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    Summary
    EudraCT Number:2015-005208-26
    Sponsor's Protocol Code Number:P13/12
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2016-04-26
    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 ConcernedFrance - ANSM
    A.2EudraCT number2015-005208-26
    A.3Full title of the trial
    CANDIDATE THERAPIES IN COMBINATION OR SEQUENTIALLY WITH TYROSINE KINASE INHIBITORS IN CHRONIC PHASE CHRONIC MYELOGENOUS LEUKAEMIA (CP-CML) PATIENTS IN COMPLETE CYTOGENETIC RESPONSE WITHOUT ACHIEVING A DEEP MOLECULAR RESPONSE: AN ADAPTIVE TRIAL BASED ON A DROP LOSER DESIGN.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CANDIDATE THERAPIES IN COMBINATION OR SEQUENTIALLY WITH TYROSINE KINASE INHIBITORS IN CHRONIC PHASE CHRONIC MYELOGENOUS LEUKAEMIA (CP-CML) PATIENTS IN COMPLETE CYTOGENETIC RESPONSE WITHOUT ACHIEVING A DEEP MOLECULAR RESPONSE: AN ADAPTIVE TRIAL BASED ON A DROP LOSER DESIGN.
    A.3.2Name or abbreviated title of the trial where available
    ACTIW
    A.4.1Sponsor's protocol code numberP13/12
    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 SponsorCentre Hospitalier de Versailles
    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 supportDGOS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre Hospitalier de Versailles
    B.5.2Functional name of contact pointcoordinatrice DRCI
    B.5.3 Address:
    B.5.3.1Street Address177, rue de Versailles
    B.5.3.2Town/ cityLE CHESNAY
    B.5.3.3Post code78150
    B.5.3.4CountryFrance
    B.5.4Telephone number33139239785
    B.5.5Fax number33139239773
    B.5.6E-maillmorisset@ch-versailles.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 ACTOS
    D.2.1.1.2Name of the Marketing Authorisation holderTAKEDA Pharma
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    CHRONIC PHASE CHRONIC MYELOGENOUS LEUKAEMIA (CP-CML)
    E.1.1.1Medical condition in easily understood language
    CHRONIC PHASE CHRONIC MYELOGENOUS LEUKAEMIA (CP-CML)
    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 19.0
    E.1.2Level LLT
    E.1.2Classification code 10058246
    E.1.2Term Chronic myelogenous leukaemia
    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 select molecules in combination or sequentially with imatinib, nilotinib, dasatinib, bosutinib or ponatinib potentially able to produce a 25% increase in the Cumulative Incidence of MR4.5 as compare to control.
    E.2.2Secondary objectives of the trial
    A. To determine the safety of selected therapies
    B. To determine the rate of MR4 by 12, 24, 36, 48 months in experimental and control arms
    C. To determine the rates of MR4.5 by 24, 36, 48 months in experimental and control arms
    D. To determine the rate of undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms
    E. To estimate treatment free remission (TFR) in patients eligible for discontinuation studies
    F. To investigate the relationship between biological activity and the clinical efficacy of the selected therapies
    G. To assess the effects of the treatments on the number and clonogenicity of CML stem cells and other biological markers of interest
    H. To estimate duration of response, progression-free survival, event free survival and overall survival.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The kinase activity of BCR-Abl and STAT5 will be assessed by respectively STAT5 and CrkL phosphorylation. The rate of phosphorylation of these proteins will perfom by western blot using PathScan® BCR/Abl Activity Assay (Cell Signaling hysically®).
    Efficacy of the combination therapy with tyrosine kinase inhibitors and pioglitazone will be assessed by monitoring by RTQ-PCR BCR-ABL/ABL ratio and STAT5 rate in CD34 positives cells every six months.
    STAT5 expression in CD34 positive cells will be assessed at month 6 and 12 by immunofluorence unsing STAT5 antibodies.

    To assess the persistence of leukemic stem cell under the complete molecular response, CD34+ cells from patients were transplanted into NOD/SCID-b2m-/- mice (intra-femoral injection, 5-104 cells). The proportion and phenotype of human cells present in the bone marrow of the mice after 5 weeks were assessed by FACS analysis. To determine the proportion of leukemic cells present, human CD45+ cells were isolated by FACS and sorted cell fraction were analysed by RT-QPCR.
    E.3Principal inclusion criteria
    These inclusion criteria will apply for all arms. Specific criteria may apply for each experimental arm.
    1. Patient aged 18y or more
    2. Signed informed consent
    3. Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL1 transcript positivity
    4. Treatment with imatinib, nilotinib, dasatinib, bosutinib or ponatinib for more than 2 years overall
    5. No switch between tyrosine kinase inhibitors within the last 3 months
    6. No dose modification within the last 3 months
    7. Complete cytogenetic response or BCR-ABLIS ≤ 1%
    8. Detectable BCR-ABL1 with BCR-ABLIS > 0.0032% (less than MR4.5)
    9. ECOG grade 0 to 2
    10. ASAT and ALAT ≤ 2.5 N
    11. Bilirubin in serum ≤ 2.5 N
    12. Women of childbearing potential must be using an adequate method of contraception
    E.4Principal exclusion criteria
    1. Pregnant or lactating women,
    2. Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment,
    3. Patient requiring anti-diabetic medication
    4. Prior history of hematopoietic stem cell transplantation (autologous or allogenic)
    5. Cardiovascular disease:
    • Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure.
    • Myocardial infarction within the previous 6 months
    • Symptomatic cardiac arrhythmia requiring treatment
    6. Grade III or IV fluid retention
    7. Known BCR-ABL kinase domain mutation
    8. CML patient not in chronic phase at diagnosis
    9. Individuals with an active malignancy
    10. Kown HIV-positivity
    E.5 End points
    E.5.1Primary end point(s)
    The primary end-point is the cumulative incidence of patients achieving a deep molecular response defined by MR4.5 or deeper (BCR-ABLIS ≤ 0.0032 %) by 12 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months
    E.5.2Secondary end point(s)
    1. Adverse events
    2. The cumulative rate of patients achieving MR4.5 by 24, 36, 48 months in experimental and control arms
    3. The cumulative rate of patients achieving MR4 by 12, 24, 36, 48 months in experimental and control arms
    4. The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms
    5. The rate of patients in treatment free remission during follow-up
    6. Measurement of number and clonogenicity of CML stem cells using the leukemic stem cell markers followed by flow cytometry analysis and the LTC-IC assay and others markers (ancillary study)
    7. Survival, progression free survival, event free survival, duration of response
    E.5.2.1Timepoint(s) of evaluation of this end point
    12, 24, 36, 48 months
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    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 No
    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 concerned25
    E.8.5The trial involves multiple Member States No
    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
    the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    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 years7
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state100
    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 Decision2016-02-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-10
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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