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    Summary
    EudraCT Number:2012-002026-78
    Sponsor's Protocol Code Number:GRASPA-AML-2012-01
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-11-12
    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 number2012-002026-78
    A.3Full title of the trial
    A Multicentre, open, randomized, controlled phase IIb trial evaluating efficacy and tolerability of GRASPA (L-asparaginase encapsulated in red blood cells) plus low-dose cytarabine vs low-dose cytarabine alone, in treatment of newly diagnosed acute myeloid leukemia (AML) patients, over 65 years, unfit for intensive chemotherapy.
    Ensayo controlado de fase IIb multicéntrico, abierto, aleatorizado, para evaluar la eficacia y la tolerancia de GRASPA (L-asparaginasa encapsulada en glóbulos rojos) más citarabina de baja dosis, comparada con citarabina de baja dosis sola, en el tratamiento de pacientes con diagnóstico reciente de leucemia mieloide aguda (LMA) mayores de 65 años no aptos para quimioterapia intensiva.
    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 Myeloid leukemia
    Ensayo clínico con GRASPA, L-asparaginasa encapsulada en glóbulos rojos, en pacientes afectados por Leucemia Mieloide aguda.
    A.3.2Name or abbreviated title of the trial where available
    GRASPA-ML
    A.4.1Sponsor's protocol code numberGRASPA-AML-2012-01
    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 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/3/13/1106.
    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 Myeloid Leukaemia
    Leucemia Mieloide 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 16.1
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid 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
    To evaluate Progression Free Survival (PFS) in AML patients older than 65 unfit for intensive chemotherapy, when treated with GRASPA (L-asparaginase encapsulated in erythrocytes) plus low-dose cytarabine compared to low-dose cytarabine alone.
    Evaluar la supervivencia libre de progresión (SLP) en pacientes con LMA mayores de 65 años no aptos para quimioterapia intensiva, al tratarlos con GRASPA (L-asparaginasa encapsulada en eritrocitos) más citarabina de baja dosis, en comparación con citarabina de baja dosis sola.
    E.2.2Secondary objectives of the trial
    To evaluate
    - Response to treatment
    - Event Free Survival
    - Overall survival
    - Patient transfusion needs
    - Patients Quality of life evolution
    - Number of hospitalization
    - Global safety of GRASPA in combination with cytarabine
    - Pharmacokinetic and pharmacodynamic parameters of GRASPA
    - Immunogenicity of GRASPA

    Exploratory: Asparagine Synthetase exploration (in bone marrow cells)
    Evaluar
    -Respuesta al tratamiento
    -Supervivencia Libre de Acontecimientos
    -Supervivencia global
    -Necesidades de transfusión del paciente
    -Evolución de la calidad de vida de los pacientes
    -Cantidad de hospitalizaciones
    -Seguridad global de GRASPA en combinación con citarabina
    -Parámetros farmacocinéticos y farmacodinámicos de GRASPA
    -Inmunogenicidad de GRASPA

    Exploratorios:Exploración de la asparagina sintetasa (en células de la médula ósea)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patient over 65 years old and less than 85 years old
    - Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic syndrome diagnosed in the 6 months prior to study enrollment
    - Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities /early death) or patient unwilling to receive intensive chemotherapy
    - WHO performance status ?2 and estimated life expectancy ? 3 months
    - Eligible to receive low-dose cytarabine treatment
    - Evidence of post-menopausal status for female (absence of menstruation for 12 months)
    - Subscription to social security insurance
    - Provision of written Informed Consent
    -Paciente mayor de 65 y menor de 85 años de edad
    -Leucemia mieloide aguda (LMA) o síndrome posmielodisplásico de diagnóstico reciente, realizado en los 6 meses previos a la inclusión en el estudio.
    -Pacientes no aptos para quimioterapia intensiva (con riesgo de sufrir toxicidades desfavorables o muerte prematura relacionadas con el tratamiento) o pacientes que no quieren recibir quimioterapia intensiva
    -Estado funcional OMS ?2 y expectativa de vida calculada ? 3 meses
    -Elegible para recibir tratamiento con citarabina de baja dosis
    -Evidencia de estado posmenopáusico en mujeres (ausencia de menstruación durante 12 meses)
    -Suscripción en seguro de la seguridad social
    -Entrega de consentimiento informado por escrito
    E.4Principal exclusion criteria
    - Patients with M3 AML of FAB classification (APL, acute promyelocytic leukemia)
    - Patients with AML involving chromosome 16 abnormalities or translocation (8:21) (CBF-AML)
    - History of grade 3-4 pancreatitis or grade 3-4 thromboembolic event (according NCI-CTCAE Version 4.0)
    - Presenting with a general or visceral contraindication including :
    * Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis. Cardiac insufficiency defined as Left Ventricular Ejection Fraction < 50% of the theoretical value
    * Plasma creatinine concentration, 2 times greater than the upper limit of laboratory ranges, except if related to AML
    * AST or ALT levels, 3.5 times greater than the upper limit of laboratory ranges, except if related to AML
    * Patient presenting evolutive cancer other than AML, except in situ basal-cell carcinoma or in situ cervix cancer
    * Severe evolutive infection, or, HIV seropositive or, active hepatitis related to B or C viral infection
    - History of Grade 3 Transfusional incident (life threatening)
    - Has known or suspected hypersensitivity or intolerance to mannitol, or heparin
    - Patient presenting contra indication to cytarabine treatment (hypersensitivity to cytarabine, antimitotic treatment, preexisting medullary aplasia, toxic degenerative encephalopathy - especially after methotrexate treatment or ioniding radiations-, yellow fever vaccination)
    - Participation in an investigational drug study within the 30 days prior to entry
    -Pacientes con LMA M3 de la clasificación FAB (LPA, leucemia promielocítica aguda)
    -Pacientes con LMA con involucramiento de anomalías o translocación del cromosoma 16 (8:21) (FUC-LMA)
    -Antecedentes de pancreatitis de grado 3 ó 4, o acontecimiento tromboembólico de grado 3 ó 4 (según INC-CCTAA, versión 4.0)
    -Pacientes que presentan una contraindicación general o visceral, tal como:
    *Enfermedad cardiovascular no controlada o grave, tal como infarto de miocardio, durante los 6 meses anteriores a la inclusión en el estudio, insuficiencia cardíaca de clase III o IV según la clasificación de la Asociación cardíaca de Nueva York (New York Heart Association, NYHA), angina no controlada, enfermedad del pericardio de importancia clínica, o amiloidosis cardíaca. Insuficiencia cardíaca según la definición de fracción de eyección ventricular izquierda < 50% del valor teórico
    *Concentración plasmática de creatinina, 2 veces mayor que el límite superior de los rangos de laboratorio, salvo que se relacione con la LMA
    *Niveles de AST o ALT 3,5 veces mayores que el límite superior de los rangos de laboratorio, salvo que se relacionen con la LMA
    *Paciente que presenta cáncer evolutivo que no sea LMA, salvo carcinoma de células basales in situ o cáncer de cuello uterino in situ
    *Infección evolutiva grave, VIH seropositivo o hepatitis activa relacionada con infección por el virus B o C
    -Antecedentes de incidentes transfusionales de grado 3 (con riesgo de vida)
    -Tiene hipersensibilidad o intolerancia, conocida o supuesta, al manitol o la heparina
    -Paciente que presenta contraindicación al tratamiento con citarabina (hipersensibilidad a la citarabina, al tratamiento antimitótico, aplasia medular preexistente, encefalopatía degenerativa tóxica, en especial después de un tratamiento con metotrexato o radiaciones ionizantes, vacunación contra la fiebre amarilla)
    -Participación en algún estudio de fármaco en investigación durante los 30 días previos a la inclusión
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS) defined as the time elapsed between treatment initiation and disease progression or death related to disease (AML or study treatment)
    Supervivencia libre de progresión (SLP), definida como el tiempo transcurrido entre el inicio del tratamiento y la progresión de la enfermedad o la muerte relacionada con la enfermedad (LMA o tratamiento del estudio)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Timepoint(s) of evaluation of Primary end points are described in E.5.1
    Criterios principales de valoración descritos en la sección 5.1
    E.5.2Secondary end point(s)
    - Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophile or platelet regeneration, CRi), Partial remission (PR)
    - Event Free Survival defined as the time elapsed between treatment initiation and treatment failure, or treatment stop/delayed from toxicity reason, or disease progression, or death from any cause
    - Overall survival defined as the time elapsed between treatment initiation and death from any cause
    - Percentage of patients who need transfusions (red cells and/or platelets), number of transfusion by patient
    - Patient quality of life (patient survey)
    - Number of hospitalization (except scheduled protocol visit)
    - General safety of GRASPA® in combination with low-dose cytarabine, specific attention to :
    * Grade 3 to 4 of Pancreatic toxicity
    * Grade 3 or 4 of hepatic toxicity, allergic reaction or thromboembolic event
    * All other non hematologic grade 4 toxicities
    (NB grading reference used : NCI CTCAE version 4.0)
    - Pharmacodynamic and pharmacokinetic parameters of GRASPA:
    * Plasmatic concentrations of asparagine, aspartate, glutamine, glutamate
    * Total L-asparaginase activity
    * Immunogenicity : titer of anti-L-asparaginase antibodies

    Exploratory endpoints :
    - Asparagine synthetase, Asparagine synthetase mRNA expression and in vitro sensitivity to asparaginase on the tumoral bone marrow cells harvested before treatment
    -Porcentaje de pacientes con remisión completa (RC), remisión completa con recuperación incompleta (regeneración de neutrófilos o plaquetas, RCi), remisión parcial (RP)
    -Supervivencia libre de acontecimientos, definida como el tiempo transcurrido entre el inicio del tratamiento y el fracaso del tratamiento, interrupción o postergación del tratamiento por motivos de toxicidad, progresión de la enfermedad o muerte por cualquier causa
    -Supervivencia global, definida como el tiempo transcurrido entre el inicio del tratamiento y la muerte por cualquier causa
    -Porcentaje de pacientes que necesitan transfusiones (glóbulos rojos y/o plaquetas), cantidad de transfusiones por paciente
    -Calidad de vida del paciente (encuesta respondida por el paciente)
    -Número de hospitalizaciones (salvo las visitas programadas del protocolo)
    -Seguridad general de GRASPA® en combinación con citarabina de baja dosis, con especial atención en:
    *Toxicidad pancreática de grado 3 a 4
    *Toxicidad hepática de grado 3 ó 4, reacción alérgica o acontecimiento tromboembólico
    *Todas las demás toxicidades de grado 4 no hematológicas
    (Nota: Referencia de clasificación usada: INC CCTAA, versión 4.0)
    -Parámetros farmacodinámicos y farmacocinéticos de GRASPA:
    *Concentraciones plasmáticas de asparagina, aspartato, glutamina, glutamato
    *Actividad total de la L-asparaginasa
    -Inmunogenicidad: título de anticuerpos anti-L-asparaginasa
    Criterios de valoración exploratorios:
    -Asparagina sintetasa, expresión de ARNm de asparagina sintetasa y sensibilidad in vitro a la asparaginasa en células tumorales de médula ósea extraídas antes del tratamiento
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoint(s) of evaluation of Secondary end points are 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) No
    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 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 Yes
    E.8.2.3.1Comparator description
    standard polychemotherapy with low dose cytarabine
    E.8.2.4Number of treatment arms in the trial2
    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 concerned40
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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 is 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 years4
    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 years4
    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 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) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 123
    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 state123
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 123
    F.4.2.2In the whole clinical trial 123
    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 Decision2014-01-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-13
    P. End of Trial
    P.End of Trial StatusCompleted
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