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    Clinical Trial Results:
    A multi-center, open-label, pharmacokinetic study of oral nilotinib in pediatric patientswith newly diagnosed chronic phase (CP) Ph+ CML, with CP or accelerated phase (AP) Ph+ CMLresistant/intolerant to imatinib and/or dasatinib, or with refractory/relapsed Ph+ ALL

    Summary
    EudraCT number
    		 2010-018419-14
    Trial protocol
    		 FR   GB   DE   NL   IT  
    Global end of trial date
    01 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2016
    First version publication date
    31 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAMN107A2120
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01077544
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000290-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to characterize the PK of nilotinib in pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or refractory/relapsed Ph+ ALL to standard therapy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Apr 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    10
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients were enrolled into 2 strata of two age groups: Group 1: at least 7 patients ages 1 year to < 10 years, and Group 2: at least 7 patients ages ≥ 10 years to < 18 years.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 1 year to < 10 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib capsules were delivered in bottles with dose strengths of 50mg, 150mg and 200mg. Patients were administered nilotinib 230 mg/m2 (per BSA) bid, orally, rounded to the nearest 50 mg (max single dose 400 mg) for 28 days (1 cycle) for up to 12 cycles prior to protocol amendment 3 and up to 24 cycles post amendment 3. Capsules were to be swallowed whole with water. Apple sauce (puréed apple) may have been used as a vehicle for dosing where capsules were not able to be swallowed whole with water.

    Arm title
    		 Group 2
    Arm description
    		 >= 10 years to <18 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    AMN107
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib capsules were delivered in bottles with dose strengths of 50mg, 150mg and 200mg. Patients were administered nilotinib 230 mg/m2 (per BSA) bid, orally, rounded to the nearest 50 mg (max single dose 400 mg) for 28 days (1 cycle) for up to 12 cycles prior to protocol amendment 3 and up to 24 cycles post amendment 3. Capsules were to be swallowed whole with water. Apple sauce (puréed apple) may have been used as a vehicle for dosing where capsules were not able to be swallowed whole with water.

    Number of subjects in period 1
    		Group 1 Group 2
    Started
    8
    7
    Completed
    5
    2
    Not completed
    3
    5
         Adverse event, non-fatal
    -
    1
         New Cancer Therapy
    3
    3
         Disease Progression
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 1 year to < 10 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid.

    Reporting group title
    Group 2
    Reporting group description
    		 >= 10 years to <18 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid.

    Reporting group values
    		 Group 1 Group 2 Total
    Number of subjects
    		 8 7 15
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 8 0 8
        Adolescents (12-17 years)
    		 0 7 7
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 6.8 ± 1.16 13.7 ± 2.81 -
    Gender, Male/Female
    Units: Participants
        Female
    		 3 4 7
        Male
    		 5 3 8

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 1 year to < 10 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid.

    Reporting group title
    Group 2
    Reporting group description
    		 >= 10 years to <18 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid.

    Primary: Summary of nilotinib non-compartmental PK parameters: Cmax

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    End point title
    		 Summary of nilotinib non-compartmental PK parameters: Cmax [1]
    End point description
    The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for PK Analysis.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    7
    7
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    405.111 ± 42.5
    402.715 ± 35.2
    No statistical analyses for this end point

    Primary: Summary of nilotinib non-compartmental PK parameters: Tmax

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    End point title
    		 Summary of nilotinib non-compartmental PK parameters: Tmax [2]
    End point description
    The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for PK Analysis.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    7
    7
    Units: hr
        median (full range (min-max))
    2 (1.02 to 7.08)
    3 (2 to 7.88)
    No statistical analyses for this end point

    Primary: Summary of nilotinib non-compartmental PK parameters: AUClast (last = 24h)

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    End point title
    		 Summary of nilotinib non-compartmental PK parameters: AUClast (last = 24h) [3]
    End point description
    The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for PK Analysis.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    7
    7
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    4160.969 ± 38.5
    5707.368 ± 51.2
    No statistical analyses for this end point

    Primary: Summary of nilotinib non-compartmental PK parameters: AUC0-12h

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    End point title
    		 Summary of nilotinib non-compartmental PK parameters: AUC0-12h [4]
    End point description
    The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for PK Analysis.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    7
    7
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    2795.782 ± 35.7
    3393.296 ± 30.4
    No statistical analyses for this end point

    Primary: Summary of nilotinib steady-state PK parameters: AUCss

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    End point title
    		 Summary of nilotinib steady-state PK parameters: AUCss [5]
    End point description
    The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 8 - Cycle 1 Day 28
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for PK Analysis.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    7
    7
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    15129.182 ± 38
    14383.076 ± 33.6
    No statistical analyses for this end point

    Primary: Summary of nilotinib steady-state PK parameters: CLF (body surface area (BSA) adjusted)

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    End point title
    		 Summary of nilotinib steady-state PK parameters: CLF (body surface area (BSA) adjusted) [6]
    End point description
    The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 8 - Cycle 1 day 28
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for PK Analysis.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    7
    7
    Units: L/h/m^2)
        geometric mean (geometric coefficient of variation)
    15.356 ± 38.7
    15.922 ± 37
    No statistical analyses for this end point

    Primary: Summary of nilotinib steady-state PK parameters: Cmin

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    End point title
    		 Summary of nilotinib steady-state PK parameters: Cmin [7]
    End point description
    The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 8 - Cycle 1 Day 28
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for PK Analysis.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    7
    7
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    804.791 ± 33.7
    1072.85 ± 20.5
    No statistical analyses for this end point

    Secondary: Number of Ph+ CML participants with confirmed complete hematologic response (CHR)

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    End point title
    		 Number of Ph+ CML participants with confirmed complete hematologic response (CHR)
    End point description
    A confirmed complete hematological response (CHR) is defined when all of the following criteria are achieved at two consecutive assessments, at least 4 weeks apart: white blood cell (WBC) count < 10 × 109/L; platelet < 450 × 109/L; basophils < 5%; no blasts and promyelocytes in peripheral blood (PB); myelocytes + metamyelocytes < 5% in PB; and no extramedullary involvement. The information used for hematological assessment was to be obtained from the laboratory and extramedullary data, all merged by patient and date.
    End point type
    Secondary
    End point timeframe
    minimum of 12 cycles (28 days per cycle)
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    5
    6
    Units: Participants
        Yes
    5
    5
        No
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Ph+ CML participants with cytogenic response

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    End point title
    		 Number of Ph+ CML participants with cytogenic response
    End point description
    Cytogenetic response was initially assessed as the percentage of Ph+ metaphases in the bone marrow (BM) and performed within 21 days prior to study entry. A major cytogenetic response (0% to 35% Ph+ metaphases test positive for the Philadelphia chromosome) combines both complete cytogenetic (CCyR) and partial cytogenetic response (PCyR). CCyR implies 0% Ph+ metaphases in the BM, PCyR is > 0% to 35%, minor cytogenetic response (mCyR) is > 35% to 65%, minimal response is > 65% to 95% and no response is > 95% Ph+ metaphases in the BM.
    End point type
    Secondary
    End point timeframe
    minimum of 12 cycles (28 days per cycle)
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    5
    6
    Units: Participants
        Complete cytogenic response (CCyR)
    2
    2
        Partial cytogenic response (PCyR)
    0
    1
        Minor cytogenic response (mCyR)
    0
    1
        Minimal
    0
    0
        None
    0
    0
        Absence of Ph+ at baseline
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Ph+ CML participants with major molecular response (MMR)

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    End point title
    		 Number of Ph+ CML participants with major molecular response (MMR)
    End point description
    The bcr-abl gene fusion encodes for a BCR-ABL fusion protein. Depending on the precise location of the fusion, the molecular weight of this protein can range from 185 to 210 kDa. Consequently BCR-ABL is referred to as p185 or p210 transcript. For the patients expressing the major BCR-ABL transcript p210, molecular response was defined and reported as the percent ratio of BCR-ABL transcripts/control gene transcripts converted to a reference standard according to the International Scale (IS). A major molecular response (MMR) is defined as a BCR-ABL/control gene ratio ≤ 0.1% (equal to a 3 log reduction in BCR-ABL transcripts) on the IS. In this study, the control gene was abl.
    End point type
    Secondary
    End point timeframe
    minimum of 12 cycles (28 days per cycle)
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    5
    6
    Units: Participants
        Yes
    1
    2
        No
    4
    4
    No statistical analyses for this end point

    Secondary: Efficacy endpoints for Ph+ ALL patients

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    End point title
    		 Efficacy endpoints for Ph+ ALL patients
    End point description
    Best Response in Ph+ ALL patients was defined as either Complete Remission (CR) with platelet recovery, Complete Remission (CR) with incomplete platelet recovery, Partial Remission (PR) or Stable disease. Stable disease was defined is defined as failure to qualify for either CR, PR, or progressive disease.
    End point type
    Secondary
    End point timeframe
    minimum of 12 cycles (28 days per cycle)
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    3
    1
    Units: Participants
        Complete Remission with platelet recovery
    2
    1
        Complete Remission w/incomplete platelet recovery
    0
    0
        Partial remission
    0
    0
        Stable disease
    1
    0
        Progressive disease
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Age 1 to less than 10 years
    Reporting group description
    		 Age 1 to less than 10 years

    Reporting group title
    Age 10 to less than 18 years
    Reporting group description
    		 Age 10 to less than 18 years

    Serious adverse events
    		 Age 1 to less than 10 years Age 10 to less than 18 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 7 (42.86%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Appendix disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Age 1 to less than 10 years Age 10 to less than 18 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Catheter site pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    3
    1
    Xerosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    7
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    4
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 7 (42.86%)
         occurrences all number
    7
    4
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    Blood uric acid increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Red blood cell count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 8 (50.00%)
    2 / 7 (28.57%)
         occurrences all number
    12
    5
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    Lymphopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 7 (42.86%)
         occurrences all number
    2
    7
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    3
    Odynophagia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Toothache
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 7 (42.86%)
         occurrences all number
    7
    4
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    2
    2
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Dry skin
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Dyshidrotic eczema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    3
    1
    Exfoliative rash
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Psoriasis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 7 (28.57%)
         occurrences all number
    6
    2
    Rash erythematous
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Rash papular
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    5
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Bone pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Muscle spasms
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Pain in extremity
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    7
    1
    Tendon pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Device related infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Fungal skin infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Lip infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    4
    Nasopharyngitis
         subjects affected / exposed
    4 / 8 (50.00%)
    0 / 7 (0.00%)
         occurrences all number
    10
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    4
    1
    Skin infection
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Tinea pedis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    2
    2
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2010
    Amendment 1: The study was in the startup phase; no patients had been enrolled to date. As this was the first planned study of AMN107 (nilotinib) in the pediatric patient population, the primary purpose of this global amendment was to further enhance safety parameters related to this population. Consistent with this goal, additional ECG monitoring, additional clarification on assessments for disease monitoring and addition of a washout period for CYP3A4 inhibitors and inducers were implemented. Finally, this amendment clarified the disease response criteria for patients with Ph+ ALL.
    17 Feb 2012
    Amendment 2: The primary purpose of this global amendment was to align all language relative to pregnancy detection and prevention with the nilotinib program language and the internal Novartis pregnancy guideline requirements. An additional purpose was to extend the duration of the study to 24 cycles to provide continued drug supply access to patients benefiting from treatment, as well as obtain additional safety, tolerability and activity data. The final purpose of this amendment was to implement some clarifications and a correction, namely, the washout period for myelosuppressive chemotherapy in exclusion criteria #10. At the time of this amendment, 7 patients were enrolled.
    07 Aug 2013
    Amendment 3: The original title, “A multi-center, open-label, pharmacokinetic study of oral nilotinib in pediatric patients with Gleevec® (imatinib)-resistant/intolerant Ph+ CML chronic phase (CP) or accelerated phase (AP) or with refractory/relapsed Ph+ ALL” was modified to the current title “A multi-center, open-label, pharmacokinetic study of oral nilotinib in pediatric patients with newly diagnosed chronic phase (CP) Ph+ CML, with CP or accelerated phase (AP) Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or with refractory/relapsed Ph+ ALL. The primary purpose of this global amendment was to expand the current patient population in order to assist in completing enrollment for the younger age group by including pediatric patients with (1) Newly diagnosed CP-Ph+ CML and (2) CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib. At the time of this amendment, 9 patients were enrolled. The inclusion of newly diagnosed CP-Ph+ CML patients reflected the approval of the adult indication in this patient group and was based on the expected positive benefit risk ratio in the pediatric population. The inclusion of dasatinib-resistant or -intolerant Ph+ CML patients was based on the feedback from the pediatric community to reflect the current clinical practice of treating newly diagnosed pediatric CP-Ph+ CML patients with second generation TKIs as well as with imatinib.
    07 Aug 2013
    Amendment 3 Continued: The expansion of the patient population was also reflected in the Pediatric Investigational Plan (PIP) and Written Request (WR), which were approved by the EMA and FDA, respectively. In addition, FDA requested the implementation of additional safety monitoring measures in newly diagnosed CP-Ph+ CML patients as a condition to enroll these patients in the study.
    14 Apr 2014
    Amendment 4: Amendment 4: The study was in the enrollment phase with a total of 12 enrolled patients as of 14-Feb-2014. Group 1 (younger age cohort; 1 year to < 10 years) had enrolled 5 patients to date as of 14-Feb-2014. Group 2 (older age cohort; ≥ 10 years to < 18 years) completed enrollment with 7 patients and an IA was conducted per protocol. As a result of the IA, the dose of 230 mg/m2 bid was confirmed as the recommended Phase II dose in the ≥ 10 years to < 18 years age group. The primary purpose of amendment 4 was to implement modifications to align with the latest version of Investigator’s Brochure of the product AMN107 (nilotinib, Tasigna®), Edition 9 dated 26-Jun-2013 (and upcoming Edition 10) regarding management of ischemic vascular or cardiovascular events.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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