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    Clinical Trial Results:
    Influence of a fatty beverage (Milk) on the absorption of erlotinib: a randomized, cross-over pharmacokinetic study (MERLOT-study)

    Summary
    EudraCT number
    		 2016-001597-15
    Trial protocol
    		 NL  
    Global end of trial date
    27 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Nov 2021
    First version publication date
    24 Nov 2021
    Other versions
    Summary report(s)
    		 Published paper MERLOT study

    Trial information

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    Trial identification
    Sponsor protocol code
    MERLOT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Erasmus MC cancer institute
    Sponsor organisation address
    Molewaterplein 40, Rotterdam, Netherlands, 3015 GD
    Public contact
    A.H.J. Mathijssen, Erasmus MC cancer institute, a.mathijssen@erasmusmc.nl
    Scientific contact
    A.H.J. Mathijssen, Erasmus MC cancer institute, a.mathijssen@erasmusmc.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: To determine the influence of the fatty beverage Milk on the systemic exposure (AUC) to erlotinib in patients with or without concomitant use of a PPI.
    Protection of trial subjects
    Study protocol was authorized by the local ethics committee
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    13
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients on active treatment with erlotinib

    Pre-assignment
    Screening details
    		 Checking for the in- and exclusion criteria (see protocol/paper/EudraCT form)

    Period 1
    Period 1 title
    Overall trial
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 arm 1
    Arm description
    		 phase A: intake without water phase B: intake with 250 ml milk
    Arm type
    		 cross-over arm

    Investigational medicinal product name
    Full milk
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Milk, 250ml every day taken concomitant with erlotinib

    Arm title
    		 arm 2
    Arm description
    		 phase A: intake with water + PPI phase B: intake with 250ml milk + PPI
    Arm type
    		 cross-over arm

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		arm 1 arm 2
    Started
    15
    15
    Completed
    15
    15
    Period 2
    Period 2 title
    baseline
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 arm 1
    Arm description
    		 phase A: intake without water phase B: intake with 250 ml milk
    Arm type
    		 cross-over arm

    Investigational medicinal product name
    Full milk
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Milk, 250ml every day taken concomitant with erlotinib

    Arm title
    		 arm 2
    Arm description
    		 phase A: intake with water + PPI phase B: intake with 250ml milk + PPI
    Arm type
    		 cross-over arm

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		arm 1 arm 2
    Started
    15
    15
    Completed
    15
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 67.5 (55 to 73.5) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    arm 1
    Reporting group description
    		 phase A: intake without water phase B: intake with 250 ml milk

    Reporting group title
    arm 2
    Reporting group description
    		 phase A: intake with water + PPI phase B: intake with 250ml milk + PPI
    Reporting group title
    arm 1
    Reporting group description
    		 phase A: intake without water phase B: intake with 250 ml milk

    Reporting group title
    arm 2
    Reporting group description
    		 phase A: intake with water + PPI phase B: intake with 250ml milk + PPI

    Primary: Change in Area Under the erlotinib plasma concentration Curve (AUC)

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    End point title
    		 Change in Area Under the erlotinib plasma concentration Curve (AUC)
    End point description
    End point type
    Primary
    End point timeframe
    geomean AUC arm A vs geomean AUC arm B
    End point values
    		 arm 1 arm 2 arm 1 arm 2
    Number of subjects analysed
    15
    15
    15
    15
    Units: ng/ml*h
        geometric mean (geometric coefficient of variation)
    23.0 ( 37 )
    22.4 ( 35 )
    11.7 ( 61 )
    11.6 ( 38 )
    Statistical analysis title
    		 Mixed effect model
    Statistical analysis description
    Given a clinically relevant difference of 30% in AUC, a within-patient standard deviation of 25%, 80% power and a two-sided significance level of 5%, 14 evaluable patients were required per study group (i.e. with or without esomeprazole) [19]; hence, a total of 28 patients had to be included. Analyses of AUC 24 and Cmax were performed on logtransformed values, since these parameters were assumed to follow a log-normal distribution [20]. Estimates for the mean differences in (log) AUC 24
    Comparison groups
    arm 1 v arm 2 v arm 1 v arm 2
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 80
         upper limit
    		 125
    Variability estimate
    Standard error of the mean

    Secondary: Change in other pharmacokinetic endpoints and toxicity

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    End point title
    		 Change in other pharmacokinetic endpoints and toxicity
    End point description
    Maximum plasma concentration (Cmax), time until Cmax (Tmax), plasma clearing (Cl) and erlotinib toxicity
    End point type
    Secondary
    End point timeframe
    total study period
    End point values
    		 arm 1 arm 2 arm 1 arm 2
    Number of subjects analysed
    15
    15
    15
    15
    Units: ug/ml
        geometric mean (geometric coefficient of variation)
    1.85 ( 38 )
    1.73 ( 21 )
    0.81 ( 55 )
    0.82 ( 40 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    total study period: 2 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    total cohort
    Reporting group description
    		 -

    Serious adverse events
    		 total cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 30 (3.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Musculoskeletal and connective tissue disorders
    Spinal fracture
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 total cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 30 (93.33%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    12
    Nausea
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    8
    Constipation
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    9
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    23 / 30 (76.67%)
         occurrences all number
    72
    Alopecia
         subjects affected / exposed
    12 / 30 (40.00%)
         occurrences all number
    34

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    NA

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32557346
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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