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    Summary
    EudraCT Number:2004-001483-51
    Sponsor's Protocol Code Number:CAMN107A2101
    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:2005-05-04
    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 number2004-001483-51
    A.3Full title of the trial
    A phase IA/II multicenter, dose-escalation study of oral AMN107 on a continuous daily dosing schedule in adult patients with Gleevec-resistant/intolerant CML in chronic or accelerated phase or blast crisis, relapsed/refractory Ph+ ALL and other hematological malignancies
    A.3.2Name or abbreviated title of the trial where available
    NA
    A.4.1Sponsor's protocol code numberCAMN107A2101
    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 SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharmaceuticals UK Limited
    B.5.2Functional name of contact pointMedical Information Services
    B.5.3 Address:
    B.5.3.1Street AddressFrimley Business Park
    B.5.3.2Town/ cityFrimley, Camberley, Surrey
    B.5.3.3Post codeGU16 7SR
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01276698370
    B.5.5Fax number01276698449
    B.5.6E-mailmedinfo.uk@novartis.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 numberEU/3/06/375
    D.3 Description of the IMP
    D.3.1Product nameTasigna
    D.3.2Product code AMN107A
    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.3.8INN - Proposed INNnilotinib
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.3Other descriptive name4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-y
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee 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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    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 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 Yes
    D.2.1.1.1Trade name Tasigna
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    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/3/06/375
    D.3 Description of the IMP
    D.3.1Product nameTasigna
    D.3.2Product code AMN107A
    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.3.8INN - Proposed INNnilotinib
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.3Other descriptive name4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-y
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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.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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee 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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    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 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
    CML in accelerated or chronic phase or blast crisis, relapsed/refractory Ph+ ALL, systemic mastocytosis, or hypereosinophilic syndrome.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10009700
    E.1.2Term CML
    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
    Phase I
    •Determine the MTD and DLT of AMN107 as a single agent when administered as an oral once-daily dose or twice daily dose to adult patients with Gleevec-resistant CML in chronic phase, accelerated phase or blast crisis, or relapsed/refractory Ph+ ALL.
    •To characterize the PK profile in plasma and, where samples are available, in tumor cells and normal hematopoietic cells
    Phase II
    •To evaluate the efficacy and safety of AMN107 in patients with imatinib-resistant or intolerant CML-BC, imatinib-resistant or intolerant CML-AP and imatinib-resistant or intolerant CML-CP
    •To evaluate safety and preliminary anticancer activity of AMN107 in relapsed/refractory patients with Ph+ ALL and in patients with HEL/CEL and SM
    E.2.2Secondary objectives of the trial
    Phase I
    •To characterize the safety and tolerability of AMN107
    •To characterize the pharmacodynamic profile of AMN107 by assessing the following changes:
    - the mutational status of Abl
    - the Bcr-Abl, Stat 5,Stat 1,Crk-L, c-kit,PDGFR,AKT phosphorylation status
    - Crk-L analysis
    •For the other secondary objectives see protocol section 2.2.1
    Phase II
    •To evaluate the population pharmacokinetics of AMN107
    CML
    1.To assess changes in Bcr-Abl transcript and Crk-L protein in malignant cells taken from the bone marrow and/or blood, and mutational analysis of Bcr-Abl
    2.To examine whether individual genetic variation in genes relating to drug metabolism, CML and the drug pathway confer differential response to AMN107.
    3.To identify gene expression patterns in tumor cells that are associated with treatment response to AMN107 or that correlate with the severity or progression of CML.
    For secondary objectives in ALL, HES/CEL and SM see protocol sections 2.2.2.2 and 2.2.3
     
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    Patients must have the following laboratory values:
    Potassium ≥ LLN (lower limit of normal) or correctable with supplements
    Total calcium (corrected for serum albumin) ≥ LLN or correctable with supplements
    Magnesium ≥ LLN or correctable with supplements
    Phosphorus ≥ LLN or correctable with supplements
    ALT and AST ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to tumor
    Alkaline phosphatase ≤ 2.5 x ULN
    Serum bilirubin ≤ 1.5 x ULN
    Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance  50 ml/min

    E.4Principal exclusion criteria
    Cytopathologically confirmed CNS infiltration
    NB: in absence of suspicion of CNS involvement, lumbar puncture is not required
    •Impaired cardiac function, including any one of the following
    •LVEF < 45% as determined by MUGA scan or echocardiogram
    •Complete left bundle branch block
    •Use of a cardiac pacemaker
    •ST depression of > 1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads
    •Congenital long QT syndrome
    •History of or presence of significant ventricular or atrial tachyarrhythmias
    •Clinically significant resting bradycardia (< 50 beats per minute)
    •QTc > 480 msec (> 450 msec in Phase II) screening ECG (using the QTcF formula)
    •Right bundle branch block plus left anterior hemiblock, bifascicular block
    •Myocardial infarction within 3 months prior to starting AMN107
    •Angina pectoris (unstable angina pectoris diagnosed or treated during the last 12 months in Phase II)
    •Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
    •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of AMN107 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
    •Use of therapeutic warfarin.
    •Acute or chronic liver or renal disease considered unrelated to tumor
    •Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
    •Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤ 1 week prior to starting study drug. Erythropoietin is allowed.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:

    1. Safety parameters, particulary dose limiting toxicity (DLT) during Cycle 1
    2. Pharmacokinetic parameters (Tmax, Cmax, AUC0-24hours)

    Phase II

    Response rates as follows:

    Arm 1(Ph+ ALL) Hematological Response (Complete response + Partial response [CR + PR])
    Arm 2 (CML-BC) Complete Hematologic Response and Major (Complete or Partial) Cytogenetic Response
    Arm 3 (CML-AP) Complete Hematologic Response and Major (Complete or Partial) Cytogenetic Response
    Arm 4 (CML-CP) Major Cytogenetic Response
    Arm 5 (HES/CEL) Complete response + Partial response [CR + PR]
    Arm 6 (SM) All categories of response better than stable disease, ie, complete remission, incomplete remission, pure clinical response, good partial response and minor response

    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 Yes
    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.8.3 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.8.5The trial involves multiple Member States Yes
    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
    The extension protocol will allow patients to continue to receive AMN107 until their end-of-study evaluation visit which is to occur no later than 30-Nov-2011 defined as the LPLV and last dose of study drug in the extension study, or as long as they remain on study, until either death, the development of intolerable toxicity or the investigator feels it is no longer in the patient's best interest to continue therapy, whichever comes first.
    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 months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-05-04. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 527
    F.4.2.2In the whole clinical trial 955
    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 continue treatment with AMN107 until the patient experiences unacceptabe toxicity that precludes any further treatment, disease progression and/or as long as the patient is benefiting at the discretion of the investiagtor.
    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 Decision2005-02-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-02-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-09-20
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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