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    Summary
    EudraCT Number:2009-012584-34
    Sponsor's Protocol Code Number:GRASPALL2009-06
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-03-06
    Trial results View 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 number2009-012584-34
    A.3Full title of the trial
    A multicentre, open, randomized, Phase II/III study, evaluating efficacy and safety of erythrocytes encapsulating L-Asparaginase (GRASPA®) versus reference L-asparaginase treatment in combination with standard polychemotherapy in patients with first recurrence of Philadelphia chromosome negative Acute Lymphoblastic Leukemia (ALL Ph-)
    Estudio de fase II / III, multicéntrico, aleatorizado y abierto, para evaluar la eficacia y la tolerancia de la L-asparraginasa encapsulada en glóbulos rojos (GRASPA®) comparado con el tratamiento con L-asparraginasa asociada con poliquimioterapia estándar, en pacientes que presentan una primera recaída de la leucemia aguda linfoblástica sin cromosoma Filadelfia (LAL Ph-).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial with GRASPA, Red Blood cells encapsulating L-Asparaginase, in patients affected by Acute Lymphoblastic leukemia at relapse
    Ensayo Clínico con GRASPA, L-asparraginasa encapsulada en glóbulos rojos (GRASPA®), en pacientes afectados por leucemia linfoblástica aguda en recaída.
    A.3.2Name or abbreviated title of the trial where available
    GRASPALL 2009-06
    A.4.1Sponsor's protocol code numberGRASPALL2009-06
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/209/2010
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorERYTECH Pharma
    B.1.3.4CountryFrance
    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 supportERYTECH Pharma
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationERYTECH Pharma
    B.5.2Functional name of contact pointJerome Bailly
    B.5.3 Address:
    B.5.3.1Street AddressBâtiment Adénine - 60 Avenue Rockefeller
    B.5.3.2Town/ cityLYON
    B.5.3.3Post code69008
    B.5.3.4CountryFrance
    B.5.4Telephone number33478 78 93 04
    B.5.5Fax number3344 78 75 56 29
    B.5.6E-mailvsemareg@erytech.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/3/06/409
    D.3 Description of the IMP
    D.3.1Product nameGRASPA
    D.3.2Product code PF001
    D.3.4Pharmaceutical form Suspension for injection
    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 INNL-asparaginase encapsulated in erythrocytes
    D.3.9.2Current sponsor codeL-asparaginase encapsulated in erythrocytes
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number78 to 146
    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.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 No
    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
    Leukemia
    Leucemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Determine the efficacy and safety of GRASPA® at a dose equivalent to 150 IU/kg of L-asparaginase combined with standard polychemotherapy in several populations of patients with first recurrence of ALL Ph-, i.e. children from 1 to 17 years old, adults from 18 to 55 years old, with or without known hypersensitivity to L-asparaginase.
    Determinar la eficacia y la tolerancia de GRASPA® a un equivalente de dosis de 150 UI/kg de L-asparraginasa combinado con poliquimioterapia estándar en varias poblaciones de pacientes con primera recaída de la LAL, Ph-, es decir, niños de 1 a 17 años, adultos de 18 a 55 años, con o sin hipersensibilidad conocida a la L-asparraginasa.
    E.2.2Secondary objectives of the trial
    - To evaluate the molecular and clinical response rate: minimal residual disease, (MRD) and complete remission (CR)
    - To evaluate the safety of GRASPA® compared to the reference L-asparaginase treatment
    - To evaluate the biological efficacy of GRASPA® compared to the reference L-asparaginase treatment by measurement of the total mean duration of plasmatic asparagine depletion in days
    - To evaluate the immunogenicity of GRASPA® compared to reference L-asparaginase treatment by the assessment of specific antibodies
    - To evaluate and compare the treatment adherence of GRASPA® and the reference L-asparaginase treatment
    - To evaluate the event-free survival (EFS), the relapse-free survival (RFS) and the overall survival (OS), 6 months and 12 months after inclusion.
    - Evaluar la tasa de respuesta molecular y clínica: enfermedad mínima residual (EMR) y remisión completa (RC).
    - Evaluar la tolerancia de GRASPA® en comparación con el tratamiento de referencia con L-asparraginasa.
    - Evaluar la eficacia biológica de GRASPA® en comparación con el tratamiento de referencia con L-asparraginasa midiendo la duración media total de la depleción de asparragina plasmática en días.
    - Evaluar la inmunogenicidad de GRASPA® en comparación con el tratamiento de referencia con L-asparraginasa mediante la evaluación de anticuerpos específicos.
    - Evaluar y comparar el cumplimiento del tratamiento de GRASPA® y del tratamiento de referencia con L-asparraginasa.
    - Evaluar la supervivencia libre de acontecimientos (SLA), la supervivencia libre de recaídas (SLR) y la supervivencia global (SG), a los 6 meses y a los 12 meses de la inclusión.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patient from 1 to 55 years old
    - Children and adolescents from 1 up to 17 years
    - Adults over 18 up to 55 years
    - Patients with
    - Patients with 1st ALL relapse, which could be either isolated bone marrow relapse, or combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma)
    OR
    - Failure to ALL first line treatment (no complete remission obtained).
    - Patient previously treated with free E.Coli L-asparaginase form or pegylated one.
    - Performance Status ? 2 (WHO score).
    - Patient informed and consent provided (the 2 parents need to consent when children below 18)
    - Paciente con edad entre 1 y 55 años
    - Niños y adolescentes: edad entre 1 y 17 años
    - Adultos: edad entre 18 y 55 años
    - Pacientes con:
    Una primera recaída de la LAL, que puede ser una recaída aislada en la médula ósea, una recaída combinada (medular y extramedular), una recaída aislada extramedular o un linfoma linfoblástico (excepto linfoma de Burkitt)
    O
    Fracaso del tratamiento de primera línea de la LAL (no se obtiene ninguna remisión completa).

    - Paciente tratado previamente con la forma libre L-asparraginasa obtenida de E. coli o la forma pegilada.
    - Estado funcional ?2 (puntuación OMS).
    - Paciente informado y consentimiento aportado (los 2 progenitores deben consentir cuando el niño tiene menos de 18 años).
    E.4Principal exclusion criteria
    - ALL t(9;22) and/or BCR-ABL positive (Philadelphia chromosome positive).
    - Patient with 2nd relapse and over.
    - Women of childbearing potential without effective contraception as well as pregnant or breast feeding women.
    - Patient unable to receive treatments used in global chemotherapy protocols, due to general or visceral conditions such as:
    - Severe cardiac impairment (NYHA grade 3 or 4 cardiomyopathy)
    - Serum creatinine 2 x ULN unless related to ALL
    - ALT or AST 5 x ULN unless related to ALL
    - Pancreatitis history
    - Other malignancy that ALL
    - Severe Infection, HIV positive, active hepatitis related to B or C virus infection
    - Trisomy 21
    - Other serious conditions according to investigator's opinion.
    - Known grade 4 allergic reaction to E.Coli L-asparaginase (according NCI-CTCAE, Version 3.0).
    - History of grade 3 transfusionnal incident.
    - Presence of specific anti-erythrocyte antibodies preventing from getting a compatible erythrocyte concentrate for the patient.
    - Patient under concomitant treatment likely to cause hemolysis.
    - Patient undergoing yellow fever vaccination.
    - Patient under phenytoine treatment.
    - Patient included in previous clinical study less than 6 weeks
    - LAL t(9;22) y/o positiva para BCR-ABL (con el cromosoma Filadelfia).
    - Paciente con una 2ª recaída o más.
    - Mujeres en edad fértil que no usan métodos anticonceptivos eficaces, así como mujeres embarazadas o durante el periodo de lactancia.
    - Paciente que no puede recibir tratamientos usados en los protocolos de quimioterapia, debido a enfermedades sistémicas o viscerales como:
    Insuficiencia cardiaca grave (miocardiopatía de grado 3 o 4 según la NYHA)
    Creatinina sérica 2 veces por encima del LSN a menos que esté relacionado con la LAL
    ALT o AST 5 veces por encima del LSN a menos que esté relacionado con la LAL
    Antecedentes de pancreatitis
    Otros cánceres además de la LAL
    Infección grave, VIH positivo, hepatitis activa relacionada con infección por el virus B o C
    Trisomía 21
    Otras enfermedades graves según la opinión del investigador.
    - Reacción alérgica conocida de grado 4 a la L-asparraginasa obtenida de E. coli (según la versión 3.0 de los CCTAA del INC).
    - Antecedentes de incidentes transfusionales de grado 3.
    - Presencia de anticuerpos específicos contra los glóbulos rojos que impiden conseguir un concentrado compatible de glóbulos rojos en el paciente.
    - Paciente con tratamiento concomitante que puede causar hemólisis.
    - Paciente que ha recibido la vacuna de la fiebre amarilla.
    - Paciente con tratamiento de fenitoína.
    - Paciente incluido en un estudio clínico previo durante las 6 semanas anteriores.
    E.5 End points
    E.5.1Primary end point(s)
    EXPLORATORY PHASE II AND CONFIRMATORY PHASE III:
    The primary endpoint combines both efficacy and toxicity endpoints as follows:
    - Efficacy endpoint at F2 block ending (i.e. Day 28):
    - Mean duration of asparagine depletion in days throughout F1-F2 blocks. Asparagine depletion will be defined as plasmatic asparagine concentration 2µM.

    - Toxicity endpoint at F2 block ending:
    - Incidence of allergic reaction, whatever the grade
    FASE II DE EXPLORACIÓN Y FASE III DE CONFIRMACIÓN:
    El criterio principal de valoración combina tanto los criterios de valoración de eficacia y de toxicidad de la siguiente manera:
    Criterio de valoración de eficacia al finalizar el bloque F2 (es decir, día 28):
    - Duración media de la depleción de asparragina en días a lo largo de los bloques F1-F2.
    La depleción de asparragina se definirá como la concentración plasmática de asparragina 2 µM.
    Criterio de valoración de toxicidad al finalizar el bloque F2:
    - Incidencia de reacción alérgica, con independencia del grado.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Timepoint(s) of evaluation of Primary end points described in E.5.1
    Criterios principales de valoración descritos en la sección 5.1
    E.5.2Secondary end point(s)
    EXPLORATORY PHASE II:
    - Molecular response rate (MRD).
    - Percentage of CR patients at F2 block ending.
    - Biological and clinical toxicity according to NCI-CTCAE (version 3.0) grading, in particular pancreatic, hepatic toxicity, deep vein thrombosis and other coagulation disorders, which are well known adverse events related to L-asparaginase.
    - Plasma concentrations of asparagine, aspartate, glutamine, glutamate and asparaginase.
    - Percentage of patient presenting with asparagine depletion (i.e. "≤2 µM") at
    different time points.

    CONFIRMATORY PHASE III:
    Secondary endpoints listed above are still used and additional following are recorded:
    - Specific anti-L-asparaginase antibodies level.
    - Ratio of performed / planned injections regarding GRASPA® and reference asparaginase treatment over the total mean duration of study treatment.
    - At 6 months and 12 months: Event free survival rate, Relapse free survival rate and Overall survival rate.
    FASE DE II EXPLORACIÓN
    - Tasa de respuesta molecular (EMR).
    - Porcentaje de pacientes con RC al finalizar el bloque F2.
    - Toxicidad biológica y clínica según los criterios CCTAA (versión 3.0) del INC, sobre todo toxicidad pancreática, hepática, trombosis venosa profunda y otros trastornos de la coagulación, que son acontecimientos adversos conocidos relacionados con la L-asparraginasa.
    - Concentraciones plasmáticas de asparragina, aspartato, glutamina, glutamato y asparraginasa.
    - Porcentaje de pacientes que presentan una depleción de asparragina (es decir, "≤2 µM") en diferentes momentos.
    FASE III DE CONFIRMACIÓN:
    Los criterios secundarios de valoración indicados anteriormente se siguen usando y se registran además los siguientes:
    - Nivel de anticuerpos específicos anti-L-asparraginasa.
    - Razón de inyecciones administradas / programadas de GRASPA® y del tratamiento de referencia con asparraginasa en la duración total media del tratamiento del estudio.
    - A los 6 meses y 12 meses:
    Tasa de supervivencia libre de acontecimientos
    Tasa de supervivencia libre de recaídas
    Tasa de supervivencia global
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoint(s) of evaluation of Secondary end points described in E.5.2
    Principales criterios secundarios de valoración descritos en la sección E.5.2
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Los pacientes alérgicos serán tratados con GRASPA®
    The allergic patients will all be treated with GRASPA®
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Estandard poliquimioterapia
    standard polychemotherapy
    E.8.2.4Number of treatment arms in the trial3
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    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 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
    Definition is provided in the protocol and as defined as last patient / last visit
    Definición is especificada en el protocolo y definida como último paciente/última visita
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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.1.1Number of subjects for this age range: 40
    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: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 18
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 80
    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)
    Plans for treatment or care after the subject has ended his/her participation in the trial are not different from the expected normal treatment
    Los planes para el tratamiento o la atención después de que el sujeto ha terminado su participación en el ensayo no es diferente del tratamiento normal esperado
    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 Decision2013-06-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-09
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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