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    Summary
    EudraCT Number:2015-004998-33
    Sponsor's Protocol Code Number:CAMN107ADE22T
    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:2016-03-07
    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 number2015-004998-33
    A.3Full title of the trial
    Multicenter prospective trial after first or second unsuccessful treatment discontinuation in chronic myeloid leukemia estimating the efficacy of nilotinib in inducing the persistence of molecular remission after stopping TKI 2nd or 3rd time
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Stopping tyrosine kinase inhibitors a second or third time after unsuccesful treatment discontinuation in chronic myeloid leukemia
    A.3.2Name or abbreviated title of the trial where available
    NAUT
    A.4.1Sponsor's protocol code numberCAMN107ADE22T
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02917720
    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 SponsorUniversity of Heidelberg
    B.1.3.4CountryGermany
    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 supportNovartis GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversität Heidelberg, Medizinische Fakultät Mannheim
    B.5.2Functional name of contact pointMCC-Studienzentrale, III. Med. Klin
    B.5.3 Address:
    B.5.3.1Street AddressTheodor-Kutzer-Ufer 1-3
    B.5.3.2Town/ cityMannheim
    B.5.3.3Post code68167
    B.5.3.4CountryGermany
    B.5.4Telephone number+496213836967
    B.5.5Fax number+49621383731500
    B.5.6E-mailnaut@medma.uni-heidelberg.de
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    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
    CML-Patients in chronic phase having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not and are pretreated at least one year with any TKI after 1st stop
    E.1.1.1Medical condition in easily understood language
    CML-Patients in chronic phase having failed a prior attempt to stop imatinib or other TKIs therapy and are pretreated at least one year with any TKI after the last stop
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    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
    Assessment of duration of MMR or better at 12 and 36 months after stopping TKI therapy a second time in patients with at least three years prior TKI treatment comprising at least two years of nilotinib treatment within this trial and maintained stable MR4 for at least one year and MR4.5 for at least 6 months
    E.2.2Secondary objectives of the trial
    • Assessment of patients who re-achieved stable MR4.5, and were proposed a 2nd stop
    • Assessment of safety profile, tolerability and AEs under nilotinib (NIL) treatment
    • Assessment of QoL profiles under NIL treatment and comparison with previous TKI therapy before switch and after stopping
    • Identification of clinical and biological factors correlating with the persistence of MMR or better after stopping TKI , gender, duration of TKI treatment, immunological status; stop according to EUROSKI criteria y/n, molecular level at first stop
    • Treatment outcome in correlation with predefined biomarkers (pDC: CD86, PD-1L, PD1 expression, genetic expression profile)
    • Estimation of overall and progression-free survival, and probabilities of a restart of TKI treatment without prior molecular relapse
    • Time to re-achievement of MR4.5 after restart of therapy
    • Assessment of incidence of any AEs (e.g. from musculoskeletal system) that arise after stopping TKI treatment a second time
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Substudy 1: Cellular immune marker
    To determine the individual response of each patient to IFN stimulation in vitro, cytokine and chemokine production of PBMC may be analyzed.
    Moreover, serum will be analyzed to evaluate cytokine/chemokine profiles associated with response.

    Substudy 2: Telomere length analysis
    The aim of the study is to investigate the prognostic role of telomere shortening in patients with CML and molecular response to TKI treatment for disease recurrence upon cessation of TKI treatment. In addition, we will compare telomere length in (predominantly) normal blood cells at treatment discontinuation (BCR-ABL/ABL ratio < 0.001) to normal cells (in case of persisting remission) vs. leukemic cells in case of disease recurrence.

    Substudy 3: Investigating the TKI withdrawal syndrome
    In EURO-SKI, in the Nordic countries a withdrawal syndrome was described in about 15-20% of patients after stopping imatinib. As has been seen after stopping for the first time, myalgia and arthralgia, especially in the upper arms and shoulders may also be expected to occur at a second stop trial.
    To further investigate the syndrome we here purpose to investigate the following parameters and correlate these with the clinical outcome:
    • Procollagen,
    • Osteocalcin
    • crosslinked N-Telopeptide, type I collagen (NTx) (ELISA)
    • PTH and/or Calcitonin (at local laboratory)
    • M-CSF

    Substudy 4: Immunological Status 2
    Currently, only few predictive factors for successful stopping are known, for example the depth of response and the duration of imatinib treatment before stop. If there is a role of B-cell mediated humoral immunity in sustaining molecular remissions in patients who stop TKI treatment is unknown.
    There is a need for tools that may help selecting patients who have optimal chance of successful discontinuation, while preventing patients who have very few chance of success from stopping. In addition, we need to gain knowledge on the mechanism of sustained remission. To meet these goals, we will perform immunological research on participants of the NAUT study.
    We expect that these immunological side-studies will, first, enable us to identify biomarkers for successful second discontinuation and, second, to find ways to modulate the immune system in order to improve the success of treatment discontinuation.

    Substudy 5: Biomarkers predicting relapse
    There is still no data about the predictive role of molecular markers at the time point of TKI discontinuation. One goal of this substudy is to analyze expression signatures of white blood cells from peripheral blood and bone marrow of CML patients at time of stopping, especially immune signatures, in order of better understanding the suppression of minimal disease.

    Substudy 6: Soluble CD62L and TACE activity
    Immunological surveillance of MRD in CML may be of particular relevance for long-term control or even cure of the disease. Vice versa, insufficient immunological MRD control may be associated with disease recurrence upon discontinuation of TKI in patients with deep molecular response. We recently demonstrated that increased shedding of CD62L from the membrane of immune cells due to increased TACE (tumor necrosis factor-alpha converting enzyme) activity and the subsequent increase of soluble CD62L (sCD62L) are closely associated to disease burden and later molecular response in CP-CML treated up-front with the 2nd generation TKI nilotinib. Whether either sCD62 or TACE activity may serve as relapse-sensing tools upon TKI discontinuation remains elusive.
    Aims: Prospective evaluation of sCD62L and TACE activity as relapse sensing tools for later molecular relapse upon discontinuation of 2nd generation TKI in CML.
    E.3Principal inclusion criteria
    • Age ≥ 18 years
    • Patients with Ph -chromosome and/or the BCR-ABL fusion gene (either b3a2 and/or b2a2) positive CML
    • CML in CP having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not
    • Pretreatment at least one year with any TKI fter 1st stop or 2nd stop, respectively
    • Written informed consent
    E.4Principal exclusion criteria
    • Previous hematological relapse after first stop of TKI.
    • Failure to any TKI at any time during CML treatment TKI according to actual ELN criteria
    • Previous planned or performed allo SCT
    • Previous AP/BC at any time in the history of the disease
    • High cardiac risk according to ESC Score
    • Contraindication against nilotinib (see following)
    • Impaired cardiac function including any of the following:
    o Use of a ventricular paced pacemaker; congenital long QT syndrome or family history of; history or presence of significant ventricular or atrial tachyarrhythmias; clinically significant resting bradycardia (<50 bpm); QTcF >450 msec at baseline, myocardial infarction before baseline; other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension).
    • Treatment with inhibitors of CYP3A4 or medications that have been well documented to prolong the QT interval is contraindicated.
    • History of acute pancreatitis within one year of study entry or medical history of chronic pancreatitis.
    • Positive hepatitis B virus serology test or HBV infection
    • Any other malignancy except if neither clinically significant nor requires active intervention.
    • Severe or uncontrolled medical conditions (i.e., uncontrolled diabetes, acute or chronic liver disease, pancreatic, or severe renal disease unrelated to tumor, active or uncontrolled infection).
    • Women who are pregnant, breast feeding, or of childbearing potential without a negative serum pregnancy test at baseline. Male or female patients of childbearing potential unwilling to use an effective barrier contraceptive method.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is molecular relapse-free survival, measured at 12 months and 36 months after 2nd or 3rd stop.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final analysis will be performed after all enrolled patients have an at least three-year follow-up after 1 Month after discontinuation (Visit S1). With regard to hypothesis testing, the probability of molecular relapsefree survival in patients without a premature restart of TKI will be estimated and the number of patients with a premature restart will not
    be part of the denominator for the hypothesis testing. However, the probability of molecular relapse-free survival based on a denominator including all recruited patients will be provided, too.
    E.5.2Secondary end point(s)
    With a maximum observation time of five years (two years nilotinib treatment and three-year follow-up after 2nd or 3rd stop), overall survival and progression-free survival probabilities are expected to be relatively high (>90% for overall survival). Thus, regression modelling will not be possible for these variables. In any case, results will be described by the Kaplan-Meier method. The probabilities of a restart of TKI treatment without prior molecular relapse will be calculated by the CIF.
    Estimation of the number of patients in MR4.5 who would be eligible for stopping TKI therapy will be based on the information gained by regression modelling.
    The number of patients who regain MR4 and MR4.5 and the time to MR4 recovery will be analysed.
    The times 12 and 36 months were chosen to be in primary focus. However, other times might prove to be particularly important, e.g. 18 or 24 months after TKI discontinuation. Depending on the outcome of molecular relapse-free survival over time, an additional logistic regression analysis will be performed at a further time emerging to be of specific interest.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The times 12 and 36 months were chosen to be in primary focus. However, other times might prove to be particularly important, e.g. 18 or 24 months after TKI discontinuation. Depending on the outcome of molecular relapse-free survival over time, an additional logistic regression analysis will be performed at a further time emerging to be of specific interest.
    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) 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.8.4.1Number of sites anticipated in Member State concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA1
    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 Yes
    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 final analysis will be performed after all enrolled patients have an at least three-year follow-up after stopping TKI
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days10
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days9
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 56
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 75
    F.4.2.2In the whole clinical trial 75
    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)
    none.
    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 Decision2016-06-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-21
    P. End of Trial
    P.End of Trial StatusOngoing
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