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    Clinical Trial Results:
    An Exploratory Phase II, Single Arm, Multicenter Study to Evaluate the Efficacy and Safety of the Combination of Pertuzumab and Herceptin (Trastuzumab) in Patients With HER2-Positive Metastatic Breast Cancer

    Summary
    EudraCT number
    2005-003493-19
    Trial protocol
    GB   IT   ES  
    Global end of trial date
    01 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Aug 2016
    First version publication date
    05 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BO17929
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01674062
    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
    02 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to make a preliminary assessment of the efficacy of pertuzumab in combination with trastuzumab in participants who have progressed on trastuzumab-based therapy, as determined by the objective response (OR) rate and/or the clinical benefit response (CBR) rate. Country of study site was known for 93 of the 95 enrolled/treated participants; thus, the 2 remaining individuals have been categorized under Canada (26 participants confirmed).
    Protection of trial subjects
    The investigator has ensured that this study was conducted in full conformance with the principles of the Declaration of Helsinki or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study must have fully adhered to the principles outlined in the Guideline for Good Clinical Practice International Council for Harmonisation (ICH) Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the participant. In other countries where the Guideline for Good Clinical Practice exists, Roche and the investigators have strictly ensured adherence to the stated provisions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 May 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    9 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    Spain: 20
    Worldwide total number of subjects
    95
    EEA total number of subjects
    67
    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)
    80
    From 65 to 84 years
    14
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 99 participants with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer were screened for Cohorts 1 and 2, of whom 66 were recruited. Following primary analysis of Cohorts 1 and 2, a total of 51 new participants were screened for Cohort 3, of whom 29 were recruited.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Arm description
    Females with HER2-positive metastatic breast cancer received dual-agent treatment with pertuzumab and trastuzumab. Recruitment for Cohorts 1 and 2 was conducted separately; however, the same regimen was administered to both sets of participants. Trastuzumab was administered via intravenous (IV) infusion as 2 milligrams per kilogram (mg/kg) once weekly, or as 6 mg/kg every 3 weeks, beginning on Day 1 of Cycle 1. Pertuzumab was administered via IV infusion at a loading dose of 840 milligrams (mg) followed by a standard dose of 420 mg every 3 weeks, beginning on Day 2 of Cycle 1. Thereafter, both medications were administered on Day 1 of each 3-week cycle. Treatment continued for a minimum of 8 cycles and could be extended until disease progression, intolerable toxicity, or death.
    Arm type
    Experimental

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was administered via IV infusion at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks. Treatment could continue until disease progression, intolerable toxicity, or death.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered via IV infusion as 2 mg/kg once weekly, or as 6 mg/kg every 3 weeks. Treatment could continue until disease progression, intolerable toxicity, or death.

    Arm title
    Pertuzumab +/- Trastuzumab (Cohort 3)
    Arm description
    Females with HER2-positive metastatic breast cancer received single-agent treatment with pertuzumab. Recruitment for Cohort 3 was conducted following primary analysis of Cohorts 1 and 2. Pertuzumab was administered via IV infusion at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks, administered on Day 1 of each 3-week cycle. Participants with documented disease progression could have trastuzumab added to the regimen, per the dosing schedule described for Cohorts 1 and 2, to receive dual-agent treatment until disease progression, intolerable toxicity, or death.
    Arm type
    Experimental

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was administered via IV infusion at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks. Treatment could continue until disease progression, intolerable toxicity, or death.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered via IV infusion as 2 mg/kg once weekly, or as 6 mg/kg every 3 weeks. Treatment could continue until disease progression, intolerable toxicity, or death.

    Number of subjects in period 1
    Pertuzumab + Trastuzumab (Cohorts 1 and 2) Pertuzumab +/- Trastuzumab (Cohort 3)
    Started
    66
    29
    Completed
    0
    0
    Not completed
    66
    29
         Death
    -
    1
         Adverse event
    1
    1
         Not specified
    8
    1
         Insufficient therapeutic response
    56
    26
         Programming error
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Reporting group description
    Females with HER2-positive metastatic breast cancer received dual-agent treatment with pertuzumab and trastuzumab. Recruitment for Cohorts 1 and 2 was conducted separately; however, the same regimen was administered to both sets of participants. Trastuzumab was administered via intravenous (IV) infusion as 2 milligrams per kilogram (mg/kg) once weekly, or as 6 mg/kg every 3 weeks, beginning on Day 1 of Cycle 1. Pertuzumab was administered via IV infusion at a loading dose of 840 milligrams (mg) followed by a standard dose of 420 mg every 3 weeks, beginning on Day 2 of Cycle 1. Thereafter, both medications were administered on Day 1 of each 3-week cycle. Treatment continued for a minimum of 8 cycles and could be extended until disease progression, intolerable toxicity, or death.

    Reporting group title
    Pertuzumab +/- Trastuzumab (Cohort 3)
    Reporting group description
    Females with HER2-positive metastatic breast cancer received single-agent treatment with pertuzumab. Recruitment for Cohort 3 was conducted following primary analysis of Cohorts 1 and 2. Pertuzumab was administered via IV infusion at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks, administered on Day 1 of each 3-week cycle. Participants with documented disease progression could have trastuzumab added to the regimen, per the dosing schedule described for Cohorts 1 and 2, to receive dual-agent treatment until disease progression, intolerable toxicity, or death.

    Reporting group values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2) Pertuzumab +/- Trastuzumab (Cohort 3) Total
    Number of subjects
    66 29 95
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.9 ± 12.6 53 ± 7.95 -
    Gender categorical
    Units: Subjects
        Female
    66 29 95
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Reporting group description
    Females with HER2-positive metastatic breast cancer received dual-agent treatment with pertuzumab and trastuzumab. Recruitment for Cohorts 1 and 2 was conducted separately; however, the same regimen was administered to both sets of participants. Trastuzumab was administered via intravenous (IV) infusion as 2 milligrams per kilogram (mg/kg) once weekly, or as 6 mg/kg every 3 weeks, beginning on Day 1 of Cycle 1. Pertuzumab was administered via IV infusion at a loading dose of 840 milligrams (mg) followed by a standard dose of 420 mg every 3 weeks, beginning on Day 2 of Cycle 1. Thereafter, both medications were administered on Day 1 of each 3-week cycle. Treatment continued for a minimum of 8 cycles and could be extended until disease progression, intolerable toxicity, or death.

    Reporting group title
    Pertuzumab +/- Trastuzumab (Cohort 3)
    Reporting group description
    Females with HER2-positive metastatic breast cancer received single-agent treatment with pertuzumab. Recruitment for Cohort 3 was conducted following primary analysis of Cohorts 1 and 2. Pertuzumab was administered via IV infusion at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks, administered on Day 1 of each 3-week cycle. Participants with documented disease progression could have trastuzumab added to the regimen, per the dosing schedule described for Cohorts 1 and 2, to receive dual-agent treatment until disease progression, intolerable toxicity, or death.

    Subject analysis set title
    Pertuzumab (Cohort 3)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Females with HER2-positive metastatic breast cancer received single-agent treatment with pertuzumab. Recruitment for Cohort 3 was conducted following primary analysis of Cohorts 1 and 2. Pertuzumab was administered via IV infusion at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks, administered on Day 1 of each 3-week cycle. The treatment regimen was maintained until disease progression, intolerable toxicity, death, and/or transition to dual-agent therapy with trastuzumab.

    Primary: Cohorts 1 and 2: Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 During Dual-Agent Treatment

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    End point title
    Cohorts 1 and 2: Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 During Dual-Agent Treatment [1] [2]
    End point description
    Tumor response was assessed using RECIST version 1.0 to determine the OR rate, or the percentage of participants with either confirmed CR or PR. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30 percent (%) decrease in the sum of the longest diameter compared to Baseline. Response was to be confirmed a minimum of 4 weeks after the initial response was documented. The OR rate was calculated as [number of participants meeting the above criteria divided by the number analyzed] multiplied by 100. All Treated Population: All randomized participants who received any amount of study medication (Cohorts 1 and 2 only).
    End point type
    Primary
    End point timeframe
    Up to approximately 9.5 years (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression)
    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: Statistical significance was assessed using the lower bound of the 80% confidence interval for the OR rate. A clinically meaningful OR rate was defined as greater than or equal to (≥) 13% of participants. Providing the lower bound of the 80% confidence interval exceeded the critical value, the study was considered positive. No p-values were generated.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Values for Cohort 3 were reported as a separate, secondary endpoint.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: percentage of participants
        number (confidence interval 80%)
    24.2 (17.4 to 32.3)
    No statistical analyses for this end point

    Primary: Cohorts 1 and 2: Percentage of Participants With a Confirmed Best Overall Response of CR, PR, or Stable Disease (SD) According to RECIST Version 1.0 During Dual-Agent Treatment

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    End point title
    Cohorts 1 and 2: Percentage of Participants With a Confirmed Best Overall Response of CR, PR, or Stable Disease (SD) According to RECIST Version 1.0 During Dual-Agent Treatment [3] [4]
    End point description
    Tumor response was assessed using RECIST version 1.0 to determine the CBR rate, or the percentage of participants with either confirmed CR or PR, or SD lasting at least 6 months. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter compared to Baseline. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Response was to be confirmed a minimum of 4 weeks after the initial response was documented. The CBR rate was calculated as [number of participants meeting the above criteria divided by the number analyzed] multiplied by 100. All Treated Population (Cohorts 1 and 2).
    End point type
    Primary
    End point timeframe
    Up to approximately 9.5 years (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression)
    Notes
    [3] - 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: Statistical significance was assessed using the lower bound of the 80% confidence interval for the CBR rate. A clinically meaningful CBR rate was defined as ≥25% of participants. Providing the lower bound of the 80% confidence interval exceeded the critical value, the study was considered positive. No p-values were generated.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Values for Cohort 3 were reported as a separate, secondary endpoint.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: percentage of participants
        number (confidence interval 80%)
    50 (41.5 to 58.5)
    No statistical analyses for this end point

    Secondary: Cohorts 1 and 2: Duration of Response According to RECIST Version 1.0

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    End point title
    Cohorts 1 and 2: Duration of Response According to RECIST Version 1.0 [5]
    End point description
    Tumor response was assessed using RECIST version 1.0 to determine OR and CBR rates. Duration of OR was defined as time from initial response of CR or PR to time of disease progression or death. Duration of CBR was defined similarly as time from initial response of CR or PR, or SD lasting at least 6 months, to time of disease progression or death. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter compared to Baseline. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Participants without progression or death following confirmed CR or PR were censored at the last tumor assessment. Duration of response was estimated using Kaplan-Meier analysis and expressed in weeks. All Treated Population (Cohorts 1 and 2 only).
    End point type
    Secondary
    End point timeframe
    Up to approximately 9.5 years (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of Cohort 3 was exploratory and was therefore not reported.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: weeks
    median (full range (min-max))
        Objective response
    40.1 (12 to 413)
        Clinical benefit response
    50.14 (12.4 to 183.7)
    No statistical analyses for this end point

    Secondary: Cohorts 1 and 2: Time to Objective Response According to RECIST Version 1.0

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    End point title
    Cohorts 1 and 2: Time to Objective Response According to RECIST Version 1.0 [6]
    End point description
    Tumor response was assessed using RECIST version 1.0 to determine the OR rate. Time to response was defined as the time from first dose to the time of initial response of CR or PR. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter compared to Baseline. Participants with disease progression were censored at the time of progression, and those with neither disease progression nor OR were censored at the last tumor assessment. Time to response was estimated using Kaplan-Meier analysis and expressed in weeks. All Treated Population (Cohorts 1 and 2 only).
    End point type
    Secondary
    End point timeframe
    Up to approximately 21 months (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression; final analysis using February 2008 cutoff date)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of Cohort 3 was exploratory and was therefore not reported.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: weeks
        median (full range (min-max))
    11.14 (4.9 to 37.3)
    No statistical analyses for this end point

    Secondary: Cohorts 1 and 2: Percentage of Participants With Disease Progression According to RECIST Version 1.0

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    End point title
    Cohorts 1 and 2: Percentage of Participants With Disease Progression According to RECIST Version 1.0 [7]
    End point description
    Tumor response was assessed using RECIST version 1.0 to assess for disease progression, defined as at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. The percentage of participants with disease progression was calculated as [number of participants meeting the above criteria divided by the number analyzed] multiplied by 100. All Treated Population (Cohorts 1 and 2 only).
    End point type
    Secondary
    End point timeframe
    Up to approximately 9.5 years (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of Cohort 3 was exploratory and was therefore not reported.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: percentage of participants
        number (not applicable)
    93.9
    No statistical analyses for this end point

    Secondary: Cohorts 1 and 2: Time to Progression (TTP) According to RECIST Version 1.0

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    End point title
    Cohorts 1 and 2: Time to Progression (TTP) According to RECIST Version 1.0 [8]
    End point description
    Tumor response was assessed using RECIST version 1.0 to assess for disease progression, defined as at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. TTP was defined as the time from first dose to the time of first documented disease progression. Participants who withdrew from the study without documented progression were censored at the last tumor assessment. TTP was estimated using Kaplan-Meier analysis and expressed in weeks. All Treated Population (Cohorts 1 and 2 only).
    End point type
    Secondary
    End point timeframe
    Up to approximately 9.5 years (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of Cohort 3 was exploratory and was therefore not reported.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: weeks
        median (full range (min-max))
    23.2 (4 to 244)
    No statistical analyses for this end point

    Secondary: Cohorts 1 and 2: Progression-Free Survival (PFS) According to RECIST Version 1.0

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    End point title
    Cohorts 1 and 2: Progression-Free Survival (PFS) According to RECIST Version 1.0 [9]
    End point description
    Tumor response was assessed using RECIST version 1.0 to assess for disease progression, defined as at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. PFS was defined as the time from first dose to the time of disease progression or death. Participants without progression or death were censored at the last tumor assessment. PFS was estimated using Kaplan-Meier analysis and expressed in weeks. All Treated Population (Cohorts 1 and 2 only).
    End point type
    Secondary
    End point timeframe
    Up to approximately 9.5 years (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of Cohort 3 was exploratory and was therefore not reported.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: weeks
        median (confidence interval 80%)
    24 (18 to 34)
    No statistical analyses for this end point

    Secondary: Cohorts 1 and 2: Percentage of Participants Who Died

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    End point title
    Cohorts 1 and 2: Percentage of Participants Who Died [10]
    End point description
    Participants were followed for survival data during and after treatment for a maximum of 3 years after the last dose until death, withdrawal of consent, or loss to follow-up. The percentage of participants who died was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. All Treated Population (Cohorts 1 and 2 only).
    End point type
    Secondary
    End point timeframe
    Up to approximately 4.5 years (during treatment; then every 4 months until death, withdrawn consent, loss to follow-up, or 3 years after last dose; final analysis using November 2010 cutoff date)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of Cohort 3 was exploratory and was therefore not reported.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: percentage of participants
        number (not applicable)
    30.3
    No statistical analyses for this end point

    Secondary: Cohorts 1 and 2: Overall Survival (OS)

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    End point title
    Cohorts 1 and 2: Overall Survival (OS) [11]
    End point description
    Participants were followed for survival data during and after treatment for a maximum of 3 years after the last dose until death, withdrawal of consent, or loss to follow-up. OS was defined as the time from first dose to the time of death from any cause. Participants who did not experience death were censored at the last known alive date. OS was estimated using Kaplan-Meier and expressed in months. All Treated Population (Cohorts 1 and 2 only). 99999 = not estimable due to insufficient follow-up at the time the analysis was conducted.
    End point type
    Secondary
    End point timeframe
    Up to approximately 4.5 years (during treatment; then every 4 months until death, withdrawn consent, loss to follow-up, or 3 years after last dose; final analysis using November 2010 cutoff date)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of Cohort 3 was exploratory and was therefore not reported.
    End point values
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Number of subjects analysed
    66
    Units: months
        median (confidence interval 80%)
    38.5 (32 to 99999)
    No statistical analyses for this end point

    Secondary: Cohort 3: Percentage of Participants With a Confirmed Best Overall Response of CR or PR According to RECIST Version 1.0 During Single-Agent Treatment With Pertuzumab

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    End point title
    Cohort 3: Percentage of Participants With a Confirmed Best Overall Response of CR or PR According to RECIST Version 1.0 During Single-Agent Treatment With Pertuzumab
    End point description
    Tumor response was assessed using RECIST version 1.0 to determine the OR rate, or the percentage of participants with either confirmed CR or PR. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter compared to Baseline. Response was to be confirmed a minimum of 4 weeks after the initial response was documented. The OR rate was calculated as [number of participants meeting the above criteria divided by the number analyzed] multiplied by 100. All Treated Population (Cohort 3 only).
    End point type
    Secondary
    End point timeframe
    Up to approximately 7.5 years (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression)
    End point values
    Pertuzumab (Cohort 3)
    Number of subjects analysed
    29
    Units: percentage of participants
        number (confidence interval 80%)
    3.4 (0.4 to 12.8)
    No statistical analyses for this end point

    Secondary: Cohort 3: Percentage of Participants With a Confirmed Best Overall Response of CR, PR, or SD According to RECIST Version 1.0 During Single-Agent Treatment With Pertuzumab

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    End point title
    Cohort 3: Percentage of Participants With a Confirmed Best Overall Response of CR, PR, or SD According to RECIST Version 1.0 During Single-Agent Treatment With Pertuzumab
    End point description
    Tumor response was assessed using RECIST version 1.0 to determine the CBR rate, or the percentage of participants with either confirmed CR or PR, or SD lasting at least 6 months. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter compared to Baseline. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Response was to be confirmed a minimum of 4 weeks after the initial response was documented. The CBR rate was calculated as [number of participants meeting the above criteria divided by the number analyzed] multiplied by 100. All Treated Population (Cohort 3 only).
    End point type
    Secondary
    End point timeframe
    Up to approximately 7.5 years (at Screening; on Day 15 of Cycles 2, 4, 6, and 8 [cycle length 3 weeks]; then every 3 months until disease progression)
    End point values
    Pertuzumab (Cohort 3)
    Number of subjects analysed
    29
    Units: percentage of participants
        number (confidence interval 80%)
    10.3 (3.9 to 21.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 9.5 years (from Day 1 until treatment discontinuation)
    Adverse event reporting additional description
    Analysis Population Description: All Treated Population.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab (Cohorts 1 and 2)
    Reporting group description
    Females with HER2-positive metastatic breast cancer received dual-agent treatment with pertuzumab and trastuzumab. Recruitment for Cohorts 1 and 2 was conducted separately; however, the same regimen was administered to both sets of participants. Trastuzumab was administered via IV infusion as 2 mg/kg once weekly, or as 6 mg/kg every 3 weeks, beginning on Day 1 of Cycle 1. Pertuzumab was administered via IV infusion at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks, beginning on Day 2 of Cycle 1. Thereafter, both medications were administered on Day 1 of each 3-week cycle. Treatment continued for a minimum of 8 cycles and could be extended until disease progression, intolerable toxicity, or death.

    Reporting group title
    Pertuzumab +/- Trastuzumab (Cohort 3)
    Reporting group description
    Females with HER2-positive metastatic breast cancer received single-agent treatment with pertuzumab. Recruitment for Cohort 3 was conducted following primary analysis of Cohorts 1 and 2. Pertuzumab was administered via IV infusion at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks, administered on Day 1 of each 3-week cycle. Participants with documented disease progression could have trastuzumab added to the regimen, per the dosing schedule described for Cohorts 1 and 2, to receive dual-agent treatment until disease progression, intolerable toxicity, or death.

    Serious adverse events
    Pertuzumab + Trastuzumab (Cohorts 1 and 2) Pertuzumab +/- Trastuzumab (Cohort 3)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 66 (18.18%)
    1 / 29 (3.45%)
         number of deaths (all causes)
    22
    17
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Toe amputation
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osmotic demyelination syndrome
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Performance status decreased
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Paranoia
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 66 (3.03%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 29 (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
    Pertuzumab + Trastuzumab (Cohorts 1 and 2) Pertuzumab +/- Trastuzumab (Cohort 3)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 66 (93.94%)
    28 / 29 (96.55%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 66 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    0
    5
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 66 (1.52%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 66 (18.18%)
    4 / 29 (13.79%)
         occurrences all number
    18
    6
    Dyspnoea
         subjects affected / exposed
    6 / 66 (9.09%)
    3 / 29 (10.34%)
         occurrences all number
    7
    3
    Oropharyngeal pain
         subjects affected / exposed
    3 / 66 (4.55%)
    3 / 29 (10.34%)
         occurrences all number
    4
    3
    Rhinorrhoea
         subjects affected / exposed
    4 / 66 (6.06%)
    0 / 29 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 66 (22.73%)
    4 / 29 (13.79%)
         occurrences all number
    18
    5
    Dizziness
         subjects affected / exposed
    9 / 66 (13.64%)
    3 / 29 (10.34%)
         occurrences all number
    14
    4
    Paraesthesia
         subjects affected / exposed
    8 / 66 (12.12%)
    0 / 29 (0.00%)
         occurrences all number
    9
    0
    Hypoaesthesia
         subjects affected / exposed
    4 / 66 (6.06%)
    0 / 29 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    24 / 66 (36.36%)
    8 / 29 (27.59%)
         occurrences all number
    35
    11
    Asthenia
         subjects affected / exposed
    9 / 66 (13.64%)
    6 / 29 (20.69%)
         occurrences all number
    17
    8
    Pyrexia
         subjects affected / exposed
    6 / 66 (9.09%)
    2 / 29 (6.90%)
         occurrences all number
    6
    3
    Chest pain
         subjects affected / exposed
    5 / 66 (7.58%)
    2 / 29 (6.90%)
         occurrences all number
    5
    2
    Chills
         subjects affected / exposed
    4 / 66 (6.06%)
    3 / 29 (10.34%)
         occurrences all number
    5
    3
    Mucosal inflammation
         subjects affected / exposed
    6 / 66 (9.09%)
    1 / 29 (3.45%)
         occurrences all number
    6
    1
    Influenza like illness
         subjects affected / exposed
    3 / 66 (4.55%)
    3 / 29 (10.34%)
         occurrences all number
    3
    3
    Oedema peripheral
         subjects affected / exposed
    5 / 66 (7.58%)
    0 / 29 (0.00%)
         occurrences all number
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 29 (3.45%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    42 / 66 (63.64%)
    16 / 29 (55.17%)
         occurrences all number
    106
    28
    Toothache
         subjects affected / exposed
    0 / 66 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    19 / 66 (28.79%)
    12 / 29 (41.38%)
         occurrences all number
    35
    18
    Vomiting
         subjects affected / exposed
    9 / 66 (13.64%)
    10 / 29 (34.48%)
         occurrences all number
    12
    12
    Constipation
         subjects affected / exposed
    9 / 66 (13.64%)
    3 / 29 (10.34%)
         occurrences all number
    12
    3
    Dyspepsia
         subjects affected / exposed
    8 / 66 (12.12%)
    2 / 29 (6.90%)
         occurrences all number
    9
    2
    Abdominal pain upper
         subjects affected / exposed
    5 / 66 (7.58%)
    4 / 29 (13.79%)
         occurrences all number
    5
    4
    Abdominal distension
         subjects affected / exposed
    3 / 66 (4.55%)
    3 / 29 (10.34%)
         occurrences all number
    3
    4
    Abdominal pain
         subjects affected / exposed
    4 / 66 (6.06%)
    2 / 29 (6.90%)
         occurrences all number
    4
    2
    Stomatitis
         subjects affected / exposed
    6 / 66 (9.09%)
    0 / 29 (0.00%)
         occurrences all number
    7
    0
    Haemorrhoids
         subjects affected / exposed
    4 / 66 (6.06%)
    0 / 29 (0.00%)
         occurrences all number
    4
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    18 / 66 (27.27%)
    5 / 29 (17.24%)
         occurrences all number
    25
    7
    Pruritus
         subjects affected / exposed
    9 / 66 (13.64%)
    4 / 29 (13.79%)
         occurrences all number
    10
    7
    Nail disorder
         subjects affected / exposed
    8 / 66 (12.12%)
    2 / 29 (6.90%)
         occurrences all number
    8
    2
    Dry skin
         subjects affected / exposed
    5 / 66 (7.58%)
    1 / 29 (3.45%)
         occurrences all number
    5
    1
    Onychoclasis
         subjects affected / exposed
    5 / 66 (7.58%)
    0 / 29 (0.00%)
         occurrences all number
    6
    0
    Rash pruritic
         subjects affected / exposed
    4 / 66 (6.06%)
    0 / 29 (0.00%)
         occurrences all number
    5
    0
    Erythema
         subjects affected / exposed
    1 / 66 (1.52%)
    2 / 29 (6.90%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 66 (18.18%)
    4 / 29 (13.79%)
         occurrences all number
    14
    4
    Myalgia
         subjects affected / exposed
    12 / 66 (18.18%)
    0 / 29 (0.00%)
         occurrences all number
    13
    0
    Back pain
         subjects affected / exposed
    4 / 66 (6.06%)
    7 / 29 (24.14%)
         occurrences all number
    7
    10
    Muscle spasms
         subjects affected / exposed
    10 / 66 (15.15%)
    1 / 29 (3.45%)
         occurrences all number
    15
    1
    Pain in extremity
         subjects affected / exposed
    6 / 66 (9.09%)
    3 / 29 (10.34%)
         occurrences all number
    6
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 66 (7.58%)
    3 / 29 (10.34%)
         occurrences all number
    5
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 66 (16.67%)
    6 / 29 (20.69%)
         occurrences all number
    18
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 66 (12.12%)
    1 / 29 (3.45%)
         occurrences all number
    11
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 66 (4.55%)
    3 / 29 (10.34%)
         occurrences all number
    4
    6
    Localised infection
         subjects affected / exposed
    5 / 66 (7.58%)
    0 / 29 (0.00%)
         occurrences all number
    6
    0
    Rhinitis
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 29 (3.45%)
         occurrences all number
    5
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 29 (3.45%)
         occurrences all number
    6
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Aug 2006
    The protocol was updated to facilitate recruitment by expanding inclusion criteria, particularly to increase the permitted number of previous chemotherapy regimens and the amount of time lapsed since the last dose of trastuzumab. Changes were also made to HER2 testing methodology, the schedule of cardiac assessments, and the statistical analysis of early termination data.
    31 Jul 2007
    This protocol amendment added the recruitment of Cohort 3 in order to assess pertuzumab as a single agent. Specifications for treatment/dosing, assessments, statistical analyses, and follow-up were updated accordingly. The inclusion criteria were modified to stipulate that those enrolled into Cohort 3 must have received the last trastuzumab dose ≥4 weeks prior to Day 1.
    19 Jun 2008
    The protocol was amended to add OS as a secondary endpoint. To allow for collection of survival data, the end of study was defined as when all participants have either died, withdrawn consent, been lost to follow-up, or reached 3 years after the last dose of study medication. The dosing and schedule of assessments were further clarified for Cohort 3, particularly for those who progressed during single-agent therapy and for whom trastuzumab was introduced to the regimen.
    24 Jun 2009
    Significant updates to the protocol included the definition of postmenopausal women, contraceptive requirements, and procedures in the event of a pregnancy. Further, the analysis of efficacy assessments in Cohort 3 was specified to occur after all participants had reached at least 8 cycles of treatment.
    18 Jan 2012
    The protocol amendment included reduction and simplification of study-related procedures and assessments for participants currently on study treatment since the primary objective of the study had, at the time, already been completed.
    07 Apr 2015
    The end of the study was initially defined to occur once all participants in all cohorts had died, withdrawn consent, been lost to follow-up, or reached 3 years after last dose of study drug. However, the protocol was amended to specify the Sponsor's intent to terminate the study while ensuring that the last remaining participant on study treatment could continue to receive treatment for as long as he/she needed and as long as adverse events were properly managed and reported.

    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.
    Although the study was designed as single-arm study, as reflected in the study title, an additional cohort was opened to evaluate the efficacy and safety of single-agent pertuzumab.
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