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    Clinical Trial Results:
    An open-label, Phase II, study to evaluate biomarkers associated with response to subsequent therapies in subjects with HER2-positive metastatic breast cancer receiving treatment with trastuzumab in combination with lapatinib or chemotherapy

    Summary
    EudraCT number
    		 2014-001220-30
    Trial protocol
    		 ES   IT   AT  
    Global end of trial date
    04 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    117165 (CLAP016A2206)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02213042
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate changes in the expression of biomarkers associated with immunomodulation.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Thailand: 3
    Worldwide total number of subjects
    42
    EEA total number of subjects
    9
    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)
    35
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Overall, 225 subjects were planned and 42 subjects were enrolled in this study

    Pre-assignment
    Screening details
    		 The study was designed to address the post-authorization measures as agreed with the Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjs into this study was challenging, and following agreement with the European Medicines Agency (EMA) enrollment into this study was halted after the enrollment of 42 of the 225 planned subjs.

    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
    		 LAP+TRAS±AI (HER2-Enriched) - Arm A
    Arm description
    		 Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator’s choice was required.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    LAP016
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in Arm A were treated with lapatinib with 1000 mg oral once-daily dose. Lapatinib was provided as 250-mg oval, biconvex, and orange film-coated tablets for oral administration. Each tablet contained 405 mg of lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib freebase per tablet.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was sourced locally from commercial stock, and was administered by iv infusion on Day 1 (+/-3 day) of the start of lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, trastuzumab was administered every 3 weeks as a 6 mg/kg maintenance dose.

    Arm title
    		 TRAS+CHEM±AI (HER2-Enriched) - Arm B
    Arm description
    		 Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator’s choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was sourced locally from commercial stock, and was administered by iv infusion on Day 1 (+/-3 day) of the start of lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, trastuzumab was administered every 3 weeks as a 6 mg/kg maintenance dose.

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The choice of chemotherapy in Arm B (comparator arm) was at the discretion of the Investigator based on previous treatment and subject status at the time of study entry. Endocrine therapy with an aromatase inhibitors (AI) was chosen at the discretion of the Investigator. The AI chosen by the Investigator at randomization was to remain the same throughout the study. The choice for the Investigators to choose from were: choose from were anastrozole (tablet), exemestane (tablet), and letrozole (tablet) and dosing was per product information.

    Arm title
    		 Non-HER2- Enriched - Arm C
    Arm description
    		 Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator’s choice was required.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    LAP016
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in Arm C were treated with lapatinib with 1000 mg oral once-daily dose. Lapatinib was provided as 250-mg oval, biconvex, and orange film-coated tablets for oral administration. Each tablet contained 405 mg of lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib freebase per tablet.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was sourced locally from commercial stock, and was administered by iv infusion on Day 1 (+/-3 day) of the start of lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, trastuzumab was administered every 3 weeks as a 6 mg/kg maintenance dose.

    Number of subjects in period 1
    		LAP+TRAS±AI (HER2-Enriched) - Arm A TRAS+CHEM±AI (HER2-Enriched) - Arm B Non-HER2- Enriched - Arm C
    Started
    17
    15
    10
    Total deaths
    11
    9
    6
    Completed
    0
    0
    0
    Not completed
    17
    15
    10
         Consent withdrawn by subject
    -
    1
    1
         Adverse event, non-fatal
    2
    1
    -
         Disease progression-incl death due to disease prog
    14
    13
    8
         Investigator discretion
    -
    -
    1
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LAP+TRAS±AI (HER2-Enriched) - Arm A
    Reporting group description
    		 Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator’s choice was required.

    Reporting group title
    TRAS+CHEM±AI (HER2-Enriched) - Arm B
    Reporting group description
    		 Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator’s choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.

    Reporting group title
    Non-HER2- Enriched - Arm C
    Reporting group description
    		 Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator’s choice was required.

    Reporting group values
    		 LAP+TRAS±AI (HER2-Enriched) - Arm A TRAS+CHEM±AI (HER2-Enriched) - Arm B Non-HER2- Enriched - Arm C Total
    Number of subjects
    		 17 15 10 42
    Age Categorical
    Units: Participants
        < 65 years
    		 14 15 6 35
        >= 65 years
    		 3 0 4 7
    Sex: Female, Male
    Units: participants
        Female
    		 17 15 10 42
        Male
    		 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 14 11 10 35
        African American
    		 1 2 0 3
        Asian
    		 1 2 0 3
        Native Hawaiian or Pacific Islander
    		 1 0 0 1

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    LAP+TRAS±AI (HER2-Enriched) - Arm A
    Reporting group description
    		 Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator’s choice was required.

    Reporting group title
    TRAS+CHEM±AI (HER2-Enriched) - Arm B
    Reporting group description
    		 Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator’s choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.

    Reporting group title
    Non-HER2- Enriched - Arm C
    Reporting group description
    		 Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator’s choice was required.

    Primary: Fold change in expression profile of genes and/or proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) from screening to approx. 3.5 years

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    End point title
    		 Fold change in expression profile of genes and/or proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) from screening to approx. 3.5 years [1] [2]
    End point description
    Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
    End point type
    Primary
    End point timeframe
    At screening and at disease progression, assessed up to approx. 3.5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not planned for this endpoint
    [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: Statistical analysis was not planned for this endpoint
    End point values
    		 LAP+TRAS±AI (HER2-Enriched) - Arm A
    Number of subjects analysed
    7
    Units: Ratio of gene expression level
    median (confidence interval 95%)
        Membrane spanning 4-domains A1; n = 5
    0.25 (0.078 to 0.589)
        POU class 2 associating factor 1; n = 5
    0.32 (0.183 to 0.543)
        CD19+; n = 5
    0.35 (0.106 to 0.904)
        Interleukin 6; n = 5
    0.36 (0.033 to 0.832)
        G antigen 1; n = 5
    0.43 (0.030 to 0.901)
        ubiquitin specific peptidase 9, Y-linked; n = 5
    0.50 (0.321 to 0.770)
        Thy-1 cell surface antigen; n = 5
    0.50 (0.113 to 0.902)
        Chemerin chemokine-like receptor 1; n = 5
    0.51 (0.345 to 0.862)
        Maj histocompatibility complx,cls II, DR beta4;n=5
    0.51 (0.320 to 0.984)
        Collectin subfamily member 12; n = 5
    0.51 (0.151 to 0.794)
        Complement C3b/C4b receptor 1 (Knops bld grp); n=5
    0.51 (0.227 to 0.901)
        CD33 molecule; n = 5
    0.56 (0.458 to 0.826)
        B-cell linker; n = 5
    0.56 (0.326 to 0.874)
        Interleukin 12A; n = 5
    0.57 (0.228 to 0.892)
        CD163+; n = 5
    0.57 (0.417 to 0.911)
        C-C motif chemokine ligand 8; n = 5
    0.58 (0.138 to 0.954)
        Chemokine (C-C motif) receptor 1; n = 5
    0.59 (0.501 to 0.792)
        POU class 2 homeobox 2; n = 5
    0.60 (0.440 to 0.944)
        Cyclin dependent kinase inhibitor 1A; n = 5
    0.62 (0.453 to 0.873)
        CD27 molecule; n = 5
    0.62 (0.357 to 0.886)
        Lymphocyte antigen 86; n = 5
    0.63 (0.383 to 0.906)
        TNF superfamily member 8; n = 5
    0.64 (0.476 to 0.879)
        CD34+; n = 5
    0.67 (0.558 to 0.863)
        Integrin subunit alpha 6; n = 5
    0.68 (0.470 to 0.827)
        C-type lectin domain containing 7A; n = 5
    0.69 (0.326 to 0.944)
        CD180 molecule; n = 5
    0.70 (0.347 to 0.869)
        Integrin subunit alpha M; n = 5
    0.72 (0.411 to 0.957)
        Toll like receptor 6; n = 5
    0.72 (0.511 to 0.836)
        Autophagy related 10; n = 5
    0.73 (0.662 to 0.864)
        C-C motif chemokine ligand 3 like 1; n = 5
    0.74 (0.499 to 0.996)
        Bone marrow stromal cell antigen 1; n = 5
    0.75 (0.345 to 0.922)
        CD22+; n = 5
    0.76 (0.629 to 0.936)
        CD37 molecule; n = 5
    0.76 (0.553 to 0.884)
        NEG_A; n = 5
    0.77 (0.674 to 0.949)
        Sperm auto antigenic protein 17; n = 5
    0.79 (0.697 to 0.968)
        CD200 molecule; n = 5
    0.79 (0.598 to 0.945)
        TNF receptor associated factor 3; n = 5
    0.82 (0.718 to 0.962)
        Interferon alpha and beta receptor subunit 1;n=5
    1.10 (1.036 to 1.124)
        TNF receptor associated factor 6; n = 5
    1.21 (1.016 to 1.332)
    No statistical analyses for this end point

    Primary: Fold change in expression profile of genes and /or proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) from screening to approx. 3.5 years

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    End point title
    		 Fold change in expression profile of genes and /or proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) from screening to approx. 3.5 years [3] [4]
    End point description
    Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
    End point type
    Primary
    End point timeframe
    At screening and at disease progression, assessed up to approx. 3.5 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not planned for this endpoint
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not planned for this endpoint
    End point values
    		 TRAS+CHEM±AI (HER2-Enriched) - Arm B
    Number of subjects analysed
    6
    Units: Ratio of gene expression level
    median (confidence interval 95%)
        C-type lectin domain containing 5A; n = 5
    0.16 (0.020 to 0.440)
        Interferon induced transmembrane protein 1; n = 5
    0.25 (0.183 to 0.421)
        Fibronectin 1; n = 5
    0.27 (0.077 to 0.393)
        C-C motif chemokine ligand 7; n = 5
    0.27 (-0.064 to 0.888)
        Triggering receptr express on myeloid cells 1;n=5
    0.27 (-0.018 to 0.959)
        Plasminogen activator, urokinase; n = 5
    0.27 (0.112 to 0.545)
        Interleukin 22 receptor subunit alpha 2; n = 5
    0.28 (0.192 to 0.425)
        C-C motif chemokine ligand 8; n = 5
    0.28 (0.044 to 0.699)
        Tmr necrosis factor(ligand)superfam memb4 gene;n=5
    0.31 (0.147 to 0.651)
        Maj histocompatibility complx, Cls I-related; n=5
    0.32 (0.139 to 0.832)
        Cathepsin L; n = 5
    0.32 (0.066 to 0.820)
        SPP-1 (Osteopontin); n = 5
    0.33 (0.076 to 0.501)
        Thy-1 cell surface antigen; n = 5
    0.34 (0.157 to 0.648)
        Transforming growth factor beta 2; n = 5
    0.35 (0.120 to 0.504)
        Hepatitis A virus cellular receptor 2; n = 5
    0.36 (0.138 to 0.614)
        Bone marrow stromal cell antigen 1; n = 5
    0.37 (0.133 to 0.864)
        C-type lectin domain containing 7A; n = 5
    0.37 (0.166 to 0.570)
        C-X-C motif chemokine ligand 5; n = 5
    0.38 (0.040 to 0.943)
        Collagen type III alpha 1 chain; n = 5
    0.40 (0.130 to 0.685)
        Complement C1s; n = 5
    0.41 (0.088 to 0.717)
        IFIT1 gene; n = 5
    0.41 (0.148 to 0.921)
        Maj histocompatibility complex, cls I, G; n=5
    0.41 (0.147 to 0.698)
        Tumour necrosis factor gene; n = 5
    0.42 (0.108 to 0.945)
        Integrin subunit beta 1; n = 5
    0.43 (0.231 to 0.864)
        Pro-melanin concentrating hormone; n = 5
    0.43 (0.081 to 0.972)
        CD86+; n = 5
    0.44 (0.102 to 0.700)
        FCGR3A SNP rs396991; n = 5
    0.44 (0.107 to 0.696)
        TNF receptor superfamily member 10c; n = 5
    0.44 (0.165 to 0.925)
        Integrin subunit alpha M; n = 5
    0.45 (0.166 to 0.797)
        TNF receptor superfamily member 11b; n = 5
    0.45 (0.114 to 0.923)
        Platelet derived growth factor C; n = 5
    0.45 (0.231 to 0.797)
        Mannan binding lectin serine peptidase 1; n = 5
    0.46 (0.304 to 0.896)
        Recombination activating 1; n = 5
    0.46 (0.394 to 0.597)
        Interleukin 22; n = 5
    0.47 (0.229 to 0.609)
        Tmr necros fact.(ligand)superfam memb 13b gene;n=5
    0.47 (0.179 to 0.697)
        BMI1 proto-oncogene, polycomb ring finger; n = 5
    0.47 (0.322 to 0.735)
        CXCL10 gene; n = 5
    0.48 (0.074 to 0.986)
        Leukocyte immunoglobulin like receptor B1; n = 5
    0.48 (0.142 to 0.747)
        MX1 gene; n = 5
    0.48 (0.155 to 0.781)
        Tmr necros fact.(ligand)superfam. memb 11 gene;n=5
    0.48 (0.227 to 0.798)
        Cathepsin S; n = 5
    0.49 (0.138 to 0.807)
        Interferon induced transmembrane protein 2; n = 5
    0.49 (0.245 to 0.887)
        LYN proto-oncogene, Src family tyrosine kinase;n=5
    0.50 (0.360 to 0.685)
        Platelet deriv. growth factor receptor beta; n=5
    0.50 (0.160 to 0.801)
        OAS3 gene; n = 5
    0.50 (0.284 to 0.899)
        CD58 molecule; n = 5
    0.50 (0.398 to 0.619)
        complement C3a receptor 1; n = 5
    0.51 (0.147 to 0.949)
        Chemokine (C-C motif) receptor 1; n = 5
    0.52 (0.159 to 0.815)
        Interleukin 24 gene; n = 5
    0.52 (0.161 to 0.706)
        Chemokine (C-X-C motif) receptor 2; n = 5
    0.53 (0.295 to 0.629)
        Strawberry notch homolog 2; n = 5
    1.13 (1.045 to 1.300)
        Zinc finger protein 205; n = 5
    1.42 (1.144 to 1.815)
        Fas associated via death domain; n = 5
    1.58 (1.107 to 2.043)
        CD3e molecule associated protein; n = 5
    1.67 (1.244 to 2.075)
        Baculoviral IAP repeat containing 5; n = 5
    1.73 (1.003 to 2.635)
        Interleukin 17 receptor B; n = 5
    2.01 (1.151 to 2.975)
    No statistical analyses for this end point

    Primary: Fold change in expression profile of genes and /or proteins for Arm C (Non-HER2- Enriched) from screening to approx. 3.5 years

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    End point title
    		 Fold change in expression profile of genes and /or proteins for Arm C (Non-HER2- Enriched) from screening to approx. 3.5 years [5] [6]
    End point description
    Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
    End point type
    Primary
    End point timeframe
    At screening and at disease progression, assessed up to approx. 3.5 years
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not planned for this endpoint
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not planned for this endpoint
    End point values
    		 Non-HER2- Enriched - Arm C
    Number of subjects analysed
    7
    Units: Ratio of gene expression level
    median (confidence interval 95%)
        Triggering recept. express on myeloid cells 1;n=5
    0.50 (0.294 to 0.995)
        Interleukin 1 receptor, type 1 gene; n = 5
    1.58 (1.235 to 2.328)
        Complement component 2; n = 5
    2.13 (1.011 to 3.567)
        Coagulation factor XII; n = 5
    2.69 (1.062 to 4.229)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    From randomization to disease progression or death, up to approx. 5.6 years
    End point values
    		 LAP+TRAS±AI (HER2-Enriched) - Arm A TRAS+CHEM±AI (HER2-Enriched) - Arm B Non-HER2- Enriched - Arm C
    Number of subjects analysed
    17
    15
    10
    Units: Months
        median (confidence interval 95%)
    6.0 (2.10 to 10.60)
    7.2 (2.10 to 14.80)
    6.0 (1.60 to 8.30)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR)

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    End point title
    		 Overall response rate (ORR)
    End point description
    Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator’s assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.
    End point type
    Secondary
    End point timeframe
    From enrollment/randomization to the end of study, approximately 5.6 years
    End point values
    		 LAP+TRAS±AI (HER2-Enriched) - Arm A TRAS+CHEM±AI (HER2-Enriched) - Arm B Non-HER2- Enriched - Arm C
    Number of subjects analysed
    17
    15
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    35.3 (14.2 to 61.7)
    33.3 (11.8 to 61.6)
    30.0 (6.7 to 65.3)
    No statistical analyses for this end point

    Secondary: Clinical benefit rate (CBR)

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    End point title
    		 Clinical benefit rate (CBR)
    End point description
    CBR is defined as percentage of subjects with a complete response (CR), partial response (PR), or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.
    End point type
    Secondary
    End point timeframe
    From enrollment/randomization the end of study, approximately 5.6 years
    End point values
    		 LAP+TRAS±AI (HER2-Enriched) - Arm A TRAS+CHEM±AI (HER2-Enriched) - Arm B Non-HER2- Enriched - Arm C
    Number of subjects analysed
    17
    15
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    35.3 (14.2 to 61.7)
    46.7 (21.3 to 73.4)
    30.0 (6.7 to 65.3)
    No statistical analyses for this end point

    Secondary: Association between biomarkers and PFS

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    End point title
    		 Association between biomarkers and PFS
    End point description
    Describe if a change at disease progression in biomarker correlates with PFS
    End point type
    Secondary
    End point timeframe
    From randomization to disease progression or death, up to approx. 5.6 years
    End point values
    		 LAP+TRAS±AI (HER2-Enriched) - Arm A TRAS+CHEM±AI (HER2-Enriched) - Arm B Non-HER2- Enriched - Arm C
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: unitless
        number (not applicable)
    Notes
    [7] - Analysis was not performed due to insufficient sample size and early stop of recruitment.
    [8] - Analysis was not performed due to insufficient sample size and early stop of recruitment.
    [9] - Analysis was not performed due to insufficient sample size and early stop of recruitment.
    No statistical analyses for this end point

    Secondary: All-Collected Deaths

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    End point title
    		 All-Collected Deaths
    End point description
    On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 168 weeks for Lapatinib, (treatment duration ranged from 151 to 164 weeks), 164 weeks for Trastuzumab (treatment duration ranged from 0 to 160 weeks), 168 weeks for Aromatase Inhibitors (treatment duration ranged from 9 to 164 weeks). Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 5.6 years.
    End point type
    Secondary
    End point timeframe
    On-treatment deaths: up to approx. 168 weeks, Total deaths: up to approx. 5.6 years
    End point values
    		 LAP+TRAS±AI (HER2-Enriched) - Arm A TRAS+CHEM±AI (HER2-Enriched) - Arm B Non-HER2- Enriched - Arm C
    Number of subjects analysed
    17
    15
    10
    Units: Participants
        Total Deaths
    11
    9
    6
        On-treatment deaths
    3
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit {LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit up to approx. 5.6 years.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    HER2-Enriched-Lapatinib(1000mg)+Trastuzumab(6mg per kg)+AI
    Reporting group description
    		 HER2-Enriched-Lapatinib(1000mg)+Trastuzumab(6mg per kg)+AI

    Reporting group title
    Non-HER2-Enriched-Lapatinib(1000mg)+Trastuzumab(6mg per kg)+AI
    Reporting group description
    		 Non-HER2-Enriched-Lapatinib(1000mg)+Trastuzumab(6mg per kg)+AI

    Reporting group title
    HER2-Enriched-Trastuzumab(6mg per kg)+Chemo+AI
    Reporting group description
    		 HER2-Enriched-Trastuzumab(6mg per kg)+Chemo+AI

    Serious adverse events
    		 HER2-Enriched-Lapatinib(1000mg)+Trastuzumab(6mg per kg)+AI Non-HER2-Enriched-Lapatinib(1000mg)+Trastuzumab(6mg per kg)+AI HER2-Enriched-Trastuzumab(6mg per kg)+Chemo+AI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 10 (20.00%)
    1 / 15 (6.67%)
         number of deaths (all causes)
    3
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast neoplasm
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         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
    Cardiac arrest
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    0 / 15 (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
    Hypoxia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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
    Sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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
    Hypoglycaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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
    Hypokalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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
    Hypomagnesaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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
    Hyponatraemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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
    Metabolic disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (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: 5%
    Non-serious adverse events
    		 HER2-Enriched-Lapatinib(1000mg)+Trastuzumab(6mg per kg)+AI Non-HER2-Enriched-Lapatinib(1000mg)+Trastuzumab(6mg per kg)+AI HER2-Enriched-Trastuzumab(6mg per kg)+Chemo+AI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 17 (88.24%)
    10 / 10 (100.00%)
    14 / 15 (93.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Tumour pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Lymphoedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 10 (20.00%)
    4 / 15 (26.67%)
         occurrences all number
    3
    2
    4
    Face oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    2
    0
    2
    Influenza like illness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    2
    Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pleurisy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    5 / 15 (33.33%)
         occurrences all number
    0
    0
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    2
    0
    5
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 10 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    5
    Blood sodium decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    2
    Weight decreased
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    2
    0
    Weight increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Incision site pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Rib fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    3
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    2
    Neuropathy peripheral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Neurotoxicity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 10 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    2
    2
    5
    Leukopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    3
    Lymphopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Neutropenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    4 / 15 (26.67%)
         occurrences all number
    1
    0
    8
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Visual impairment
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    3
    0
    2
    Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    9 / 17 (52.94%)
    6 / 10 (60.00%)
    1 / 15 (6.67%)
         occurrences all number
    22
    8
    1
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 10 (30.00%)
    5 / 15 (33.33%)
         occurrences all number
    1
    4
    5
    Stomatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    3
    Vomiting
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 10 (40.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    5
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    5 / 15 (33.33%)
         occurrences all number
    0
    0
    5
    Dermatitis acneiform
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Dry skin
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Nail discolouration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Nail disorder
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    1
    Nail dystrophy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    1
    Pruritus
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Rash
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    6
    0
    3
    Rash maculo-papular
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Skin toxicity
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    19
    Pain in extremity
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Paronychia
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    5
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 10 (30.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    Hyperkalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Hypermagnesaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 10 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2014
    Amendment 1 was issued following feedback from various countries to not include a third biopsy. At the time of this amendment, no subjects were enrolled.
    23 Mar 2017
    Amendment 2 was issued when 42 subjects were enrolled and study recruitment was halted, the key changes included changes to the primary and secondary objectives as described below. The primary objective of the study was updated to remove the evaluation of changes in the expression of biomarkers associated with HER family, apoptosis, and ABC transporters. The amended primary objective evaluated the changes in the expression of biomarkers associated with immunomodulation. The secondary objectives were updated to remove OS and PFS on first next line and subsequent lines of anticancer therapies. Patient-reported outcomes (PRO) and health-related quality of life (HRQOL) objectives were also removed. An exploratory objective was included to explore the changes in molecular subtype determined by PAM50 assay and selected biomarkers.
    15 May 2017
    Amendment 3 was issued subsequent to the acquisition of GlaxoSmithKline (GSK) compound GW572016 by Novartis, when 42 subjects had received treatment (with 34 having completed or discontinued study treatment). The protocol was amended to remove references to GlaxoSmithKline and its staff and these were either deleted or replaced with that of Novartis and its authorized agents to align with the change of sponsorship. Administrative changes were made to align with Novartis processes and procedures.

    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
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