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The European Union Clinical Trials Register   allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   43844   clinical trials with a EudraCT protocol, of which   7282   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
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    EudraCT Number:2012-005629-65
    Sponsor's Protocol Code Number:RG_12-269
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-12-30
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2012-005629-65
    A.3Full title of the trial
    Management of Transformed Chronic myeloid leukaemia: Ponatinib and Intensive chemotherapy: a dose finding study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Management of Transformed Chronic myeloid leukaemia: Ponatinib and Intensive chemotherapy: a dose-finding study
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberRG_12-269
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN98986889
    A.5.4Other Identifiers
    Name:CAS CODENumber:HM1018
    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 SponsorUniversity of Birmingham
    B.1.3.4CountryUnited Kingdom
    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 supportBloodwise TAP
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportAriad Pharmaceuticals
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Birmingham
    B.5.2Functional name of contact pointMirjana Sirovica
    B.5.3 Address:
    B.5.3.1Street AddressCRCTU, Centre for Clinical Haematology, Queen Elizabeth Hospital
    B.5.3.2Town/ cityEdgbaston
    B.5.3.3Post codeB15 2TH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01213717866
    B.5.5Fax number01213717874
    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 holderHaupt Pharma Amareg GmbH
    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 numberC (2010) 789
    D.3 Description of the IMP
    D.3.1Product nameIclusig
    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 1114544-31-8
    D.3.9.3Other descriptive nameIclusig
    D.3.9.4EV Substance CodeAS1
    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. 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Myeloid Leukaemia (CML) in Blast Phase
    E.1.1.1Medical condition in easily understood language
    CML is a cancer of the white blood cells which build up, disrupting the normal balance of cells in the blood and bone marrow. In Blast phase, the cancer invades the bone marrow and other organs.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10009013
    E.1.2Term Chronic myeloid leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this trial is to find a safe and effective dose of a drug called Ponatinib when used in combination with chemotherapy in patients with Chronic Myeloid Leukaemia (CML) whose disease has moved in to blast phase.
    E.2.2Secondary objectives of the trial
    To find out how safe it is to treat patients in Blast Phase Chronic Myeloid Leukaemia with ponatinib and chemotherapy. To find out how effective this combination (ponatinib and chemotherapy) is by the end of the trial, to find out how good ponatinib is at maintaining a response to treatment once the combination (ponatinib and chemotherapy) treatment has ended (and after Stem Cell Transplant - if applicable to the patient), and how long that response can be maintained (i.e. until the patients leukaemia relapses or progresses).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. Blood Sample Collection for Biobank
    Objective: To study biology of blast crisis CML (genetic, epigenetic, proteomic, metabolomic etc.) and assess drug sensitivity/insensitivity.
    Chronic myeloid leukaemia provides several tractable clinical and laboratory characteristics that allow us to study response to therapy at a clonal level – particularly the ability to grow colonies which contain sufficient numbers of cells for simultaneous genotyping and phenotypic analyses. Blood samples collected in this study will also be used to undertake genome-wide characterisation of patient-specific features that determine response and resistance to therapy. It is proposed to use respectively high-throughput sequencing, transcriptional profiling (at clonal level), epigenetic approaches and signalling studies to characterise patient-specific factors that determine response to therapy. By focusing on samples from patients in a prospective clinical trial and integrating results, genome-wide insights into the patient-specific genetic and epigenetic factors that determine response to treatment can be achieved.
    All projects requesting cells from the Biobank will require approval from the NCRI CML Working Party before samples can be released to the researcher.

    2. Buccal Cell Sample collection for Biobank
    Objective: To study biology of blast crisis CML (genetic, epigenetic, proteomic, metabolomic etc)
    A sample of buccal cells will be requested at baseline. If this sample proves insufficient to analyse, a further sample of constitutional DNA (hair follicle) will be requested at a later date if the patient consents.
    This sample should be shipped to the Biobank with the baseline blood.
    All projects requesting cells from the Biobank will require approval from the NCRI CML Working Party before samples can be released to the researcher.
    E.3Principal inclusion criteria
    All of the following:
    • Ph-positive or BCR-ABL positive CML in blastic transformation. Defined as one or more of the following being present:
    o Blasts ≥30% in peripheral blood or bone marrow
    o Extramedullary blast proliferation or large foci or clusters of blasts in the bone marrow biopsy
    • Age: ≥16
    • Suitable for intensive chemotherapy (FLAG-IDA)
    • Adequate renal function defined as serum creatinine ≤1.5 X upper limit of normal (ULN)
    • Adequate liver function defined as:
    o Total bilirubin < 1.5 X ULN, unless due to Gilbert’s syndrome
    o Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5 X ULN (< 5 X ULN if liver involvement with leukaemia. Patients with disordered liver function >5 X ULN due to leukaemia may enter with a dose reduction of FLAG-IDA as per local guidelines and will be considered on a per patient basis following discussion with the Chief Investigator and Trial Office.)
    • Normal pancreatic status defined as:
    o Serum Amylase ≤ 1.5 X ULN
    • Normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤470 ms in females.
    • 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 until 4 months after the last dose of ponatinib.
    • Ability to comply with study procedures, in the Investigator’s opinion.
    • Valid Informed Consent
    E.4Principal exclusion criteria
    • Any of the following will exclude:
    • Received chemotherapy other than hydroxycarbamide, anagrelide, low dose arabinosylcytarabine (LDAC), steroids, or interferon within 4 weeks of registration
    • Changed TKI therapy more than once since confirmation of blast phase CML or had prior treatment with ponatinib at any time.
    • Previous treatment with intensive acute leukaemia-style chemotherapy (FLAG-IDA). (Unless treatment was during an initial blast phase which returned to chronic phase for a prolonged period of time and the patient is now in a second blast phase.)
    • Prior allogeneic or autologous Stem Cell Transplant
    • Significant or active cardiovascular disease, specifically including but not restricted to:
    o Myocardial infarction, stroke or revascularization within 12 months prior to registration
    o History of clinically significant atrial arrhythmia
    o Any history of or ventricular arryhthmia
    o Unstable angina or transient ischemic attack within 6 months prior to registration
    o Congestive heart failure within 6 months prior to registration
    o Left ventricular ejection fraction (LVEF) less than lower limit of normal within 6 months prior to registration
    o Any history of unprovoked venous thromboembolism including deep venous thrombosis or pulmonary embolism
    o Uncontrolled hypertension (sustained diastolic blood pressure >90 mm Hg; systolic >140 mm Hg).
    • History of acute pancreatitis within 1 year prior to registration
    • History of chronic pancreatitis.
    • Uncontrolled hypertriglyceridaemia (>450 mg/dL)
    • Are pregnant or lactating
    • Are known galactose intolerant
    • Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or Bone Marrow biopsy) within 14 days prior to registration
    • Suffer from any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the safety of the study treatment
    E.5 End points
    E.5.1Primary end point(s)
    Tolerability; Identification of the dose of ponatinib that can be safely delivered in combination with chemotherapy (FLAG-IDA) is defined in terms of dose limiting toxicities.
    Dose Limiting Toxicity will be defined as:
    • Before the start of the second cycle of combination therapy or up to 8 weeks from the start of the first cycle of combination therapy, whichever is sooner:
    o Grade 3 or 4 clinically significant non-haematological toxicity that cannot be managed with optimal medical care and that in the opinion of the investigator is related to the ponatinib and is likely to endanger the life of the patient or result in long term effects
    o Pancreatitis grade 2 or above
    o Increased serum amylase grade 3 or 4*
    o Prolongation of the QT interval grade 3 or 4
    o Myocardial infarction
    o Stroke
    o Development or progression of a thromboembotic event requiring revascularisation
    o Unprovoked venous thromboembolism

    • Toxicities will be measured and graded according to Version 4 CTCAE criteria.

    *In cases where the patient displays an increased serum amylase level but no clinical signs of pancreatitis, please test the pancreatic isoenzyme level to differentiate between pancreatic and salivary amylase levels. If the pancreatic amylase level is within the ULN but the salivary amylase level is not, this would not be classified as a DLT and treatment may continue. Similarly, some ethnic populations, particularly African individuals may display a high normal level of amylase due to salivary amylase as opposed to pancreatic amylase. It is recommended to test isoenzyme levels to confirm if this is the case.

    Efficacy: Haematological response (HR) or cytogenetic response (CyR)
    HR is defined as achieving all the following criteria:
    Platelets >50x10^9/L (unsupported)
    Neutrophils >1.0 x10^9/L (unsupported)
    Blasts < 5% peripheral blood and bone marrow (where assessable)

    CyR is defined as achieving at least a minor cytogenetic response (i.e. <65 % Ph+ cells)

    An assessment for the primary outcome measure must be conducted prior to commencing the 2nd cycle of therapy. This can be at any time from 4-8 weeks after commencing combination therapy following haematological recovery to at least neutrophils ≥1.0x10^9/L and Platelets ≥ 50 x10^9/L. An assessment should be carried out at 8 weeks after commencing combination therapy if haematological recovery is not achieved.
    Given the heterogeneity of blast crisis CML and the advanced stage of disease, there may be instances of DLTs or reports of efficacy (as defined above) that occur outside of the 8 week period. If such events occur outside of the 8 week period but prior to the TSC meeting being conducted, the events will be formally reported to the TSC to take into consideration during their review of each patient.

    Cumulative reports of safety and efficacy from previously enrolled patients will also be reported to the TSC for consideration.

    Patients who are unable to be formally evaluated for tolerability and efficacy due to withdrawal, treatment discontinuation or death, that is unrelated to treatment, before commencing the second cycle of therapy, may be replaced depending on the nature of the withdrawal/discontinuation. The trials office will notify centres of any patient replacement.

    If a patient is evaluable for the tolerability outcome but not the efficacy outcome, the efficacy outcome may be inferred, as described in Section
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 cycles (8-16 weeks) of ponatinib in combination with chemotherapy (FLAG-IDA) for the tolerability/efficacy
    1 cycle (4-8 weeks)for the dose limiting toxicities
    1 cycle (4-8 weeks)for the efficacy
    E.5.2Secondary end point(s)
    • Toxicity profile of ponatinib + chemotherapy (FLAG-IDA) within 6 months or up to transplant (whichever time point arrives first). Toxicities will be measured and graded according to the CTCAE criteria version 4.
    • Complete Cytogenetic Response (CCyR) within 2 cycles of treatment
    • Major Molecular Response (MMR) within 2 cycles of treatment
    • Haematological response within 2 cycles of treatment
    • 3 year disease free survival (DFS)
    • 3 year overall survival (OS)
    • 1 and 3 year relapse rate post allogeneic transplant or maintenance therapy
    • 1 and 3 year treatment related mortality
    • Incidence of Cytomegalovirus (CMV) reactivation rate and Graft Versus Host Disease (GVHD) post-transplant
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 months for toxicity profile of ponatinib and chemotherapy
    8-16 weeks for complete cytogenetic response
    8-16 weeks for haematological response
    8-16 weeks for major molecular response
    3 years for disease free survival and overall survival
    1 year and 3 years for the relapse rates and mortality
    Any GVHD that happens within the first 100 days after SCT is considered acute GVHD (aGVHD). GVHD occurring after 100 days post-SCT is termed chronic GVHD (cGVHD).
    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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E. trial type description
    Phase 1 study to determine the optimal dose of ponatinib in combination with intensive chemotherapy.
    E.7.2Therapeutic exploratory (Phase II) No
    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 No
    E.8.1.2Open No
    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. trial design description
    Efftox design version 4.0.12 for dose escalation and de-escalation decisions
    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 concerned14
    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 end of trial will be the last patient's last visit. The Trials Office will notify the MHRA and main REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of 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 months0
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 2
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 3
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 15
    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)
    Incyte Biosciences International Sàrl are providing the drug free of charge for as long as the patient requires it (i.e. until disease relapse or death)
    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 Decision2014-01-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-11
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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