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    Summary
    EudraCT Number:2010-023409-37
    Sponsor's Protocol Code Number:AMLSG_15-10
    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:2010-12-14
    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 number2010-023409-37
    A.3Full title of the trial
    Randomized Phase III Study of Low-Dose Cytarabine and Etoposide with or without All-Trans Retinoic Acid in Older Patients not Eligible for Intensive Chemotherapy with Acute Myeloid Leukemia and NPM1 Mutation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized Phase III Study of Low-Dose Cytarabine and Etoposide with or without All-Trans Retinoic Acid in Older Patients not Eligible for Intensive Chemotherapy with Acute Myeloid Leukemia and NPM1 Mutation
    Randomisierte Phase III Studie zu niedrig dosiertem Cytarabin und
    Etoposid mit oder ohne All-trans Retinsäure bei älteren, für eine
    intensive Chemotherapie ungeeigneten Patienten mit einer akuten
    myeloischen Leukämie und NPM1-Genmutation
    A.3.2Name or abbreviated title of the trial where available
    AMLSG 15-10
    A.4.1Sponsor's protocol code numberAMLSG_15-10
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01237808
    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 SponsorUniversity Hospital Ulm
    B.1.3.4CountryGermany
    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 supportUniversity Hospital Ulm
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportBundesministerium für Bildung und Forschung
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Ulm
    B.5.2Functional name of contact pointAMLSG Clinical Trials Office
    B.5.3 Address:
    B.5.3.1Street AddressAlbert-Einstein-Allee 23
    B.5.3.2Town/ cityUlm
    B.5.3.3Post code89081
    B.5.3.4CountryGermany
    B.5.4Telephone number+49731500 56072
    B.5.5Fax number+49731500 45905
    B.5.6E-mailaml.sekretariat@uniklinik-ulm.de
    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.2.1.1.1Trade name Vesanoid®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Pharma AG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.1Product nameall-trans retinoic acid
    D.3.2Product code ATRA
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTretinoin
    D.3.9.1CAS number 302-79-4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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
    Adult patients (>60) with AML and NPM1 mutation ineligible for intensive chemotherapy
    E.1.1.1Medical condition in easily understood language
    Adult patients (>60) with AML and NPM1 mutation ineligible for intensive chemotherapy
    ältere, für eine intensive Chemotherapie ungeeignete Patienten (>60) mit einer akuten myeloischen Leukämie und NPM1-Genmutation
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Efficacy Objective
    Evaluation of overall survival after treatment with low-dose cytarabine and etoposide with or without all-trans retinoic acid (ATRA) in patients with acute myeloid leukemia (AML) and nucleophosmin-1 (NPM1) mutation ineligible for intensive treatment
    E.2.2Secondary objectives of the trial
    Secondary Efficacy Objectives
    Evaluation of efficacy based on complete remission (CR) rates, event-free survival (EFS), and cumulative incidences of relapse and deaths in CR

    Safety and QoL Objectives
    • Evaluation of safety based on toxicity
    • Evaluation of safety based on duration of neutropenia and leukopenia after each treatment cycle, incidence of infections, duration of hospitalization
    • Assessment of quality of live
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Patients with confirmed diagnosis of acute myeloid leukemia according to the World Health Organization (WHO) classification (including de novo AML, t-AML and s-AML)
    •Presence of NPM1 mutation as assessed in one of the central AMLSG reference laboratories.
    •Age > 60 years. There is no upper age limit.
    •No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if needed for up to 10 days during the diagnostic screening phase.
    •Signed written informed consent
    •Men must give their informed consent that they do not father a baby and must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy while on therapy and for 3 month after the last dose of chemotherapy.
    •WHO performance status ≤ 3
    •Patients not eligible for intensive chemotherapy according to at least one of the following criteria
    -HCT-CI Score >2 (see Appendix F)
    -Patient’s decision
    -age ≥ 75 years
    E.4Principal exclusion criteria
    •All other AML subtypes, in particular those AML with other recurrent genetic changes (according to WHO 2008):
    - AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
    - AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
    - AML with t(15;17)(q22;q12); PML-RARA (or other translocations involving RARA)
    - AML with t(9;11)(p22;q23); MLLT3-MLL (or other translocations involving MLL)
    - AML with t(6;9)(p23;q34); DEK-NUP214
    - AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
    •No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician and all other treating physicians about study participation
    •Bleeding disorder independent of leukemia
    •Uncontrolled infection
    •Known positive for HIV, HBV or HCV
    •Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or ALP >2.5x upper normal serum level, not attributable to AML; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)
    •Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
    •Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint
    Overall Survival (OS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    at the end of the trial
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints
    •Rates of CR
    •Cumulative incidences of relapse (CIR) and death in CR (CID)
    •Event-free survival (EFS)

    Safety Endpoints
    •Rate of early deaths (ED)/hypoplastic deaths (HD)
    •Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.0), timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during different treatment cycles
    •Incidence of infection after each treatment cycle
    •Duration of neutropenia and thrombocytopenia as well as duration of hospitalization after each treatment cycle

    QoL Endpoint
    •Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics according to Messerer et al.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety will be monitored by internal and external supervision. After cohorts of 25 patients,
    the analyses of the safety end points will be performed and results will be sent to the
    internal monitoring board (principle investigator, chairs of the AMLSG, biostatistician, AMLSG Steering Committee). Twelve-monthly, a study report comprising the safety end
    point report, a summary as well as a complete list of serious adverse events (SAE), results
    of blinded central versus on-site disease assessment and a summary of study con-duct to
    assess protocol adherence will be sent to the external Data Monitoring and Safety Board
    (DMSB). The DMSB will have to answer within 1 month with a common statement
    concerning the further conduct of the study.
    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 No
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned45
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    this information is provided in the protocol: 13.2, 11
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    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 years8
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 29
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 115
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state124
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 144
    F.4.2.2In the whole clinical trial 144
    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)
    After finishing all study relevant procedures, therapy and follow-up period, the patient will be followed in terms of routine aftercare and treated if necessary by the primary responsible hematologic-oncologic center.
    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 Decision2011-01-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-03-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-07-13
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