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    Summary
    EudraCT Number:2012-004092-40
    Sponsor's Protocol Code Number:CAMN107I2201
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-04-22
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2012-004092-40
    A.3Full title of the trial
    A single-arm, multicenter, nilotinib treatment-free remission study in patients with BCR-ABL1 positive Chronic Myelogenous Leukemia in chronic phase who have achieved durable minimal residual disease (MRD) status on first line nilotinib treatment
    Et enkeltarmet multicenter forsøg vedrørende nilotinib-behandlingsfri remission hos patienter med BCR-ABL1 positiv kronisk myeloid leukæmi i kronisk fase, der har opnået vedvarende minimal resterende sygdom (MRD) på første linje nilotinib-behandling (EnestFreedom)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical research study evaluating the possibility to suspend the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients who have very small amount of leukemia cells remaining after nilotinib (Tasigna) treatment.
    Et enkeltarmet multicenter forsøg vedrørende nilotinib-behandlingsfri remission hos patienter med BCR-ABL1 positiv kronisk myeloid leukæmi i kronisk fase, der har opnået vedvarende minimal resterende sygdom (MRD) på første linje nilotinib-behandling (EnestFreedom)
    A.4.1Sponsor's protocol code numberCAMN107I2201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01784068
    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 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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Healthcare A/S
    B.5.2Functional name of contact pointKlinisk Forskningsafdeling
    B.5.3 Address:
    B.5.3.1Street AddressEdvard Thomsens Vej 14
    B.5.3.2Town/ cityKøbenhavn S
    B.5.3.3Post code2300
    B.5.3.4CountryDenmark
    B.5.6E-mailskriv.til@dkma.dk
    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
    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.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 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 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) 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
    Adult patients treated with a planned dose of nilotinib 300 mg BID (or at a reduced dose level of 400 mg QD if required from the perspective of tolerance) for a minimum of 2 calendar years for newly diagnosed BCR-ABL positive Chronic Myelogenous Leukemia in chronic phase and have achieved MR 4.5 (BCR-ABL ≤ 0.0032% IS) at any time point before being enrolled in the study
    E.1.1.1Medical condition in easily understood language
    Adult patients with CML who have been treated with nilotinib (Tasigna) for at least two years and who have achieved a certain level of molecular response prior to study entry.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054352
    E.1.2Term Chronic phase chronic myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the percentage of patients who are in Major Molecular Response (MMR) at 48 weeks after starting the treatment-free remission (TFR) phase (patients who required re-initiation of treatment will be considered as non-responders)
    E.2.2Secondary objectives of the trial
    1) To determine the percentage of patients who are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 weeks after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
    2) To determine the percentage of patients who are in MMR at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
    3) To determine the percentage of patients who are in MR4.5 at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
    4) To determine the percentage of patients in MMR at 48, 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase of nilotinib irrespective of whether or not patients required reinitiation of treatment
    Additional objectives apply
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study have to meet all of the
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    following criteria; additional inclusion criteria may apply as per protocol:
    1) Male or female patients ≥18 years of age
    2) Minimum of 2 calendar years of nilotinib treatment with at least the
    last 12 months of nilotininb treatment prior to pre-screening at the
    approved total daily dose of 600 mg or at a reduced dose of 400 mg QD if
    required from the perspective of tolerance for BCR-ABL positive CML in
    documented chronic phase at the time of diagnosis
    3) Evidence of typical BCR-ABL transcripts [b3a2 (e14a2) and/or b2a2
    (e13a2)] at the time of CML-CP diagnosis i.e. prior to first start of TKI
    treatment which are amenable to standardized RT-PCR quantification"
    4) Patient in MR4.5 at prescreening at Novartis designated lab
    5) ECOG performance status of 0-2
    6) Adequate end organ function as defined by:
    • Direct bilirubin ≤ 1.5 x ULN, except for i) patients with documented
    Gilbert's syndrome for whom any bilirubin value is allowed and ii) for
    patients with asymptomatic hyperbilirubinemia (liver transaminases and
    alkaline phosphatase within normal range)
    • SGOT(AST) and SGPT(ALT) ≤ 3 x ULN i.e. equivalent to ≤ Grade 1 NCICTCAE
    v.4.03
    • Serum lipase ≤ 2 x ULN i.e. equivalent to ≤ Grade 2 NCI-CTCAE v.4.03
    • Alkaline phosphatase ≤ 2.5 x ULN
    • Serum creatinine < 1.5 x ULN
    7) Patients must have the following electrolyte values within normal
    limits or corrected to be within normal limits with supplements prior to
    first dose of study medication:
    • Potassium (suggested keep to prevent issues with QT and/or rhythm
    abnormalities)
    • Magnesium (suggested keep to prevent issues with QT and/or rhythm
    abnormalities)
    • Total calcium (corrected for serum albumin)
    8) Patients must have normal marrow function as defined:
    • Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
    • Hemoglobin ≥ 9.0 g/dL
    • Platelets ≥ 100 x 109/L
    Additional inclusion criteria are defined in the protocol.
    E.4Principal exclusion criteria
    criteria:
    1) Previous treatment with BCR-ABL inhibitors other than nilotinib for
    more than a total cumulative duration of 4 weeks
    2) Previous treatment with alpha-interferon of any duration
    3) Previous anticancer agents for CML other than nilotinib except for
    cytoreduction after CML diagnosis until up to 4 weeks after first dose of
    nilotinib
    4) Known second chronic phase of CML after previous progression to
    AP/BC
    5) Poorly controlled diabetes mellitus (defined as HbA1c > 9%)
    6) Impaired cardiac function as defined in the protocol
    7) History of acute pancreatitis within 1 year of study entry or past
    medical history of chronic pancreatitis
    8) Known presence of significant congenital or acquired bleeding
    disorder unrelated to cancer
    9) History of another active malignancy within 5 years prior to study
    entry with the exception of previous or concomitant basal cell skin
    cancer and previous carcinoma in situ treated curatively
    10) Treatment with other investigational agents (defined as not used in
    accordance with the approved indication) within 4 weeks of Day 1
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    11) Patients actively receiving therapy with strong CYP3A4 inhibitors
    and/or inducers, and the treatment cannot be either discontinued or
    switched to a different medication prior to starting study drug.
    12) Patients actively receiving therapy with herbal medicines that are
    strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be
    either discontinued or switched to a different medication prior to
    starting study drug. These herbal medicines may include Echinacea,
    (including E. purpurea, E. angustifolia and E. pallida), Piperine,
    Artemisinin, St. John's Wort, and Ginkgo.
    13) Patients who are currently receiving treatment with any medications
    that have the potential to prolong the QT interval and the treatment
    cannot be either safely discontinued or switched to a different
    medication prior to starting study drug. (Please see
    http://crediblemeds.org/everyone/composite-list-all-qtdrugs/ for a list
    of agents that prolong the QT interval)
    14) 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)
    15) Pregnant or nursing (lactating) women, where pregnancy is defined
    as the state of a female after conception and until the termination of
    gestation, confirmed by a positive hCG laboratory test.
    16) Women of child-bearing potential, defined as all women
    physiologically capable of becoming pregnant, unless they are using
    highly effective methods of contraception during the study and for 14
    days after the final dose of nilotinib. Highly effective contraception is
    defined in the protocol.
    Additional exclusion criteria are defined in the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    BCR-ABL ≤ 0.1% IS (MMR or MR3) at 48 weeks after starting the treatment-free remission (TFR) phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase.
    E.5.1.1Timepoint(s) of evaluation of this end point
    48 weeks after starting the TFR phase
    E.5.2Secondary end point(s)
    1) BCR-ABL ≤ 0.0032% IS (MR4.5) at 48 weeks after starting the treatment-free remission (TFR) phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase.
    2) BCR-ABL ≤ 0.1% IS (MMR) at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9, and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks , and in the firsts 6, 7, 8, 9, and 10 years after starting the TFR phase.
    3) BCR-ABL ≤ 0.0032% IS (MR4.5) at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9, and 10 years after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks, and in the first 6, 7, 8, 9, and 10 years after starting the TFR phase.
    4) BCR-ABL ≤ 0.1% IS (MMR) at 48, 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) 48 weeks after starting the TFR phase
    2) - 4) at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9, and 10 years after starting the TFR.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 Information not present in EudraCT
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA117
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Austria
    Belgium
    Bulgaria
    China
    Colombia
    Denmark
    France
    Germany
    Greece
    Hungary
    Ireland
    Italy
    Japan
    Netherlands
    Poland
    Spain
    Sweden
    United Kingdom
    United States
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years11
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years12
    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: 171
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 44
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 180
    F.4.2.2In the whole clinical trial 215
    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)
    All patients still on study treatment at the time of End of Study, or if the study is stopped early, will be transitioned to prescribed nilotinib. Should nilotinib not be commercially available Novartis will have a transition plan in place to ensure that patients continue to have access to nilotinib without any interruption in treatment. Any patients who are in TFR at the End of the Study will be referred to their primary oncologist for continued monitoring of their level of BCR-ABL transcript.
    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 Decision2013-04-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-08
    P. End of Trial
    P.End of Trial StatusOngoing
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