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    Summary
    EudraCT Number:2017-004674-34
    Sponsor's Protocol Code Number:P16/23
    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:2018-07-19
    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 number2017-004674-34
    A.3Full title of the trial
    OPEN LABEL PHASE 2 STUDY ON THE EFFICACY AND TOLERANCE OF A COMBINATION OF PONATINIB AND 5-AZACITIDINE IN CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS
    Etude de phase II évaluant la tolérance et l’efficacité de la combinaison du Ponatinib et de la 5-azacitidine dans les leucémies myeloïdes chroniques en phase d’accélération ou en transformation blastique myéloïde.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    OPEN LABEL PHASE 2 STUDY ON THE EFFICACY AND TOLERANCE OF A COMBINATION OF PONATINIB AND 5-AZACITIDINE IN CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS
    Etude de phase II évaluant la tolérance et l’efficacité de la combinaison du Ponatinib et de la 5-azacitidine dans les leucémies myeloïdes chroniques en phase d’accélération ou en transformation blastique myéloïde.
    A.3.2Name or abbreviated title of the trial where available
    PONAZA
    A.4.1Sponsor's protocol code numberP16/23
    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 supportINCYTE BIOSCIENCES France
    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 pointCharlotte LETERME - Project Manager
    B.5.3 Address:
    B.5.3.1Street Address177 rue de Versailles
    B.5.3.2Town/ cityLE CHESNAY Cedex
    B.5.3.3Post code78157
    B.5.3.4CountryFrance
    B.5.4Telephone number+33139239779
    B.5.5Fax number+33139239773
    B.5.6E-mailcleterme@ght78sud.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 PONATINIB
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namePonatinib
    D.3.4Pharmaceutical form Capsule
    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 MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS
    leucémies myeloïdes chroniques en phase d’accélération ou en transformation blastique myéloïde
    E.1.1.1Medical condition in easily understood language
    CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS
    leucémies myeloïdes chroniques en phase d’accélération ou en transformation blastique myéloïde
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    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
    To determine the overall survival of patients with CML-AP (cohort A) and CML-BC (cohort-B) treated with the combination ponatinib and 5-azacitidine by 2 years
    E.2.2Secondary objectives of the trial
    A. To determine the safety of selected therapies
    B. To assess the rate of CHR
    C. To assess the cytogenetic response
    D. To assess the molecular response
    E. To assess the rate of reversion to chronic phase CML
    F. To estimate the duration of response, event-free survival.
    G. To investigate the relationship between clinical efficacy and biological markers: mutations and methylation status.
    H. To estimate the rate of patients bridged to allogenic transplant
    I. To estimate survival after transplant and post-transplant relapse rate
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient aged 18y or more
    2. Signed informed consent
    3. Patient with Philadelphia chromosome positive CML in first blast crisis:
    CML-BP is defined by the presence of ≥ 20% blasts in the bone marrow and/or peripheral blood or the presence of extramedullary disease.
    4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3.
    5. Have adequate renal function as defined by the following criterion: Serum creatinine ≤ 1.5 × upper limit of normal (ULN) for institution
    6. Have adequate hepatic function as defined by the following criteria:
    a- Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert’s syndrome or CML
    b- Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN unless related to the disease
    c- Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN unless related to the disease
    7. Have normal pancreatic status as defined by the following criterion: Serum lipase and/or amylase ≤ 1.5 × ULN
    8. Have normal QTcF interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
    9. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
    10. Agree to use an effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile).
    11. Have fully recovered (≤ grade 1, returned to baseline, or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug
    12. Patient affiliated to or beneficiary of the French National Health service.
    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. Prior history of hematopoietic stem cell transplantation
    4. 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
    5. Individuals with another active malignancy
    6. Patients at high risk or very high risk of arterio-veinous occlusive disease defined by European CVD score
    7. Previously treated by 5-azacitidine or cytotoxic chemotherapy other than hydroxyurea
    8. Diagnosis of malignant disease within the previous 12 months (excluding base cell carcinoma, "in-situ" carcinoma of the cervix or breast or other local malignancy excised or irradiated with a high probability of cure)
    9. Known active viral infection with Human Immunodeficiency Virus (HIV) or Hepatitis type B or C
    10. Are taking medications with a known risk of Torsades de Pointes.
    11. Have active central nervous system (CNS) disease as evidenced by cytology or pathology.
    12. Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 150 mmHg). Patients with hypertension should be under treatment on study entry to affect blood pressure control.
    13. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the drug
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival (OS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 years
    E.5.2Secondary end point(s)
    1. Adverse events - NCI-CTC Version 4.0
    2. Cumulative rate of patients achieving CHR
    3. Cumulative rate of patients achieving complete cytogenetic responses
    4. Cumulative rate of patients achieving molecular responses
    5. Cumulative rate of patients reverting to chronic phase CML
    6. Analysis of clonal architecture, methylation profile, bcr-abl mutations and cytogenetics in blast crisis and AP at baseline, and in case of relapse or failure.
    7. Event free survival, duration of response
    8. Number of patients allocated to allogenic transplant
    9. Survival after transplant and post-transplantation relapse rate
    E.5.2.1Timepoint(s) of evaluation of this end point
    2 years
    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 No
    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 Yes
    E.6.13.1Other scope of the trial description
    Overall survival
    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 No
    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 concerned28
    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 No
    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 recruitment duration is extended from 48 months to 54 months (until DEC 2023). The aim is to achieve 20 patients in total in the MBC-CML cohort.
    The cohort AP-CML is closed to inclusion.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 40
    F.1.3Elderly (>=65 years) No
    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 state40
    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 24 months of treatment (primary endpoint), patients included in the study may continue administration of ITK at the investigator’s discretion. Ponatinib will no longer be supplied by the sponsor.

    Switching to commercial Ponatinib is possible if the following criteria are met:
    - Use of Ponatinib according to the marketing authorization (MA)
    - Minimum duration of experimental treatment with Ponatinib: 24 months (primary endpoint)
    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 Decision2018-08-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-25
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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