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    Summary
    EudraCT Number:2010-020414-28
    Sponsor's Protocol Code Number:AP24534-10-201
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2010-12-20
    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 ConcernedUK - MHRA
    A.2EudraCT number2010-020414-28
    A.3Full title of the trial
    A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Not applicable
    A.3.2Name or abbreviated title of the trial where available
    Not applicable
    A.4.1Sponsor's protocol code numberAP24534-10-201
    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, Ltd.
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAriad Pharmaceuticals, Ltd.
    B.5.2Functional name of contact pointDan Bollag
    B.5.3 Address:
    B.5.3.1Street Address1 Northumberland Avenue
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC2N 5BW
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+0044207 872 5869
    B.5.5Fax number+0044207 872 5611
    B.5.6E-maildan.bollag@ariad.com
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberC (2010) 789
    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 HCl
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    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 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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberC (2010) 789
    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 HCl
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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
    Patients with Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
    E.1.1.1Medical condition in easily understood language
    Not applicable
    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 15.0
    E.1.2Level LLT
    E.1.2Classification code 10024329
    E.1.2Term Leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is:
    1. To determine the efficacy of ponatinib in patients with chronic myeloid leukemia in chronic, accelerated or blast phase or with Ph+ Acute Lymphoblastic Leukemia who are either:
    - resistant or intolerant to either dasatinib or nilotinib,
    or
    - have the T315I mutation.
    E.2.2Secondary objectives of the trial
    1. To further characterize the anti-leukemia activity of ponatinib in these patients as evidenced by clinical responses, molecular responses, and clinical outcomes;
    2. To characterize the molecular genetic status of patients; and
    3. To examine the safety of ponatinib in these patients.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL (defined in Sections 12.3 and 12.4 of the protocol pages 53 and 54 ).
    a. All patients must have screening bone marrow (BM) cytogenetics with conventional banding performed within 42 days prior to initiating treatment.
    b. Examination of at least 20 metaphases is required. If less than 20 metaphases are examined, the BM aspirate should be repeated. Patients must either meet criterion 2 or 3:
    2. Be previously treated with and resistant, or intolerant, to either dasatinib or nilotinib: For resistance or intolerance criteria please refer to protocol pages 50-51.
    OR
    3. Develop the T315I mutation after any TKI therapy.
    3.1 Patients with T315I mutation after any TKI need not have been treated with dasatinib or nilotinib.
    3.2 Patients with T315I in CP must have less than a CCyR (>0% Ph+).
    3.3 Patients with T315I in AP, BP, or Ph+ ALL must have less than a MaHR.
    3.4 Patients with any history of T315I mutation will be eligible for study participation. However, only those patients who carry a T315I mutation that is detected by direct sequencing in a pre-treatment blood sample using the study’s central laboratory will be analyzed in the T315I subset. Details are provided in Section 12.5.
    Patients must meet all of the remaining criteria to be eligible for the study:
    4. Patients must be ≥18 years old.
    5. Provide written informed consent.
    6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
    7. Minimum life expectancy of 3 months or more.
    8. Adequate renal function defined as serum creatinine < 1.5× upper limit of normal (ULN) for institution.
    9. Adequate hepatic function defined as:
    a. Total bilirubin <1.5 × ULN,
    b. Alanine aminotransferase (ALT [SGPT]) and aspartate aminotransferase (AST [SGOT]) < 2.5 × ULN for institution (< 5 x ULN if liver involvement with leukemia),
    c. Prothrombin time (PT) < 1.5 × ULN.
    10. Normal pancreatic status defined as:
    a. Lipase ≤ 1.5 × ULN,
    d. Amylase ≤ 1.5 × ULN.
    11. Normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
    12. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
    13. Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study.
    14. Ability to comply with study procedures, in the Investigator’s opinion.


    E.4Principal exclusion criteria
    Patients are not eligible for participation in the study if they meet any of the following exclusion criteria:
    1. Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously administered.
    Received other therapies as follows:
    a. For CP and AP patients, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib, 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.
    b. For BP patients, received chemotherapy within 14 days prior to the first dose of ponatinib. Otherwise 2a applies.
    c. For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of ponatinib, or vincristine within 7 days prior to the first dose of ponatinib, or received other chemotherapy within 14 days prior to the first dose of ponatinib. Otherwise, 2a applies.
    d. All patients are excluded if they have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously administered.

    3. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of on-going graft-versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy.
    4. Take medications that are known to be associated with Torsades de Pointes. These medications are listed in Attachment B.
    5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
    6. Have previously been treated with ponatinib.
    7. Patient with CML CP are excluded if they are in CCyR.
    8. Patients with CML AP, BP, or Ph+ ALL are excluded if they are in MaHR.
    9. Have active central nervous system (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.
    10. Have significant or active cardiovascular disease, specifically including, but not restricted to:
    a. Myocardial infarction within 3 months prior to first dose of ponatinib,
    b. History of clinically significant atrial arrhythmia or any ventricular arrhythmia,
    c. Unstable angina within 3 months prior to first dose of ponatinib,
    d. Congestive heart failure within 3 months prior to first dose of ponatinib.
    11. Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
    12. Have a history of pancreatitis or alcohol abuse.
    13. Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
    14. Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered ponatinib.
    15. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years).
    16. Are pregnant or lactating. Women of childbearing potential must agree to effective contraception from the time of signing informed consent through the Follow-up Visit, approximately 30 days after last dose of ponatinib.
    17. Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.
    18. Have ongoing or active infection (including known history of human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]). Testing for these viruses is not required in the absence of history.
    19. Suffer from any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the study drug.
    E.5 End points
    E.5.1Primary end point(s)
    -For CML patients in Chronic Phase (CP), for Major Cytogenetic response (MCyR): C3D28, end of cycles 6, 9, 12, 15, 18, 21, 24, 26 and at the End of treatment visit
    -For CML patients in Acute Phase (AP) or Blast Phase (BP) or Ph+ ALL for Major Hematologic response (MaHR): C1D1, C1D8, C1D15, C1D22, C2D1, C2D15, C3D1, C3D15, and on D1 and D15 from cycles 4 to 26 and at the end of treatment visit
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. For CML patients in CP at study entry: major cytogenetic response (MCyR), defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR).
    2. For CML patients in AP at study entry: major hematologic response (MaHR), defined as complete hematologic response (CHR) or no evidence of leukemia (NEL).
    3. For CML patients in BP at study entry or Ph+ ALL patients: MaHR, consisting of CHR or NEL.
    E.5.2Secondary end point(s)
    -For CML patients in CP:
    -for Complete hematologic response (CHR) : C1D1, C1D8, C1D15, C1D22, C2D1, C2D15, C3D1, C3D15, D1 from cycle 4 to 13 and D28 from cycles 15, 18, 21, 24, 26 and at the end of treatment visit.
    -for confirmed Major Cytogenetic Response (MCyR): C3D28, end of cycles 6, 9, 12, 15, 18, 21, 24, 26 and at the end of treatment visit
    -for Molecular response: C3D28, end of cycles 6, 9, 12, 15, 18, 21, 24, 26 and at the End of treatment visit
    -For CML patients in AP or BP or Ph+ ALL
    -For Cytogenetic response: C1D28, C2D28, and at the end of even cycles 4 to 26 and at the end of treatment visit.
    -For Molecular response: C2D28, and at the end of even cycles 4 to 26 and at the end of treatment visit.
    -For all patients: time to response, duration of response, progression-free-survival, and overall survival
    -For all patients: safety and tolerabitlity
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. For CML patients in CP:
    a. Hematologic responses: CHR;
    b. Cytogenetic responses: confirmed MCyR; and
    c. Molecular responses: major molecular response (MMR).
    2. For CML patients in AP or BP or Ph+ ALL patients:
    a. Cytogenetic responses: CCyR, PCyR, confirmed MCyR; and
    b. Molecular responses: MMR.
    3. For all patients: time to response, duration of response, progression free survival, and overall survival.
    4. For all patients: safety and tolerability.
    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 Yes
    E.6.11Pharmacogenomic Yes
    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 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 Yes
    E.8.1.7.1Other trial design description
    Open enrollment
    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.8.2.4Number of treatment arms in the trial1
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    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
    Australia
    Belgium
    France
    Germany
    Italy
    Korea, Democratic People's Republic of
    Netherlands
    Singapore
    Spain
    Sweden
    United Kingdom
    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
    Last patient, last visit
    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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 65
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 236
    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)
    Patients may be able to continue treatment on a companion extension study that is under development at this point of time.
    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 Decision2011-01-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-02-21
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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