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    Clinical Trial Results:
    Randomized 1. Line treatment with gemcitabine, capecitabine, oxaliplatin vs gemcitabin and cisplatin to patients with cholangiocarcinoma.

    Summary
    EudraCT number
    2013-004854-46
    Trial protocol
    DK  
    Global end of trial date
    01 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Sep 2020
    First version publication date
    17 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GI 1333
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Herlev University Hospital, Department of Oncology
    Sponsor organisation address
    Herlev Ringvej 75, Herlev, Denmark, 2730
    Public contact
    Oncology Department, Herlev University Hospital, 0045 38682329, ole.larsen@regionh.dk
    Scientific contact
    Oncology Department, Herlev University Hospital, 0045 38682329, ole.larsen@regionh.dk
    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
    30 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Progression free survival
    Protection of trial subjects
    Patients that signed informed consent and fulfilling eligibility criteria were included. Continued monitoring of standard safety parameters during treatment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Jun 2014
    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
    Denmark: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    47
    From 65 to 84 years
    52
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was opened for recruitment in June 2014 and closed for enrollment in November 2017 per protocol. Patients were included at 2 sites in Denmark.

    Pre-assignment
    Screening details
    Eligible patients were 18 years or older with histopathological diagnosis of nonresectable, recurrent, or metastatic BTC or a cytologic diagnosis in combination with radiological findings. Intrahepatic, perihilar, extrahepatic, and gallbladder cancers could be included—but not ampullary cancer. ECOG PS 0 or 1, bilirubin not above 2xULN.

    Pre-assignment period milestones
    Number of subjects started
    100
    Intermediate milestone: Number of subjects
    pre-treatment: 100
    Number of subjects completed
    96

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Protocol deviation: 2
    Reason: Number of subjects
    rapid progression of disease: 2
    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CapOxGem
    Arm description
    Oxaliplatin and gemcitabine every 2 weeks combined with continuos capecitabine
    Arm type
    Experimental

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    oxaliplatin 50 mg/m2 every second week (infusion time of 30 min) until progression of disease

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    gemcitabine 1000 mg/m2 every second week (infusion time of 30 min) until progression of disease

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    capecitabine 650 mg/m2 twice-daily, continuously until progression of disease

    Arm title
    CisGem
    Arm description
    Cisplatin and Gemcitabine on day 1 and 8 of each 3-week cycle, until progression of disease
    Arm type
    Active comparator

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    cisplatin 25 mg/m2 (infusion time of 60 min) on day 1 and day 8, repeated every 3 weeks until progression of disease (with restriction to accumulated dose of max 400 mg/m2)

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    gemcitabine 1000 mg/m2 (infusion time of 30 min) on day 1 and day 8, repeated every 3 weeks until progression of disease

    Number of subjects in period 1 [1]
    CapOxGem CisGem
    Started
    47
    49
    Completed
    41
    38
    Not completed
    6
    11
         Adverse event, serious fatal
    -
    1
         Physician decision
    -
    1
         Adverse event, non-fatal
    4
    7
         early death
    2
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 4 patient did not complete pre-treatment period

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CapOxGem
    Reporting group description
    Oxaliplatin and gemcitabine every 2 weeks combined with continuos capecitabine

    Reporting group title
    CisGem
    Reporting group description
    Cisplatin and Gemcitabine on day 1 and 8 of each 3-week cycle, until progression of disease

    Reporting group values
    CapOxGem CisGem Total
    Number of subjects
    47 49 96
    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 (full range (min-max))
    65 (21 to 85) 65 (39 to 82) -
    Gender categorical
    Units: Subjects
        Female
    24 26 50
        Male
    23 23 46
    ECOG performance status
    Units: Subjects
        ECOG PS 0
    23 23 46
        ECOG PS 1
    24 26 50

    End points

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    End points reporting groups
    Reporting group title
    CapOxGem
    Reporting group description
    Oxaliplatin and gemcitabine every 2 weeks combined with continuos capecitabine

    Reporting group title
    CisGem
    Reporting group description
    Cisplatin and Gemcitabine on day 1 and 8 of each 3-week cycle, until progression of disease

    Primary: Progression free Survival

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    End point title
    Progression free Survival [1]
    End point description
    End point type
    Primary
    End point timeframe
    Scans were performed every 12 weeks until progression of disease
    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: Sample size to small to compare the groups.
    End point values
    CapOxGem CisGem
    Number of subjects analysed
    47
    49
    Units: months
        median (confidence interval 95%)
    5.7 (3.0 to 7.8)
    7.3 (6.0 to 8.7)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    time from randomisation to death (censoring at database lock Aug 2019)
    End point values
    CapOxGem CisGem
    Number of subjects analysed
    47
    49
    Units: months
        median (confidence interval 95%)
    8.7 (6.5 to 11.2)
    12.0 (8.3 to 16.7)
    No statistical analyses for this end point

    Secondary: Tumor response

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    End point title
    Tumor response
    End point description
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks during treatment
    End point values
    CapOxGem CisGem
    Number of subjects analysed
    47
    49
    Units: subjects
        Complete Response
    0
    0
        Partial Response
    8
    8
        Stable Disease
    20
    31
        Progression
    14
    5
        Not assessable
    5
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first treatment to 28 days after last treatment with the trial
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI-CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    CapOxGem
    Reporting group description
    Oxaliplatin and gemcitabine every 2 weeks combined with continuos capecitabine

    Reporting group title
    CisGem
    Reporting group description
    Cisplatin and Gemcitabine on day 1 and 8 of each 3-week cycle, until progression of disease

    Serious adverse events
    CapOxGem CisGem
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 47 (34.04%)
    19 / 49 (38.78%)
         number of deaths (all causes)
    44
    46
         number of deaths resulting from adverse events
    0
    2
    Vascular disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 47 (4.26%)
    6 / 49 (12.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
    Additional description: patient in CapOxGem - allergic reaction to oxaliplatin patient in CisGem- allergic reaction to concomitant medication (not study treatment)
         subjects affected / exposed
    1 / 47 (2.13%)
    12 / 49 (24.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    Additional description: as symptom for COPD exacerbation
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiotoxicity
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: Non-STEMI
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stroke
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oral hemorrhage
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    ureteral stones
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
    Additional description: Summarised term Infection, includes cases of biliary tract infection, gasteroentritis, infection with unknow focus, pancreatitis, urinary tract infection
         subjects affected / exposed
    3 / 47 (6.38%)
    5 / 49 (10.20%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    hyperglycemia
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    CapOxGem CisGem
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 47 (100.00%)
    49 / 49 (100.00%)
    Investigations
    Neutropenia
         subjects affected / exposed
    4 / 47 (8.51%)
    30 / 49 (61.22%)
         occurrences all number
    4
    30
    Thrombocytopenia
         subjects affected / exposed
    10 / 47 (21.28%)
    16 / 49 (32.65%)
         occurrences all number
    10
    16
    Vascular disorders
    Thromoembolic event
         subjects affected / exposed
    7 / 47 (14.89%)
    12 / 49 (24.49%)
         occurrences all number
    7
    12
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    41 / 47 (87.23%)
    24 / 49 (48.98%)
         occurrences all number
    41
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 47 (21.28%)
    17 / 49 (34.69%)
         occurrences all number
    10
    17
    Febrile neutropenia
         subjects affected / exposed
    0 / 47 (0.00%)
    5 / 49 (10.20%)
         occurrences all number
    0
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    37 / 47 (78.72%)
    36 / 49 (73.47%)
         occurrences all number
    37
    36
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 47 (2.13%)
    10 / 49 (20.41%)
         occurrences all number
    1
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    35 / 47 (74.47%)
    34 / 49 (69.39%)
         occurrences all number
    35
    34
    Vomiting
         subjects affected / exposed
    20 / 47 (42.55%)
    15 / 49 (30.61%)
         occurrences all number
    20
    15
    Diarrhoea
         subjects affected / exposed
    19 / 47 (40.43%)
    9 / 49 (18.37%)
         occurrences all number
    19
    9
    Hepatobiliary disorders
    Biliary tract disorder
         subjects affected / exposed
    9 / 47 (19.15%)
    2 / 49 (4.08%)
         occurrences all number
    9
    2
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    20 / 47 (42.55%)
    0 / 49 (0.00%)
         occurrences all number
    20
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    33 / 47 (70.21%)
    40 / 49 (81.63%)
         occurrences all number
    33
    40

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2015
    In treatment arm CisGem, the treatment with Cisplatin was limited to an accumulated dose of max 400 mg/m2

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/32698410
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