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    Summary
    EudraCT Number:2016-000618-30
    Sponsor's Protocol Code Number:11272
    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:2018-06-12
    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 number2016-000618-30
    A.3Full title of the trial
    Phase 2 Clinical Trial with Ponatinib as a Second Line Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to prior First Line Tyrosine Kinase Inhibitor Treatment
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ponatinib for Treatment of Patients with CP-CML after treatment with other TKI has failed
    A.3.2Name or abbreviated title of the trial where available
    PONS
    A.4.1Sponsor's protocol code number11272
    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 SponsorGWT-TUD GmbH
    B.1.3.4CountryGermany
    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 International S.à.r.l.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGWT-TUD GmbH
    B.5.2Functional name of contact pointFachbereich MEDIZIN
    B.5.3 Address:
    B.5.3.1Street AddressFreiberger Strasse 33
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01067
    B.5.3.4CountryGermany
    B.5.4Telephone number+4935125933100
    B.5.5Fax number+4935125933198
    B.5.6E-mailmedical.consulting@g-wt.de
    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 Iclusig
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences UK Ltd
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePonatinib
    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
    Adult patients (age ≥ 18) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) who have proven to be resistant or intolerant to prior first line Tyrosine Kinase Inhibitor Treatment
    E.1.1.1Medical condition in easily understood language
    Adult patients (age ≥ 18) suffering from Chronic Myeloid Leukemia in Chronic Phase and who are resistant or intolerant to earlier treatment with another Tyrosine Kinase Inhibitor
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Major molecular response (MMR) by 12 months of treatment with second line Ponatinib treatment
    E.2.2Secondary objectives of the trial
    - Rate, time and dose to first clinical manifestation of vascular toxicity related to 2nd line therapy with Ponatinib
    - Rate of MCyR, CCyR and MR4 by 3, 6, 12, 18, 24 months
    - Rate of MMR by 3, 6, 18, 24 months
    - Time to CCyR, MMR, MCyR, MR4
    - Durations of hematologic, cytogenetic, molecular response
    - Occurrence of bar-abl mutations in Ponatinib-resistant CP-CML patients
    - Time to progression and overall survival
    - Cardiovascular safety
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients ≥18 years old
    2. Diagnosis of Ph-positive (by cytogenetics) or BCR-ABL-positive (by PCR) CP-CML
    3. Patients should have demonstrated to have:
    • Either a failure of a prior 1st line TKI treatment*,** with either imatinib, dasatinib or nilotinib. A failure is defined as per European LeukemiaNet (ELN) recommendations:
    o Less than CHR and/or Ph+ > 95% at or beyond 3 months
    o No cytogenetic response (Ph+>35%) and/or BCR-ABL1 >10% at or beyond 6 months
    o BCR-ABL (on international scale) >1% and/or Ph+ >0% at or beyond 12 months
    o Less than MMR at or beyond 18 months
    o Loss of response or development of mutations or other clonal chromosomal abnormalities at any time during the first line TKI treatment
    • or an intolerance to prior TKI treatment* (TKI related intolerance) defined as grade 3 or 4 toxicity, or persistent grade 2 toxicity despite optimal management including dose adjustment, or in a patient where dose reductions are considered to be not in the patient’s best interest to obtain an adequate response. At time of enrollment intolerant patients should:
    • have lost major molecular response -or-
    • not have achieved or have lost major molecular response
    (*) Patients with intolerance/failure to TKI combination therapy with Asciminib or PEG-IFN could be considered as eligible after consolidation with CPI.)
    (**) Patients that received TKI as medical treatment for CML for no longer than 2 weeks duration prior to First Line TKI therapy are categorized as First Line regimen.)
    4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
    5. Adequate hepatic function as defined by the following criteria:
    • Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert’s syndrome, in which case it should be ≤ 3.0xULN)
    6. Adequate renal function as defined by the following criterion:
    • Creatinine clearance of ≥ 50 mL/min
    7. Adequate pancreatic function as defined by the following criterion:
    • Serum lipase and amylase ≤1.5×ULN
    8. For patients of childbearing potential, a negative pregnancy test must be documented prior to enrollment. Postmenopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential
    9. Female and male patients who are fertile must agree to use effective forms of contraception with their sexual partners from signing off the informed consent form for this study until 3 months after the end of treatment
    10. Provision of written informed consent and specifically the consent to the collection and processing of health-related data
    11. Willingness and ability to comply with scheduled visits and study procedures
    12. Patients should have discontinued therapy with prior TKI (except hydroxyurea), at least 48 hours prior to start of study therapy
    13. Fully recovered from the acute effects of prior cancer therapy before initiation of study drug
    14. Patients must have had an eye examination confirming no objectives towards study participation by the ophthalmologist within 8 weeks prior to first treatment. . It is recommended to use Ophthalmoscopy to perform the eye examination (additional tests may be used as clinically indicated or as per physician discretion).The eye examinations should test the retinal vasculature
    E.4Principal exclusion criteria
    1. Any 1st line anti-CML treatment other than TK (apart from therapy with hydroxyurea)
    2. Any 2nd line therapy with a tyrosine kinase inhibitor (>1 EMA approved TKI for CML, or any investigational non EMA-approved TKI)
    3. Concurrent participation in any other clinical trial involving another investigational drug*** within 4 weeks prior to enrollment and throughout participation in PONS-Study
    (*** relates to participation during treatment phase/ investigational drug application phase)
    4. NYHA cardiac class 3-4 heart disease
    5. Cardiac Symptoms within the past 12 months prior recruitment: Patients meeting the following criteria are not eligible:
    • History of unstable angina, myocardial infarction, TIA, stroke, peripheral arterial occlusive disease or pulmonary embolism
    • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
    • Prolonged QTc interval on pre-entry electrocardiogram (> 450 ms in men, > 470 ms in women) on the Fridericia correction formula
    • Congestive heart failure (NYHA Class III or IV) within 3 months prior to first dose of ponatinib
    6. Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders
    7. Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 140 mmHg or diastolic > 90 mmHg)
    8. Pregnant or breast-feeding women are excluded
    9. Patients with history of pancreatitis
    10. Patients in accelerated or blast phase, or patients who have ever been documented to be in blast phase CML, are excluded. The definitions of excluded CML phases are as follows:
    • Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow
    • Accelerated phase CML: presence of any of the following features:
    o Peripheral or marrow blasts 15% or more
    o Peripheral or marrow basophils 20% or more
    o Thrombocytopenia < 100 x 10^9/L unrelated to therapy
    o Documented extramedullary blastic disease outside liver or spleen
    • Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study, but analyzed separately
    11. Patients showing an intolerance to the active substance or to any of the other ingredients of the test drug
    12. Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
    13. Patients who may be dependent on the sponsor, trial site or investigator
    14. Patients with active SARS-CoV-2 infection
    E.5 End points
    E.5.1Primary end point(s)
    MMR by 12 months of treatment with 2nd line Ponatinib treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    at end of study
    E.5.2Secondary end point(s)
    Rate, time and dose to first clinical manifestation of vascular toxicity related to 2nd line therapy with Ponatinib
    - Rate of MCyR, CCyR and MR4 by 3, 6, 12, 18, 24 months
    - Rate of MMR by 3, 6, 18, 24 months
    - Time to CCyR, MMR, MCyR, MR4
    - Durations of hematologic, cytogenetic, molecular response
    - Occurrence of bar-abl mutations in Ponatinib-resistant CP-CML patients
    - Time to progression and overall survival
    - Cardiovascular safety
    E.5.2.1Timepoint(s) of evaluation of this end point
    at end of 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 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 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.8.2.4Number 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 concerned13
    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
    Last visit of last patient / LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    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: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state54
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 54
    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)
    standard medical treatment
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-10-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-06-22
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