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    Clinical Trial Results:
    A Randomized, Open Label, Multicenter Phase IIIb Study Comparing Two Trastuzumab Dosing Regimens, Each in Combination With Cisplatin/Capecitabine Chemotherapy, as First-Line Therapy in Patients With HER2-Positive Metastatic Gastric or Gastro-Esophageal Junction Adenocarcinoma Who Have Not Received Prior Treatment for Metastatic Disease

    Summary
    EudraCT number
    2011-001526-19
    Trial protocol
    DE   ES   GB   IT   CZ   HU   PT   PL  
    Global end of trial date
    25 Aug 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Oct 2016
    First version publication date
    22 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BO27798
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01450696
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    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
    25 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study was designed to evaluate the effect of Herceptin (trastuzumab) administered at a loading dose of 8 milligrams per kilogram (mg/kg) followed by 6 mg/kg every three weeks (q3w) as standard of care versus a loading dose of Herceptin at 8 mg/kg followed by 10 mg/kg along with cisplatin and capecitabine, to test whether it produced higher trastuzumab exposure and might have resulted in improved survival duration.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Dec 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 16
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    China: 77
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 13
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Peru: 7
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Serbia: 10
    Country: Number of subjects enrolled
    Turkey: 38
    Country: Number of subjects enrolled
    Ukraine: 26
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    296
    EEA total number of subjects
    39
    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)
    170
    From 65 to 84 years
    125
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 248 participants (124 participants per group) were randomized in the study up to data cutoff date of 13 February 2015, and 48 additional participants (24 participants per group) were randomized between data cutoff date of 13 February 2015 and end of study (25 August 2015) for additional safety data.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Capecitabine + Cisplatin + Herceptin (6 mg/kg)
    Arm description
    Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg every three weeks (q3w) as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 milligrams per meter-squared (mg/m^2) intravenously q3w plus capecitabine 800 mg/m^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
    Arm type
    Active comparator

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin was administered IV at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg or 10 mg/kg (depending upon treatment assignment) q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

    Arm title
    Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Arm description
    Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m^2 intravenously q3w plus capecitabine 800 mg/m^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
    Arm type
    Experimental

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin was administered IV at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg or 10 mg/kg (depending upon treatment assignment) q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

    Number of subjects in period 1
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Started
    148
    148
    Treated (Safety Population)
    147
    147
    Completed
    0
    0
    Not completed
    148
    148
         Death
    77
    84
         Never treated
    1
    1
         Non-compliance
    1
    -
         Study terminated by Sponsor
    53
    58
         Consent withdrawn by subject
    13
    2
         Lost to follow-up
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Capecitabine + Cisplatin + Herceptin (6 mg/kg)
    Reporting group description
    Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg every three weeks (q3w) as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 milligrams per meter-squared (mg/m^2) intravenously q3w plus capecitabine 800 mg/m^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).

    Reporting group title
    Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Reporting group description
    Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m^2 intravenously q3w plus capecitabine 800 mg/m^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).

    Reporting group values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg) Total
    Number of subjects
    148 148 296
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.5 ± 10.6 62.4 ± 10.7 -
    Gender categorical
    Units: Subjects
        Female
    32 37 69
        Male
    116 111 227

    End points

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    End points reporting groups
    Reporting group title
    Capecitabine + Cisplatin + Herceptin (6 mg/kg)
    Reporting group description
    Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg every three weeks (q3w) as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 milligrams per meter-squared (mg/m^2) intravenously q3w plus capecitabine 800 mg/m^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).

    Reporting group title
    Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Reporting group description
    Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m^2 intravenously q3w plus capecitabine 800 mg/m^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).

    Primary: Percentage of Participants Who Died - Full Analysis Set (FAS)

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    End point title
    Percentage of Participants Who Died - Full Analysis Set (FAS) [1]
    End point description
    The percentage of participants who died as of the analysis data cutoff date of 13 February 2015 was reported among participants from the FAS with available data. The FAS population included all participants who were randomized in this study. Here, number of subjects analyzed reflects the number of participants who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    124
    124
    Units: percentage of participants
        number (not applicable)
    46.8
    54
    No statistical analyses for this end point

    Primary: Overall Survival - FAS

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    End point title
    Overall Survival - FAS
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival was estimated among participants from the FAS using the Kaplan-Meier approach. The 95 percent (%) confidence interval (CI) for median was computed using the method of Brookmeyer and Crowley. FAS population. Here, number of participants analyzed reflects the number of participants who were evaluable for this outcome measure.
    End point type
    Primary
    End point timeframe
    From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    124
    124
    Units: months
        median (confidence interval 95%)
    12.485 (10.086 to 13.864)
    10.612 (9.363 to 12.419)
    Statistical analysis title
    Stratified Analysis
    Statistical analysis description
    Stratified analysis included stratum of creatinine clearance (45 to 59 milliliters per minute [mL/min] and greater than or equal to [≥] 60 mL/min). Hazard ratio was estimated by Cox regression.
    Comparison groups
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) v Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2401
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.78
    Statistical analysis title
    Unstratified Analysis
    Statistical analysis description
    Unstratified analysis. Hazard ratio was estimated by Cox regression.
    Comparison groups
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) v Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1285
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    1.88

    Secondary: Percentage of Participants Who Died - Per Protocol Set (PPS)

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    End point title
    Percentage of Participants Who Died - Per Protocol Set (PPS)
    End point description
    The percentage of participants who died as of the analysis data cutoff date of 13 February 2015 was reported among participants from the PPS. The PPS included all participants who were found to have a trastuzumab minimum plasma concentration (Cmin) less than (<) 12 micrograms per milliliter (μg/mL) on treatment Day 21 of Cycle 1 following the initial loading dose of 8 mg/kg.
    End point type
    Secondary
    End point timeframe
    From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    33
    32
    Units: percentage of participants
        number (not applicable)
    51.5
    59.4
    No statistical analyses for this end point

    Secondary: Overall Survival - PPS

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    End point title
    Overall Survival - PPS
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival was estimated among participants from the PPS using the Kaplan-Meier approach. The 95% CI for median was computed using the method of Brookmeyer and Crowley. PPS population.
    End point type
    Secondary
    End point timeframe
    From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    33
    32
    Units: months
        median (confidence interval 95%)
    10.809 (8.082 to 14.752)
    9.363 (5.552 to 14.357)
    Statistical analysis title
    Stratified Analysis
    Statistical analysis description
    Stratified analysis included stratum of creatinine clearance (45 to 59 mL/min and ≥60 mL/min). Hazard ratio was estimated by Cox regression.
    Comparison groups
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) v Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9931
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    2.04
    Statistical analysis title
    Unstratified Analysis
    Statistical analysis description
    Unstratified analysis. Hazard ratio was estimated by Cox regression.
    Comparison groups
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) v Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9458
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    2.02

    Secondary: Percentage of Participants With Disease Progression or Death - PPS

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    End point title
    Percentage of Participants With Disease Progression or Death - PPS
    End point description
    Disease progression was defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as a ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including Baseline (nadir). In addition to the relative increase of 20%, the sum was also required to demonstrate an absolute increase of ≥5 millimeters (mm). The percentage of participants who died or experienced disease progression as of the analysis data cutoff date of 13 February 2015 was reported among participants from the PPS. PPS population.
    End point type
    Secondary
    End point timeframe
    From date of randomization until first occurrence of disease progression or death; assessed every 6 weeks (up to approximately 31 months or data cutoff date of 13 February 2015)
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    33
    32
    Units: percentage of participants
        number (not applicable)
    75.8
    81.3
    No statistical analyses for this end point

    Secondary: Progression-Free Survival - PPS

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    End point title
    Progression-Free Survival - PPS
    End point description
    Progression-free survival was defined as the time between the day of randomization and the date of first documentation of disease progression or date of death, whichever occurred first, measured following RECIST Version 1.1 criteria. Disease progression was defined as a ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including Baseline (nadir). In addition to the relative increase of 20%, the sum was also required to demonstrate an absolute increase of ≥5 mm. The 95% CI for median was computed using the method of Brookmeyer and Crowley. PPS population.
    End point type
    Secondary
    End point timeframe
    From date of randomization until first occurrence of disease progression or death; assessed every 6 weeks (up to approximately 31 months or data cutoff date of 13 February 2015)
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    33
    32
    Units: months
        median (confidence interval 95%)
    5.388 (2.793 to 7.721)
    4.37 (2.727 to 6.834)
    Statistical analysis title
    Stratified Analysis
    Statistical analysis description
    Stratified analysis included stratum of creatinine clearance (45 to 59 mL/min and ≥60 mL/min). Hazard ratio was estimated by Cox regression.
    Comparison groups
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) v Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6759
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    2.02
    Statistical analysis title
    Unstratified Analysis
    Statistical analysis description
    Unstratified analysis. Hazard ratio was estimated by Cox regression.
    Comparison groups
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) v Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5764
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    2.05

    Secondary: Percentage of Participants With Objective Response - PPS

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    End point title
    Percentage of Participants With Objective Response - PPS
    End point description
    Objective response was defined as the occurrence of either a complete response (CR) or partial response (PR) as determined by RECIST Version 1.1 based on investigator assessment. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) were required to have reduction in short axis to <10 mm. PR was defined as a ≥30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. The 95% CI was constructed using Blyth-Still-Casella method. PPS population.
    End point type
    Secondary
    End point timeframe
    From date of randomization until first occurrence of disease progression or death; assessed every 6 weeks (up to approximately 31 months or data cutoff date of 13 February 2015)
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    33
    32
    Units: percentage of participants
        number (confidence interval 95%)
    57.6 (40.12 to 73.16)
    50 (31.89 to 68.11)
    Statistical analysis title
    Difference in Response Rates
    Statistical analysis description
    The 95% CI for difference in response rates was constructed using the normal approximation to the binomial distribution.
    Comparison groups
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) v Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5402
    Method
    Chi-squared
    Parameter type
    Difference in response rates
    Point estimate
    -7.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -31.75
         upper limit
    16.6
    Statistical analysis title
    Odds Ratio
    Comparison groups
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) v Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    1.96

    Secondary: Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS

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    End point title
    Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS
    End point description
    Cmin samples were obtained in all participants randomized to receive Herceptin (FAS). The observed Cmin was recorded, averaged among all participants, and expressed in μg/mL. FAS population. Here, number of subjects analyzed reflects the number of participants who were evaluable for this endpoint. Here also, "n" reflects the number of participants who were evaluable for each category in the respective arms.
    End point type
    Secondary
    End point timeframe
    Day 21 of Cycle 1, 2, 3, 4, 5, 7, 9, 11 (cycle length = 21 days)
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    100
    99
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=100,99)
    17.1 ± 14.3
    18.1 ± 18.1
        Cycle 2 (n=93,76)
    19.2 ± 8.8
    35.3 ± 19.4
        Cycle 3 (n=77,71)
    23.2 ± 11.8
    40.7 ± 20.6
        Cycle 4 (n=73,61)
    25.9 ± 12.1
    47.6 ± 20.2
        Cycle 5 (n=70,60)
    26.7 ± 10.6
    49.3 ± 23.2
        Cycle 7 (n=51,44)
    31.4 ± 14.2
    58.1 ± 27.6
        Cycle 9 (n=31,24)
    33.7 ± 17.6
    61 ± 23.9
        Cycle 11 (n=24,16)
    32.5 ± 14.7
    68.4 ± 35.9
    No statistical analyses for this end point

    Secondary: Trastuzumab Serum Concentration on Day 1 of Cycle 1 - FAS

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    End point title
    Trastuzumab Serum Concentration on Day 1 of Cycle 1 - FAS
    End point description
    Trastuzumab serum concentration samples were obtained in all participants randomized to receive Herceptin (FAS). The observed concentration values were recorded, averaged among all participants, and expressed in μg/mL. FAS population. Here, number of subjects analyzed reflects the number of participants who were evaluable for this endpoint. Here also, "n" reflects the number of participants who were evaluable for each category in the respective groups.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 minutes) and within 15 minutes after end of 2-hour Herceptin infusion on Day 1 of Cycle 1 (cycle length = 21 days)
    End point values
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Number of subjects analysed
    110
    111
    Units: μg/mL
    arithmetic mean (standard deviation)
        Pre-dose (n=109,110)
    0.168 ± 1.69
    0.0204 ± 0.123
        End of infusion (n=110,111)
    126 ± 59.6
    137 ± 55.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015)
    Adverse event reporting additional description
    Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Capecitabine + Cisplatin + Herceptin (6 mg/kg)
    Reporting group description
    Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m^2 intravenously q3w plus capecitabine 800 mg/m^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).

    Reporting group title
    Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Reporting group description
    Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m^2 intravenously q3w plus capecitabine 800 mg/m^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).

    Serious adverse events
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 147 (23.81%)
    38 / 147 (25.85%)
         number of deaths (all causes)
    77
    84
         number of deaths resulting from adverse events
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphatic duct injury
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         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
    Anaemia
         subjects affected / exposed
    7 / 147 (4.76%)
    6 / 147 (4.08%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 147 (2.04%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 147 (0.00%)
    4 / 147 (2.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 147 (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
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 147 (3.40%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 147 (2.72%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Renal failure
         subjects affected / exposed
    3 / 147 (2.04%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective spondylitis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 147 (1.36%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Sepsis
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tinea pedis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 147 (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
    Capecitabine + Cisplatin + Herceptin (6 mg/kg) Capecitabine + Cisplatin + Herceptin (10 mg/kg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    123 / 147 (83.67%)
    122 / 147 (82.99%)
    Investigations
    Weight decreased
         subjects affected / exposed
    10 / 147 (6.80%)
    17 / 147 (11.56%)
         occurrences all number
    10
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 147 (6.12%)
    3 / 147 (2.04%)
         occurrences all number
    10
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    47 / 147 (31.97%)
    40 / 147 (27.21%)
         occurrences all number
    62
    55
    Leukopenia
         subjects affected / exposed
    26 / 147 (17.69%)
    24 / 147 (16.33%)
         occurrences all number
    49
    61
    Neutropenia
         subjects affected / exposed
    61 / 147 (41.50%)
    69 / 147 (46.94%)
         occurrences all number
    109
    142
    Thrombocytopenia
         subjects affected / exposed
    14 / 147 (9.52%)
    14 / 147 (9.52%)
         occurrences all number
    19
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 147 (5.44%)
    2 / 147 (1.36%)
         occurrences all number
    11
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 147 (10.88%)
    11 / 147 (7.48%)
         occurrences all number
    20
    12
    Fatigue
         subjects affected / exposed
    25 / 147 (17.01%)
    23 / 147 (15.65%)
         occurrences all number
    33
    30
    Oedema peripheral
         subjects affected / exposed
    9 / 147 (6.12%)
    6 / 147 (4.08%)
         occurrences all number
    10
    8
    Pyrexia
         subjects affected / exposed
    15 / 147 (10.20%)
    14 / 147 (9.52%)
         occurrences all number
    19
    19
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 147 (5.44%)
    7 / 147 (4.76%)
         occurrences all number
    11
    8
    Abdominal pain upper
         subjects affected / exposed
    12 / 147 (8.16%)
    11 / 147 (7.48%)
         occurrences all number
    13
    12
    Constipation
         subjects affected / exposed
    19 / 147 (12.93%)
    25 / 147 (17.01%)
         occurrences all number
    24
    35
    Diarrhoea
         subjects affected / exposed
    24 / 147 (16.33%)
    30 / 147 (20.41%)
         occurrences all number
    36
    42
    Nausea
         subjects affected / exposed
    55 / 147 (37.41%)
    55 / 147 (37.41%)
         occurrences all number
    105
    109
    Vomiting
         subjects affected / exposed
    36 / 147 (24.49%)
    42 / 147 (28.57%)
         occurrences all number
    71
    83
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    7 / 147 (4.76%)
    13 / 147 (8.84%)
         occurrences all number
    7
    17
    Renal failure
         subjects affected / exposed
    5 / 147 (3.40%)
    8 / 147 (5.44%)
         occurrences all number
    7
    8
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    14 / 147 (9.52%)
    20 / 147 (13.61%)
         occurrences all number
    14
    23
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    32 / 147 (21.77%)
    27 / 147 (18.37%)
         occurrences all number
    47
    41
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 147 (3.40%)
    10 / 147 (6.80%)
         occurrences all number
    8
    14
    Hypocalcaemia
         subjects affected / exposed
    9 / 147 (6.12%)
    9 / 147 (6.12%)
         occurrences all number
    10
    12
    Hypokalaemia
         subjects affected / exposed
    6 / 147 (4.08%)
    15 / 147 (10.20%)
         occurrences all number
    7
    19
    Hyponatraemia
         subjects affected / exposed
    3 / 147 (2.04%)
    8 / 147 (5.44%)
         occurrences all number
    3
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Aug 2011
    - Clarified the instructions for collection of pharmacokinetic samples for serial measurements of trastuzumab concentrations in case of dose delay of Herceptin. - Revised actions and maximum hold times for study drug administration for non-hematological Grade 3 and Grade 4 (excluding cardiac) and hematological toxicities (neutropenia) that were not specifically attributable to one component of study treatment but related to study treatment. - Clarified instructions for the reloading dose of Herceptin in case of delayed dose beyond 7 days for the higher dose Herceptin (8 mg/kg loading dose followed by 10 mg/kg q3w) and the standard of care dose Herceptin (8 mg/kg loading dose followed by 6 mg/kg q3w) treatment arms. - Provided revised guidance for dose modifications and timeframe of dose delay due to hematological toxicity attributable to capecitabine or cisplatin and revised platelet count threshold for assessment of need for dose modification or delay of capecitabine and/or cisplatin.
    06 Aug 2013
    - Provided clarification and updated instructions to Protocol B for the pharmacokinetic sampling schedule in case of delay of Herceptin administration. - The cardiac safety follow-up timeline was extended from 6 to 24 months. - An inclusion criterion (lung or liver plus at least one other organ in addition to the primary tumor must be involved by metastatic gastric tumor) was clarified by specifying the acceptability of metastases in other locations such as distant lymph node, peritoneum, and malignant pleural effusion as a second site of metastasis. - Updated exclusion criterion to add basal cell carcinoma of the skin within the last five years prior to enrollment was an allowed malignancy. Reporting instructions for abnormal liver function tests were included to address the identification/reporting of potential drug-induced liver injury (DILI). - Extracellular domain (ECD) analyses were included in Cycles 2 to 5 of the main study in order to ensure that a sufficient number of data were collected for the second pharmacokinetic interim analysis in order to fully understand the distribution of the shed ECD concentrations in participants with metastatic gastric cancer (MGC), and to enable an accurate assessment of whether the increase in HER2 ECD levels would have an impact on serum trastuzumab pharmacokinetics. These analyses were incorporated into the protocol to support the EMA issued Follow-Up Measure (FUM 70.1, 70.2, and 70.3) for the MGC filing in Europe (Type II Variation on EME/HC/000278/II/47).

    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.
    Trial was stopped for futility based on pre-planned interim analysis results.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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