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    EudraCT Number:2008-004551-30
    Sponsor's Protocol Code Number:ICORG08-02NilotinibCMLTrial
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-01-07
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2008-004551-30
    A.3Full title of the trial
    A phase II multi-center, open-label, study of Nilotinib at a dose of 300mg twice daily in adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP)
    A.3.2Name or abbreviated title of the trial where available
    ICORG 08-02
    A.4.1Sponsor's protocol code numberICORG08-02NilotinibCMLTrial
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorICORG
    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 support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Tasigna
    D. of the Marketing Authorisation holderNovartis Europharm Ltd., Wimblehurst Road, Horsham, West Sussex UK
    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 nameTasigna (Nilotinib)
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAMN107 / Nilotinib
    D.3.9.3Other descriptive nameTasigna
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number50 to 200
    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) Information not present in EudraCT
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D. medicinal product typeNilotinib is a protein tyrosine kinase (TK) inhibitor, which selectively inhibits TK activity of Bcr-Abl. It exists as the monohydrate form of the hydrochloride salt.
    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
    Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10058246
    E.1.2Term Chronic myelogenous 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
    To establish the Complete Cytogenetic Response Rate at 6 months.
    E.2.2Secondary objectives of the trial
    1. To establish the Complete Cytogenetic Response Rates (CCyR) at 3, 9, 12, 18 and 24 months
    2. To establish Molecular Response Rates (MMR/CMR) at 3, 6, 9, 12,18 and 24 months
    3. To establish the safety of a twice daily dose of Nilotinib 300mg
    4. To correlate pharmacokinetic data with response rates and toxicity
    5. To correlate Bcr-Abl results using the GeneXpert system with international standardized QPCR
    6. To estimate the prevalence of Bcr-Abl mutations prior to and during therapy with nilotinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Male or female patients ≥ 18 years of age
    • ECOG performance status 0, 1, or 2
    • Patients with CML-CP within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis). Standard conventional cytogenetic analysis must be done on bone marrow. FISH cannot be used.
    • Diagnosis of chronic myelogenous leukemia in chronic phase with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations (presence of BCR-ABL a review of a minimum 20 metaphases is required).
    • Documented chronic phase CML will meet all the criteria defined by:
    1. <15% blasts in peripheral blood and bone marrow
    2. <30% blasts plus promyelocytes in peripheral blood and bone marrow,
    3. <20% basophils in the peripheral blood,
    4. ≥100 x 109/L (≥100,000/mm3) platelets
    5. No evidence of extramedullary leukemic involvement, with the exception of
    • Adequate end organ function as defined by:
    1. total bilirubin <1.5xULN
    2. AST and ALT <2.5xULN
    3. estimated GFR of ≥ 30 ml/min
    4. Serum amylase and lipase ≤1.5xULN
    5. Aklaline phosphatase ≤ 2.5 xULN unless considered tumor related
    • Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before initiation of study drug
    • Patients must have the following laboratory values (≥(lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication:-
    1. Potassium ≥LLN
    2. Magnesium ≥ LLN
    3. Phosphorous ≥ LLN
    4. Total calcium, (corrected for serum albumin) ≥ LLN
    • Ability to provide written informed consent prior to any study related screening procedures being performed.
    E.4Principal exclusion criteria
    • Patients who are considered Ph- because they do not have a confirmed cytogenetic diagnosis of Philadelphia Chromosome with (9,22) translocation
    • Previously documented T315I mutations
    • Any previous exposure to dasatinib or any other medical treatment for CML. Exceptions are imatinib which will be allowed for up to 2 weeks and Hydroxyurea and Anagrelide which will be allowed for up to 4 weeks.
    Impaired cardiac function including any one of the following:-
    *LVEF<45% or below the institutional lower limit of the normal range (whichever is higher) as determined by echocardiogram
    *Inability to determine the QT interval on ECG
    *Complete left bundle branch block
    *Congenital long QT syndrome or a known family history of long QT syndrome.
    *History of or presence of clinically significant ventricular or atrial tachyarrhythmias
    *Clinically significant resting brachycardia (<50 beats per minute).
    *QTc>450 msec on the average of three serial baseline ECG (using the QTcF formula). If QTcF>450msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-scanned for QTc.
    *History of clinically documented myocardial infarction within past 12 months
    *History of unstable angina (during the last 12 months)
    *Other clinically significant heart disease (e.g. congestive heart failure or uncontrolled hypertension).
    • Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection).
    • History of significant congenital or acquired bleeding disorder unrelated to cancer.
    • Major surgery within 4weeks prior to day-1 of study or who have not recovered from prior surgery.
    • Treatment with other investigational agents within 30 days of Day-1.
    • History of non-compliance to medical regimens or inability to grant consent
    • Patients with other primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention
    • Patients actively receiving therapy with strong CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu/flockhart/table.htm. The Principal Investigator must be contacted if a patient needs to be started on any of these drugs during study treatment.
    • Patients actively receiving therapy with strong CYP3A4 inducers, (e.g. Dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John’s Wort) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu.flockhart/table.htm. The Principal Investigator must be contacted if a patient needs to be started on any of these drugs during study treatment.
    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
    • History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis.
    • Acute or chronic liver, pancreatic or severe renal disease considered unrelated to CML
    • Patients who are currently receiving treatment with any medications that have the potential to prolong QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. (Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a comprehensive list of agents that prolong the QT interval.)
    • Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential).
    E.5 End points
    E.5.1Primary end point(s)
    - Cytogenetic response will be assessed every 3 months by bone marrow aspiration, with evaluation of a minimum of 20 metaphases, until achievement of a complete cytogenetic response (CCyR). Molecular response will be assessed every 3 months using quantitative PCR for Bcr-Abl.
    - The rate of CCyR at 6 months will be the primary efficacy endpoint.
    - The rate of major and complete molecular responses over time will be secondary efficacy endpoints.
    - Patients will also undergo assessment for evidence of extramedullary disease

    The efficacy of Nilotinib 300mg BD will be compared with the efficacy of imatinib (400mg and 800mg) and Nilotinib 400mg BD as front line therapy in studies already reported (IRIS, MD Anderson and Italian studies).
    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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Information not present in EudraCT
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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 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 Yes
    E. description
    There is no comparator
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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 years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 40
    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 Decision2009-01-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-01-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-02-15
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