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    Summary
    EudraCT Number:2004-001483-51
    Sponsor's Protocol Code Number:CAMN107A2101
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-09-23
    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 ConcernedDenmark - DHMA
    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 CML in accelerated phase or blast crisis, relapsed/refractory Ph+ ALL, and other hematologic malignancies
    A.3.2Name or abbreviated title of the trial where available
    NA
    A.4.1Sponsor's protocol code numberCAMN107A2101
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberNA
    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 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 Information not present in EudraCT
    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 nameAMN107
    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 INNNA
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107-AAA.001
    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 chronic or accelerated phase or blast crisis, relapsed/refractory Ph+ ALL, and other hematologic malignancies
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •Determine the maximum tolerated dose (MTD) and dose-limiting toxicity DLT of AMN107 as a single agent when administered as an oral once-daily dose to adult patients with Gleevec-resistant CML in 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
    E.2.2Secondary objectives of the trial
    •At the MTD, to characterize the safety and tolerability of AMN107, including acute and chronic toxicities in patients with Gleevec-resistant CML in accelerated phase or blast crisis, relapsed/refractory Ph+ ALL, systemic mastocytosis, or hypereosinophilic syndrome
    •To characterize the pharmacodynamic profile of AMN107 by assessing changes in the following parameters pre- and post-therapy:
    - the mutational status of Abl
    - the Bcr-Abl phosphorylation status
    - Stat 5 analysis/Stat 1 analysis
    - Crk-L analysis
    - QRT PCR analysis
    •To investigate tumor-specific mutations and compare gene expression change in tumor cells with blood cell and plasma
    •To investigate the effects of genetic variation in drug metabolism genes, hematologic malignancy genes and drug target genes on patient response
    •To obtain blood samples from patients at the MTD dose level to perform pharmacogenetic analyses.
    •At the MTD, to evaluate safety and preliminary anticancer activity
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    •Patients with a cytopathologically confirmed diagnosis of Ph+ ALL who are either relapsed after or refractory to standard therapy, or patients with CML in blast crisis, or CML patients in accelerated phase who are resistant to Gleevec®. Patients with Ph+ ALL who have minimal residual disease following stem cell transplantation may only be enrolled during the dose escalation portion of the study.
    •Following MTD determination, patients with a cytopathologically confirmed diagnosis of either CML in chronic phase who are Gleevec® resistant (Post text supplement 6), systemic mastocytosis or hypereosinophilic syndrome/ chronic eosinophilic leukemia. Patients with systemic mastocytosis or hypereosinophilia must have a clinical indication for treatment. HES/CEL patients should meet standard disease-definition criteria (Coutre and Gotlib 2004). Systemic mastocytosis patients should meet standard disease-definition criteria (Tefferi and Pardanani 2004)
    •Following MTD determination, patients with any of the eligible diseases who are Gleevec® intolerant (defined as patients who have discontinued Gleevec® therapy due to a grade 3 or 4 adverse event and have not had a major response to Gleevec®).
    •Age ≥ 18 years old
    •WHO Performance Status of ≤ 2 (Post-text suppl. 3)
    •Patients must have the following laboratory values:
    •Cytoreductive therapy with vincristine or cyclophosphamide is permitted up to 7 days prior to first administration of AMN107. Corticosteroids can be administered up to 48 hours prior to first administration of AMN107. Hydroxyurea is permitted as clinically indicated during the dose escalation phase
    •Potassium ≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication
    •Total calcium (corrected for serum albumin) ≥ LLN or correctable with supplements
    •Magnesium ≥ LLN or corrected to within normal limits with supplements prior to the first dose of study medication
    •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
    •Written informed consent
    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% or below institutional lower limit of the normal range (which ever is higher) 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 > 450 msec on screening ECG (using the QTcF formula)
    •Right bundle branch block plus left anterior hemiblock, bifascicular block
    •Myocardial infarction within 12 months prior to starting AMN107
    •Unstable angina diagnosed or treated during the past 12 months
    •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.
    •Patients who are currently receiving treatment with any of the medications listed in Post-text supplement 4 (Amendment 8) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Post-text supplement 4 (Amendment 8) have the potential to prolong the QT interval or are CYP3A4 inhibitors.
    •Patients who have received chemotherapy ≤ 1 week (6 weeks for nitrosurea or mitomycin-C) or who are within 5 half-lives of their last dose chemotherapy dose prior to starting study drug or who have not recovered from side effects of such therapy.
    •Patients who have received Gleevec® ≤ 1 week or who have not recovered from side effects of such therapy.
    •Patients who have received immunotherapy ≤1 week prior to starting study drug or who have not recovered from side effects of such therapy
    •Patients who have received any investigational drug ≤ 4 weeks or investigational cytotoxic agent within 1 week (or who are within 5 half-lives of a previous investigational cytotoxic agent) prior to starting study drug or who have not recovered from side effects of such therapy
    •Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation < 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
    •Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
    •Patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of AMN107). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug
    •Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
    •Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
    •Patients unwilling or unable to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    Dose escalation phase (phase I):

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

    Dose expansion phase (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 Information not present in EudraCT
    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
    Last visit of last subject
    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 2005-09-23. 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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 155
    F.4.2.2In the whole clinical trial 269
    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 Decision2005-10-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-10-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-09-20
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