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    Clinical Trial Results:
    A Phase II, multi-center, open-label, neoadjuvant, randomized study of weekly paclitaxel with or without LCL161 in patients with triple negative breast cancer Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2012-000677-23
    Trial protocol
    		 GB   ES   IE   IT   BE   CZ   DE  
    Global end of trial date
    18 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2018
    First version publication date
    18 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLCL161A2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01617668
    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,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 61324111,
    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
    18 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with TNBC, analyzed separately in the gene expression signature negative and positive groups.
    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
    22 Aug 2012
    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
    Australia: 4
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    209
    EEA total number of subjects
    106
    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)
    194
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 215 patients were randomized to receive the study treatment. 105 gene expression signature positive patients were randomized to LCL161+paclitaxel (N=51) or paclitaxel only (N=54). 110 gene expression signature negative patients were randomized to LCL161+paclitaxel (N=55) or paclitaxel only (N=55).

    Pre-assignment
    Screening details
    		 Only 50 of 54 pts in the Paclitaxel without LCL161 (Positive group) received study drug; Only 53 of 55 pts in the Paclitaxel without LCL161 (Negative group) received study drug.

    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
    		 Paclitaxel with LCL161 (Positive group)
    Arm description
    		 Patients who were gene signature positive were randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCL161
    Investigational medicinal product code
    LCL161
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCL161 (1800 mg once weekly) was supplied as film-coated tablets of 300 mg strength and was administered orally and was given for 12 weeks.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was given as 80 mg/m2 weekly and was administered as infusion.

    Arm title
    		 Paclitaxel without LCL161 (Positive group)
    Arm description
    		 Patients who were gene signature positive were randomized to the control arm received paclitaxel 80 mg/m2 weekly for 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was given as 80 mg/m2 weekly and was administered as infusion.

    Arm title
    		 Paclitaxel with LCL161 (Negative group)
    Arm description
    		 Patients who were gene signature negative were randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCL161
    Investigational medicinal product code
    LCL161
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCL161 (1800 mg once weekly) was supplied as film-coated tablets of 300 mg strength and was administered orally and was given for 12 weeks.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was given as 80 mg/m2 weekly and was administered as infusion.

    Arm title
    		 Paclitaxel without LCL161 (Negative group)
    Arm description
    		 Patients who were gene signature negative were randomized to the control arm received paclitaxel 80 mg/m2 weekly for 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was given as 80 mg/m2 weekly and was administered as infusion.

    Number of subjects in period 1
    		Paclitaxel with LCL161 (Positive group) Paclitaxel without LCL161 (Positive group) Paclitaxel with LCL161 (Negative group) Paclitaxel without LCL161 (Negative group)
    Started
    51
    50
    55
    53
    Completed
    38
    41
    32
    38
    Not completed
    13
    9
    23
    15
         Physician decision
    1
    2
    3
    -
         Adverse event, non-fatal
    7
    -
    12
    5
         Progressive Disease
    4
    4
    6
    9
         Subject/guardian decision
    1
    3
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paclitaxel with LCL161 (Positive group)
    Reporting group description
    		 Patients who were gene signature positive were randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks.

    Reporting group title
    Paclitaxel without LCL161 (Positive group)
    Reporting group description
    		 Patients who were gene signature positive were randomized to the control arm received paclitaxel 80 mg/m2 weekly for 12 weeks.

    Reporting group title
    Paclitaxel with LCL161 (Negative group)
    Reporting group description
    		 Patients who were gene signature negative were randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks.

    Reporting group title
    Paclitaxel without LCL161 (Negative group)
    Reporting group description
    		 Patients who were gene signature negative were randomized to the control arm received paclitaxel 80 mg/m2 weekly for 12 weeks.

    Reporting group values
    		 Paclitaxel with LCL161 (Positive group) Paclitaxel without LCL161 (Positive group) Paclitaxel with LCL161 (Negative group) Paclitaxel without LCL161 (Negative group) Total
    Number of subjects
    		 51 50 55 53 209
    Age, Customized
    Units: Participants
        < 65 years
    		 46 46 52 50 194
        >= 65 years
    		 5 4 3 3 15
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 49.4 ± 9.83 48.4 ± 11.08 47.8 ± 10.46 49 ± 8.92 -
    Gender, Male/Female
    Units: Participants
        Female
    		 51 50 55 53 209
        Male
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Paclitaxel with LCL161 (Positive group)
    Reporting group description
    		 Patients who were gene signature positive were randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks.

    Reporting group title
    Paclitaxel without LCL161 (Positive group)
    Reporting group description
    		 Patients who were gene signature positive were randomized to the control arm received paclitaxel 80 mg/m2 weekly for 12 weeks.

    Reporting group title
    Paclitaxel with LCL161 (Negative group)
    Reporting group description
    		 Patients who were gene signature negative were randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks.

    Reporting group title
    Paclitaxel without LCL161 (Negative group)
    Reporting group description
    		 Patients who were gene signature negative were randomized to the control arm received paclitaxel 80 mg/m2 weekly for 12 weeks.

    Subject analysis set title
    FAS: LCL161 + Paclitaxel (gene expression signature positive)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was composed of all patients who received at least one full or partial dose of LCL161 + paclitaxel or one full or partial dose of paclitaxel alone. Unless otherwise specified, patients were classified according to treatment arm assigned (two randomized treatment arms) and gene expression signature status (positive or negative) determined at randomization as reported in interactive voice response system (IVRS). Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    FAS: Paclitaxel only (gene expression signature positive)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients randomized to the control arm for gene expression signature positive received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS1: LCL161 + Paclitaxel (gene expression signature negative)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    FAS: Paclitaxel only (gene expression signature negative)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients randomized to the control arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS1: LCL161 + Paclitaxel
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Efficacy Analysis Set 1 (EAS1) was composed of all patients who receive at least one full or partial dose of LCL161 + paclitaxel or one full or partial dose of paclitaxel alone with a valid gene expression signature score. Patients were classified according to treatment received and gene expression signature status derived from the continuous score. Patients with the gene expression signature score of 0.6661 or higher were classified in a gene expression signature positive group. Patients with a score below 0.6661 were classified as gene expression signature negative. Patients randomized to the experimental arm who received LCL161 1800 mg once weekly + paclitaxel 80 mg/m2 weekly for 12 weeks.

    Subject analysis set title
    EAS1: Paclitaxel only
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the control arm who received paclitaxel 80 mg/m2 weekly for 12 weeks.

    Subject analysis set title
    EAS1: LCL161 + Paclitaxel (gene expression signature positive)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS1: Paclitaxel only (gene expression signature positive)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the control arm for gene expression signature positive received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS1: Paclitaxel only (gene expression signature negative)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the control arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS1: LCL161 + Paclitaxel (gene expression signature positive)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS1: Paclitaxel only (gene expression signature positive)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the control arm for gene expression signature positive received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS1: LCL161 + Paclitaxel (gene expression signature negative)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS1: Paclitaxel only (gene expression signature negative)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the control arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS2: LCL161 + Paclitaxel (gene expression signature positive)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Efficacy Analysis Set 2 (EAS2) was the same as EAS1 except that the threshold for classifying a patient into the positive gene group was 0.7716. Patients with the gene expression signature score of 0.7716 or higher were classified in a gene expression signature positive group. Patients with a score below 0.7716 were classified as gene expression signature negative. Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS2: Paclitaxel only (gene expression signature positive)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the control arm for gene expression signature positive received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS2: LCL161 + Paclitaxel (gene expression signature negative)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    EAS2: Paclitaxel only (gene expression signature negative)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients randomized to the control arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    PAS: LCL161 + Paclitaxel (gene expression signature negative)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 1800 mg once weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.

    Subject analysis set title
    PAS: LCL161
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients randomized to the LCL161 1800 mg once weekly for 12 weeks.

    Primary: Pathological complete response (pCR) rate in breast after 12 weeks of therapy

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    End point title
    		 Pathological complete response (pCR) rate in breast after 12 weeks of therapy
    End point description
    pCR rate was defined as histopathologically confirmed absence of invasive disease in the breast. To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with triple negative breast cancer. Analyses were performed separately in the gene expression signature negative and positive groups. This analysis was based on Bayesian design using a binomial distribution for the data with a beta prior. The method of dispersion used in this study is Credible Interval (Crl) and not Confidence Interval (CI). Median values are posterior medians of pCR rate for each group.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Paclitaxel with LCL161 (Positive group) Paclitaxel without LCL161 (Positive group) Paclitaxel with LCL161 (Negative group) Paclitaxel without LCL161 (Negative group)
    Number of subjects analysed
    51
    50
    55
    53
    Units: Percentage of Participants
        median (confidence interval 95%)
    24.9 (14.5 to 37.8)
    23.4 (13.3 to 36.2)
    6.9 (2.2 to 15.5)
    9.1 (3.3 to 18.6)
    Statistical analysis title
    		 Difference - pCR rate (%) within signature -ve grp
    Comparison groups
    Paclitaxel with LCL161 (Negative group) v Paclitaxel without LCL161 (Negative group)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Posterior med. diff -pCR rate b/w groups
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.7
         upper limit
    		 8.3
    Statistical analysis title
    		 Difference - pCR rate (%) within signature +ve grp
    Comparison groups
    Paclitaxel with LCL161 (Positive group) v Paclitaxel without LCL161 (Positive group)
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Posterior med. diff -pCR rate b/w groups
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 18

    Primary: Number of participants with Pathological complete response (pCR) in breast after 12 weeks of therapy

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    End point title
    		 Number of participants with Pathological complete response (pCR) in breast after 12 weeks of therapy [1]
    End point description
    To assess the number of patients who experienced a pathological response in breast. No statistical hypothesis test was done.
    End point type
    Primary
    End point timeframe
    12 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical hypothesis test was done for this endpoint.
    End point values
    		 Paclitaxel with LCL161 (Positive group) Paclitaxel without LCL161 (Positive group) Paclitaxel with LCL161 (Negative group) Paclitaxel without LCL161 (Negative group)
    Number of subjects analysed
    51
    50
    55
    53
    Units: Participants
    13
    12
    4
    5
    No statistical analyses for this end point

    Primary: Difference in pCR rates between treatment arms

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    End point title
    		 Difference in pCR rates between treatment arms [2]
    End point description
    pCR rate was defined as histopathologically confirmed absence of invasive disease in the breast. To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with triple negative breast cancer. Analyses were performed separately in the gene expression signature negative and positive groups. This analysis was based on the posterior distribution of the difference in pCR rates between the experimental and control arms of the study, within each gene expression signature group. The measure median was used as these values are medians of posterior distribution of difference of pCR rate between treatment arms based on a Bayesian model. 95% Confidence interval is actually 95% credible interval. No statistical hypothesis test was done.
    End point type
    Primary
    End point timeframe
    12 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical hypothesis test was done for this endpoint.
    End point values
    		 Paclitaxel with LCL161 (Positive group) Paclitaxel without LCL161 (Positive group) Paclitaxel with LCL161 (Negative group) Paclitaxel without LCL161 (Negative group)
    Number of subjects analysed
    51
    50
    55
    53
    Units: Difference in PCR Rate
        median (confidence interval 95%)
    1.5 (-15 to 18)
    999.99 (99.99 to 9999.99)
    -2 (-12.7 to 8.3)
    999.99 (99.99 to 9999.99)
    No statistical analyses for this end point

    Secondary: Posterior distribution of difference in pCR rates between gene expression signature groups (EAS1)

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    End point title
    		 Posterior distribution of difference in pCR rates between gene expression signature groups (EAS1)
    End point description
    To assess whether use of the gene expression signature identifies tumors more likely to respond to treatment with LCL161 and paclitaxel. The measure median was used as these values are medians of posterior distribution of difference of pCR rate between gene signature positive and gene signature negative groups based on a Bayesian model. 95% Confidence interval is actually 95% credible interval.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 EAS1: LCL161 + Paclitaxel
    Number of subjects analysed
    105
    Units: Difference in pCR rate
        median (confidence interval 95%)
    18.2 (5 to 32.4)
    No statistical analyses for this end point

    Secondary: Posterior distribution of difference in pCR rates between gene expression groups within treatment (EAS1)

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    End point title
    		 Posterior distribution of difference in pCR rates between gene expression groups within treatment (EAS1)
    End point description
    To assess whether use of the gene expression signature identifies tumors more likely to respond to treatment with paclitaxel only. The measure median was used as these values are medians of posterior distribution of difference of pCR rate between gene signature positive and gene signature negative groups based on a Bayesian model. 95% Confidence interval is actually 95% credible interval.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 EAS1: Paclitaxel only
    Number of subjects analysed
    102
    Units: Difference in pCR rate
        median (confidence interval 95%)
    13.3 (-0.4 to 27.5)
    No statistical analyses for this end point

    Secondary: pCR rate in breast after 12 weeks of therapy with single agent LCL161 and LCL161 + paclitaxel, regardless of gene signature status (EAS1)

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    End point title
    		 pCR rate in breast after 12 weeks of therapy with single agent LCL161 and LCL161 + paclitaxel, regardless of gene signature status (EAS1)
    End point description
    To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with triple negative breast cancer regardless of tumor gene expression signature status. This comparison is between the 2 study treatments, regardless of gene signature status. The measure median was used as these values are medians of posterior distribution of pCR rate for each treatment group. 95% Confidence interval is actually 95% credible interval.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 EAS1: LCL161 + Paclitaxel EAS1: Paclitaxel only
    Number of subjects analysed
    105
    102
    Units: Percentage of Participants
        median (confidence interval 95%)
    15.5 (9.6 to 22.8)
    15.7 (9.8 to 23.3)
    No statistical analyses for this end point

    Secondary: pCR rate in breast, regional nodes and axilla (EAS1)

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    End point title
    		 pCR rate in breast, regional nodes and axilla (EAS1)
    End point description
    To assess other indicators of disease response for the LCL161 + paclitaxel combination compared to paclitaxel alone. The pCR in breast, regional nodes, and axilla were determined based on the America Joint Committee on Cancer Staging [AJCC] stages T1c, T2, N0-N2, M0) were (AJCC) pathologic staging recorded on the eCRF: a patient was considered to be a responder in breast, regional nodes, and axilla if the pathological complete response was reported for breast and if the regional lymph nodes staging was pN0 (including i-, mol-, mol+). The measure median was used as these values are medians of posterior distribution of pCR rate for each group based on a Bayesian model. 95% Confidence interval is actually 95% credible interval.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 EAS1: LCL161 + Paclitaxel (gene expression signature positive) EAS1: Paclitaxel only (gene expression signature positive) EAS1: Paclitaxel only (gene expression signature negative) EAS1: LCL161 + Paclitaxel (gene expression signature negative)
    Number of subjects analysed
    50
    51
    51
    55
    Units: Percentage of Participants
        median (confidence interval 95%)
    21.5 (11.8 to 34)
    19.1 (10 to 31.2)
    5.5 (1.5 to 13.9)
    6.9 (2.2 to 15.5)
    No statistical analyses for this end point

    Secondary: Rates of breast conserving surgery and mastectomy - assessed by percentage of patients who underwent breast conserving surgery, masectomy and no surgery (EAS1)

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    End point title
    		 Rates of breast conserving surgery and mastectomy - assessed by percentage of patients who underwent breast conserving surgery, masectomy and no surgery (EAS1)
    End point description
    To assess other indicators of disease response for the LCL161 + paclitaxel combination compared to paclitaxel alone. Rates of breast conserving surgery and mastectomy also contributed to the overall assessment of disease response and were summarized by treatment arm within each gene expression signature status. For this analysis, patients with multicentric breast cancer were excluded, as all patients in this group were expected to be treated with mastectomy.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 EAS1: LCL161 + Paclitaxel (gene expression signature positive) EAS1: Paclitaxel only (gene expression signature positive) EAS1: LCL161 + Paclitaxel (gene expression signature negative) EAS1: Paclitaxel only (gene expression signature negative)
    Number of subjects analysed
    48
    45
    51
    47
    Units: Percentage of participants
    number (not applicable)
        Breast Conserving Surgery
    60.4
    60
    49
    44.7
        Mastectomy
    25
    26.7
    23.5
    29.8
        No Surgery
    14.6
    13.3
    27.5
    25.5
    No statistical analyses for this end point

    Secondary: Caspase 3 activation in tumor by immunohistochemistry (IHC) - EAS1

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    End point title
    		 Caspase 3 activation in tumor by immunohistochemistry (IHC) - EAS1
    End point description
    To evaluate whether combination treatment with LCL161 and paclitaxel is associated with increased apoptosis compared to weekly paclitaxel alone. To evaluate whether combination treatment with LCL161 and paclitaxel was associated with increased apoptosis compared to weekly paclitaxel alone, cleaved caspase 3 activation in tumor by IHC was examined. Gene expression signature status is derived based on continuous gene expression signature score using cut-off 0.6661 (positive: score ≥ 0.6661; negative: score <0.6661); cycle = 28 days; each patient had either C1D2 or C1D9
    End point type
    Secondary
    End point timeframe
    Baseline, Post-baeline at Cycle 1, Day 2 (C1D2) or Cycle 1, Day 9 (C1D9)
    End point values
    		 EAS1: LCL161 + Paclitaxel (gene expression signature negative) EAS1: LCL161 + Paclitaxel (gene expression signature positive) EAS1: Paclitaxel only (gene expression signature positive) EAS1: Paclitaxel only (gene expression signature negative)
    Number of subjects analysed
    55
    50
    51
    51
    Units: % of positive tumor cells
    arithmetic mean (standard deviation)
        EAS1-Baseline (n: 20, 16, 21, 22)
    1.4 ± 3.3
    1.5 ± 1.6
    1.4 ± 1.3
    2.1 ± 2.8
        EAS1 Post-Baseline (n: 20, 16, 21, 22)
    3.1 ± 3.1
    2.6 ± 1.4
    2.4 ± 1.7
    3.1 ± 6.1
    No statistical analyses for this end point

    Secondary: Caspase 3 activation in tumor by immunohistochemistry (IHC) - EAS2

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    End point title
    		 Caspase 3 activation in tumor by immunohistochemistry (IHC) - EAS2
    End point description
    To evaluate whether combination treatment with LCL161 and paclitaxel is associated with increased apoptosis compared to weekly paclitaxel alone. To evaluate whether combination treatment with LCL161 and paclitaxel was associated with increased apoptosis compared to weekly paclitaxel alone, cleaved caspase 3 activation in tumor by IHC was examined. Cycle = 28 days; each patient had either C1D2 or C1D9
    End point type
    Secondary
    End point timeframe
    Baseline, Post-baeline at Cycle 1, Day 2 or Cycle 1, Day 9
    End point values
    		 EAS2: LCL161 + Paclitaxel (gene expression signature positive) EAS2: Paclitaxel only (gene expression signature positive) EAS2: LCL161 + Paclitaxel (gene expression signature negative) EAS2: Paclitaxel only (gene expression signature negative)
    Number of subjects analysed
    34
    29
    71
    73
    Units: % of positive tumor cells
    arithmetic mean (standard deviation)
        EAS2-Baseline (n: 13, 11, 28, 27)
    1.3 ± 1.8
    1.6 ± 1.4
    1.5 ± 2.9
    1.9 ± 2.6
        EAS2 Post-Baseline (n:13, 11, 28, 27)
    2.3 ± 1.4
    2.7 ± 1.9
    3.2 ± 2.7
    2.9 ± 5.6
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) parameters of LCL161 only for Cmax

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    End point title
    		 Pharmacokinetics (PK) parameters of LCL161 only for Cmax
    End point description
    To evaluate the PK of LCL161 when given in combination with paclitaxel.
    End point type
    Secondary
    End point timeframe
    cycle 1 day 1, cycle 4 day 15
    End point values
    		 PAS: LCL161 + Paclitaxel (gene expression signature negative)
    Number of subjects analysed
    97
    Units: ng/mL
    median (full range (min-max))
        Cycle 1 Day 1 (n:97)
    2230 (186 to 4740)
        Cycle 4 Day 15 (n:47)
    2310 (491 to 5250)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) parameters of LCL161 only for Tmax

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    End point title
    		 Pharmacokinetics (PK) parameters of LCL161 only for Tmax
    End point description
    To evaluate the PK of LCL161 when given in combination with paclitaxel. The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data for LCL161.
    End point type
    Secondary
    End point timeframe
    cycle 1 day 1, cycle 4 day 15
    End point values
    		 PAS: LCL161
    Number of subjects analysed
    97
    Units: hours
    median (full range (min-max))
        Cycle 1 Day 1 (n:97)
    3.72 (0.5 to 5.8)
        Cycle 4 Day 15 (n:47)
    3.5 (1 to 4.2)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) parameters of LCL161 only for AUClast

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    End point title
    		 Pharmacokinetics (PK) parameters of LCL161 only for AUClast
    End point description
    To evaluate the PK of LCL161 when given in combination with paclitaxel
    End point type
    Secondary
    End point timeframe
    cycle 1 day 1, cycle 4 day 15
    End point values
    		 PAS: LCL161
    Number of subjects analysed
    97
    Units: ng*hr/mL
    median (full range (min-max))
        Cycle 1 Day 1 (n:97)
    5250.7 (465.8 to 13379)
        Cycle 4 Day 15 (n:47)
    5522.58 (1070.8 to 13745.5)
    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 reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    LCL161 + paclitaxel
    Reporting group description
    		 LCL161 + paclitaxel

    Reporting group title
    Paclitaxel
    Reporting group description
    		 Paclitaxel

    Serious adverse events
    		 LCL161 + paclitaxel Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 106 (42.45%)
    7 / 103 (6.80%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEELING COLD
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    19 / 106 (17.92%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    16 / 25
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAPHYLACTIC SHOCK
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOKINE RELEASE SYNDROME
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    3 / 106 (2.83%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    IMMOBILE
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    10 / 106 (9.43%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    SINUS TACHYCARDIA
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISSEMINATED INTRAVASCULAR COAGULATION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPH NODE PAIN
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    POLYARTHRITIS
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    3 / 106 (2.83%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE INFECTION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    4 / 106 (3.77%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    4 / 106 (3.77%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LCL161 + paclitaxel Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 106 (100.00%)
    101 / 103 (98.06%)
    Vascular disorders
    FLUSHING
         subjects affected / exposed
    6 / 106 (5.66%)
    7 / 103 (6.80%)
         occurrences all number
    8
    9
    HOT FLUSH
         subjects affected / exposed
    17 / 106 (16.04%)
    15 / 103 (14.56%)
         occurrences all number
    23
    17
    HYPERTENSION
         subjects affected / exposed
    3 / 106 (2.83%)
    6 / 103 (5.83%)
         occurrences all number
    3
    8
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    16 / 106 (15.09%)
    11 / 103 (10.68%)
         occurrences all number
    27
    15
    CHILLS
         subjects affected / exposed
    12 / 106 (11.32%)
    4 / 103 (3.88%)
         occurrences all number
    14
    5
    FATIGUE
         subjects affected / exposed
    48 / 106 (45.28%)
    38 / 103 (36.89%)
         occurrences all number
    62
    40
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    6 / 106 (5.66%)
    0 / 103 (0.00%)
         occurrences all number
    8
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    12 / 106 (11.32%)
    3 / 103 (2.91%)
         occurrences all number
    15
    5
    PYREXIA
         subjects affected / exposed
    44 / 106 (41.51%)
    9 / 103 (8.74%)
         occurrences all number
    67
    10
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    8 / 106 (7.55%)
    1 / 103 (0.97%)
         occurrences all number
    8
    1
    HYPERSENSITIVITY
         subjects affected / exposed
    7 / 106 (6.60%)
    6 / 103 (5.83%)
         occurrences all number
    11
    7
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    9 / 106 (8.49%)
    10 / 103 (9.71%)
         occurrences all number
    11
    10
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    30 / 106 (28.30%)
    10 / 103 (9.71%)
         occurrences all number
    33
    11
    DYSPNOEA
         subjects affected / exposed
    24 / 106 (22.64%)
    7 / 103 (6.80%)
         occurrences all number
    28
    7
    EPISTAXIS
         subjects affected / exposed
    15 / 106 (14.15%)
    9 / 103 (8.74%)
         occurrences all number
    16
    9
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    16 / 106 (15.09%)
    4 / 103 (3.88%)
         occurrences all number
    16
    7
    PNEUMONITIS
         subjects affected / exposed
    6 / 106 (5.66%)
    0 / 103 (0.00%)
         occurrences all number
    6
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    8 / 106 (7.55%)
    8 / 103 (7.77%)
         occurrences all number
    8
    8
    INSOMNIA
         subjects affected / exposed
    22 / 106 (20.75%)
    17 / 103 (16.50%)
         occurrences all number
    26
    25
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    15 / 106 (14.15%)
    11 / 103 (10.68%)
         occurrences all number
    18
    12
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    13 / 106 (12.26%)
    8 / 103 (7.77%)
         occurrences all number
    16
    11
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    8 / 106 (7.55%)
    3 / 103 (2.91%)
         occurrences all number
    12
    3
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    10 / 106 (9.43%)
    2 / 103 (1.94%)
         occurrences all number
    14
    4
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    8 / 106 (7.55%)
    3 / 103 (2.91%)
         occurrences all number
    13
    3
    Injury, poisoning and procedural complications
    PROCEDURAL PAIN
         subjects affected / exposed
    7 / 106 (6.60%)
    9 / 103 (8.74%)
         occurrences all number
    7
    9
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    12 / 106 (11.32%)
    7 / 103 (6.80%)
         occurrences all number
    17
    7
    DYSGEUSIA
         subjects affected / exposed
    24 / 106 (22.64%)
    9 / 103 (8.74%)
         occurrences all number
    32
    9
    HEADACHE
         subjects affected / exposed
    35 / 106 (33.02%)
    18 / 103 (17.48%)
         occurrences all number
    48
    29
    HYPOAESTHESIA
         subjects affected / exposed
    2 / 106 (1.89%)
    6 / 103 (5.83%)
         occurrences all number
    3
    7
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    13 / 106 (12.26%)
    28 / 103 (27.18%)
         occurrences all number
    14
    34
    NEUROTOXICITY
         subjects affected / exposed
    11 / 106 (10.38%)
    10 / 103 (9.71%)
         occurrences all number
    15
    12
    PARAESTHESIA
         subjects affected / exposed
    9 / 106 (8.49%)
    4 / 103 (3.88%)
         occurrences all number
    10
    9
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    25 / 106 (23.58%)
    17 / 103 (16.50%)
         occurrences all number
    30
    19
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    27 / 106 (25.47%)
    13 / 103 (12.62%)
         occurrences all number
    32
    15
    NEUTROPENIA
         subjects affected / exposed
    33 / 106 (31.13%)
    9 / 103 (8.74%)
         occurrences all number
    58
    15
    Eye disorders
    VISION BLURRED
         subjects affected / exposed
    7 / 106 (6.60%)
    1 / 103 (0.97%)
         occurrences all number
    7
    1
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    11 / 106 (10.38%)
    8 / 103 (7.77%)
         occurrences all number
    13
    9
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    7 / 106 (6.60%)
    4 / 103 (3.88%)
         occurrences all number
    12
    4
    CONSTIPATION
         subjects affected / exposed
    24 / 106 (22.64%)
    24 / 103 (23.30%)
         occurrences all number
    28
    24
    DIARRHOEA
         subjects affected / exposed
    76 / 106 (71.70%)
    23 / 103 (22.33%)
         occurrences all number
    160
    35
    DRY MOUTH
         subjects affected / exposed
    10 / 106 (9.43%)
    3 / 103 (2.91%)
         occurrences all number
    11
    5
    DYSPEPSIA
         subjects affected / exposed
    12 / 106 (11.32%)
    10 / 103 (9.71%)
         occurrences all number
    15
    10
    NAUSEA
         subjects affected / exposed
    45 / 106 (42.45%)
    32 / 103 (31.07%)
         occurrences all number
    70
    41
    STOMATITIS
         subjects affected / exposed
    26 / 106 (24.53%)
    18 / 103 (17.48%)
         occurrences all number
    32
    20
    VOMITING
         subjects affected / exposed
    21 / 106 (19.81%)
    16 / 103 (15.53%)
         occurrences all number
    33
    19
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    72 / 106 (67.92%)
    69 / 103 (66.99%)
         occurrences all number
    72
    70
    ERYTHEMA
         subjects affected / exposed
    10 / 106 (9.43%)
    8 / 103 (7.77%)
         occurrences all number
    13
    13
    NAIL DISORDER
         subjects affected / exposed
    5 / 106 (4.72%)
    6 / 103 (5.83%)
         occurrences all number
    5
    6
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    8 / 106 (7.55%)
    3 / 103 (2.91%)
         occurrences all number
    8
    3
    PRURITUS
         subjects affected / exposed
    28 / 106 (26.42%)
    9 / 103 (8.74%)
         occurrences all number
    37
    11
    RASH
         subjects affected / exposed
    44 / 106 (41.51%)
    27 / 103 (26.21%)
         occurrences all number
    55
    33
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    21 / 106 (19.81%)
    15 / 103 (14.56%)
         occurrences all number
    25
    18
    BACK PAIN
         subjects affected / exposed
    10 / 106 (9.43%)
    8 / 103 (7.77%)
         occurrences all number
    12
    8
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    11 / 106 (10.38%)
    6 / 103 (5.83%)
         occurrences all number
    16
    7
    MYALGIA
         subjects affected / exposed
    23 / 106 (21.70%)
    18 / 103 (17.48%)
         occurrences all number
    83
    51
    PAIN IN EXTREMITY
         subjects affected / exposed
    11 / 106 (10.38%)
    6 / 103 (5.83%)
         occurrences all number
    12
    8
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    10 / 106 (9.43%)
    3 / 103 (2.91%)
         occurrences all number
    13
    3
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    12 / 106 (11.32%)
    5 / 103 (4.85%)
         occurrences all number
    13
    5
    HYPERGLYCAEMIA
         subjects affected / exposed
    6 / 106 (5.66%)
    8 / 103 (7.77%)
         occurrences all number
    6
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Oct 2012
    The primary purpose of this amendment was to evaluate the performance of the gene expression signature as a means of identifying patients more likely to respond to treatment with paclitaxel and LCL161. This amendment expanded the size of the study to incorporate patients with gene expression signature positive and negative disease, and compared the response to treatment in these two populations.
    29 Jan 2013
    Two changes have been made to satisfy local regulatory requirements in Ireland. All patients in the experimental treatment arm were to receive dexamethasone as a premedication for paclitaxel + LCL161. In addition, for patients who were scheduled to undergo surgery, recovery from chemotherapy included laboratory evidence of hematological recovery.
    16 Dec 2013
    This amendment resulted in three changes to the protocol. In addition to the planned analysis for futility in the gene expression signature positive group, an interim futility analysis was also now to be done separately for patients in the signature negative group. To maximize the efficiency of the data collection and analysis, this was to be done when the interim analysis was performed for the positive group (approximately 50 patients in the positive group). In response to requests from trial Investigators, inclusion criterion #5 was changed to allow the treatment of patients with Stage T1c disease by AJCC criteria. Compared with other breast cancer subtypes triple negative breast cancer has a higher risk of visceral metastasis, and patients with T1c disease often receive chemotherapy in the neoadjuvant setting where response to treatment can be assessed. Also, alternative methods of assessment for HER2/ErbB2 are also now allowed, a change to inclusion criterion #2.
    01 Apr 2014
    Under Amendment 3, eligibility was expanded to include patients with T1c, N0-2, M0 disease. A recent health authority reviewing Amendment 3 requested that patients with T1c disease not be enrolled unless the response to treatment is found to be acceptably high after reviewing the results of the pending interim analysis. Based on the feedback from a Health Authority, Novartis decided to modify the Inclusion criterion #5 to restrict enrollment to patients with AJCC T2, N0-2, M0 disease. As per the health authority, this change could be reconsidered after review of the interim analysis data. If so, an appropriate amendment was to be filed.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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