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    Clinical Trial Results:
    Effect of Perioperative AntiHER2 Therapy on Early Breast Cancer Study - Biological Phase

    Summary
    EudraCT number
    		 2008-005466-30
    Trial protocol
    		 GB  
    Global end of trial date
    19 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2024
    First version publication date
    03 Jan 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CCR3104
    Additional study identifiers
    ISRCTN number
    		 ISRCTN15004993
    US NCT number
    		 NCT01104571
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Institute of Cancer Research
    Sponsor organisation address
    Cotswold Road, Sutton, United Kingdom, SM2 5NG
    Public contact
    Trial Manager- EPHOS-B trial, Trial Manager- EPHOS-B trial, 44 2087224349, ephos-b-icrctsu@icr.ac.uk
    Scientific contact
    Trial Manager- EPHOS-B trial, Trial Manager- EPHOS-B trial, 44 2087224349, ephos-b-icrctsu@icr.ac.u
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    Southmoor Road, Manchester, United Kingdom, M23 9LT
    Public contact
    Research and Development Manager, Manchester University NHS Foundation Trust, 44 01612914045,
    Scientific contact
    Research and Development Manager, Manchester University NHS Foundation Trust, 44 0161 291 4045,
    Sponsor organisation name
    University of Manchester
    Sponsor organisation address
    Brunswick Street, Manchester, United Kingdom, M13 9PL
    Public contact
    Research and Development Manager, University of Manchester, 44 01612752728, clinicaltrials@manchester.ac.uk
    Scientific contact
    Nigel Bundred, University of Manchester, 44 0161 275 2725, clinicaltrials@manchester.ac.uk
    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
    19 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The Effect of Perioperative Anti-HER2 therapy on Early Breast Cancer Study – Biological phase (EPHOS-B) was designed to assess whether either single-agent lapatinib or trastuzumab given as perioperative treatment had effects on Ki67 and/or apoptosis compared with no anti-HER2 therapy prior to surgery (part 1). Emerging evidence from the NeoSphere trial on the safety and efficacy of combination anti-HER2 therapy led to a protocol amendment, enabling patient allocation between control, trastuzumab alone, or the combination of lapatinib and trastuzumab (part 2). Therefore, the main aim is to determine whether pre-operative treatment of HER2 positive breast cancer patients with anti HER2 therapy increases cell death and/or decreases proliferation.
    Protection of trial subjects
    Patients had to be willing to undergo adjuvant chemotherapy and trastuzumab postsurgery as per standard of care and provide written informed consent for participation and donation of tissue and blood samples. Patients with significant cardiac abnormalities were ineligible. Baseline left ventricular ejection fraction (LVEF) ≥55% was required for trial entry. The trial was conducted in accordance with Good Clinical Practice Guidelines and the Declaration of Helsinki.
    Background therapy
    		 The human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor amplified or overexpressed in 15% to 20% of breast cancers. HER2 lacks a specific ligand, and signaling occurs after the formation of heterodimers with HER1 and HER3 (1). Targeting this pathway improves outcomes for patients with HER2-positive breast cancer.
    Evidence for comparator
    		 Trastuzumab interacts with the extracellular domain of the HER2 protein to inhibit its function, but the mechanism of action is incompletely understood. Lapatinib blocks the HER1/2 internal tyrosine kinase domain and inhibits proliferation of HER2-positive cancers as shown in a small preoperative trial. Changes in proliferation biomarkers, including Ki67, predict clinical response and long-term outcome after 2 weeks of endocrine therapy in estrogen receptor (ER)-positive breast cancer. Incompletely excised breast cancers requiring re-excision within 48 days of surgery showed a significant increase in proliferation if they were HER2-positive, but not if they were HER2-negative. Preventing these early changes provides a rationale for window-of-opportunity studies investigating response to short-term treatment, enhancing prospects for personalizing medicine by identifying tumors sensitive to anti-HER2 therapy (without added chemotherapy).
    Actual start date of recruitment
    15 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 257
    Worldwide total number of subjects
    257
    EEA total number of subjects
    0
    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)
    210
    From 65 to 84 years
    47
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 257 patients were recruited from 21 UK centers; 130 entered part 1 between November 15, 2010, and July 29, 2013, and 127 entered part 2 between August 6, 2013 and September 10, 2015. The main results of the trial were presented after a median follow-up was 6 years (IQR, 5.2–7.4), and published in 2022 (See links below).

    Pre-assignment
    Screening details
    		 Patients that met the eligibility criteria were recruited into the study. In short, newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery within 28 days. Patients had to be willing to undergo adjuvant chemotherapy and trastuzumab postsurgery as per standard of care. Baseline LVEF>=55% was required.

    Period 1
    Period 1 title
    EPHOS-B Part 1&2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 - Trastuzumab
    Arm description
    		 Peri-operative trastuzumab, starting 11 days (+2 or -1day) prior to surgery on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pre-operative 6mg/kg given iv days 1 & 8 (accelerated dosing) commencing 11 days pre-surgery (+2 or -1 day). After surgery, 2mg/kg on Day 15 -19

    Arm title
    		 Part 1 - Lapatinib
    Arm description
    		 Lapatinib for 28 days commencing 11 days 11 days (+2 or -1day) prior to surgery
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1500 mgs daily (6 tablets of 250mg) for 28 days, to be taken all in one single dose

    Arm title
    		 Part 1 - Control
    Arm description
    		 No perioperative treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Part 2 - Trastuzumab
    Arm description
    		 Peri-operative trastuzumab, starting 11 days (+2 or -1day) prior to surgery on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pre-operative 6mg/kg given iv days 1 & 8 (accelerated dosing) commencing 11 days pre-surgery (+2 or -1 day). After surgery, 2mg/kg on Day 15 -19

    Arm title
    		 Part 2 - Combination
    Arm description
    		 Peri-operative treatment, starting 11 days (+2 or -1day) prior to surgery: - Trastuzumab, on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery - Lapatinib for 28 days commencing 11 days 11 days (+2 or -1day) prior to surgery
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pre-operative 6mg/kg given iv days 1 & 8 (accelerated dosing) commencing 11 days pre-surgery (+2 or -1 day). After surgery, 2mg/kg on Day 15 -19

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mgs daily (4 tablets of 250mg) for 28 days, to be taken all in one single dose

    Arm title
    		 Part 2 - Control
    Arm description
    		 No perioperative treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Started
    57
    51
    22
    32
    66
    29
    Completed
    55
    49
    22
    32
    65
    28
    Not completed
    2
    2
    0
    0
    1
    1
         Consent withdrawn by subject
    1
    2
    -
    -
    -
    -
         Protocol deviation
    1
    -
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 - Trastuzumab
    Reporting group description
    		 Peri-operative trastuzumab, starting 11 days (+2 or -1day) prior to surgery on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery

    Reporting group title
    Part 1 - Lapatinib
    Reporting group description
    		 Lapatinib for 28 days commencing 11 days 11 days (+2 or -1day) prior to surgery

    Reporting group title
    Part 1 - Control
    Reporting group description
    		 No perioperative treatment

    Reporting group title
    Part 2 - Trastuzumab
    Reporting group description
    		 Peri-operative trastuzumab, starting 11 days (+2 or -1day) prior to surgery on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery

    Reporting group title
    Part 2 - Combination
    Reporting group description
    		 Peri-operative treatment, starting 11 days (+2 or -1day) prior to surgery: - Trastuzumab, on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery - Lapatinib for 28 days commencing 11 days 11 days (+2 or -1day) prior to surgery

    Reporting group title
    Part 2 - Control
    Reporting group description
    		 No perioperative treatment

    Reporting group values
    		 Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control Total
    Number of subjects
    		 57 51 22 32 66 29 257
    Age categorical
    Units: Subjects
        <35
    		 2 0 0 1 1 1 5
        35-49
    		 27 24 5 10 19 8 93
        50-59
    		 12 15 10 17 22 9 85
        60-69
    		 11 11 6 4 20 7 59
        70-79
    		 5 1 1 0 3 4 14
        >=80
    		 0 0 0 0 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 57 51 22 32 66 29 257
        Male
    		 0 0 0 0 0 0 0
    Menopausal Status
    Units: Subjects
        Pre-menopausal
    		 24 21 4 11 25 9 94
        Peri-menopausal
    		 33 30 18 21 41 20 163
    Grade
    Units: Subjects
        Grade 1
    		 3 0 0 0 2 0 5
        Grade 2
    		 20 21 9 14 26 13 103
        Grade 3
    		 28 24 13 17 36 14 132
        Unknown
    		 6 6 0 1 2 2 17
    Tumour size (cm)
    Units: Subjects
        <2cm
    		 26 21 11 19 39 18 134
        2-5cm
    		 25 27 10 13 26 11 112
        >=5cm
    		 6 3 1 0 1 0 11
    ER status
    Units: Subjects
        Negative
    		 20 20 7 11 15 12 85
        Positive
    		 37 31 15 21 51 17 172
    PgR status
    Units: Subjects
        Negative
    		 20 23 8 16 28 17 112
        Positive
    		 21 17 6 8 18 5 75
        Missing
    		 16 11 8 8 20 7 70

    End points

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    End points reporting groups
    Reporting group title
    Part 1 - Trastuzumab
    Reporting group description
    		 Peri-operative trastuzumab, starting 11 days (+2 or -1day) prior to surgery on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery

    Reporting group title
    Part 1 - Lapatinib
    Reporting group description
    		 Lapatinib for 28 days commencing 11 days 11 days (+2 or -1day) prior to surgery

    Reporting group title
    Part 1 - Control
    Reporting group description
    		 No perioperative treatment

    Reporting group title
    Part 2 - Trastuzumab
    Reporting group description
    		 Peri-operative trastuzumab, starting 11 days (+2 or -1day) prior to surgery on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery

    Reporting group title
    Part 2 - Combination
    Reporting group description
    		 Peri-operative treatment, starting 11 days (+2 or -1day) prior to surgery: - Trastuzumab, on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery - Lapatinib for 28 days commencing 11 days 11 days (+2 or -1day) prior to surgery

    Reporting group title
    Part 2 - Control
    Reporting group description
    		 No perioperative treatment

    Primary: ki67 biological response

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    End point title
    		 ki67 biological response
    End point description
    A patient is classed as having had a Ki67 biological response if they have had a relative decrease in Ki67 of >30% between baseline and surgery. Percentage change will be defined as ((surgery score+0.1) – (pre-treatment score+0.1)/pre-treatment score+0.1)*100.
    End point type
    Primary
    End point timeframe
    From baseline biopsy to surgery (2-weeks approx)
    End point values
    		 Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Number of subjects analysed
    49 [1]
    44
    22
    31
    49
    28
    Units: Patients
        Response
    18
    29
    1
    14
    36
    2
        Non-response
    31
    15
    21
    17
    13
    26
    Notes
    [1] - Patients who had paired biopsy and surgery ki67 analysis
    Statistical analysis title
    		 Lapatinib vs Control (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Control
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Control (all)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Control v Part 2 - Trastuzumab v Part 2 - Control
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Combination vs Control (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Control
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Combination vs Trastuzumab (Part 2)
    Comparison groups
    Part 2 - Trastuzumab v Part 2 - Combination
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Lapatinib (Part 1)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Lapatinib
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Fisher exact
    Confidence interval

    Primary: Apoptosis biological response

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    End point title
    		 Apoptosis biological response
    End point description
    A patient is classed as having had an apoptosis biological response if they have had a relative increase in apoptosis of >30% between baseline and surgery. Percentage change will be defined as ((surgery score+0.1) – (pre-treatment score+0.1)/pre-treatment score+0.1)*100.
    End point type
    Primary
    End point timeframe
    From baseline biopsy to surgery (2-weeks approx)
    End point values
    		 Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Number of subjects analysed
    38
    37
    19
    30
    41
    28
    Units: Patients
        Response
    7
    2
    7
    11
    8
    10
        Non-response
    31
    35
    12
    19
    33
    18
    Statistical analysis title
    		 Lapatinib vs Control (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Control
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Control (all)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Control v Part 2 - Trastuzumab v Part 2 - Control
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Combination vs Control (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Control
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Combination vs Trastuzumab (Part 2)
    Comparison groups
    Part 2 - Trastuzumab v Part 2 - Combination
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Lapatinib (Part 1)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Lapatinib
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 Fisher exact
    Confidence interval

    Primary: Change in proliferation measured by Ki67

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    End point title
    		 Change in proliferation measured by Ki67
    End point description
    Fall in proliferation between diagnosis and surgery: Change in proliferation measured by Ki67 immunohistochemical assessment (%) at diagnosis and at surgery. Percentage change will be defined as ((surgery score+0.1) – (pre-treatment score+0.1)/pre-treatment score+0.1)*100.
    End point type
    Primary
    End point timeframe
    From baseline biopsy to surgery (2-weeks approx)
    End point values
    		 Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Number of subjects analysed
    49
    44
    22
    31
    49
    28
    Units: %
        median (inter-quartile range (Q1-Q3))
    -14 (-51 to 6)
    -43 (-68 to -21)
    2 (-9 to 15)
    -26 (-46 to -6)
    -49 (-78 to -25)
    -2 (-15 to 7)
    Statistical analysis title
    		 Lapatinib vs Control (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Control
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Control (all)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Control v Part 2 - Trastuzumab v Part 2 - Control
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Combination vs Control (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Control
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Combination vs Trastuzumab (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Trastuzumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0054
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Lapatinib (Part 1)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Lapatinib
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0034
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in apoptosis

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    End point title
    		 Change in apoptosis
    End point description
    Change in the tumour morphological apoptosis and activated caspase 3 measured at diagnosis and at surgery. Percentage change will be defined as ((surgery score+0.1) – (pre-treatment score+0.1)/pre-treatment score+0.1)*100.
    End point type
    Primary
    End point timeframe
    From baseline biopsy to surgery (2-weeks approx)
    End point values
    		 Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Number of subjects analysed
    38
    37
    19
    30
    41
    28
    Units: %
        median (inter-quartile range (Q1-Q3))
    -5 (-18 to 21)
    -25 (-42 to 1)
    24 (-10 to 57)
    4 (-32 to 48)
    -34 (-56 to 10)
    -2 (-15 to 63)
    Statistical analysis title
    		 Lapatinib vs Control (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Control
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Control (all)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Control v Part 2 - Trastuzumab v Part 2 - Control
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Combination vs Control (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Control
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Combination vs Trastuzumab (Part 2)
    Comparison groups
    Part 2 - Trastuzumab v Part 2 - Combination
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Lapatinib (Part 1)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Lapatinib
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Relapse Free Survival

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    End point title
    		 Relapse Free Survival
    End point description
    Time from randomization to local, regional, distant tumor recurrence, or death from any cause, with second primary cancers censored.
    End point type
    Secondary
    End point timeframe
    5-year Relapse free survival
    End point values
    		 Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Number of subjects analysed
    57
    51
    22
    32
    66
    29
    Units: %
        number (confidence interval 95%)
    88 (76 to 94)
    90 (77 to 96)
    95 (77 to 99)
    87 (69 to 95)
    92 (83 to 97)
    90 (71 to 97)
    Statistical analysis title
    		 Lapatinib vs Control (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Control
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Control (all)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Control v Part 2 - Trastuzumab v Part 2 - Control
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Combination vs Control (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Control
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.64
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Combination vs Trastuzumab (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Trastuzumab
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Lapatinib (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Trastuzumab
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to local recurrence

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    End point title
    		 Time to local recurrence [2]
    End point description
    This is defined as time from randomisation to first confirmed local recurrence. Patients who were alive and disease free at the end of follow-up were censored at the date last seen alive; patients who died were censored at date of death. Patients who have had a prior distant recurrence or second primary cancer were censored at the confirmation of this relapse.
    End point type
    Secondary
    End point timeframe
    5-year relapse-free rate
    Notes
    [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: No local recurrences occurred in Part 1.
    End point values
    		 Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Number of subjects analysed
    32
    66
    29
    Units: %
        number (confidence interval 95%)
    97 (79 to 99)
    97 (88 to 99)
    100 (100 to 100)
    Statistical analysis title
    		 Combination vs Control (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Control
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Combination vs Trastuzumab (Part 2)
    Comparison groups
    Part 2 - Trastuzumab v Part 2 - Combination
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to distant recurrence

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    End point title
    		 Time to distant recurrence
    End point description
    End point type
    Secondary
    End point timeframe
    5-year recurrence-free rate
    End point values
    		 Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Number of subjects analysed
    57
    51
    22
    32
    66
    29
    Units: %
        number (confidence interval 95%)
    88 (76 to 94)
    90 (77 to 96)
    95 (72 to 99)
    87 (69 to 95)
    94 (85 to 98)
    90 (71 to 97)
    Statistical analysis title
    		 Lapatinib vs Control (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Control
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Combination vs Control (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Control
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Control (all)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Control v Part 2 - Trastuzumab v Part 2 - Control
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Combination vs Trastuzumab (Part 2)
    Comparison groups
    Part 2 - Trastuzumab v Part 2 - Combination
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Lapatinib (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Trastuzumab
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    5 year overall survival
    End point values
    		 Part 1 - Trastuzumab Part 1 - Lapatinib Part 1 - Control Part 2 - Trastuzumab Part 2 - Combination Part 2 - Control
    Number of subjects analysed
    57
    51
    22
    32
    66
    29
    Units: %
        number (confidence interval 95%)
    91 (80 to 96)
    98 (87 to 99)
    100 (100 to 100)
    93 (76 to 98)
    98 (90 to 99)
    90 (71 to 97)
    Statistical analysis title
    		 Lapatinib vs Control (Part 1)
    Comparison groups
    Part 1 - Lapatinib v Part 1 - Control
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Lapatinib (Part 1)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Lapatinib
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Combination vs Control (Part 2)
    Comparison groups
    Part 2 - Combination v Part 2 - Control
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.047
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Combination vs Trastuzumab (Part 2)
    Comparison groups
    Part 2 - Trastuzumab v Part 2 - Combination
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Trastuzumab vs Control (all)
    Comparison groups
    Part 1 - Trastuzumab v Part 1 - Control v Part 2 - Trastuzumab v Part 2 - Control
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.64
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Ater randomisation and within 30 days of the last administration of perioperative (28 days) trastuzumab or lapatinib. Cardiac toxicity up to 5 years post randomisation
    Adverse event reporting additional description
    Any untoward medical occurrence or effect that occurs after randomisation and within 30 days of the last administration of perioperative (28 days) trastuzumab or lapatinib. An additional cardiac assessment after treatment but before adjuvant chemotherapy was introduced as of April 2014, affecting 90/127 part 2 patients.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Part 1&2 - Trastuzumab
    Reporting group description
    		 Peri-operative trastuzumab, starting 11 days (+2 or -1day) prior to surgery on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery

    Reporting group title
    Part 1 - Lapatinib
    Reporting group description
    		 Lapatinib for 28 days commencing 11 days 11 days (+2 or -1day) prior to surgery

    Reporting group title
    Part 2 - Combination
    Reporting group description
    		 Peri-operative treatment, starting 11 days (+2 or -1day) prior to surgery: - Trastuzumab, on Day 1 and 8, and between Day 15 and Day 19 i.e. after surgery - Lapatinib for 28 days commencing 11 days 11 days (+2 or -1day) prior to surgery

    Serious adverse events
    		 Part 1&2 - Trastuzumab Part 1 - Lapatinib Part 2 - Combination
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 87 (6.90%)
    5 / 49 (10.20%)
    5 / 65 (7.69%)
         number of deaths (all causes)
    10
    4
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 87 (0.00%)
    2 / 49 (4.08%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 49 (2.04%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 49 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 49 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 49 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 49 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 49 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 49 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 49 (2.04%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 87 (1.15%)
    2 / 49 (4.08%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 49 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 49 (2.04%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Breast cellulitis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 49 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Part 1&2 - Trastuzumab Part 1 - Lapatinib Part 2 - Combination
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 87 (5.75%)
    41 / 49 (83.67%)
    51 / 65 (78.46%)
    Cardiac disorders
    Ejection fraction abnormal
    Additional description: An additional cardiac assessment after treatment but before adjuvant chemotherapy was introduced as of April 2014, affecting 90/127 part 2 patients. The assessment was done on 70/90 part 2 patients - but number exposed can't be changed below.
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 49 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Diahorrea was recorded retrospectively, and only whether patient had experienced episode or not (not number of episodes)
         subjects affected / exposed
    4 / 87 (4.60%)
    25 / 49 (51.02%)
    37 / 65 (56.92%)
         occurrences all number
    4
    25
    37
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Rash was assessed retrospectively, and only if patients had experienced an episode - number of episodes not collected.
         subjects affected / exposed
    1 / 87 (1.15%)
    38 / 49 (77.55%)
    33 / 65 (50.77%)
         occurrences all number
    1
    38
    33

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Apr 2010
    Changes to Patient Information Sheet and consent forms
    08 Sep 2011
    Addition of Northern Ireland as a location in the UK plus addition of sites and changes to Patient Information Sheet, Consent form and protocol.
    01 Oct 2012
    Updated protocol, updated GP letter, changes to labelling of Investigational Medicinal Product
    10 Apr 2013
    Protocol -updated • IMP label Amendment (Lapatinib 1000mg) • PIS/CFs (Pathway A, B, and Non Biological) • Patient Summaries (Pathway A, B, and Non Biological) • GP letter updated • Patient Card updated • Change of Principal Investigators at two sites
    18 Dec 2013
    Additional assessment of cardiac function: The EPHOS-B IDMC stated that, although there did not appear to be a safety concern around symptomatic left ventricular dysfunction, a more detailed study of cardiac function was necessary to reassure clinicians that there were no adverse cardiac sequelae caused by the administration of anti-her2 therapies in the peri-operative period. To this end the inclusion of an assessment of cardiac function in the post-operative period prior to the initiation of systemic adjuvant chemotherapy was then mandatory. Updates to Patient Information Sheet and consent. Change of PI at one centre
    26 Apr 2018
    A change in the legal name of one of the three EPHOS-B Co-Sponsors. On 1 October 2017, University Hospital of South Manchester (UHSM) and Central Manchester University Hospitals NHS Foundation Trust joined together as a single organisation, called Manchester University NHS Foundation Trust (MFT). The effective date of transfer of responsibilities from UHSM to MFT was therefore 1 October 2017. The EPHOS-B Co-Sponsors are The Institute of Cancer Research, The University of Manchester and Manchester University NHS Foundation Trust.
    04 Sep 2019
    Updates to protocol- n 2015 Novartis acquired the GSK oncology portfolio and therefore references to GSK have been updated in the protocol where appropriate, plus administrative changes and removal for the requirement for annual cardiac assessments

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35165099
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