (ER) evaluada mediante citofluorometría en pacientes adultos hasta 55 años con leucemia linfoblástica aguda (LLA) de alto riesgo (AR) sin cromosoma Filadelfia (Ph-) con buena respuesta (ER<0.1%) después del tratamiento de inducción
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of Blinatumomab in adult patients up to 55 years with acute lymphoblastic leukemia
    Estudio para evaluar el efecto del Blinatumomab en pacientes adultos hasta 55 años con leucemia linfoblástica aguda
    A.4.1Sponsor's protocol code numberPETHEMA-BLIN-01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFUNDACIÓN PETHEMA
    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 supportAMGEN
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFUNDACIÓN PETHEMA
    B.5.2Functional name of contact pointJuan José Lahuerta Palacios
    B.5.3 Address:
    B.5.3.1Street AddressProfesor Martín Lagos s/n
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28040
    B.5.4Telephone number0034913303011
    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 Yes
    D. name BLINCYTO
    D. of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for concentrate 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.3.9.2Current sponsor codeBLINATUMOMAB
    D.3.9.3Other descriptive nameBLINATUMOMAB
    D.3.9.4EV Substance CodeSUB35403
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38.5
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Acute lymphoblastic leukaemia
    Leucemia Linfoblástica Aguda
    E.1.1.1Medical condition in easily understood language
    Acute lymphoblastic leukaemia
    Leucemia Linfoblástica Aguda
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10000844
    E.1.2Term Acute lymphoblastic leukaemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the MRD reduction rate, determined by flow cytometry, after early consolidation following the inclusion of blinatumomab administered during the early consolidation phase in patients ≤ 55 years with high-risk Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukaemia (ALL) with MRD < 0.1% (< 1×10–3) after induction therapy
    Evaluar la frecuencia de la reducción de la ER, determinada por citometría de flujo, después de la consolidación precoz tras la inclusión de blinatumomab administrado durante la fase de consolidación precoz en pacientes ≤ 55 años con leucemia linfoblástica aguda (LLA) de alto riesgo (AR) sin cromosoma Filadelfia (Ph-) con ER<0,1% (<1x10-3) tras el tratamiento de inducción
    E.2.2Secondary objectives of the trial
    • To assess the MRD reduction rate, determined by flow cytometry, after late consolidation phase.
    • To assess 5-year disease-free survival.
    • To assess 5-year overall survival.
    • To assess the extent of MRD reduction.
    • To compare these efficacy results with those of similar patients treated with standard consolidation therapy without blinatumomab (Protocol ALL-AR-11), measured as a comparison of the percentages of patients reaching a MRD level of < 0.01% (< 1×10–4) at the end of the consolidation in this trial and in the ALL-AR-11 study.
    • To assess the MRD kinetics during maintenance therapy and during the follow-up period once the ALL treatment has been completed.
    • To assess the safety of treatment with blinatumomab administered during early and late consolidation
    • Evaluar la frecuencia de la reducción de la ER, determinada por citometría de flujo, después de la consolidación tardía
    • Evaluar la supervivencia libre de enfermedad a 5 años
    • Evaluar la supervivencia global a 5 años
    • Evaluar la profundidad de la reducción de la ER.
    • Comparar estos resultados de eficacia con los de pacientes similares tratados con terapia de consolidación estándar sin blinatumomab (Protocolo ALL-AR-11), medida como comparación de los porcentajes de pacientes que alcancen un nivel de ER<0,01% (<1x10-4) al final de la consolidación en el presente ensayo y en el estudio ALL-HR-11.
    • Evaluar la cinética de la ER durante el tratamiento de mantenimiento y durante el periodo de seguimiento una vez finalizado el tratamiento de la LLA.
    • Evaluar la seguridad del tratamiento con blinatumomab administrado durante la consolidación precoz y la tardía.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women between 18 to 55 years of age, both inclusive.
    2. Patients with Philadelphia chromosome-negative or BCR-ABL-negative, CD19-positive ALL, with high-risk characteristics. The definition of high-risk ALL implies the presence of one or more of the following factors:
    - Aged 30–55 years.
    - Leukocytes > 30×109/l in B-precursor ALL.
    - Any of the following cytogenetic or molecular abnormalities:
    o 11q23 abnormalities, or proven MLL rearrangement.
    o Complex karyotype (more than 5 chromosome abnormalities).
    - Pro-B ALL, regardless of the number of leukocytes.
    3. Previous treatment according to routine clinical practice in Spanish centres, in accordance with the PETHEMA protocol for patients with high-risk ALL (ALL-AR-11), in complete remission (MRD < 0.1%) (< 1×10–3) centralised assessment through flow cytometry) after induction therapy.
    4. ECOG < 2.
    5. Ability to understand the study and willingness to sign the written informed consent form
    1. Mujeres o varones entre 18 y 55 años de edad, ambos incluidos
    2. Pacientes con LLA sin cromosoma Filadelfia o BCR-ABL negativo, CD19 positivo, con características de alto riesgo. La definición de LLA de alto riesgo implica la presencia de uno o más de los siguientes factores:
    - Edad 30-55 años.
    - Leucocitos > 30x109/L en LLA de precursores B
    - Alguna de las siguientes alteraciones citogenéticas o moleculares:
    o Alteraciones en 11q23, o demostración del reordenamiento MLL.
    o Cariotipo complejo (más de 5 alteraciones cromosómicas)
    - LLA Pro-B, independientemente de la cifra de leucocitos.
    3. Tratamiento previo según la práctica clínica habitual en centros españoles, de acuerdo al protocolo de PETHEMA para pacientes con LLA de alto riesgo (LAL-AR-11), en remisión completa (ER <0,1% (<1x10-3) evaluación centralizada por citometría de flujo) después del tratamiento de inducción.
    4. ECOG <2.
    5. Capacidad para entender el estudio y voluntad de firmar el consentimiento informado por escrito
    E.4Principal exclusion criteria
    1. ALL with Philadelphia chromosome (Ph +).
    2. Burkitt's leukemia (mature B phenotype) according to the WHO classification.
    3. T cell ALL
    4. ALL of precursors B with high risk characteristics with ER ≥0.1% (≥1x10-3) after receiving
    induction chemotherapy.
    5. Previous history or presence of clinically significant disease of the central nervous system
    (CNS): epilepsy, seizures, paresis, aphasia, stroke, brain injuries
    severe, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,
    6. Presence or history of autoimmune disease with potential CNS involvement.
    7. Radiotherapy in the 2 weeks prior to the start of treatment with blinatumomab.
    8. Immunotherapy (eg, rituximab) in the 4 weeks prior to the start of treatment with
    9. Any product under investigation for leukemia in the 4 weeks prior to the start of the
    treatment with blinatumomab.

    10. Treatment with any investigational medication after signing the consent
    11. Candidate candidate for allogeneic transplantation of hematopoietic progenitors (TPH) in the
    moment of inclusion.
    12. Known hypersensitivity to immunoglobulins or to any component of the product in
    13. Abnormal laboratory values:
    to. AST (SGOT) and / or ALT (SGPT) and / or alkaline phosphatase ≥5  LSN.
    b. Total bilirubin ≥1.5  ULN (except if it is related to Gilbert's disease or
    c. Creatinine ≥1.5  LSN.
    d. Creatinine clearance calculated <50 ml / min.
    and. Hemoglobin ≥9 g / dl (transfusion allowed).
    14. History of malignant disease different from ALL in the 5 years prior to the start of treatment
    with blinatumomab, with the exception of basal or squamous cell carcinoma of the skin or
    carcinoma in situ of the cervix
    15. Non-controlled active infection, or any other concurrent medical condition or disease that
    it is considered that it interferes with the performance of the study according to the researcher's criteria.
    16. HIV infection or chronic infection with hepatitis B virus (HBs Ag positive) or virus of the
    Hepatitis C (anti-HCV positive).
    17. Pregnant or lactating women.
    18. Women of childbearing age who are not willing to use effective contraception during
    Participation in the study and until at least 3 months later. Men who are not willing to
    take measures to avoid pregnancy of the couple during participation in the study and
    less until 3 months later.
    19. Previous treatment with blinatumomab.
    20. Patients who do not want or can not comply with the protocol.
    1. LLA con cromosoma Filadelfia (Ph+).
    2. Leucemia de Burkitt (fenotipo B maduro) según la clasificación de la OMS.
    3. LLA de células T.
    4. LLA de precursores B con características de alto riesgo con ER ≥0.1% (≥1x10-3) después de recibir quimioterapia de inducción.
    5. Historia previa o presencia de enfermedad clínicamente significativa del sistema nervioso central (SNC): epilepsia, convulsiones, paresia, afasia, accidente cerebrovascular, lesiones cerebrales graves, demencia, enfermedad de Parkinson, enfermedad cerebelosa, síndrome orgánico cerebral, psicosis.
    6. Presencia o antecedentes de enfermedad autoinmune con afectación potencial del SNC.
    7. Radioterapia en las 2 semanas previas al inicio del tratamiento con blinatumomab.
    8. Inmunoterapia (p. ej., rituximab) en las 4 semanas previas al inicio del tratamiento con blinatumomab.
    9. Cualquier producto en investigación para la leucemia en las 4 semanas previas al inicio del tratamiento con blinatumomab.
    10. Tratamiento con cualquier medicamento en investigación después de la firma del consentimiento informado.
    11. Paciente candidato para trasplante alogénico de progenitores hematopoyéticos (TPH) en el momento de la inclusión.
    12. Hipersensibilidad conocida a las inmunoglobulinas o a cualquier componente del producto en investigación.
    13. Valores anormales de laboratorio:
    a. AST (SGOT) y/o ALT (SGPT) y/o fosfatasa alcalina ≥5 × LSN.
    b. Bilirrubina total ≥1.5 × LSN (excepto si está relacionada con la enfermedad de Gilbert o Meulengracht).
    c. Creatinina ≥1,5 × LSN.
    d. Aclaramiento de creatinina calculado <50 ml/min.
    e. Hemoglobina ≥9 g/dl (transfusión permitida).
    14. Historial de enfermedad maligna diferente a la LLA en los 5 años previos al inicio del tratamiento con blinatumomab, con la excepción de carcinoma basocelular o escamoso de la piel o de carcinoma in situ del cuello uterino
    15. Infección activa no controlada, o cualquier otra enfermedad o condición médica concurrente que se considere que interfiere con la realización del estudio según criterio del investigador.
    16. Infección por VIH o infección crónica por el virus de la hepatitis B (HBs Ag positivo) o virus de la hepatitis C (anti-VHC positivo).
    17. Mujeres embarazadas o en periodo de lactancia.
    18. Mujeres en edad fértil que no estén dispuestas a utilizar un método anticonceptivo eficaz durante la participación en el estudio y hasta al menos 3 meses después. Varones que no estén dispuestos a tomar medidas para evitar el embarazo de la pareja durante la participación en el estudio y al menos hasta 3 meses después.
    19. Tratamiento previo con blinatumomab.
    20. Pacientes que no quieran o no puedan cumplir con el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study will be the percentage of patients achieving MRD < 0.01% (< 1×10–4).
    La variable principal del estudio será el porcentaje de pacientes que alcanzan un nivel de ER <0,01% (<1x10-4).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Percentage of patients achieving MRD < 0.01% (< 1×10–4) at the end of early consolidation.
    Porcentaje de pacientes que alcanzan un nivel de ER <0,01% (<1x10-4) al final de la consolidación precoz
    E.5.2Secondary end point(s)
    • Percentage of patients achieving MRD < 0.01% (< 1×10–4).
    • Disease-free survival.
    • Overall survival.
    • Levels of minimal residual disease.
    • Toxicity profile of the treatment with blinatumomab.
    • Porcentaje de pacientes con ER<0,01% (<1x10-4).
    • Supervivencia libre de enfermedad.
    • Supervivencia global.
    • Niveles de enfermedad residual.
    • Perfil de toxicidad del tratamiento con blinatumomab.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • MRD < 0.01% (< 1×10–4) at the end of late consolidation.
    • 5-year disease-free survival.
    • 5-year overall survival.
    • Levels of minimal residual disease: after treatment with blinatumomab , during the maintenance period (every 3 months) and during follow-up after discontinuing treatment (every 3 months for the first 2 years after completing CT, every 6 months during year 3 and at the end of the follow-up)
    • Toxicity profile of the treatment with blinatumomab administered after two consolidation cycles.
    • ER<0,01% (<1x10-4) al final de la consolidación tardía
    • Supervivencia libre de enfermedad a 5 años
    • Supervivencia global a 5 años
    • Niveles de enfermedad residual: tras el tratamiento con blinatumomab, durante el período de mantenimiento y durante el seguimiento tras el cese del tratamiento (cada 3 meses durante los 2 primeros años después de finalizar la QT), cada 6 meses durante el tercer año y hasta finalizar el seguimiento, anualmente).
    • Perfil de toxicidad del tratamiento con blinatumomab administrado tras dos ciclos de consolidación.
    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 No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    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 concerned13
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 38
    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 state38
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 38
    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)
    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 Decision2018-04-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-13
    P. End of Trial
    P.End of Trial StatusOngoing
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