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    The EU Clinical Trials Register currently displays   37989   clinical trials with a EudraCT protocol, of which   6231   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2014-001617-12
    Sponsor's Protocol Code Number:AP24534-14-203
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-08-04
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNorway - NOMA
    A.2EudraCT number2014-001617-12
    A.3Full title of the trial
    A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients with Resistant Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety of a Range of Doses
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients with Resistant Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety of a Range of Doses
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberAP24534-14-203
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02467270
    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 SponsorARIAD Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportARIAD Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationARIAD Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointSara Green
    B.5.3 Address:
    B.5.3.1Street Address26 Landsdowne Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number1617503 7019
    B.5.5Fax number1617225 2688
    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. name Iclusig
    D. of the Marketing Authorisation holderARIAD Pharma Ltd.
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/716 - treatment of CML
    D.3 Description of the IMP
    D.3.1Product nameponatinib
    D.3.2Product code AP24534
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNPonatinib
    D.3.9.1CAS number 943319-70-8
    D.3.9.2Current sponsor codeAP24534
    D.3.9.3Other descriptive namePonatinib hydrochloride
    D.3.9.4EV Substance CodeSUB91901
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 45
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Myeloid Leukemia
    E.1.1.1Medical condition in easily understood language
    Chronic Phase Chronic Myeloid 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 18.0
    E.1.2Level LLT
    E.1.2Classification code 10054352
    E.1.2Term Chronic phase chronic 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 characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, and 15 mg daily) in patients with chronic phase CML who are resistant to at least two tyrosine kinase inhibitors (TKIs), as measured by major cytogenetic response by 12 months.
    E.2.2Secondary objectives of the trial
    To characterize, according to ponatinib starting dose, the rates of Vascular Occlusive Events (VOEs), AEs (Adverse Events), and serious AEs (SAEs).

    To evaluate safety differences according to ponatinib starting dose among the 3 starting dose cohorts, particularly for VOEs.

    To characterize the exposure-response and exposure-toxicity relationships between PK parameters and selected safety and efficacy measures.

    To characterize, according to ponatinib starting dose, the rates of cytogenetic responses and molecular responses; durability will be assessed by evaluating molecular response (MR)2 and major molecular response (MMR) at 12, 18, and 24 months.

    To characterize, according to ponatinib starting dose, the rate of discontinuation, dose reductions, and interruptions.

    To characterize, according to ponatinib starting dose, the rates of hematologic responses.

    To evaluate, according to ponatinib starting dose, time to response, duration of response, and survival outcomes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All patients must meet all of the following inclusion criteria for study entry:
    1. Have chronic phase CML and are resistant to at least two prior tyrosine kinase inhibitors.
    a. The diagnosis of CML will be made using standard hematopathologic and cytogenetic criteria. Chronic phase CML will be defined by all of the following:
    i < 15% blasts in bone marrow
    ii < 30% blasts plus promyelocytes in bone marrow
    iii < 20% basophils in peripheral blood
    iv ≥ 100 × 109/L platelets (≥ 100,000/mm3)
    v No evidence of extramedullary disease except hepatosplenomegaly
    vi No prior diagnosis of AP- or BP-CML
    b. Cytogenetic assessment at screening must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome.
    i Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques
    ii Conventional chromosome banding must be performed
    iii A minimum of 20 metaphases must be assessable at entry
    c. Resistance to prior TKI therapy is defined as follows (patients must meet at least 1 criterion):
    i Three months after the initiation of prior TKI therapy: No cytogenetic response (> 95% Ph+) or failure to achieve CHR
    ii Six months after the initiation of prior TKI therapy: Less than a minor cytogenetic response (> 65% Ph+)
    iii Twelve months after the initiation of prior TKI therapy: Less than a PCyR (> 35% Ph+)
    iv At any time after the initiation of prior TKI therapy, the development of new BCR-ABL kinase domain mutations in the absence of MCyR
    v At any time after the initiation of prior TKI therapy, the development of new clonal evolution in the absence of MCyR
    vi At any time after the initiation of prior TKI therapy, the loss of any
    cytogenetic response (from complete [0%] or partial [1% to 35%] to anything less than a partial response; or from minor [36% to 65%], or minimal [66% to 95%] to a response at least 1 grade worse), confirmed in at least 2 consecutive analyses separated by at least 4 weeks

    2. Be male or female patients ≥ 18 years old.
    3. Have an ECOG performance status of 0, 1, or 2.
    4. Have adequate renal function as defined by the following criterion:
    a. Serum creatinine ≤ 1.5 × ULN for institution
    5. Have adequate hepatic function as defined by the following criteria:
    a. Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert’s syndrome
    b. ALT ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic involvement of the liver is present
    c. AST ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic involvement of the liver is present
    6. Have normal pancreatic status as defined by the following criterion:
    a. Serum lipase and amylase ≤ 1.5 × ULN
    7. Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
    8. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
    9. Agree to use an effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile).
    10. Provide written informed consent.
    11. Be willing and able to comply with scheduled visits and study procedures.
    12. Have fully recovered (≤ grade 1, returned to baseline, or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug.
    E.4Principal exclusion criteria
    Patients are not eligible for participation in the study if they meet any of the following exclusion criteria:
    1. Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is longer, prior to receiving study drug.
    2. Received interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the
    first dose of ponatinib, or have not recovered (> grade 1 by NCI CTCAE, v4.0) from AEs (except alopecia), due to agents previously administered.
    3. Have undergone autologous or allogeneic SCT < 60 days prior to receiving the first dose of ponatinib; have any evidence of ongoing GVHD or GVHD requiring immunosuppressive therapy.
    4. Are being considered for HSCT within 6-12 months of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial).
    5. Are taking medications with a known risk of Torsades de Pointes
    6. Have previously been treated with ponatinib.
    7. Are in MCyR, defined as CCyR, PCyR, or MR2, which is ≤1% BCR-ABLIS.
    8. Have active CNS disease as evidenced by cytology or pathology; in the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.
    9. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
    a. Any history of MI, unstable angina, cerebrovascular accident, or TIA
    b. Any history of peripheral vascular infarction, including visceral infarction
    c. Any revascularization procedure, including the placement of a stent
    d. Congestive heart failure (NYHA class III or IV) within 6 months prior to enrollment, or LVEF less than lower limit of normal, per local institutional standards, within 6 months prior to enrollment
    e. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia
    f. Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrollment
    10. Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 150 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
    11. Have poorly controlled diabetes, defined as HbA1c values over the previous year of > 7.5% (59 mmol/mol) on more than 3 occasions; patients with preexisting, well-controlled, diabetes are not excluded.
    12. Have a significant bleeding disorder unrelated to CML.
    13. Have a history of alcohol abuse.
    14. Have a history of either acute pancreatitis within 1 year of study or of chronic pancreatitis.
    15. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
    16. Have a history of another malignancy, other than cervical cancer in situ or nonmetastatic basal cell or squamous cell carcinoma of the skin; the exception is if patients have been
    disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
    17. Are pregnant or lactating.
    18. Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement) within 14 days prior to first dose of ponatinib.
    19. Have an ongoing or active infection; this includes, but is not limited to, the requirement for intravenous antibiotics.
    20. Have a known history of human immunodeficiency infection; testing is not required in the absence of prior documentation or known history.
    21. 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)
    MCyR by 12 months for each dose cohort (MCyR is defined as PCyR, CCyR, or ≤ 1% BCR-ABLIS (eg, MR2), which is equivalent to CCyR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 12 months of treatment and the final analysis will be done at the end of the study
    E.5.2Secondary end point(s)
    a. Rate of VOEs in each dose cohort
    b. Rate of AEs in each dose cohort
    c. Rate of SAEs in each dose cohort

    Exposure-response and exposure-toxicity relationships of AUC and Cmax at steady state on efficacy outcomes (including MCyR, MR2, and MMR) and safety outcomes (VOEs and AEs that occur in at least 30 patients)

    Cytogenetic response rates: CCyR by and at 12 months

    Molecular response rates: MR2, MR3/MMR, MR4, and MR4.5 at 3-month intervals and MR1 (≤ 10% BCR-ABLIS) at 3 months

    Hematologic response rates: Complete hematologic response (CHR)

    a. Rate of discontinuation due to AEs in each dose cohort
    b. Dose reductions (prior to response) in each dose cohort
    c. Dose interruptions in each dose cohort

    Duration of response:
    a. Rates of MR2 and MMR at 12, 18, and 24 months
    b. Rate of MCyR at 12, 18, and 24 months

    Duration of response in responders

    Time to response

    Rate of progression to accelerated phase (AP-) or blast phase (BP-) CML

    Progression Free Survival

    Overall Survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    At each visit and the final analysis will be done at the end 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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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. 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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. description
    This is a controlled study of ponatinib at three different starting doses.
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA46
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Czech Republic
    Hong Kong
    Korea, Republic of
    United Kingdom
    United States
    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
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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: 330
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 Yes
    F. of other specific vulnerable populations
    Patients with incurable diseases
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 244
    F.4.2.2In the whole clinical trial 450
    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)
    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 Decision2015-10-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-05
    P. End of Trial
    P.End of Trial StatusOngoing
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