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    Summary
    EudraCT Number:2015-000968-34
    Sponsor's Protocol Code Number:CAMN107ADE20
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-08-03
    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 number2015-000968-34
    A.3Full title of the trial
    A Phase IV single arm, multicenter, open-label study assessing deep molecular response in adult patients with newly diagnosed Philadelphia chromosome positive CML in chronic phase after two years of treatment with nilotinib 300mg BID
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase IV single arm, multicenter, open-label study assessing deep molecular response in adult patients with newly diagnosed Philadelphia chromosome positive CML in chronic phase after two years of treatment with nilotinib 300mg BID
    A.4.1Sponsor's protocol code numberCAMN107ADE20
    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 SponsorNovartis Pharma GmbH
    B.1.3.4CountryGermany
    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 supportNovartis Pharma GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma GmbH
    B.5.2Functional name of contact pointMedizinischer infoservice
    B.5.3 Address:
    B.5.3.1Street AddressRoonstr. 25
    B.5.3.2Town/ cityNürnberg
    B.5.3.3Post code90429
    B.5.3.4CountryGermany
    B.5.4Telephone number+491802232300
    B.5.5Fax number+4991127312160
    B.5.6E-mailinfoservice.novartis@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 Yes
    D.2.1.1.1Trade name Tasigna 150 mg
    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 namenilotinib
    D.3.2Product code AMN107
    D.3.4Pharmaceutical form Capsule, hard
    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 INNNILOTINIB
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.4EV Substance CodeSUB25225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    The trial aims to evaluate the efficacy and quality of life of nilotinib 300mg BID in patients with chronic myleoid leukemia in chronic phase.
    E.1.1.1Medical condition in easily understood language
    The trial evaluates the proportion of patients with deep molecular response MR4.5 (IS) after two years of treatment with nilotinib 300mg BID.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10009700
    E.1.2Term CML
    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
    To evaluate the proportion of patients who are in deep molecular response MR4.5 (IS) at 24 months of study treatment, measured in a standardized EUTOS MR4.5 laboratory.
    E.2.2Secondary objectives of the trial
    To determine the proportion of patients who are in deep molecular response MR4 (IS) at 24 months of study treatment.
    To determine the proportion of patients who are in MMR at 12 months of study treatment.
    To determine the proportion of patients who are in CCyR at 6 months of study treatment.
    To evaluate progression-free survival (PFS) and time to progression to AP/BC.
    To evaluate quality of life of 300mg nilotinib BID therapy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients at least 18 years of age
    2. ECOG 0, 1, or 2.
    3. Patients within 6 months of diagnosis of CML in chronic phase with cytogenetic confirmation of Ph+ [t(9;22)
    translocation]; if the bone marrow sample is taken within 12 weeks of the start of study treatment but before the
    patient consents, the bone marrow should not be repeated after the patient formally consents to the study.
    4. 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 hepatosplenomegaly.
    5. Patients must be previously untreated for CML with the exception of 6 months treatment with hydroxyurea and a
    maximum of 6 weeks treatment with imatinib
    6. Adequate end organ function as defined by:
    • Total bilirubin < 1.5 x ULN (upper limit of normal) except know Mb. Gilbert
    • AST (SGOT), ALT (SGPT) < 3 x ULN or ≤ 5.0 x ULN if considered due to leukemia
    • Creatinine < 1.5 x ULN
    • Serum amylase and lipase ≤ 1.5 x ULN
    • Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related.
    7. Normal serum levels ≥ LLN (lower limit of normal) of potassium, magnesium, total calcium corrected for serum albumin
    or phosphorus, or correctable to within normal limits with supplements, prior to the first dose of study medication
    8. Ability to provide written informed consent prior to any study related screening procedures being performed.
    E.4Principal exclusion criteria
    1. Contraindication to excipients in study medication
    2. Known impaired cardiac function, including any of the following:
    • 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 bradycardia (<50 beats per minute)
    • QTcF >450 msec (using the QTcF formula). If QTcF > 450 msec and electrolytes are not within normal ranges,
    electrolytes should be corrected and the patient re tested for the QTc
    • History of clinically documented myocardial infarction within 12 months prior to study entry
    • History of unstable angina during the last 12 months
    • Other clinical significant heart disease (congestive heart failure)
    3. History of acute (within 1 year of starting study medication) or chronic pancreatitis
    4. Severe and/or uncontrolled concurrent medical conditions that in the opinion of the investigator could cause
    unacceptable safety risks or compromise compliance with the protocol (e.g., acute artherothrombotic events (such as
    ischemic heart disease, acute peripheral arterial occlusive disease, symptomatic carotid stenosis/cerebrovascular
    accident), uncontrolled diabetes mellitus, active or uncontrolled infections, uncontrolled severe hypertension, and
    uncontrolled severe dyslipidemia, acute or chronic liver or severe renal disease.
    5. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
    6. History of significant congenital or acquired bleeding disorder unrelated to cancer
    7. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers
    (see http://medicine.iupui.edu/clinpharm/ddis/main-table/)
    or medications that have the potential to prolong the QT interval
    (see https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf) which cannot be either discontinued or switched to
    a different medication prior to starting study drug
    8. Patients who have not recovered from prior surgery
    9. Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior
    to baseline and (d) 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).
    Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are
    using highly effective methods of contraception during dosing and for 14 days after the final dose of nilotinib. Patients
    using an oral hormonal contraception method should complete their monthly treatment course. Highly effective
    contraception methods include:
    • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
    • Combination of any two of the following (a+b or a+c, or b+c) listed below:
    a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception
    b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
    In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
    10. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active
    intervention with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ
    treated curatively
    11. Treatment with other investigational agents within 30 days of Day 1
    12. Patients not able to understand and to comply with study instructions and requirements
    13. Refusal to give informed consent
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is the rate of MR4.5 at 24 months of study treatment measured in a standardized EUTOS MR4.5 laboratory. MR4.5 is defined as either (i) detectable disease ≤ 0.0032% BCR-ABLIS or (ii) undetectable disease in cDNA with 32 000 – 99 999 ABL1 transcripts or 77 000 – 239 999 GUSB transcripts.
    E.5.1.1Timepoint(s) of evaluation of this end point
    evaluation will take place for all patients after 24 months of study treatment
    E.5.2Secondary end point(s)
    MR4 (IS)
    - MR4 (IS) is defined in this study as either (i) detectable disease ≤0.01% BCR-ABLIS or (ii) undetectable disease in cDNA with 10 000 – 31 999 ABL1 transcripts or 24.000 – 76 999 GUSB transcripts.
    - The rate of MR4 (IS) at 24 months of study treatment will be computed by dividing the number of patients who fit the definition of response at 24 months by the total number of patients in the analysis set.
    MMR
    - MMR is defined as a ≥3 log reduction from the standardized baseline or ≤ 0.1% BCR-ABLIS
    - The rate of MMR at 12 months of study treatment will be computed by dividing the number of patients who fit the definition of response at 12 months by the total number of patients in the analysis set
    CCyR
    - Complete cytogenetic response is defined as 0% Ph+ metaphases
    - Rate of CCyR at 6 months of study treatment will be calculated by dividing the number of patients who fit the definition of response at 6 month by the total number of Ph+ patients in the analysis set
    Outcome
    - Time to progression to AP/BC is defined as the time from the date of start of study treatment to the date of earliest transformation to AP/BC, or CML-related death. Rates of progression at various time points will also be provided.
    - Progression-free survival is defined as the time from the date of start of study treatment to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause, whichever is earlier.
    E.5.2.1Timepoint(s) of evaluation of this end point
    evaluation will take place for all patients after 24 months of study treatment
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 concerned107
    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 patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state170
    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)
    The investigator decides about further treatment after the end of the study in the best interest of the patient. Tasigna is commercially available.
    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 Decision2015-08-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-07
    P. End of Trial
    P.End of Trial StatusOngoing
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