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    Summary
    EudraCT Number:2012-002026-78
    Sponsor's Protocol Code Number:GRASPA-AML-2012-01
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-11-07
    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 ConcernedGermany - BfArM
    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,eryaspase) plus low-dose cytarabine vs low-dose cytarabine alone, in treatment of newly diagnosed acute myeloid leukemia (AML) elderly patients, unfit for intensive chemotherapy.
    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
    A.3.2Name or abbreviated title of the trial where available
    ENFORCE 1
    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 INNeryaspase
    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
    E.1.1.1Medical condition in easily understood language
    Leukemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    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 Overall Survival (OS) in AML patients 65 to 85 years old unfit for intensive chemotherapy, when treated with GRASPA (L-asparaginase encapsulated in erythrocytes) plus low-dose cytarabine compared to low-dose cytarabine alone.
    E.2.2Secondary objectives of the trial
    To evaluate
    - Response to treatment
    - Progression-free Survival (PFS)
    - Relapse Free Survival
    - Patient transfusion needs
    - Patients Quality of life evolution
    - Number of hospitalization
    - Safety of GRASPA in combination with cytarabine
    - Pharmacokinetic and pharmacodynamic parameters of GRASPA
    - Immunogenicity of GRASPA
    - Asparagine Synthetase exploration (in bone marrow)
    - Biomarker cytogenetic testing
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients aged from 65 to 85 years old included
    - 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) due to the presence of one or more of the following criteria:
    o Dependence in activities of daily living owing to the presence of comorbidities other than those resulting from the deterioration caused by the neoplastic disease.
    o Presence in the patient's medical history of three or more of the following comorbidities, even if they are under control with proper treatment:
    - Congestive heart failure
    - Other chronic cardiovascular diseases
    - Chronic obstructive pulmonary disease
    - Cerebrovascular disease
    - Peripheral neuropathy
    - Chronic kidney failure
    - Hypertension
    - Diabetes mellitus
    - Systemic vasculitis
    - Severe arthritis
    o Presence of geriatric syndromes such as fecal or urinary incontinence, spontaneous bone fractures, mild and moderate dementia, or patients who fall repeatedly.
    OR
    Patient unwilling to receive intensive chemotherapy
    • Eligible to receive low-dose cytarabine treatment
    • ECOG performance status ≤ 2
    • Female patients of childbearing potential and males must agree to use
    adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) for the duration of study treatment and for 6 months after the last dose of Cytarabine or 3 months after last dose of GRASPA (whichever is the longest).
    • Negative serum pregnancy test at study entry for female subjects of childbearing potential
    • Subscription to social security insurance (if applicable, in accordance with local regulations)
    • Ability to understand, and willingness to sign, a written informed consent document and to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
    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)
    • Patient with secondary AML subsequent to prior malignant blood disorder such as:
    o Myelodysplastic syndrome diagnosed more than 6 months before study entry
    o Myeloproliferative syndrome
    • Prior therapy to AML (standard therapy or investigational agents)
    • Inadequate organ function :
    o 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.
    o Serum creatinine concentration > 2 x ULN (Upper Limit of Normal)
    o AST or ALT levels > 3.5xULN or 5xULN if related to AML
    o Total bilirubin > 2 x ULN
    o INR > 1.5, unless patient under chronic treatment with anticoagulants (in this case, INR should be within expected ranges for the specific condition)
    o Insulin-dependent or uncontrolled diabetes mellitus
    • Concurrent malignancies other than AML requiring chemotherapy
    • Severe active infection, HIV seropositivity, known active hepatitis B or
    C infection
    • Known or suspected hypersensitivity or intolerance to mannitol
    • Contraindication to cytarabine treatment (according to country specific
    approved Cytarabine SPC)
    • Breastfeeding or lactating women
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival (OS) defined as the time elapsed between randomization
    and death from any cause
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis for OS will take place once all patients have completed 12 months in the study
    E.5.2Secondary end point(s)
    • Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophil or platelet regeneration, CRi), Partial remission (PR)
    • Progression-free survival (PFS) defined as the time elapsed between randomization and resistant disease or relapse or death from any cause
    • Relapse Free Survival defined only for patients who achieved CR or CRi as the time elapsed between date of CR/CRi and date of disease relapse or 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 hospitalizations (except scheduled protocol visit)
    • Safety of GRASPA® in combination with low-dose cytarabine, with specific attention to:
    o Grade 3 or 4 of Pancreatic toxicity
    o Grade 3 or 4 of hepatic toxicity, allergic reaction or coagulation event
    o All other non-hematologic Grade 4 toxicities (NB grading reference used : NCI CTCAE version 4.0)
    • Pharmacodynamic and pharmacokinetic parameters of GRASPA:
    o Plasma concentrations of asparagine, aspartate, glutamine, glutamate
    o Whole blood L-asparaginase activity
    • Immunogenicity : titer of anti-L-asparaginase antibodies
    • Asparagine synthetase, Asparagine synthetase mRNA expression and in vitro sensitivity to asparaginase on the tumor bone marrow cells harvested before treatment
    • Biomarker cytogenetic testing (optional)
    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
    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
    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
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    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 state15
    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
    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 Decision2014-06-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-03-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-11-10
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