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    Clinical Trial Results:
    Phase II of randomized study of the continuous versus standard capecitabine treatment in patients with metastatic breast cance”

    Summary
    EudraCT number
    		 2004-002759-15
    Trial protocol
    		 ES  
    Global end of trial date
    30 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2020
    First version publication date
    13 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    XEL-CONT-VS ESTANDAR
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00418028
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Miguel Martín. GEICAM (Spanish Breast Cancer Research Group Foundation).
    Sponsor organisation address
    Av. de los Pirineos, San Sebastián de los Reyes/Madrid, Spain, 28703
    Public contact
    GEICAM (Spanish Breast Cancer Research Group Foundation)., GEICAM (Spanish Breast Cancer Research Group Foundation)., +34 916592870, inicio_ensayos@geicam.org
    Scientific contact
    GEICAM (Spanish Breast Cancer Research Group Foundation)., GEICAM (Spanish Breast Cancer Research Group Foundation)., +34 916592870, inicio_ensayos@geicam.org
    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
    03 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess non-inferiority in terms of time to progression within one year of capecitabine treatment group in continuous administration versus capecitabine treatment group in standard administration.
    Protection of trial subjects
    Each patient was monitored on a regular basis in order to detect potential adverse events. Before each cycle administration was evaluated white cell count, neutrophils/granulocytes, hemoglobin and platelet count, total bilirubin, GOT/GPT, alkaline phosphatase total protein, clearance of creatinine (calculated), serum creatinine and also physical examination and functional status (ECOG).
    Background therapy
    		 The approved capecitabine regimen in monotherapy in metastatic breast cancer is 1,250 mg/m2 twice daily, two weeks on one week off. Dose modifications are often required due to appearance of severehand-foot syndrome. We tested a continuous regimen with lower daily dose but similar cumulative dose trying to reduce the severity of adverse events maintaining the efficacy
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Nov 2004
    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
    Spain: 192
    Worldwide total number of subjects
    192
    EEA total number of subjects
    192
    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)
    118
    From 65 to 84 years
    73
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between November 2004 and August 2010, 195 patients were randomly assigned to Cint (97) and Ccont (98) in 13 GEICAM sites in Spain. Three patients never received treatment, leaving 192 for ITT analysis (95 Cint; 97 Ccont); 5 patients in each treatment arm had major protocol violations, leaving 182 PP evaluable patients.

    Pre-assignment
    Screening details
    		 To be eligible, patients had to be over age 18, have confirmed histologicaladenocarcinoma of the breast that was metastatic or inoperable locally advanced and negative for HER2/neu overexpression. Patients were excluded if they had prior severe reactions or hypersensitivity to fluoropyrimidines.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A, Cint
    Arm description
    		 Capecitabine doses of 1250 mg/m2 orally twice-daily (morning and evening which is the equivalent to one 2500mg/m2 dose) during 14 days, in 3 week cycles with a resting period of 7 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 1250 mg/m2 orally twice-daily (morning and evening which is the equivalent to one 2500mg/m2 dose) during 14 days, in 3 week cycles with a resting period of 7 days.

    Arm title
    		 Arm B, Ccont
    Arm description
    		 Capecitabine at doses of 800 mg/m2 twice daily continuously, without rest periods, over the entire 21-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 1250 mg/m2 orally twice-daily (morning and evening which is the equivalent to one 2500mg/m2 dose) during 14 days, in 3 week cycles with a resting period of 7 days.

    Number of subjects in period 1
    		Arm A, Cint Arm B, Ccont
    Started
    95
    97
    Completed
    90
    92
    Not completed
    5
    5
         Protocol deviation
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A, Cint
    Reporting group description
    		 Capecitabine doses of 1250 mg/m2 orally twice-daily (morning and evening which is the equivalent to one 2500mg/m2 dose) during 14 days, in 3 week cycles with a resting period of 7 days.

    Reporting group title
    Arm B, Ccont
    Reporting group description
    		 Capecitabine at doses of 800 mg/m2 twice daily continuously, without rest periods, over the entire 21-day cycle.

    Reporting group values
    		 Arm A, Cint Arm B, Ccont Total
    Number of subjects
    		 95 97 192
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 54 64 118
        From 65-84 years
    		 40 33 73
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 61 (34 to 87) 59 (29 to 81) -
    Gender categorical
    Units: Subjects
        Female
    		 95 97 192
        Male
    		 0 0 0
    Menopausal status
    Units: Subjects
        Premenopausal
    		 32 37 69
        Postmenopausal
    		 62 60 122
        No data
    		 1 0 1
    Eastern Cooperative Oncology Group (ECOG) status
    ECOG score runs from 0 to 5, with 0 denoting perfect health and 5 death. 0 - Asymptomatic 1 - Symptomatic but completely ambulatory 2 - Symptomatic, <50% in bed during the day 3 - Symptomatic, >50% in bed, but not bedbound 4 - Bedbound 5 - Death
    Units: Subjects
        ECOG 0
    		 41 44 85
        ECOG 1
    		 21 27 48
        ECOG 2
    		 3 0 3
        Missing
    		 30 26 56
    Hormone receptor status
    Units: Subjects
        Positive
    		 75 76 151
        Negative
    		 18 16 34
        Unknown
    		 2 5 7
    Type of metastases
    Units: Subjects
        Visceral
    		 72 78 150
        Non-visceral
    		 23 19 42
    Metastatic sites
    Units: Subjects
        1 site
    		 41 50 91
        2 sites
    		 27 25 52
        ≥3 sites
    		 26 22 48
        Missing
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Arm A, Cint
    Reporting group description
    		 Capecitabine doses of 1250 mg/m2 orally twice-daily (morning and evening which is the equivalent to one 2500mg/m2 dose) during 14 days, in 3 week cycles with a resting period of 7 days.

    Reporting group title
    Arm B, Ccont
    Reporting group description
    		 Capecitabine at doses of 800 mg/m2 twice daily continuously, without rest periods, over the entire 21-day cycle.

    Primary: Time to Progresion (TTP) after 1 year

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    End point title
    		 Time to Progresion (TTP) after 1 year
    End point description
    Time to Progresion (TTP) is defined as the time (in months) from the moment the patient starts the study treatment to the date of progressive disease. That is, a patient has an event is she progresses or dies due to progressive disease.F or this analysis we are including all patients belonging to the PP Population (182 patients: 90 under treatment A and 92 under treatment B).
    End point type
    Primary
    End point timeframe
    After 1 year from the treatment start day.
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    73
    82
    Units: Events
    53
    62
    Statistical analysis title
    		 Non-Inferiority
    Comparison groups
    Arm A, Cint v Arm B, Ccont
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -3.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.83
         upper limit
    		 10.82
    Variability estimate
    Standard deviation

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    Time to Progression (TTP) is defined as the time (in months) from the moment the patient starts the study treatment to the date of an Event. Event was defined as Progressive Disease (PD) or Death due to PD, whichever happens first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). If a patient did not progresses or dies due to PD during the treatment but she receives an antitumoral treatment, after the end of the study treatment, it is censored. If the patient does neither progresses nor dies due to PD, and she does not receive an antitumoral treatment, after the end of the study treatment, it is censored.
    End point type
    Secondary
    End point timeframe
    Through the study treatment, an average of 5 months.
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    90
    92
    Units: Months
        median (confidence interval 95%)
    8.68 (6.55 to 11.18)
    6.84 (6.02 to 8.06)
    Statistical analysis title
    		 Non-Inferiority
    Statistical analysis description
    If we assume that the non-inferiority level is up to 15% lower (equivalent to a median progression-free time of 3 months), for a one-sided error α=0.05, and 80% power, are necessary 88 patients per group. Considering an dropout rate of around 10%, the number of patients would be 98 per group.
    Comparison groups
    Arm A, Cint v Arm B, Ccont
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0996
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.313
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.948
         upper limit
    		 1.817

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Overall Response Rate (complete response plus partial responses) was evaluated using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), every 3 cycles of chemotherapy (each cycle last 3 weeks) and at the end of treatment (at 21 weeks from the start of treatment).
    End point type
    Secondary
    End point timeframe
    Through the study treatment, an average of 5 months.
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    90
    92
    Units: Participants
    76
    68
    No statistical analyses for this end point

    Secondary: Response Duration (RD)

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    End point title
    		 Response Duration (RD)
    End point description
    Response duration is computed for all patients with Partial Response or Complete Response, during the treatment period, as the time from the moment the Partial or Complete Response is reported to the date the patient Progresses or Dies, whichever happens first. A patient is censored if she does not progress or die. In these cases Response duration is computed as the time from the moment the Partial or Complete Response is reported to the last contact date.
    End point type
    Secondary
    End point timeframe
    Time from the moment the Partial or Complete Response is reported to the date the patient Progresses or Dies, whichever happens first, assessed up to 72 weeks.
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    30
    29
    Units: Months
        median (confidence interval 95%)
    10.07 (7.96 to 16.71)
    7.01 (4.11 to 12.43)
    Statistical analysis title
    		 Superiority
    Comparison groups
    Arm A, Cint v Arm B, Ccont
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4934
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 2.1

    Secondary: Time to treatment failure (TTF)

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    End point title
    		 Time to treatment failure (TTF)
    End point description
    Time to treatment failure (TTF) is defined as the time (in months) from the moment the patient starts the study treatment to the end of treatment date (due to death, progressive disease, adverse events, patient's decision or investigator criteria. If a patient did not end the treatment, it is censored. The censoring date is the date of the last dose received.
    End point type
    Secondary
    End point timeframe
    Time (in months) from the moment the patient starts the study treatment to the end of treatment date (due to death, progressive disease, adverse events, patient's decision or investigator criteria, assessed up to 72 months.
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    90
    92
    Units: Months
        median (confidence interval 95%)
    5.41 (4.34 to 8.03)
    5.87 (3.55 to 7.14)
    Statistical analysis title
    		 Superiority
    Comparison groups
    Arm A, Cint v Arm B, Ccont
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4686
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.115
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.49

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progresion Free Survival (PFS) is defined as the time (in months) from the moment the patient starts the study treatment to the date of progressive disease. That is, a patient has an event is she progresses or dies for any reason. If a patient did not progresses or dies during the treatment but she receives an antitumoral treatment, after the end of the study treatment, it is censored. The censoring date is the first follow up date when she receives the antitumoral treament. In this case, the time from the moment the patient starts the study treatment to the start date of the antitumoral treatment is computed as the time to progression. If the patient does neither progresses nor dies, and she does not receive an antitumoral treatment, after the end of the study treatment, it is censored. In this case, the time from the moment the patient starts the study treatment to the last date of contact is computed as the time to progression.
    End point type
    Secondary
    End point timeframe
    Time from the moment the patient starts the study treatment to the date of progressive disease assessed up to 84 months.
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    90
    92
    Units: Months
        median (confidence interval 95%)
    8.55 (5.92 to 10.26)
    6.84 (6.02 to 8.06)
    Statistical analysis title
    		 Superiority
    Comparison groups
    Arm A, Cint v Arm B, Ccont
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1901
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.2379
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8985
         upper limit
    		 1.7054

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    An event is defined as death. A patient is censored if she does not die. The censoring date is last contact date.
    End point type
    Secondary
    End point timeframe
    Time to survival is the number of months from the study treatment start date to the date of death, assessed up to 100 months.
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    90
    92
    Units: Months
        median (confidence interval 95%)
    28.55 (23.85 to 34.21)
    23.29 (18.16 to 32.27)
    Statistical analysis title
    		 Superiority
    Comparison groups
    Arm A, Cint v Arm B, Ccont
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8014
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9589
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6908
         upper limit
    		 1.3309

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    A patient experiences a Clinical Benefit if the following is satisfied: The patient has Complete response (CR), Partial Response (PR) or Stable Disease (SD) and it continues during more than 3 months. The time has been calculated as the months from “CR” “PR” or “SD” (the first one) until the first of the following dates: progression date, new treatment during follow-up date or last contact date.
    End point type
    Secondary
    End point timeframe
    Months from CR, PR or SD (the first one) until Progression date, new treatment or last contact date.
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    82
    88
    Units: Events
    54
    54
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) rate per year

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    End point title
    		 Progression Free Survival (PFS) rate per year
    End point description
    Progresion Free Survival rate per year is defined as percentage of survival each year.
    End point type
    Secondary
    End point timeframe
    One year
    End point values
    		 Arm A, Cint Arm B, Ccont
    Number of subjects analysed
    90
    92
    Units: percentage
        12 months
    31
    26
        24 months
    12
    8
        36 months
    9
    7
        48 months
    5
    3
        60 months
    5
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the study treatment (Metastatic Breast Cancer patients), up to 30 weeks approximately.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Arm A, Cint
    Reporting group description
    		 Capecitabine doses of 1250 mg/m2 orally twice-daily (morning and evening which is the equivalent to one 2500mg/m2 dose) during 14 days, in 3 week cycles with a resting period of 7 days.

    Reporting group title
    Arm B, Ccont
    Reporting group description
    		 Capecitabine at doses of 800 mg/m2 twice daily continuously, without rest periods, over the entire 21-day cycle.

    Serious adverse events
    		 Arm A, Cint Arm B, Ccont
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 95 (29.47%)
    21 / 97 (21.65%)
         number of deaths (all causes)
    81
    72
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Thrombosis/thrombus/embolism
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pain
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 95 (3.16%)
    4 / 97 (4.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pleural effusion (non-malignant)
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Calcium, serum-high (hypercalcemia)
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac General
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasovagal episode
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion (non-malignant)
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neurology
         subjects affected / exposed
    2 / 95 (2.11%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Neutrophils/granulocytes (ANC/AGC)
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebolymphatic cording
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 95 (6.32%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mucositis/stomatitis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash: hand-foot skin reaction
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    2 / 95 (2.11%)
    0 / 97 (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
    Febrile neutropenia
         subjects affected / exposed
    2 / 95 (2.11%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC
         subjects affected / exposed
    3 / 95 (3.16%)
    4 / 97 (4.12%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A, Cint Arm B, Ccont
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    94 / 95 (98.95%)
    95 / 97 (97.94%)
    Investigations
    Neutrophils/granulocytes (ANC/AGC) Grade 3-4
         subjects affected / exposed
    9 / 95 (9.47%)
    2 / 97 (2.06%)
         occurrences all number
    9
    2
    Nervous system disorders
    Neuropathy: sensory Grade 1-2
         subjects affected / exposed
    6 / 95 (6.32%)
    7 / 97 (7.22%)
         occurrences all number
    6
    7
    Dizziness Grade 1-2
         subjects affected / exposed
    5 / 95 (5.26%)
    2 / 97 (2.06%)
         occurrences all number
    5
    2
    Blood and lymphatic system disorders
    Hemoglobin Grade 1-2
         subjects affected / exposed
    33 / 95 (34.74%)
    20 / 97 (20.62%)
         occurrences all number
    33
    20
    Neutrophils/granulocytes (ANC/AGC) Grade 1-2
         subjects affected / exposed
    18 / 95 (18.95%)
    9 / 97 (9.28%)
         occurrences all number
    18
    9
    Platelets Grade 1-2
         subjects affected / exposed
    9 / 95 (9.47%)
    4 / 97 (4.12%)
         occurrences all number
    9
    4
    Leukocytes (total WBC) Grade 1-2
         subjects affected / exposed
    6 / 95 (6.32%)
    5 / 97 (5.15%)
         occurrences all number
    6
    5
    General disorders and administration site conditions
    Fatigue (asthenia, lethargy, malaise) Grade 1-2
         subjects affected / exposed
    43 / 95 (45.26%)
    36 / 97 (37.11%)
         occurrences all number
    43
    36
    Fatigue (asthenia, lethargy, malaise) Grade 3-4
         subjects affected / exposed
    14 / 95 (14.74%)
    6 / 97 (6.19%)
         occurrences all number
    14
    6
    Weight loss Grade 1-2
         subjects affected / exposed
    6 / 95 (6.32%)
    4 / 97 (4.12%)
         occurrences all number
    6
    4
    Pain Grade 1-2
         subjects affected / exposed
    25 / 95 (26.32%)
    13 / 97 (13.40%)
         occurrences all number
    25
    13
    Gastrointestinal disorders
    Diarrhea Grade 1-2
         subjects affected / exposed
    28 / 95 (29.47%)
    24 / 97 (24.74%)
         occurrences all number
    28
    24
    Diarrhea Grade 3-4
         subjects affected / exposed
    19 / 95 (20.00%)
    6 / 97 (6.19%)
         occurrences all number
    19
    6
    Mucositis/stomatitis (functional/symptomatic) Grade 1-2
         subjects affected / exposed
    25 / 95 (26.32%)
    26 / 97 (26.80%)
         occurrences all number
    25
    26
    Mucositis/stomatitis (functional/symptomatic) Grade 3-4
         subjects affected / exposed
    11 / 95 (11.58%)
    2 / 97 (2.06%)
         occurrences all number
    11
    2
    Nausea Grade 1-2
         subjects affected / exposed
    25 / 95 (26.32%)
    17 / 97 (17.53%)
         occurrences all number
    25
    17
    Vomiting Grade 1-2
         subjects affected / exposed
    19 / 95 (20.00%)
    14 / 97 (14.43%)
         occurrences all number
    19
    14
    Anorexia Grade 1-2
         subjects affected / exposed
    20 / 95 (21.05%)
    2 / 97 (2.06%)
         occurrences all number
    20
    2
    Constipation Grade 1-2
         subjects affected / exposed
    9 / 95 (9.47%)
    8 / 97 (8.25%)
         occurrences all number
    9
    8
    Dysphagia (difficulty swallowing) Grade 1-2
         subjects affected / exposed
    6 / 95 (6.32%)
    4 / 97 (4.12%)
         occurrences all number
    6
    4
    Heartburn/dyspepsia Grade 1-2
         subjects affected / exposed
    6 / 95 (6.32%)
    2 / 97 (2.06%)
         occurrences all number
    6
    2
    Distension/bloating Grade 1-2
         subjects affected / exposed
    5 / 95 (5.26%)
    1 / 97 (1.03%)
         occurrences all number
    5
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea (shortness of breath) Grade 1-2
         subjects affected / exposed
    3 / 95 (3.16%)
    5 / 97 (5.15%)
         occurrences all number
    3
    5
    Skin and subcutaneous tissue disorders
    Rash: hand-foot skin reaction Grade 1-2
         subjects affected / exposed
    35 / 95 (36.84%)
    38 / 97 (39.18%)
         occurrences all number
    35
    38
    Rash: hand-foot skin reaction Grade 3-4
         subjects affected / exposed
    39 / 95 (41.05%)
    41 / 97 (42.27%)
         occurrences all number
    39
    41
    Nail changes Grade 1-2
         subjects affected / exposed
    10 / 95 (10.53%)
    11 / 97 (11.34%)
         occurrences all number
    10
    11
    Hair loss/alopecia (scalp or body) Grade 1-2
         subjects affected / exposed
    3 / 95 (3.16%)
    8 / 97 (8.25%)
         occurrences all number
    3
    8
    Infections and infestations
    Infection with unknown ANC Grade 1-2
         subjects affected / exposed
    11 / 95 (11.58%)
    10 / 97 (10.31%)
         occurrences all number
    11
    10
    Metabolism and nutrition disorders
    ALT, SGPT (serum glutamic pyruvic transaminase) Grade 1-2
         subjects affected / exposed
    19 / 95 (20.00%)
    16 / 97 (16.49%)
         occurrences all number
    19
    16
    AST, SGOT(serum glutamic oxaloacetic transaminase) Grade 1-2
         subjects affected / exposed
    22 / 95 (23.16%)
    14 / 97 (14.43%)
         occurrences all number
    22
    14
    Bilirubin (hyperbilirubinemia) Grade 1-2
         subjects affected / exposed
    12 / 95 (12.63%)
    14 / 97 (14.43%)
         occurrences all number
    12
    14
    GGT (gamma-Glutamyl transpeptidase) Grade 1-2
         subjects affected / exposed
    9 / 95 (9.47%)
    8 / 97 (8.25%)
         occurrences all number
    9
    8
    Alkaline phosphatase Grade 1-2
         subjects affected / exposed
    6 / 95 (6.32%)
    5 / 97 (5.15%)
         occurrences all number
    6
    5
    Glucose, serum-high (hyperglycemia) Grade 1-2
         subjects affected / exposed
    5 / 95 (5.26%)
    1 / 97 (1.03%)
         occurrences all number
    5
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Oct 2007
    - Reorder the primary and secondary objectives of the study. - Modify the sample size calculation according to the new main valuation variable. - Extend the recruitment period to include sufficient number of patients according to the new sample size. - Modify the evaluation methods according to these objectives. - Rework the statistical analysis section
    26 May 2008
    - To clarify some of the inclusion and exclusion criteria. The suggested changes do not substantially change the population under test. - Expand the use of bisphosphonates and corticosteroids in patients with bone metastases. - Update the toxicity coding system from the NCI v 2.0 system to NCI 3.0. - To add a new secondary objective: to evaluate the relationship between enzyme polymorphisms related to the metabolism of Capecitabine, and its toxicity and efficacy. - Addition of two new sites - Clarify some aspects of the protocol that may give rise to erroneous interpretations; such as, for example, the section referring to the Xeloda dose reduction guidelines in the event of the adverse effect of Palmar-plantar erythrodysesthesia syndrome.
    26 Feb 2010
    Increase sample size: The primary objective was based on obtaining 88 evaluable patients per group, total 176, not including any prediction of losses. Based on the fact that the usual percentage of losses in metastatic studies is approximately 10%, it is intended to increase the number of expected subjects to 196 recruited patients to finally obtain the 176 evaluable patients.
    23 Sep 2011
    - Incorporation of a Secondary Objective: The magnitude of the progression-free survival rate at one year is a reasonably important objective, given its behavior as a predictor of overall survival in patients with breast cancer. - Modification in the definitions of Population and Efficacy: The variables of time to an event or survival times are widely used variables in the field of cancer treatment, however, some scientific publications show discrepancies in the definitions of these variables in different clinical trials which can lead to difficulties in interpreting their results and comparability between trials. The objective of this amendment is to standardize the terminology according to the definitions contemplated by the regulatory agencies.

    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/25601966
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