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    Clinical Trial Results:
    Feasibility study of chemoradiation, TRAstuzumab and Pertuzumab in resectable HER2+ esophageal carcinoma

    Summary
    EudraCT number
    		 2013-004111-42
    Trial protocol
    		 NL  
    Global end of trial date
    24 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Aug 2020
    First version publication date
    19 Aug 2020
    Other versions
    Summary report(s)
    		 JCO_TRAP

    Trial information

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    Trial identification
    Sponsor protocol code
    TRAP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02120911
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AMC
    Sponsor organisation address
    Meibergdreef 9, Amsterdam, Netherlands, 1105AZ
    Public contact
    Laurien Verkleij (trialmedonc@amc.uva.nl), Amsterdam UMC, +31 205668440, trialmedonc@amc.uva.nl
    Scientific contact
    Laurien Verkleij (trialmedonc@amc.uva.nl), Amsterdam UMC, +31 205668440, trialmedonc@amc.uva.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
    19 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the feasibility of preoperative treatment with pertuzumab and trastuzumab combined with preoperative chemoradiation (carboplatin, paclitaxel and radiation) in terms of percentage of completion with trastuzumab and pertuzumab.
    Protection of trial subjects
    Several measures were put in place to protect trial subjects: 1. If symptoms (e.g. fever, chills, headache, pruritus, nausea) occured during administration of study drugs, infusion was slowed down/interrupted. 2. Premedication was applied if patients experienced infusion-associated symptoms ; premedication was standard applied for chemoradiotherapy 3. Dose delays were permitted for presumed trastuzumab/pertuzumab related toxicity 4. Upon unacceptable toxicity, patients were withdrawn from the study 5. Patients were monitored carefully during and following each cycle
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2014
    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
    Netherlands: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    22
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from January 2014 to Sept 2019, in 7 centers in the Netherlands (Amsterdam UMC AMC, Catharina hospital, NKI-AvL, LUMC, UMCG, Anthonius hospital, Elisabeth hospital)

    Pre-assignment
    Screening details
    		 57 patients were primarily enrolled at 7 centers in the Netherlands. 17 patients were ineligible, due to not meeting all inclusion criteria (n=11) or not wanting to participate in the trial (n=6).

    Period 1
    Period 1 title
    Baseline Characteristics (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 TRAP cohort
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered intravenously on day 1 of each treatment cycle, using an initial dose of 4 mg/kg on day 1, followed by doses of 2 mg/kg weekly up to week 6. From week 7 onwards trastuzumab was administered at a dose of 6 mh/kg every three weeks

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pertuzumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was administered intravenously on day 1, 22, 43, 64, and 85, using a fixed dose of 840 mg.

    Number of subjects in period 1
    		TRAP cohort
    Started
    40
    Completed
    40

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline Characteristics
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Characteristics Total
    Number of subjects
    		 40 40
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 22 22
        From 65-84 years
    		 18 18
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 63 (44 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 33 33
    ECOG Performance Status
    ECOG performance status
    Units: Subjects
        ECOG PS 0
    		 33 33
        ECOG PS 1
    		 7 7
    HER2 status
    HER2-status
    Units: Subjects
        HER2 2+
    		 11 11
        HER2 3+
    		 29 29
    Clinical Tumor stage
    cT stage
    Units: Subjects
        cT2
    		 11 11
        cT3
    		 26 26
        cT4
    		 1 1
        cTx
    		 2 2
    Clinical Nodal stage
    cN stage
    Units: Subjects
        cN0
    		 8 8
        cN1
    		 27 27
        cN2
    		 5 5
    Tumor length
    Tumor length in cm
    Units: cm
        arithmetic mean (standard deviation)
    		 6.3 ( 2.7 ) -
    LVEF
    LVEF
    Units: Percentage
        median (full range (min-max))
    		 64 (52 to 87) -

    End points

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    End points reporting groups
    Reporting group title
    TRAP cohort
    Reporting group description
    		 -

    Subject analysis set title
    Feasibility
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Feasibility

    Primary: Feasibility

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    End point title
    		 Feasibility
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 cycle 1 to the end of planned treatment
    End point values
    		 TRAP cohort Feasibility
    Number of subjects analysed
    40
    40
    Units: Participants
        Completed all treatment cycles with study drugs
    33
    33
        No full completion of all treatment cycles
    7
    7
    Statistical analysis title
    		 Feasibility Test
    Statistical analysis description
    A one-sample test was used for binomial proportion with normal approximation and a one-sided p-value of <0.05. Feasibility was defined as more than or equal to 80% of patients completing treatment with trastuzumab and pertuzumab, whereas less than or equal to 62% was unfeasible.
    Comparison groups
    TRAP cohort v Feasibility
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 t-test, 1-sided
    Parameter type
    		 % of completion
    Point estimate
    80
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 80
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [1] - One-sample test
    [2] - P-value <0.05 was considered as statistically significant

    Secondary: Survival

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    End point title
    		 Survival
    End point description
    End point type
    Secondary
    End point timeframe
    From trial initiation to a median of 32.1 months follow-up
    End point values
    		 TRAP cohort
    Number of subjects analysed
    40
    Units: Percentage
    number (not applicable)
        1-year OS
    90
        1-year PFS
    82.5
        3-year OS
    72.3
        3-year PFS
    71.3
    No statistical analyses for this end point

    Secondary: Response

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    End point title
    		 Response
    End point description
    End point type
    Secondary
    End point timeframe
    Following resection
    End point values
    		 TRAP cohort
    Number of subjects analysed
    38 [3]
    Units: Participants
        Mandard 1
    13
        Mandard 2
    10
        Mandard 3
    10
        Mandard 4
    3
        Mandard 5
    2
    Notes
    [3] - 2 patients did not receive resection due to death of pulmonary fibrosis and interval metastases.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were monitored from start of treatment end of follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4.3
    Reporting groups
    Reporting group title
    Baseline Cohort4
    Reporting group description
    		 -

    Serious adverse events
    		 Baseline Cohort4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 40 (27.50%)
         number of deaths (all causes)
    11
         number of deaths resulting from adverse events
    1
    Investigations
    Creatinin increase
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Anastomotic Leakage
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Flank Pain
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Melena
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhea
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Fibrosis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Pneumonia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Baseline Cohort4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 40 (100.00%)
    Investigations
    Hypophosphatemia
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Cardiac disorders
    Cardiac symptoms
         subjects affected / exposed
    6 / 40 (15.00%)
         occurrences all number
    6
    Nervous system disorders
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    30 / 40 (75.00%)
         occurrences all number
    30
    Pain
         subjects affected / exposed
    18 / 40 (45.00%)
         occurrences all number
    18
    Odynophagia
         subjects affected / exposed
    11 / 40 (27.50%)
         occurrences all number
    11
    Alopecia
         subjects affected / exposed
    9 / 40 (22.50%)
         occurrences all number
    9
    Hoarseness
         subjects affected / exposed
    6 / 40 (15.00%)
         occurrences all number
    6
    Infusion related reaction
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    5
    Chills
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Sore throat
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Epistaxis
         subjects affected / exposed
    9 / 40 (22.50%)
         occurrences all number
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    28 / 40 (70.00%)
         occurrences all number
    28
    Diarrhea
         subjects affected / exposed
    29 / 40 (72.50%)
         occurrences all number
    29
    Vomiting
         subjects affected / exposed
    18 / 40 (45.00%)
         occurrences all number
    18
    Constipation
         subjects affected / exposed
    14 / 40 (35.00%)
         occurrences all number
    14
    Dyspaghia
         subjects affected / exposed
    16 / 40 (40.00%)
         occurrences all number
    16
    Dysgeusia
         subjects affected / exposed
    7 / 40 (17.50%)
         occurrences all number
    7
    Dyspepsia
         subjects affected / exposed
    6 / 40 (15.00%)
         occurrences all number
    6
    Oral mucositis
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Hematemesis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Dyspnea
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    14 / 40 (35.00%)
         occurrences all number
    14
    Dry skin
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    5
    Infections and infestations
    Infection
         subjects affected / exposed
    11 / 40 (27.50%)
         occurrences all number
    11
    Flu/Malaise
         subjects affected / exposed
    10 / 40 (25.00%)
         occurrences all number
    10
    Fever
         subjects affected / exposed
    7 / 40 (17.50%)
         occurrences all number
    7
    Esophagitis
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    11 / 40 (27.50%)
         occurrences all number
    11
    Dehydration
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    5

    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.
    None reported
    For support, Contact us.
    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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