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    Summary
    EudraCT Number:2014-000200-10
    Sponsor's Protocol Code Number:GFM-DAC-CMML
    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:2014-05-26
    Trial 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 number2014-000200-10
    A.3Full title of the trial
    A Randomized Phase III study of Decitabine (DAC) with or without Hydroxyurea (HY) versus HY in patients with advanced proliferative Chronic Myelomonocytic Leukemia (CMML)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of Decitabine with or without Hydroxyurea in people with with advanced proliferative Chronic Myelomonocytic Leukemia (CMML)
    A.4.1Sponsor's protocol code numberGFM-DAC-CMML
    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 SponsorGroupe Francophone des Myélodysplasies (GFM)
    B.1.3.4CountryFrance
    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 supportJanssen-Cilag
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGroupe Francophone des Myélodysplasies (GFM)
    B.5.2Functional name of contact pointDirectrice du GFM
    B.5.3 Address:
    B.5.3.1Street Address1 avenue Claude Vellefaux
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75475
    B.5.3.4CountryFrance
    B.5.4Telephone number33171207059
    B.5.5Fax number33171207038
    B.5.6E-mailfatiha.chermat@sls.aphp.fr
    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 DACOGEN
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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/3/06/370
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    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 INNDECITABINE
    D.3.9.1CAS number 2353-33-5
    D.3.9.2Current sponsor codeDAC
    D.3.9.3Other descriptive nameDacogen
    D.3.9.4EV Substance CodeSUB06932MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Hydroxycarbamide
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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/3/03/154
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    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 INNHYDROXYCARBAMIDE
    D.3.9.1CAS number 127-07-1
    D.3.9.2Current sponsor codenot applicable
    D.3.9.3Other descriptive nameHydroxyurea
    D.3.9.4EV Substance CodeSUB08076MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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
    Proliferative Chronic Myelomonocytic Leukemia (CMML)
    E.1.1.1Medical condition in easily understood language
    Chronic Myelomonocytic Leukemia
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10054350
    E.1.2Term Chronic myelomonocytic 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
    Events will include
    - Death from any cause
    - Disease Progression, defined as one of the following:
    - (i) at any time point: transformation to AML according to WHO criteria (≥20% circulating blasts, or ≥20% marrow blasts and with an increase ≥ 50% from baseline) (ii) after at least 6 cycles of treatment: doubling of bone marrow blasts to > 10%, and worsening of cytopenias (any of the following) lasting for > 4 weeks:
    o At least 50% decrement from baseline or maximum response in granulocytes or platelets or
    o In case of RBC transfusion independence prior to randomization: reduction in Hgb by 2 g/dL or RBC transfusion dependence ≥ 4 RBC units / 8 weeks or
    o In case of RBC transfusion dependence prior to randomization: increase in RBC transfusion dependence by ≥ 4 RBC units / 8 weeks compared to baseline
    - (iii) after at least 3 cycles of treatment: Progression of myeloproliferation (despite maximal HY or DAC dosing; in the absence of concomitant infection) defined as
    E.2.2Secondary objectives of the trial
    To compare between the two arms:
    •Overall Survival
    •Cumulative AML progression
    •Overall and Complete Response Rates at 3 and 6 cycles
    •Response duration
    •Toxicity (hematological and non hematological)
    •Health Care Resource usage
    •Prognostic factors of response and overall survival with DAC and HY, using in particular:
    -The Spanish-Italian, the German and the French published prognostic scores
    -Somatic mutations
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A/ Age ≥ 18

    B/ CMML diagnosis according to WHO criteria
    - Stable excess in blood monocytes, > 1 G/L and accounting for > 10% WBC
    - Lack of bcr-abl rearrangement (or Philadelphia chromosome). There should be at least one BCR-ABL test (cytogenetics or molecular biology) dating from the date of CMML diagnosis up to date of screening.
    - Bone marrow blast cells < 20%
    - Dysplasia of at least one lineage or clonality marker or blood monocytosis during more than 3 months w/o other explanation
    - Blood and marrow smears will be reviewed at each country’s level, but morphologist meetings at the 3 country level are planned for better harmonization and review of difficult cases

    C/ WBC ≥ 13 G/L
    Measured on two successive CBC at least two weeks apart, outside of a context of infection and before initiation of treatment by Hydroxyurea.

    D/ Either D1 or D2

    D1/ At least two of the following criteria, reviewed at each country’s level: (modified from Wattel et al. Blood 1996)
    - Marrow blasts >= 5 %
    - Clonal cytogenetic abnormality (other than t(5;12) (q33; p13) and isolated loss of Y chromosome )
    - Anemia (Hb < 10 g/dL)
    - ANC > 16 G/l (in absence of infection)
    - Thrombocytopenia (platelet count < 100 G/L)
    - Splenomegaly > 5 cm below costal margin (spleen size should also be measured by an imaging technique)
    Or:

    D2/ Extramedullary involvement: Including documented cutaneous, pleural or pericardial effusion.

    E/ No prior treatment (except supportive care, or ESA, or short term (< 6 weeks before the screening date) HY in patients presenting with high WBC counts). The 6-week period for HY treatment can be prolonged to no more than 8 weeks in patients to allow complete exclusion of donor availability in patients fit for allogeneic stem cell transplantation lacking sibling donors.

    F/ Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale.

    G/ Adequate organ function including the following
    - Hepatic : total bilirubin < 1.5 times upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to intra medullary hemolysis or Gilbert syndrome) , alanine transaminase (ALT) and aspartate transaminase (AST) < 3xULN
    - Renal : serum creatinine < 2 x ULN

    H/ Signed Informed consent

    I/ Negative pregnancy and adequate contraception (including in male patients wishing to father) if relevant.
    Female subjects of chilbearing potential* must:

    * A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:
    - Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer therapy does not rule out childbearing potential)
    - Premature ovarian failure confirmed by a specialist gynaecologist
    - Previous bilateral salpingo-oophorectomy, or hysterectomy
    - XY genotype, Turner syndrome, uterine agenesis.

    Agree to have a medically supervised pregnancy test on the day of the study visit or in the 3 days prior to the study visit once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. The test should ensure the subject is not pregnant when she starts treatment.

    Agree to have a medically supervised pregnancy test every 4 weeks including 4 weeks after the end of study treatment, except in the case of confirmed tubal sterilization. These pregnancy tests should be performed on the day of the study visit or in the 3 days prior to the study visit. This requirement also applies to women of childbearing potential who practice complete and continued abstinence

    Agree to use, and to be able to comply with, effective contraception without interruption, 4 weeks before starting study drug throughout the entire duration study drug therapy (including doses interruptions) and for 3 months after the end of the study drug therapy even if she has amenorrhoea. This applies unless the subject commits to absolute and continuous abstinence confirmed on a monthly basis, to avoid pregnancy for the duration of study.

    The following can be considered to be examples of suitable methods of contraception for female patients: implant, levonorgestrel-releasing intrauterine system (IUS), medroxyprogesterone acetate depot, tubal sterilisation, sexual intercourse with a vasectomised male partner only (vasectomy must be confirmed by two negative semen analyses), ovulation inhibitory progesterone-only pills (i.e., desogestrel).
    If not established on effective contraception, the female subject must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated.



    E.4Principal exclusion criteria
    -Myeloproliferative / myelodysplastic syndrome other than CMML
    -Patients eligible for allogeneic bone marrow transplantation with an identified donor
    -CMML with t(5 ;12) or PDGFR rearrangement that may be treated with imatinib
    -Pregnant or breastfeeding
    -Performance status > 2 on the ECOG Scale.
    -Serious concomitant systemic disorder, including active bacterial, fungal or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the stud
    -Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, or other tumors if not active during the last 3 years)
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is Event-Free Survival , defined as the time between study entry and the date of last visit or the date of the first event occurring.

    Events will include:

    - Death from any cause
    - Blast progression after at least 6 cycles of treatment: doubling of bone marrow blasts to > 10% , and worsening of cytopenias (any of the following) lasting for > 4 weeks:
    o At least 50% decrement from baseline or maximum response in granulocytes or platelets or
    o In case of RBC transfusion independence prior to randomization: reduction in Hgb by 2 g/dL or RBC transfusion dependence ≥ 4 RBC units / 8 weeks or
    - In case of RBC transfusion dependence prior to randomization: increase in RBC transfusion dependence by ≥ 4 RBC units / 8 weeks compared to baseline.
    - Transformation to AML according to WHO criteria (>20% blasts in peripheral blood or bone marrow) and corresponding, for bone marrow, to an increase by at least 50% compared to bone marrow blast count at study entry.
    - Progression by myeloproliferation defined as ≥ 50% increase in spleen volume by imaging technique measurement, or doubling in WBC compared to study entry, despite maximal HY or DAC dosing, after at least 3 cycles of treatment, in the absence of concomitant infection.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The response rate will be evaluated after three and six cycles, according to IWG 2006 criteria
    E.5.2Secondary end point(s)
    Overall Survival (OS), defined as the time between study entry and the date of last visit or death.

    Cumulative incidence of AML, according to WHO criteria (>20% blasts in peripheral blood or bone marrow), and corresponding to an increase by at least 50% compared to peripheral and bone marrow blast count at study entry.

    Overall and Complete Response Rates at 3 and 6 cycles according to IWG 2006 criteria
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Overall Survival
    - Cumulative incidence of AML
    - Overall and Complete Response Rates
    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 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 concerned26
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA66
    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
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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) Yes
    F.1.2.1Number of subjects for this age range: 168
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 168
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 108
    F.4.2.2In the whole clinical trial 168
    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)
    none
    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 Decision2014-08-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-08-16
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