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    Summary
    EudraCT Number:2012-002026-78
    Sponsor's Protocol Code Number:GRASPA-AML-2012-01
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-10-18
    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 ConcernedItaly - Italian Medicines Agency
    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.
    Studio clinico di fase IIb, multicentrico, in aperto, randomizzato, controllato, per valutare l’efficacia e la tollerabilità di GRASPA (L-asparaginasi incapsulata nei globuli rossi) in associazione a citarabina a basso dosaggio nel confronto con la sola citarabina, nel trattamento di pazienti con nuova diagnosi di leucemia mieloide acuta (LMA) di età superiore a 65 anni e non idonei a chemioterapia 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
    Studio Clinico con GRASPA, L-Asparaginasi incapsulata in globuli rossi, in pazienti affetti da Leucemia Mieloide Acuta
    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 Acuta
    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 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.
    Valutare la sopravvivenza libera da progressione (PFS, progression-free survival) nei pazienti di età superiore a 65 anni che presentano LMA non idonea alla chemioterapia intensiva, trattati con GRASPA in associazione a citarabina a basso dosaggio nel confronto con la citarabina a basso dosaggio in monoterapia.
    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)
    Valutare:
    - La risposta al trattamento
    - La sopravvivenza senza eventi
    - La sopravvivenza globale
    - Le necessità di trasfusione del paziente
    - L’evoluzione della qualità della vita
    - Il numero di ricoveri in ospedale
    - La tollerabilità generale di GRASPA associato a citarabina
    - I parametri farmacocinetici e farmacodinamici di GRASPA
    - L’immunogenicità di GRASPA

    Esplorativo:
    - Esplorazione dell’asparagina sintetasi (su cellule di midollo osseo)
    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
    Pazienti ambosessi di età superiore a 65 anni e inferiore a 85
    - Leucemia mieloblastica acuta (LMA) di nuova diagnosi o post-sindrome mielodisplasica diagnosticata nei 6 mesi precedenti l’inclusione nello studio
    - Non idonei a chemioterapia intensiva (rischio di subire tossicità maggiori/sopraggiungere di decesso precoce a causa della chemioterapia intensiva) e/o volontà di non ricevere chemioterapia intensiva
    - Livello prestazionale OMS di grado inferiore o uguale a 2 e con aspettativa di vita superiore a 3 mesi
    - Idoneo a ricevere un trattamento con citarabina a basso dosaggio
    - Stato post-menopausa confermato per le donne (assenza di mestruazioni da oltre 12 mesi)
    - Beneficiari di un regime di previdenza sociale
    - Che abbiano firmato il consenso informato
    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
    - LMA di tipo M3 secondo la classificazione FAB (APL, leucemia promielocitica)
    - Anomalie genetiche del cromosoma 16 o traslocazione t(8:21) (CBF-AML)
    - Precedente di pancreatite o di evento tromboembolico di grado 3-4 (secondo NCI-CTCAE versione 4.0)
    - Presentanti una controindicazione generale o di carattere viscerale ai trattamenti intensivi tra cui:
    * malattia cardiovascolare grave o evolutiva tra cui infarto miocardico nei 6 mesi precedenti l’inclusione, insufficienza cardiaca di classe III o IV secondo la New York Heart Association (NYHA), angina pectoris non controllata, malattia del pericardio clinicamente significativa o amiloidosi cardiaca. Insufficienza cardiaca con una frazione di eiezione del ventricolo sinistro < 50% del valore teorico
    * Concentrazione di creatinina plasmatica superiore a 2 volte il limite superiore di laboratorio, tranne nei casi in cui è collegata alla LMA
    * Concentrazione di AST o ALT superiore a 3,5 volte il limite superiore di laboratorio, tranne nei casi in cui è collegata alla LMA
    * Esistenza di un cancro evolutivo diverso dalla LMA a eccezione dei carcinomi basocellulari in situ o cancro in situ del collo dell’utero
    * Infezione grave evolutiva, o sieropositività al virus HIV, o epatite attiva legata al virus dell’epatite B o C
    - Precedente di incidente trasfusionale di grado 3 (minaccia immediata per la vita)
    - Precedente noto o sospetto di ipersensibilità o di intolleranza al mannitolo o all’eparina
    - Presentanti una controindicazione al trattamento con citarabina (ipersensibilità, altro trattamento antimicotico concomitante, aplasia midollare preesistente, encefalopatia tossica degenerativa – in particolare dopo impiego di metotrexato o trattamento con radiazioni ionizzanti – in associazione al vaccino antiamarillico [febbre gialla])
    - Partecipazione a un altro studio clinico nei 30 ultimi giorni prima dell’inclusione.
    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)
    Sopravvivenza libera da progressione (PFS, progression free survival) definita come la durata fra l’inizio del trattamento e il sopraggiungere della progressione della malattia o il decesso collegato alla malattia o conseguenze del suo trattamento
    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
    I tempi di valutazione dell'endpoint primario sono descritti in E.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
    - Tasso di remissione completa (RC), remissione completa con rigenerazione ematologica incompleta (neutrofili o piastrine, CRi), remissione parziale (RP)
    - Sopravvivenza libera da eventi (EFS event free survival) definita come la durata fra l’inizio del trattamento e il fallimento del trattamento o interruzione o sospensione del trattamento a causa di tossicità, o progressione della malattia o decesso per qualsiasi causa
    - Sopravvivenza globale (OS, overall survival) definita come la durata fra l’inizio del trattamento e il decesso per qualsiasi causa
    - Percentuale di pazienti che fanno ricorso a trasfusioni, numero di trasfusioni per pazienti (concentrati eritrocitari o piastrinici)
    - Qualità della vita del paziente (questionario per il paziente)
    - Numero di ricoveri in ospedale durante lo studio (con l’esclusione delle visite previste dal protocollo)
    - Tollerabilità generale di GRASPA associato a citarabina a basso dosaggio. Sarà data attenzione particolare a:
    * Tossicità pancreatiche di grado 3-4
    * Tossicità epatiche di grado 3-4, reazioni allergiche di grado 3-4 o eventi tromboembolici di grado 3-4
    (NB manuale di riferimento per la classificazione degli eventi: NCI-CTCAE versione 4.0)
    * Qualsiasi altro evento non ematologico di grado 4
    - Parametri farmacocinetici e farmacodinamici di GRASPA.
    * Concentrazioni plasmatiche di asparagina, aspartato, glutammina, glutammato
    * Attività dell’asparaginasi totale
    - Immunogenicità: titolo anticorpale anti-L-asparaginasi

    Criteri esplorativi:
    - L’espressione dell’asparagina sintetasi e del RNA messaggero corrispondente, e la sensibilità in vitro all’asparaginasi verrà valutata su cellule tumorali midollari prelevate prima del trattamento.
    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
    I tempi di valutazione degli endpoints secondari sono descritti in 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 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) 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
    chiemioterapia standard con bassa dose di citarabina
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Ultima Visita Ultimo Soggetto (LVLS)
    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
    I piani di trattamento o cure dopo che il soggetto ha terminato la sua partecipazione allo studio non sono diversi da quelli normalmente previsti
    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 Decision2014-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-12-23
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