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    Clinical Trial Results:
    A Phase III, Randomized, Multicenter, Open-Label, Two-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Patients With HER2-Positive Early Breast Cancer

    Summary
    EudraCT number
    		 2017-004897-32
    Trial protocol
    		 GB   DE   ES   BE   CZ   PL   IT  
    Global end of trial date

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Dec 2020
    First version publication date
    10 Jul 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    WO40324
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03493854
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche, Ltd.
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, 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
    Interim
    Date of interim/final analysis
    04 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jul 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the non-inferiority of the Cycle 7 (pre-dose Cycle 8) serum trough concentration (Ctrough) of pertuzumab by subcutaneous (SC) injection within the pertuzumab and trastuzumab fixed-dose combination (FDC) SC compared with pertuzumab by intravenous (IV) infusion.
    Protection of trial subjects
    This study is conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. All participants are required to read and sign an informed consent form prior to participation in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jun 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Brazil: 27
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Japan: 41
    Country: Number of subjects enrolled
    Korea, Republic of: 35
    Country: Number of subjects enrolled
    Mexico: 21
    Country: Number of subjects enrolled
    Poland: 61
    Country: Number of subjects enrolled
    Russian Federation: 64
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Taiwan: 19
    Country: Number of subjects enrolled
    Thailand: 9
    Country: Number of subjects enrolled
    Ukraine: 21
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    500
    EEA total number of subjects
    243
    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)
    441
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 607 patients were screened, 500 of whom were randomized.

    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
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
    Arm description
    		 Participants received 8 cycles of investigator's choice of neoadjuvant chemotherapy. This included either: 1) 4 cycles of dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks (Q2W) (given with granulocyte colony-stimulating factor [G-CSF] support as needed according to local guidelines) followed by paclitaxel QW for 12 weeks; or 2) 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab was given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    RO4368451
    Other name
    Pertuzumab IV; Perjeta
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab is administered as a fixed non-weight-based dose of 840-milligram (mg) intravenous (IV) loading dose and then 420-mg IV maintenance dose once every 3 weeks (Q3W).

    Investigational medicinal product name
    Trastuzumab IV
    Investigational medicinal product code
    RO0452317
    Other name
    Herceptin
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab is administered as an 8-milligram per kilogram (mg/kg) intravenous (IV) loading dose and then 6-mg/kg IV maintenance dose once every 3 weeks (Q3W).

    Investigational medicinal product name
    Trastuzumab SC
    Investigational medicinal product code
    Other name
    Trastuzumab and hyaluronidase-oysk; Herceptin Hylecta
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    After surgery (from Cycle 9 onwards), participants in Arm A will be allowed to switch from trastuzumab intravenous (IV) to trastuzumab subcutaneous (SC), at the discretion of the investigator, in the countries where trastuzumab SC is routinely used. For participants who switch, a fixed dose of 600 mg trastuzumab SC (irrespective of the patient’s weight) will be administered in the adjuvant phase.

    Arm title
    		 Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Arm description
    		 Participants received 8 cycles of investigator's choice of neoadjuvant chemotherapy. This included either: 1) 4 cycles of ddAC Q2W (given with G-CSF support as needed according to local guidelines) followed by paclitaxel once every week (QW) for 12 weeks; or 2) 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The fixed-dose combination (FDC) of pertuzumab and trastuzumab was given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of the FDC of pertuzumab and trastuzumab SC for a total of 18 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fixed dose combination of pertuzumab and trastuzumab
    Investigational medicinal product code
    RO7198574
    Other name
    PH FDC SC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The fixed-dose combinatinon (FDC) of pertuzumab and trastuzumab is administered subcutaneously (SC) at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab once every 3 weeks (Q3W).

    Number of subjects in period 1
    		Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Started
    252
    248
    Received at Least One Dose of Study Drug
    252
    248
    Completed Neoadjuvant Phase
    242
    234
    Completed Surgery
    239
    234
    Completed Adjuvant Treatment Phase
    0
    0
    Started Treatment-Free Follow-Up
    19
    17
    Completed
    0
    0
    Not completed
    252
    248
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    4
    3
         Ongoing Adjuvant Treatment
    229
    228
         Ongoing in Follow-Up
    18
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
    Reporting group description
    		 Participants received 8 cycles of investigator's choice of neoadjuvant chemotherapy. This included either: 1) 4 cycles of dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks (Q2W) (given with granulocyte colony-stimulating factor [G-CSF] support as needed according to local guidelines) followed by paclitaxel QW for 12 weeks; or 2) 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab was given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles.

    Reporting group title
    Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Reporting group description
    		 Participants received 8 cycles of investigator's choice of neoadjuvant chemotherapy. This included either: 1) 4 cycles of ddAC Q2W (given with G-CSF support as needed according to local guidelines) followed by paclitaxel once every week (QW) for 12 weeks; or 2) 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The fixed-dose combination (FDC) of pertuzumab and trastuzumab was given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of the FDC of pertuzumab and trastuzumab SC for a total of 18 cycles.

    Reporting group values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy Total
    Number of subjects
    		 252 248 500
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 219 222 441
        From 65-84 years
    		 33 26 59
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 50.3 ± 10.8 51.7 ± 10.7 -
    Sex: Female, Male
    Units: Participants
        Female
    		 250 248 498
        Male
    		 2 0 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 32 42 74
        Not Hispanic or Latino
    		 200 189 389
        Unknown or Not Reported
    		 20 17 37
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 10 10 20
        Asian
    		 54 51 105
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 3 3 6
        White
    		 164 165 329
        More than one race
    		 2 3 5
        Unknown or Not Reported
    		 19 16 35
    Randomization Stratification Factors: Hormone Receptor Status
    Hormone receptor status was based on central assessment of participant samples for estrogen receptor (ER) and progesterone receptor (PgR) negativity or positivity.
    Units: Subjects
        ER Negative and PgR Negative
    		 97 96 193
        ER Positive and PgR Positive
    		 155 151 306
        Unknown
    		 0 1 1
    Randomization Stratification Factors: Clinical Stage at Presentation
    Units: Subjects
        Stage II-IIIA
    		 201 198 399
        Stage IIIB-IIIC
    		 51 50 101
    Randomization Stratification Factors: Neoadjuvant Chemotherapy Regimen
    AC = doxorubicin plus cyclophosphamide; ddAC = dose-dense doxorubicin plus cyclophosphamide
    Units: Subjects
        ddAC Followed by Paclitaxel
    		 120 120 240
        AC Followed by Docetaxel
    		 132 128 260

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
    Reporting group description
    		 Participants received 8 cycles of investigator's choice of neoadjuvant chemotherapy. This included either: 1) 4 cycles of dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks (Q2W) (given with granulocyte colony-stimulating factor [G-CSF] support as needed according to local guidelines) followed by paclitaxel QW for 12 weeks; or 2) 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab was given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles.

    Reporting group title
    Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Reporting group description
    		 Participants received 8 cycles of investigator's choice of neoadjuvant chemotherapy. This included either: 1) 4 cycles of ddAC Q2W (given with G-CSF support as needed according to local guidelines) followed by paclitaxel once every week (QW) for 12 weeks; or 2) 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The fixed-dose combination (FDC) of pertuzumab and trastuzumab was given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of the FDC of pertuzumab and trastuzumab SC for a total of 18 cycles.

    Primary: Trough Serum Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8)

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    End point title
    		 Trough Serum Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8)
    End point description
    The observed pertuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by >20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a subcutaneous injection site other than thigh was used, if the Cycle 8 pre-dose and post-dose samples were switched, and an assay error impacting Ctrough measurement.
    End point type
    Primary
    End point timeframe
    Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    203 [1]
    206 [2]
    Units: micrograms per millilitre (μg/mL)
        geometric mean (geometric coefficient of variation)
    72.4 ± 34.1
    88.7 ± 33.6
    Notes
    [1] - Per Protocol PK analysis population
    [2] - Per Protocol PK analysis population
    Statistical analysis title
    		 Non-inferiority of Ctrough Pertuzumab SC vs. IV
    Statistical analysis description
    The null hypothesis was that the pertuzumab Arm A SC dose is inferior to the pertuzumab Arm B IV dose (i.e., the CtroughSC/CtroughIV geometric mean ratio of the SC dose of pertuzumab relative to the IV dose is not greater than 0.8).
    Comparison groups
    Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy v Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.22
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 1.31
    Notes
    [3] - The null hypothesis could be rejected and non-inferiority concluded if the lower bound of the 90% confidence interval of the geometric mean ratio was ≥0.8.

    Secondary: Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8)

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    End point title
    		 Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8)
    End point description
    The observed trastuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by >20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a subcutaneous injection site other than thigh was used, if the Cycle 8 pre-dose and post-dose samples were switched, and an assay error impacting Ctrough measurement.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    203 [4]
    206 [5]
    Units: micrograms per milllilitre (μg/mL)
        geometric mean (geometric coefficient of variation)
    43.2 ± 34.7
    57.5 ± 37.0
    Notes
    [4] - Per Protocol PK analysis population
    [5] - Per Protocol PK analysis population
    Statistical analysis title
    		 Non-inferiority of Ctrough Trastuzumab SC vs. IV
    Statistical analysis description
    The null hypothesis was that the trastuzumab Arm B SC dose is inferior to the Arm A trastuzumab IV dose (i.e., the CtroughSC/CtroughIV geometric mean ratio of the SC dose of trastuzumab relative to the IV dose is not greater than 0.8).
    Comparison groups
    Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy v Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 1.43
    Notes
    [6] - The null hypothesis could be rejected and non-inferiority concluded if the lower bound of the 90% confidence interval of the geometric mean ratio was ≥0.8. Non-inferiority was tested in hierarchical order after the primary outcome measure, to adjust for multiple statistical testing and control the type I error at one sided 5% significance level.

    Secondary: Percentage of Participants with Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment

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    End point title
    		 Percentage of Participants with Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment
    End point description
    Total pCR (tpCR) was defined as eradication of invasive disease in the breast and axilla; that is, ypT0/is ypN0, according to the local pathologists’ assessment. Pathologic response to therapy was determined at the time of surgery. The tpCR rate is the percentage of participants in the ITT population who achieved a tpCR. Participants with missing data for tpCR (i.e., do not undergo surgery or have an invalid pCR assessment) were included in the analysis and classified as non-responders. Rates of tpCR were calculated in each treatment arm and were assessed using the difference between the Arm B: Pertuzumab and Trastuzumab FDC SC and the Arm A: Pertuzumab IV and Trastuzumab IV tpCR rates and corresponding 95% Clopper-Pearson confidence intervals (CIs). The difference between the tpCR rates along with corresponding 95% Hauck-Anderson CIs were calculated. The lower bound of the CI will reliably reflect the largest tpCR difference that can be considered unlikely.
    End point type
    Secondary
    End point timeframe
    Following completion of surgery (up to 33 weeks)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    252
    248
    Units: Percentage of participants
        number (confidence interval 95%)
    59.5 (53.2 to 65.6)
    59.7 (53.3 to 65.8)
    Statistical analysis title
    		 Difference in tpCR Rates SC vs. IV
    Comparison groups
    Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy v Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    Method
    Parameter type
    		 Difference in tpCR Rate
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.67
         upper limit
    		 8.97
    Notes
    [7] - Descriptive analysis only. tpCR was analyzed outside of a hypothesis-testing framework and according to the methodology outlined in the outcome measure description.

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Invasive Disease-Free Survival (iDFS; Excluding Second Primary Non-Breast Cancer [SPNBC]) Criteria

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Invasive Disease-Free Survival (iDFS; Excluding Second Primary Non-Breast Cancer [SPNBC]) Criteria
    End point description
    iDFS (excluding SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.
    End point type
    Secondary
    End point timeframe
    Up to 5.5 years
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [8] - There are no results to report at this time because data collection is ongoing.
    [9] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria
    End point description
    Invasive disease-free survival (iDFS) including second primary non-breast cancer (SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. It also includes SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site).
    End point type
    Secondary
    End point timeframe
    Up to 5.5 years
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [10] - There are no results to report at this time because data collection is ongoing.
    [11] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria
    End point description
    Event-free survival (EFS) excluding second primary non-breast cancer (SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.
    End point type
    Secondary
    End point timeframe
    Up to 5.5 years
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [12] - There are no results to report at this time because data collection is ongoing.
    [13] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria
    End point description
    Event-free survival (EFS) including second primary non-breast cancer (SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. It also includes SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site).
    End point type
    Secondary
    End point timeframe
    Up to 5.5 years
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [14] - There are no results to report at this time because data collection is ongoing.
    [15] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria
    End point description
    The distant recurrence-free interval (DRFI) is defined as the time between randomization and the date of distant breast cancer recurrence.
    End point type
    Secondary
    End point timeframe
    Up to 5.5 years
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [16] - There are no results to report at this time because data collection is ongoing.
    [17] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival
    End point description
    Overall survival is defined as the time from randomization to death from any cause.
    End point type
    Secondary
    End point timeframe
    Up to 5.5 years
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [18] - There are no results to report at this time because data collection is ongoing.
    [19] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Safety Summary of the Number of Participants With at Least One Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4)

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    End point title
    		 Safety Summary of the Number of Participants With at Least One Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4)
    End point description
    The adverse event (AE) severity grading scale for the NCI CTCAE v4.0 was used for assessing AE severity. Any AEs that were not specifically listed in the NCI CTCAE, v4.0 were graded per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From Baseline until 28 days after last dose of study drug; up to the primary completion date (up to 1 year, 1 month)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    252
    248
    Units: Participants
        Any Adverse Event (AE): Any Grade
    251
    248
        Any AE: Grade 1
    11
    9
        Any AE: Grade 2
    107
    118
        Any AE: Grade 3
    87
    79
        Any AE: Grade 4
    45
    41
        Any AE: Grade 5
    1
    1
        Any AE: Grades 3 to 5
    133
    121
        Any Serious AE
    45
    40
        Anaphylaxis and Hypersensitivity AEs
    5
    4
        Infusion/Admin.-Related Reactions Within 24 hrs
    34
    43
        Serious Rash/Skin Reactions
    0
    1
        Diarrhoea
    139
    145
        Cardiac Dysfunction
    41
    41
        Interstitial Lung Disease
    2
    3
        Neutropenia/Febrile Neutropenia
    133
    119
        Serious Mucositis
    4
    3
        Pregnancy- and Neonatal-Related AEs
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With a Primary Cardiac Event

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    End point title
    		 Number of Participants With a Primary Cardiac Event
    End point description
    A primary cardiac event is defined as the occurrence of either of the following events: - Incidence of a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III or IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%; or - Cardiac death, defined as: Definite cardiac death (due to heart failure, myocardial infarction, or documented primary arrhythmia); or, Probable cardiac death (sudden unexpected death within 24 hours of a definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, infarction, arrhythmia] without documented etiology).
    End point type
    Secondary
    End point timeframe
    From Baseline until 28 days after last dose of study drug; up to the primary completion date (up to 1 year, 1 month)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    252
    248
    Units: Participants
        Any Primary Cardiac Event
    0
    2
        Heart Failure and Significant LVEF Decline
    0
    1
        Cardiac Death (Definite or Probable)
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With a Secondary Cardiac Event

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    End point title
    		 Number of Participants With a Secondary Cardiac Event
    End point description
    A secondary cardiac event is defined as asymptomatic or mildly symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II, defined as a left ventricular ejection fraction (LVEF) decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% confirmed by a second assessment within approximately 3 weeks
    End point type
    Secondary
    End point timeframe
    From Baseline until 28 days after last dose of study drug; up to the primary completion date (up to 1 year, 1 month)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    252
    248
    Units: Participants
        Any Secondary Cardiac Event
    9
    4
        Identified by Initial LVEF Assessments
    9
    4
        Confirmed by Second LVEF Assessment
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline

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    End point title
    		 Number of Participants with Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline
    End point description
    Clinical laboratory tests were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest (worst) severity grade (according to NCI-CTCAE v4.0) post-baseline. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a medical intervention or a change in concomitant therapy. For a participant with multiple post-baseline abnormalities, only the highest (worst) grade for a given laboratory test is reported. 'Any Grade' indicates the total number of participants with a post-baseline abnormality of any grade for the specified test. Abs. = absolute count; SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate transaminase; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine transaminase
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycles 1 to 8 (up to 21 weeks)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    252
    248
    Units: Participants
        Albumin, Low - Any Grade
    49
    39
        Albumin, Low - Grade 1
    40
    34
        Albumin, Low - Grade 2
    8
    5
        Albumin, Low - Grade 3
    1
    0
        Alkaline Phosphatase, High - Any Grade
    34
    41
        Alkaline Phosphatase, High - Grade 1
    32
    40
        Alkaline Phosphatase, High - Grade 2
    2
    1
        SGPT/ALT, High - Any Grade
    166
    138
        SGPT/ALT, High - Grade 1
    146
    123
        SGPT/ALT, High - Grade 2
    14
    12
        SGPT/ALT, High - Grade 3
    6
    3
        SGOT/AST, High - Any Grade
    137
    113
        SGOT/AST, High - Grade 1
    129
    110
        SGOT/AST, High - Grade 2
    6
    1
        SGOT/AST, High - Grade 3
    2
    2
        Creatinine, High - Any Grade
    193
    194
        Creatinine, High - Grade 1
    187
    186
        Creatinine, High - Grade 2
    5
    8
        Creatinine, High - Grade 3
    1
    0
        Glucose, Low - Any Grade
    22
    21
        Glucose, Low - Grade 1
    18
    21
        Glucose, Low - Grade 2
    3
    0
        Glucose, Low - Grade 3
    1
    0
        Glucose, High - Any Grade
    3
    4
        Glucose, High - Grade 3
    3
    4
        Hemoglobin, Low - Any Grade
    231
    220
        Hemoglobin, Low - Grade 1
    131
    138
        Hemoglobin, Low - Grade 2
    90
    76
        Hemoglobin, Low - Grade 3
    10
    6
        Hemoglobin, High - Any Grade
    10
    4
        Hemoglobin, High - Grade 1
    10
    4
        Lymphocytes, Abs., Low - Any Grade
    140
    138
        Lymphocytes, Abs., Low - Grade 1
    29
    19
        Lymphocytes, Abs., Low - Grade 2
    59
    67
        Lymphocytes, Abs., Low - Grade 3
    45
    48
        Lymphocytes, Abs., Low - Grade 4
    7
    4
        Lymphocytes, Abs., High - Any Grade
    3
    3
        Lymphocytes, Abs., High - Grade 1
    3
    3
        Neutrophils, Total, Abs., Low - Any Grade
    108
    106
        Neutrophils, Total, Abs., Low - Grade 1
    27
    35
        Neutrophils, Total, Abs., Low - Grade 2
    29
    22
        Neutrophils, Total, Abs., Low - Grade 3
    16
    24
        Neutrophils, Total, Abs., Low - Grade 4
    36
    25
    No statistical analyses for this end point

    Secondary: Summary of the Number of Participants With at Least One Adverse Event, Severity Determined According to NCI CTCAE v4, Over the Course of the Entire Study

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    End point title
    		 Summary of the Number of Participants With at Least One Adverse Event, Severity Determined According to NCI CTCAE v4, Over the Course of the Entire Study
    End point description
    The adverse event (AE) severity grading scale for the NCI CTCAE v4.0 was used for assessing AE severity. Any AEs that were not specifically listed in the NCI CTCAE, v4.0 were graded per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From Baseline until end of study (up to 5.5 years)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: Participants
    Notes
    [20] - There are no results to report at this time because data collection is ongoing.
    [21] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Number of Participants With a Primary Cardiac Event Over the Course of the Entire Study

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    End point title
    		 Number of Participants With a Primary Cardiac Event Over the Course of the Entire Study
    End point description
    A primary cardiac event is defined as the occurrence of either of the following events: - Incidence of a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III or IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%; or - Cardiac death, defined as: Definite cardiac death (due to heart failure, myocardial infarction, or documented primary arrhythmia); or, Probable cardiac death (sudden unexpected death within 24 hours of a definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, infarction, arrhythmia] without documented etiology).
    End point type
    Secondary
    End point timeframe
    From Baseline until end of study (up to 5.5 years)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: Participants
    Notes
    [22] - There are no results to report at this time because data collection is ongoing.
    [23] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Number of Participants With a Secondary Cardiac Event Over the Course of the Entire Study

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    End point title
    		 Number of Participants With a Secondary Cardiac Event Over the Course of the Entire Study
    End point description
    A secondary cardiac event is defined as asymptomatic or mildly symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II, defined as a left ventricular ejection fraction (LVEF) decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% confirmed by a second assessment within approximately 3 weeks.
    End point type
    Secondary
    End point timeframe
    From Baseline until end of study (up to 5.5 years)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: Participants
    Notes
    [24] - There are no results to report at this time because data collection is ongoing.
    [25] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Secondary: Number of Participants with Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline Over the Course of the Entire Study

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    End point title
    		 Number of Participants with Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline Over the Course of the Entire Study
    End point description
    Clinical laboratory tests were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest (worst) severity grade (according to NCI-CTCAE v4.0) post-baseline. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a medical intervention or a change in concomitant therapy. For a participant with multiple post-baseline abnormalities, only the highest (worst) grade for a given laboratory test is reported. 'Any Grade' indicates the total number of participants with a post-baseline abnormality of any grade for the specified test.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycles 1 to 22 (1 cycle is 3 weeks), during treatment-free follow-up every 3 months for 1 year, then every 6 months until end of study (up to 5.5 years)
    End point values
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Number of subjects analysed
    0 [26]
    0 [27]
    Units: Participants
    Notes
    [26] - There are no results to report at this time because data collection is ongoing.
    [27] - There are no results to report at this time because data collection is ongoing.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline until 28 days after last dose of study drug; up to the primary completion date (up to 1 year, 1 month)
    Adverse event reporting additional description
    After informed consent but prior to first dose, only serious adverse events (AEs) caused by protocol-mandated intervention were reported. After initiation of study drug, all AEs were reported until 28 days after the last dose of study drug. After this period, only drug-related serious AEs, heart failure, pregnancies, and malignancies were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy
    Reporting group description
    		 Participants received 8 cycles of investigator's choice of neoadjuvant chemotherapy. This included either: 1) 4 cycles of dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks (Q2W) (given with granulocyte colony-stimulating factor [G-CSF] support as needed according to local guidelines) followed by paclitaxel QW for 12 weeks; or 2) 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab were given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles.

    Reporting group title
    Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Reporting group description
    		 Participants received 8 cycles of investigator's choice of neoadjuvant chemotherapy. This included either: 1) 4 cycles of ddAC Q2W (given with G-CSF support as needed according to local guidelines) followed by paclitaxel once every week (QW) for 12 weeks; or 2) 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The fixed-dose combination (FDC) of pertuzumab and trastuzumab was given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of the FDC of pertuzumab and trastuzumab SC for a total of 18 cycles.

    Serious adverse events
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 252 (17.86%)
    40 / 248 (16.13%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    RENAL CELL CARCINOMA
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    EMBOLISM
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILIAC ARTERY OCCLUSION
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LITHIASIS
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    4 / 252 (1.59%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BREAST HAEMATOMA
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST INFLAMMATION
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METRORRHAGIA
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    CLOSTRIDIUM TEST POSITIVE
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    1 / 252 (0.40%)
    3 / 248 (1.21%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLAP NECROSIS
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMATOMA
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ARRHYTHMIA
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    SEIZURE
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    10 / 252 (3.97%)
    9 / 248 (3.63%)
         occurrences causally related to treatment / all
    9 / 10
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAL INCONTINENCE
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS HAEMORRHAGIC
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL TOXICITY
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL FAILURE
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    GOITRE
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    PERIOSTITIS
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (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
    ANAL ABSCESS
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ESCHERICHIA BACTERAEMIA
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MASTITIS
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    1 / 252 (0.40%)
    3 / 248 (1.21%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PSEUDOMONAS INFECTION
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    250 / 252 (99.21%)
    248 / 248 (100.00%)
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    26 / 252 (10.32%)
    19 / 248 (7.66%)
         occurrences all number
    26
    19
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    76 / 252 (30.16%)
    70 / 248 (28.23%)
         occurrences all number
    122
    131
    FATIGUE
         subjects affected / exposed
    56 / 252 (22.22%)
    69 / 248 (27.82%)
         occurrences all number
    97
    98
    INJECTION SITE REACTION
         subjects affected / exposed
    2 / 252 (0.79%)
    32 / 248 (12.90%)
         occurrences all number
    2
    63
    MALAISE
         subjects affected / exposed
    13 / 252 (5.16%)
    15 / 248 (6.05%)
         occurrences all number
    18
    21
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    48 / 252 (19.05%)
    36 / 248 (14.52%)
         occurrences all number
    65
    47
    OEDEMA PERIPHERAL
         subjects affected / exposed
    20 / 252 (7.94%)
    17 / 248 (6.85%)
         occurrences all number
    21
    19
    PYREXIA
         subjects affected / exposed
    35 / 252 (13.89%)
    28 / 248 (11.29%)
         occurrences all number
    44
    35
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    30 / 252 (11.90%)
    33 / 248 (13.31%)
         occurrences all number
    30
    34
    DYSPNOEA
         subjects affected / exposed
    11 / 252 (4.37%)
    24 / 248 (9.68%)
         occurrences all number
    13
    25
    EPISTAXIS
         subjects affected / exposed
    34 / 252 (13.49%)
    27 / 248 (10.89%)
         occurrences all number
    39
    31
    RHINORRHOEA
         subjects affected / exposed
    9 / 252 (3.57%)
    14 / 248 (5.65%)
         occurrences all number
    10
    15
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    28 / 252 (11.11%)
    37 / 248 (14.92%)
         occurrences all number
    33
    40
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    48 / 252 (19.05%)
    35 / 248 (14.11%)
         occurrences all number
    55
    40
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    37 / 252 (14.68%)
    26 / 248 (10.48%)
         occurrences all number
    45
    31
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    14 / 252 (5.56%)
    9 / 248 (3.63%)
         occurrences all number
    15
    9
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    49 / 252 (19.44%)
    40 / 248 (16.13%)
         occurrences all number
    108
    85
    WEIGHT DECREASED
         subjects affected / exposed
    13 / 252 (5.16%)
    23 / 248 (9.27%)
         occurrences all number
    13
    24
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    31 / 252 (12.30%)
    16 / 248 (6.45%)
         occurrences all number
    77
    49
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    32 / 252 (12.70%)
    9 / 248 (3.63%)
         occurrences all number
    47
    9
    PROCEDURAL PAIN
         subjects affected / exposed
    23 / 252 (9.13%)
    30 / 248 (12.10%)
         occurrences all number
    24
    30
    RADIATION SKIN INJURY
         subjects affected / exposed
    18 / 252 (7.14%)
    20 / 248 (8.06%)
         occurrences all number
    18
    20
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    22 / 252 (8.73%)
    21 / 248 (8.47%)
         occurrences all number
    27
    23
    DYSGEUSIA
         subjects affected / exposed
    35 / 252 (13.89%)
    41 / 248 (16.53%)
         occurrences all number
    42
    51
    HEADACHE
         subjects affected / exposed
    50 / 252 (19.84%)
    36 / 248 (14.52%)
         occurrences all number
    58
    58
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    31 / 252 (12.30%)
    28 / 248 (11.29%)
         occurrences all number
    40
    31
    PARAESTHESIA
         subjects affected / exposed
    19 / 252 (7.54%)
    22 / 248 (8.87%)
         occurrences all number
    22
    27
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    34 / 252 (13.49%)
    38 / 248 (15.32%)
         occurrences all number
    37
    39
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    103 / 252 (40.87%)
    83 / 248 (33.47%)
         occurrences all number
    129
    99
    LEUKOPENIA
         subjects affected / exposed
    34 / 252 (13.49%)
    18 / 248 (7.26%)
         occurrences all number
    47
    25
    NEUTROPENIA
         subjects affected / exposed
    61 / 252 (24.21%)
    51 / 248 (20.56%)
         occurrences all number
    106
    85
    Eye disorders
    DRY EYE
         subjects affected / exposed
    8 / 252 (3.17%)
    13 / 248 (5.24%)
         occurrences all number
    9
    13
    LACRIMATION INCREASED
         subjects affected / exposed
    13 / 252 (5.16%)
    13 / 248 (5.24%)
         occurrences all number
    13
    14
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    13 / 252 (5.16%)
    18 / 248 (7.26%)
         occurrences all number
    15
    22
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    14 / 252 (5.56%)
    18 / 248 (7.26%)
         occurrences all number
    17
    25
    CONSTIPATION
         subjects affected / exposed
    52 / 252 (20.63%)
    54 / 248 (21.77%)
         occurrences all number
    66
    67
    DIARRHOEA
         subjects affected / exposed
    138 / 252 (54.76%)
    144 / 248 (58.06%)
         occurrences all number
    256
    235
    DYSPEPSIA
         subjects affected / exposed
    26 / 252 (10.32%)
    31 / 248 (12.50%)
         occurrences all number
    29
    36
    HAEMORRHOIDS
         subjects affected / exposed
    9 / 252 (3.57%)
    21 / 248 (8.47%)
         occurrences all number
    9
    21
    NAUSEA
         subjects affected / exposed
    152 / 252 (60.32%)
    146 / 248 (58.87%)
         occurrences all number
    301
    274
    STOMATITIS
         subjects affected / exposed
    60 / 252 (23.81%)
    62 / 248 (25.00%)
         occurrences all number
    84
    84
    VOMITING
         subjects affected / exposed
    45 / 252 (17.86%)
    48 / 248 (19.35%)
         occurrences all number
    64
    66
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    177 / 252 (70.24%)
    191 / 248 (77.02%)
         occurrences all number
    179
    191
    DERMATITIS
         subjects affected / exposed
    11 / 252 (4.37%)
    16 / 248 (6.45%)
         occurrences all number
    11
    16
    DRY SKIN
         subjects affected / exposed
    31 / 252 (12.30%)
    33 / 248 (13.31%)
         occurrences all number
    33
    34
    ERYTHEMA
         subjects affected / exposed
    12 / 252 (4.76%)
    15 / 248 (6.05%)
         occurrences all number
    12
    17
    NAIL DISCOLOURATION
         subjects affected / exposed
    16 / 252 (6.35%)
    22 / 248 (8.87%)
         occurrences all number
    16
    22
    NAIL DISORDER
         subjects affected / exposed
    14 / 252 (5.56%)
    15 / 248 (6.05%)
         occurrences all number
    14
    16
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    12 / 252 (4.76%)
    15 / 248 (6.05%)
         occurrences all number
    12
    15
    PRURITUS
         subjects affected / exposed
    18 / 252 (7.14%)
    8 / 248 (3.23%)
         occurrences all number
    21
    10
    RASH
         subjects affected / exposed
    44 / 252 (17.46%)
    30 / 248 (12.10%)
         occurrences all number
    55
    36
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    45 / 252 (17.86%)
    38 / 248 (15.32%)
         occurrences all number
    50
    44
    BACK PAIN
         subjects affected / exposed
    10 / 252 (3.97%)
    19 / 248 (7.66%)
         occurrences all number
    13
    22
    BONE PAIN
         subjects affected / exposed
    11 / 252 (4.37%)
    18 / 248 (7.26%)
         occurrences all number
    16
    22
    MYALGIA
         subjects affected / exposed
    43 / 252 (17.06%)
    53 / 248 (21.37%)
         occurrences all number
    52
    61
    PAIN IN EXTREMITY
         subjects affected / exposed
    16 / 252 (6.35%)
    13 / 248 (5.24%)
         occurrences all number
    18
    14
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    21 / 252 (8.33%)
    19 / 248 (7.66%)
         occurrences all number
    21
    23
    PARONYCHIA
         subjects affected / exposed
    6 / 252 (2.38%)
    15 / 248 (6.05%)
         occurrences all number
    6
    15
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    22 / 252 (8.73%)
    24 / 248 (9.68%)
         occurrences all number
    26
    27
    URINARY TRACT INFECTION
         subjects affected / exposed
    12 / 252 (4.76%)
    13 / 248 (5.24%)
         occurrences all number
    15
    15
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    46 / 252 (18.25%)
    40 / 248 (16.13%)
         occurrences all number
    63
    45
    HYPOKALAEMIA
         subjects affected / exposed
    18 / 252 (7.14%)
    15 / 248 (6.05%)
         occurrences all number
    18
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2018
    Protocol version 2 provided additional clarifications and corrected inconsistencies regarding the inclusion criteria, observation periods following IMPs administration, management of hypersensitivity, tumor staging, PK sampling process, reasons for discontinuation, and LVEF assessments. None of these updates constituted a major change to the protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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