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    Clinical Trial Results:
    A Phase 2/3, Multi-Center, Open-Label, Randomized Study of Weekly nab®-Paclitaxel in Combination with Gemcitabine or Carboplatin, Compared to Gemcitabine/Carboplatin, as First Line Treatment in Subjects with Estrogen Receptor (ER), Progesterone Receptor (PgR), and HER2 Negative (Triple Negative) Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2013-000113-20
    Trial protocol
    		 AT   ES   DE   GB   IT   PT   GR   FR  
    Global end of trial date
    28 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Nov 2017
    First version publication date
    12 Nov 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ABI-007-MBC-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01881230
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Ileana Elias M.D., Celgene, 01 647-968-4300, ilelias@celgene.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
    16 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluate the benefit and risk profiles of the two nab-paclitaxel experimental arms and identify which nab-paclitaxel combination that will be used in the Phase 3 portion of the study.
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection and Biomarker Consent
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    United States: 83
    Country: Number of subjects enrolled
    Brazil: 19
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    United Kingdom: 13
    Worldwide total number of subjects
    191
    EEA total number of subjects
    80
    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)
    140
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multicenter study was conducted by investigators in 11 countries in North America, Europe, Australia and South America, and enrolled participants at a total of 86 sites.

    Pre-assignment
    Screening details
    		 Participants were randomized 1:1:1 stratified by disease free interval (≤ 1 year; > 1 year), to facilitate the selection of the nab-paclitaxel experimental arm for evaluation in the Phase 3 portion of the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: nab-Paclitaxel plus Gemcitabine
    Arm description
    		 Participants received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by intravenous (IV) administration followed by gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nab-Paclitaxel
    Investigational medicinal product code
    ABI-007
    Other name
    Abraxane
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by intravenous (IV) administration Days 1 and 8 of each 21-day treatment cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Gemzar
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration of each 21-day treatment cycle.

    Arm title
    		 Arm B: nab-Paclitaxel + Carboplatin
    Arm description
    		 Participants received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by IV administration followed by Carboplatin area under the curve 2 (AUC 2) on Days 1 and 8 in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Paraplatin
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin AUC 2 on days 1 and 8 of each 21-day treatment cycle.

    Investigational medicinal product name
    nab-Paclitaxel
    Investigational medicinal product code
    ABI-007
    Other name
    Abraxane
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by IV administration on days 1 and 8 of each 21-day treatment cycle.

    Arm title
    		 Arm C: Gemcitabine + Carboplatin
    Arm description
    		 Participants received Gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration, followed by carboplatin AUC 2 on Days 1 and 8 by IV administration in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Gemzar
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration of each 21-day treatment cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Paraplatin
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin AUC 2 on days 1 and 8 of each 21-day treatment cycle.

    Number of subjects in period 1
    		Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Started
    61
    64
    66
    Safety Population
    60
    64
    64
    Treated as Randomized
    60
    64
    64
    Treatment Discontinuation
    60
    64
    64
    Completed
    0
    0
    0
    Not completed
    61
    64
    66
         Adverse event, serious fatal
    2
    -
    1
         Physician decision
    4
    3
    6
         Untreated: Withdrawal before study start
    1
    -
    -
         Untreated: Miscellaneous
    -
    -
    1
         Miscellaneous
    3
    3
    -
         Given commercial drug
    -
    -
    2
         Consent withdrawn by subject
    6
    4
    6
         Adverse event, non-fatal
    9
    13
    12
         Symptomatic deterioration
    3
    3
    1
         Untreated: Death
    -
    -
    1
         Progressive Disease
    31
    35
    36
         Non-compliance with study drug
    1
    2
    -
         Protocol deviation
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: nab-Paclitaxel plus Gemcitabine
    Reporting group description
    		 Participants received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by intravenous (IV) administration followed by gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Reporting group title
    Arm B: nab-Paclitaxel + Carboplatin
    Reporting group description
    		 Participants received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by IV administration followed by Carboplatin area under the curve 2 (AUC 2) on Days 1 and 8 in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Reporting group title
    Arm C: Gemcitabine + Carboplatin
    Reporting group description
    		 Participants received Gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration, followed by carboplatin AUC 2 on Days 1 and 8 by IV administration in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Reporting group values
    		 Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin Total
    Number of subjects
    		 61 64 66 191
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 43 48 49 140
        From 65-84 years
    		 18 16 17 51
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.7 ( 12.16 ) 54.3 ( 11.96 ) 56.7 ( 10.87 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 61 64 66 191
        Male
    		 0 0 0 0
    Race
    Units: Subjects
        Black or African American
    		 9 6 8 23
        White
    		 50 55 54 159
        Unknown or Not Reported
    		 2 3 4 9
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG performance status is used by doctors and researchers to assess how a subject's disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)
    Units: Subjects
        0 = Fully Active
    		 34 38 42 114
        1 = Restrictive but ambulatory
    		 25 26 22 73
        2 = Ambulatory but unable to work
    		 1 0 0 1
        Missing
    		 1 0 2 3
    Disease Free Interval by Clinical Interpretation
    Disease Free Interval is defined as period of being absent of disease less than or equal to one year or free of disease greater than one year.
    Units: Subjects
        ≤ 1 year
    		 17 16 20 53
        > 1 year
    		 43 48 45 136
        Missing
    		 1 0 1 2
    Stage of Primary Diagnosis
    Stage of Diagnosis as indicated in the American Joint Committee on Cancer Staging Manual (AJCC)
    Units: Subjects
        Stage 0
    		 0 1 0 1
        Stage IA
    		 7 6 11 24
        Stage IB
    		 0 0 0 0
        Stage IIA
    		 14 9 15 38
        Stage IIB
    		 8 7 9 24
        Stage IIIA
    		 9 10 3 22
        Stage IIIB
    		 3 3 5 11
        Stage IIIC
    		 3 3 2 8
        Stage IV
    		 11 17 10 38
        Missing
    		 6 8 11 25
    Triple-Negative at Primary Diagnosis
    Triple-Negative Breast Cancer defined as estrogen receptor (ER) negative, progesterone receptor (PgR) negative, and human epidermal growth factor receptor 2 (HER2) negative.
    Units: Subjects
        Triple Negative Breast Cancer
    		 51 53 48 152
        Non-Display of Triple Negative Breast Cancer
    		 10 11 18 39
    Triple-Negative at Latest Diagnosis
    Triple-Negative Breast Cancer defined as estrogen receptor (ER) negative, progesterone receptor (PgR) negative, and human epidermal growth factor receptor 2 (HER2) negative
    Units: Subjects
        Triple-Negative at Latest Diagnosis
    		 60 62 65 187
        Non-Display of Triple Negative Breast Cancer
    		 1 2 1 4
    Time from Diagnosis to lst Reported Disease/Relapse
    Units: months
        arithmetic mean (standard deviation)
    		 38.8 ( 49.46 ) 29.9 ( 37.18 ) 50.9 ( 62.60 ) -
    Time from First Documented Metastatic Disease/Relapse to Randomization
    Units: months
        arithmetic mean (standard deviation)
    		 2.1 ( 5.08 ) 4.2 ( 18.39 ) 1.6 ( 1.70 ) -
    Time from Primary Diagnosis to Randomization
    Units: months
        arithmetic mean (standard deviation)
    		 43.7 ( 54.60 ) 35.5 ( 40.51 ) 52.5 ( 62.37 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: nab-Paclitaxel plus Gemcitabine
    Reporting group description
    		 Participants received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by intravenous (IV) administration followed by gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Reporting group title
    Arm B: nab-Paclitaxel + Carboplatin
    Reporting group description
    		 Participants received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by IV administration followed by Carboplatin area under the curve 2 (AUC 2) on Days 1 and 8 in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Reporting group title
    Arm C: Gemcitabine + Carboplatin
    Reporting group description
    		 Participants received Gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration, followed by carboplatin AUC 2 on Days 1 and 8 by IV administration in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Primary: Kaplan-Meier Estimates of Progression-Free Survival (PFS) Based on Investigator Assessment.

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    End point title
    		 Kaplan-Meier Estimates of Progression-Free Survival (PFS) Based on Investigator Assessment.
    End point description
    PFS was defined as the time from the date of randomization to the date of disease progression or death from any cause on or prior to the data cutoff date for the statistical analysis, whichever occurred earlier. Tumor responses were assessed using triple-negative metastatic breast cancer, Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and defined as: Complete response (CR) is the disappearance of all target lesions; Partial response (PR) occurs when at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable disease is neither sufficient shrinkage to qualify for a PR nor sufficient increase of lesions to qualify for Progressive disease (PD); Progressive Disease- is at least a 20% increase in the sum of diameters of target lesions from nadir. Intent to Treat (ITT) population includes all randomized participants regardless of whether they received any (Investigational Product) IP or had any efficacy assessments collected.
    End point type
    Primary
    End point timeframe
    From date of randomization to data cut-off date of 16 December 2016; total length of time on study was 31 months for Arm A, 34 months for Arm B and 35 months for Arm C
    End point values
    		 Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Number of subjects analysed
    61
    64
    66
    Units: months
        median (confidence interval 95%)
    5.5 (4.1 to 7.0)
    8.3 (5.7 to 10.6)
    6.0 (4.7 to 7.2)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    For stratified analysis, the stratified log-rank test and stratified Cox proportional hazards model were used, where the stratification factor is the disease free interval (<= 1 year; > 1 year).
    Comparison groups
    Arm B: nab-Paclitaxel + Carboplatin v Arm A: nab-Paclitaxel plus Gemcitabine
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0183
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.692
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.089
         upper limit
    		 2.629
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    For stratified analysis, the stratified log-rank test and stratified Cox proportional hazards model were used, where the stratification factor is the disease free interval (<= 1 year; > 1 year).
    Comparison groups
    Arm B: nab-Paclitaxel + Carboplatin v Arm C: Gemcitabine + Carboplatin
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0152
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.581
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.373
         upper limit
    		 0.904
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    For stratified analysis, the stratified log-rank test and stratified Cox proportional hazards model were used, where the stratification factor is the disease free interval (<= 1 year; > 1 year).
    Comparison groups
    Arm C: Gemcitabine + Carboplatin v Arm A: nab-Paclitaxel plus Gemcitabine
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8599
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.676
         upper limit
    		 1.597

    Secondary: Percentage of Participants with an Objective Confirmed Complete or Partial Overall Response by Investigator Assessment.

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    End point title
    		 Percentage of Participants with an Objective Confirmed Complete or Partial Overall Response by Investigator Assessment.
    End point description
    Percentage of participants with an objective confirmed complete or partial overall response according to RECIST 1.1 and defined as: A complete response (CR) was the disappearance of all target lesions; a partial response is at least a 30% decrease in the sum of diameters of target lesions from baseline; stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for Progressive disease (PD); progressive disease- is at least a 20% increase in the sum of diameters of target lesions from nadir. Intent to treat (ITT) includes all randomized participants regardless of whether they received any IP or had any efficacy assessments collected.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 6 weeks; from date of randomization to data cut-off date of 16 December 2016; total length of time on study was 31 months for Arm A, 34 months for Arm B and 35 months for Arm C.
    End point values
    		 Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Number of subjects analysed
    61
    64
    66
    Units: percentage of subjects
        number (confidence interval 95%)
    39.3 (27.1 to 52.7)
    73.4 (60.9 to 83.7)
    43.9 (31.7 to 56.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Initiated Cycle 6 Receiving Doublet Combination Therapy

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    End point title
    		 Percentage of Participants who Initiated Cycle 6 Receiving Doublet Combination Therapy
    End point description
    The percentage of participants who initiated Cycle 6 receiving doublet combination therapy was one of the criteria. ITT includes all randomized participants regardless of whether they received any IP or had any efficacy assessments collected. ITT population for those who initiated Cycle 6 doublet combination therapy.
    End point type
    Secondary
    End point timeframe
    Cycle 6.
    End point values
    		 Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Number of subjects analysed
    61
    64
    66
    Units: percentage of participants
        number (confidence interval 95%)
    55.7 (42.5 to 68.5)
    64.1 (51.1 to 75.7)
    50.0 (37.4 to 62.6)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimates of Overall Survival

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    End point title
    		 Kaplan-Meier Estimates of Overall Survival
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death (from any cause). The ITT population includes all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.
    End point type
    Secondary
    End point timeframe
    From date of randomization to data cut-off date of 16 December 2016; total length of time on study was 31 months for Arm A, 34 months for Arm B and 35 months for Arm C.
    End point values
    		 Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Number of subjects analysed
    61
    64
    66
    Units: months
        median (confidence interval 95%)
    12.1 (9.4 to 15.9)
    16.8 (11.3 to 20.6)
    12.6 (10.1 to 16.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratios and associated two-sided 95% confidence intervals were estimated using stratified Cox proportional hazard model. The stratification factor is the disease free interval (≤ 1 year; > 1 year).
    Comparison groups
    Arm B: nab-Paclitaxel + Carboplatin v Arm A: nab-Paclitaxel plus Gemcitabine
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1579
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.375
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.882
         upper limit
    		 2.143
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Hazard ratios and associated two-sided 95% confidence intervals were estimated using stratified Cox proportional hazard model. The stratification factor is the disease free interval (≤ 1 year; > 1 year).
    Comparison groups
    Arm B: nab-Paclitaxel + Carboplatin v Arm C: Gemcitabine + Carboplatin
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2945
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.796
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.221
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Hazard ratios and associated two-sided 95% confidence intervals were estimated using stratified Cox proportional hazard model. The stratification factor is the disease free interval (≤ 1 year; > 1 year).
    Comparison groups
    Arm C: Gemcitabine + Carboplatin v Arm A: nab-Paclitaxel plus Gemcitabine
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6691
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.101
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.708

    Secondary: Number of Participants with Treatment Emergent Adverse Events

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events
    End point description
    Treatment-emergent adverse events (TEAEs) were defined as any AEs that began or worsened with an onset date on or after the date of the first dose of IP through 28 days after the last dose. A serious AE (SAE) is any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was graded based on the participant's symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); Grade 1 = Mild – transient or mild discomfort; no medical intervention required; Grade 2 = Moderate – mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death. The safety population includes all randomized subjects who received at least 1 dose of IP.
    End point type
    Secondary
    End point timeframe
    From randomization through to 28 days after the last dose of IP; up to data cut off date of 16 Dec 2016; maximum treatment duration of study drug exposure was 108.3 weeks for Arm A, 83 weeks for Arm B, 110.1 weeks for Arm C
    End point values
    		 Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Number of subjects analysed
    60
    64
    64
    Units: participants
        Any TEAE
    60
    63
    64
        Any Grade 3 or Higher TEAE
    46
    51
    54
        Treatment-related TEAE
    59
    62
    60
        Treatment-related, Grade 3 or Higher TEAE
    35
    43
    46
        Serious TEAE
    22
    20
    25
        Treatment-related Serious TEAE
    10
    9
    13
        TEAE Leading to Discontinuation (D/C) of IP
    16
    29
    15
        Treatment Related (TR) TEAE Leading to D/C of IP
    12
    27
    12
        TEAE Leading to Dose Reduction (DR) of IP
    23
    20
    25
        Treatment related TEAE Leading to DR of IP
    31
    20
    23
        TEAE Leading to Dose Interruption (DI) of IP
    27
    50
    50
        TR TEAE Leading to DI of IP
    16
    44
    44
        TEAE leading to D/C of nab-Paclitaxel
    11
    17
    0
        TR TEAE leading to D/C of nab-Paclitaxel
    22
    13
    0
        TEAE leading to DR of nab-Paclitaxel
    21
    19
    0
        TR TEAE leading to DR of nab-Paclitaxel
    31
    19
    0
        TEAE leading to DI of nab-Paclitaxel
    27
    50
    0
        TR TEAE leading to DI of nab-Paclitaxel
    13
    44
    0
        TEAE leading to D/C of Gemcitabine
    7
    0
    13
        TR TEAE leading to D/C of Gemcitabine
    18
    0
    9
        TEAE leading to DR of Gemcitabine
    18
    0
    25
        TR TEAE leading to DR of Gemcitabine
    31
    0
    23
        TEAE leading to DI of Gemcitabine
    24
    0
    49
        TR TEAE leading to DI of Gemcitabine
    0
    0
    43
        TEAE leading to D/C of Carboplatin
    0
    28
    15
        TR TEAE leading to D/C of Carboplatin
    0
    25
    12
        TEAE leading to DR of Carboplatin
    0
    17
    21
        TR TEAE leading to DR of Carboplatin
    0
    17
    20
        TEAE leading to DI of Carboplatin
    0
    50
    50
        TR TEAE leading to DI of Carboplatin
    0
    44
    43
        TEAE Leading to Death
    2
    1
    2
        Treatment Related TEAE leading to death
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Dose Modifications (Reductions and Interruptions)

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    End point title
    		 Percentage of Participants Experiencing Dose Modifications (Reductions and Interruptions)
    End point description
    The number of participants with dose modifications occurring during the treatment period. Dose reductions and interruptions are typically caused by clinically significant laboratory abnormalities and /or TEAEs/toxicities. The safety population includes all randomized participants who received at least 1 dose of IP.
    End point type
    Secondary
    End point timeframe
    From date of first dose to data cut off of date of 16 December 2016; maximum treatment duration of study drug exposure was 108.3 weeks for nab-paclitaxel + gemcitabine, 83 weeks for nab-paclitaxel + carboplatin, 110.1 weeks for gemcitabine + Carboplatin
    End point values
    		 Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Number of subjects analysed
    60
    64
    64
    Units: percentage of participants
    number (not applicable)
        ≥ 1 DR for both IPs
    33.3
    46.9
    51.6
        ≥ one DI for both IPs
    38.3
    70.3
    73.4
        ≥ one dose missed for both IPs
    48.3
    45.3
    56.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Discontinued From all Study Treatment Due to TEAEs

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    End point title
    		 Percentage of Participants who Discontinued From all Study Treatment Due to TEAEs
    End point description
    Treatment-emergent adverse events (TEAEs) were defined as any AEs that begin or worsen with an onset date on or after the date of the first dose of IP through 28 days after the last dose. The Safety/Treated population includes all randomized participants who received at least 1 dose of IP.
    End point type
    Secondary
    End point timeframe
    From date of first dose to data cut off of date of 16 December 2016; maximum treatment duration of study drug exposure was 108.3 weeks for nab-paclitaxel + gemcitabine, 83 weeks for nab-paclitaxel + carboplatin, 110.1 weeks for gemcitabine + carboplatin.
    End point values
    		 Arm A: nab-Paclitaxel plus Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Number of subjects analysed
    60
    64
    64
    Units: percentage of participants
        number (confidence interval 95%)
    21.7 (12.1 to 34.2)
    26.6 (16.3 to 39.1)
    21.9 (12.5 to 34.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization through to 28 days after the last dose of IP; up to the data cut-off date of 16 December 2016; AEs collected and monitored for 39 months.
    Adverse event reporting additional description
    Maximum treatment duration of study drug exposure was 108.3 weeks for Arm A, 83 weeks for Arm B and 110.1 weeks for Arm C.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Arm A: nab-Paclitaxel + Gemcitabine
    Reporting group description
    		 Subjects received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by intravenous (IV) administration followed by gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration of each 21-day treatment cycle. Subjects continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Reporting group title
    Arm B: nab-Paclitaxel + Carboplatin
    Reporting group description
    		 Subjects received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by IV administration followed by Carboplatin AUC 2 on Days 1 and 8 of each 21-day treatment cycle. Subjects continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Reporting group title
    Arm C: Gemcitabine + Carboplatin
    Reporting group description
    		 Subjects received Gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration, followed by carboplatin AUC 2 on Days 1 and 8 by IV administration of each 21-day treatment Subjects continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

    Serious adverse events
    		 Arm A: nab-Paclitaxel + Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 60 (36.67%)
    20 / 64 (31.25%)
    25 / 64 (39.06%)
         number of deaths (all causes)
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to bone
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Metastases to meninges
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Cough
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Dyspnoea
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Pneumothorax
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Pulmonary embolism
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract congestion
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Palpitations
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Pericardial effusion
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Headache
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Sensory disturbance
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 64 (3.13%)
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 64 (4.69%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Haematochezia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nodular regenerative hyperplasia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Breast cellulitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Cellulitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Device related sepsis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Endocarditis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Localised infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Viral infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    0 / 64 (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
    Dehydration
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: nab-Paclitaxel + Gemcitabine Arm B: nab-Paclitaxel + Carboplatin Arm C: Gemcitabine + Carboplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 60 (98.33%)
    63 / 64 (98.44%)
    62 / 64 (96.88%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    1
    0
    4
    Hot flush
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 64 (7.81%)
    2 / 64 (3.13%)
         occurrences all number
    4
    5
    2
    Hypertension
         subjects affected / exposed
    8 / 60 (13.33%)
    4 / 64 (6.25%)
    1 / 64 (1.56%)
         occurrences all number
    8
    5
    1
    Lymphoedema
         subjects affected / exposed
    2 / 60 (3.33%)
    6 / 64 (9.38%)
    3 / 64 (4.69%)
         occurrences all number
    2
    6
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    13 / 60 (21.67%)
    10 / 64 (15.63%)
    15 / 64 (23.44%)
         occurrences all number
    58
    31
    36
    Chills
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 64 (4.69%)
    2 / 64 (3.13%)
         occurrences all number
    6
    4
    2
    Fatigue
         subjects affected / exposed
    33 / 60 (55.00%)
    32 / 64 (50.00%)
    24 / 64 (37.50%)
         occurrences all number
    82
    60
    34
    Generalised oedema
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    5
    0
    0
    Influenza like illness
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 64 (6.25%)
    2 / 64 (3.13%)
         occurrences all number
    3
    5
    2
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 60 (10.00%)
    3 / 64 (4.69%)
    2 / 64 (3.13%)
         occurrences all number
    7
    3
    2
    Oedema peripheral
         subjects affected / exposed
    17 / 60 (28.33%)
    12 / 64 (18.75%)
    10 / 64 (15.63%)
         occurrences all number
    33
    18
    11
    Pain
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 64 (4.69%)
    6 / 64 (9.38%)
         occurrences all number
    3
    3
    8
    Pyrexia
         subjects affected / exposed
    12 / 60 (20.00%)
    5 / 64 (7.81%)
    8 / 64 (12.50%)
         occurrences all number
    24
    6
    13
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    3 / 60 (5.00%)
    9 / 64 (14.06%)
    2 / 64 (3.13%)
         occurrences all number
    3
    13
    3
    Hypersensitivity
         subjects affected / exposed
    0 / 60 (0.00%)
    5 / 64 (7.81%)
    0 / 64 (0.00%)
         occurrences all number
    0
    7
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
    5 / 64 (7.81%)
         occurrences all number
    0
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 60 (20.00%)
    17 / 64 (26.56%)
    7 / 64 (10.94%)
         occurrences all number
    22
    19
    8
    Dyspnoea
         subjects affected / exposed
    7 / 60 (11.67%)
    15 / 64 (23.44%)
    11 / 64 (17.19%)
         occurrences all number
    14
    19
    20
    Dyspnoea exertional
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 64 (6.25%)
    1 / 64 (1.56%)
         occurrences all number
    3
    5
    1
    Epistaxis
         subjects affected / exposed
    3 / 60 (5.00%)
    5 / 64 (7.81%)
    2 / 64 (3.13%)
         occurrences all number
    3
    6
    2
    Nasal congestion
         subjects affected / exposed
    0 / 60 (0.00%)
    6 / 64 (9.38%)
    1 / 64 (1.56%)
         occurrences all number
    0
    6
    1
    Oropharyngeal pain
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 64 (7.81%)
    0 / 64 (0.00%)
         occurrences all number
    4
    6
    0
    Pleural effusion
         subjects affected / exposed
    5 / 60 (8.33%)
    2 / 64 (3.13%)
    1 / 64 (1.56%)
         occurrences all number
    7
    2
    1
    Rhinorrhoea
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
    1 / 64 (1.56%)
         occurrences all number
    3
    2
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
    3 / 64 (4.69%)
         occurrences all number
    3
    2
    3
    Depression
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 64 (3.13%)
    7 / 64 (10.94%)
         occurrences all number
    4
    2
    7
    Insomnia
         subjects affected / exposed
    8 / 60 (13.33%)
    12 / 64 (18.75%)
    11 / 64 (17.19%)
         occurrences all number
    12
    13
    11
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 60 (10.00%)
    0 / 64 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    16
    0
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 60 (10.00%)
    0 / 64 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    11
    0
    9
    Weight decreased
         subjects affected / exposed
    8 / 60 (13.33%)
    4 / 64 (6.25%)
    3 / 64 (4.69%)
         occurrences all number
    12
    4
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 60 (1.67%)
    5 / 64 (7.81%)
    1 / 64 (1.56%)
         occurrences all number
    1
    6
    1
    Fall
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 64 (7.81%)
    1 / 64 (1.56%)
         occurrences all number
    6
    5
    1
    Overdose
         subjects affected / exposed
    1 / 60 (1.67%)
    6 / 64 (9.38%)
    2 / 64 (3.13%)
         occurrences all number
    1
    8
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 64 (1.56%)
    3 / 64 (4.69%)
         occurrences all number
    3
    1
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 60 (5.00%)
    11 / 64 (17.19%)
    9 / 64 (14.06%)
         occurrences all number
    3
    15
    10
    Dysgeusia
         subjects affected / exposed
    9 / 60 (15.00%)
    9 / 64 (14.06%)
    4 / 64 (6.25%)
         occurrences all number
    12
    17
    5
    Headache
         subjects affected / exposed
    17 / 60 (28.33%)
    14 / 64 (21.88%)
    12 / 64 (18.75%)
         occurrences all number
    21
    18
    13
    Hypoaesthesia
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 64 (6.25%)
    2 / 64 (3.13%)
         occurrences all number
    2
    17
    2
    Neuropathy peripheral
         subjects affected / exposed
    4 / 60 (6.67%)
    11 / 64 (17.19%)
    3 / 64 (4.69%)
         occurrences all number
    7
    21
    3
    Neurotoxicity
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 64 (4.69%)
    0 / 64 (0.00%)
         occurrences all number
    17
    10
    0
    Paraesthesia
         subjects affected / exposed
    4 / 60 (6.67%)
    7 / 64 (10.94%)
    2 / 64 (3.13%)
         occurrences all number
    4
    16
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    14 / 60 (23.33%)
    14 / 64 (21.88%)
    5 / 64 (7.81%)
         occurrences all number
    27
    26
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    25 / 60 (41.67%)
    33 / 64 (51.56%)
    30 / 64 (46.88%)
         occurrences all number
    58
    77
    104
    Leukopenia
         subjects affected / exposed
    4 / 60 (6.67%)
    12 / 64 (18.75%)
    14 / 64 (21.88%)
         occurrences all number
    9
    18
    53
    Lymphopenia
         subjects affected / exposed
    1 / 60 (1.67%)
    6 / 64 (9.38%)
    5 / 64 (7.81%)
         occurrences all number
    3
    8
    13
    Neutropenia
         subjects affected / exposed
    24 / 60 (40.00%)
    43 / 64 (67.19%)
    44 / 64 (68.75%)
         occurrences all number
    76
    155
    258
    Thrombocytopenia
         subjects affected / exposed
    8 / 60 (13.33%)
    18 / 64 (28.13%)
    34 / 64 (53.13%)
         occurrences all number
    35
    53
    112
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 64 (6.25%)
    1 / 64 (1.56%)
         occurrences all number
    2
    4
    1
    Vision blurred
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    3
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 60 (6.67%)
    9 / 64 (14.06%)
    5 / 64 (7.81%)
         occurrences all number
    5
    17
    6
    Abdominal pain upper
         subjects affected / exposed
    5 / 60 (8.33%)
    7 / 64 (10.94%)
    5 / 64 (7.81%)
         occurrences all number
    5
    8
    6
    Constipation
         subjects affected / exposed
    13 / 60 (21.67%)
    27 / 64 (42.19%)
    25 / 64 (39.06%)
         occurrences all number
    18
    35
    36
    Diarrhoea
         subjects affected / exposed
    25 / 60 (41.67%)
    26 / 64 (40.63%)
    13 / 64 (20.31%)
         occurrences all number
    42
    41
    16
    Dry mouth
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
    1 / 64 (1.56%)
         occurrences all number
    3
    2
    1
    Dyspepsia
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
    4 / 64 (6.25%)
         occurrences all number
    3
    2
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    1
    Nausea
         subjects affected / exposed
    26 / 60 (43.33%)
    34 / 64 (53.13%)
    27 / 64 (42.19%)
         occurrences all number
    54
    65
    55
    Stomatitis
         subjects affected / exposed
    5 / 60 (8.33%)
    14 / 64 (21.88%)
    8 / 64 (12.50%)
         occurrences all number
    12
    24
    8
    Vomiting
         subjects affected / exposed
    18 / 60 (30.00%)
    13 / 64 (20.31%)
    11 / 64 (17.19%)
         occurrences all number
    29
    18
    22
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    33 / 60 (55.00%)
    25 / 64 (39.06%)
    7 / 64 (10.94%)
         occurrences all number
    41
    35
    8
    Dry skin
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    3
    1
    0
    Erythema
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 64 (7.81%)
    3 / 64 (4.69%)
         occurrences all number
    9
    9
    3
    Pruritus
         subjects affected / exposed
    5 / 60 (8.33%)
    9 / 64 (14.06%)
    4 / 64 (6.25%)
         occurrences all number
    6
    12
    5
    Rash
         subjects affected / exposed
    8 / 60 (13.33%)
    3 / 64 (4.69%)
    2 / 64 (3.13%)
         occurrences all number
    8
    4
    3
    Rash maculo-papular
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Rash pruritic
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    3
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 60 (21.67%)
    9 / 64 (14.06%)
    7 / 64 (10.94%)
         occurrences all number
    17
    15
    11
    Back pain
         subjects affected / exposed
    3 / 60 (5.00%)
    14 / 64 (21.88%)
    6 / 64 (9.38%)
         occurrences all number
    4
    18
    7
    Bone pain
         subjects affected / exposed
    7 / 60 (11.67%)
    5 / 64 (7.81%)
    8 / 64 (12.50%)
         occurrences all number
    7
    7
    12
    Muscular weakness
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
    4 / 64 (6.25%)
         occurrences all number
    1
    3
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 64 (4.69%)
    3 / 64 (4.69%)
         occurrences all number
    6
    3
    4
    Musculoskeletal pain
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
    4 / 64 (6.25%)
         occurrences all number
    1
    3
    6
    Myalgia
         subjects affected / exposed
    14 / 60 (23.33%)
    14 / 64 (21.88%)
    4 / 64 (6.25%)
         occurrences all number
    22
    36
    7
    Neck pain
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 64 (4.69%)
    4 / 64 (6.25%)
         occurrences all number
    3
    3
    8
    Pain in extremity
         subjects affected / exposed
    8 / 60 (13.33%)
    7 / 64 (10.94%)
    4 / 64 (6.25%)
         occurrences all number
    11
    7
    4
    Spinal pain
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    3
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 60 (3.33%)
    5 / 64 (7.81%)
    1 / 64 (1.56%)
         occurrences all number
    2
    5
    1
    Cellulitis
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 64 (3.13%)
    0 / 64 (0.00%)
         occurrences all number
    11
    2
    0
    Folliculitis
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    4
    1
    0
    Influenza
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 64 (6.25%)
    2 / 64 (3.13%)
         occurrences all number
    1
    4
    3
    Sinusitis
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
    0 / 64 (0.00%)
         occurrences all number
    4
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 60 (10.00%)
    7 / 64 (10.94%)
    2 / 64 (3.13%)
         occurrences all number
    8
    9
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 60 (5.00%)
    11 / 64 (17.19%)
    6 / 64 (9.38%)
         occurrences all number
    6
    12
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 60 (25.00%)
    14 / 64 (21.88%)
    10 / 64 (15.63%)
         occurrences all number
    18
    22
    12
    Dehydration
         subjects affected / exposed
    6 / 60 (10.00%)
    1 / 64 (1.56%)
    3 / 64 (4.69%)
         occurrences all number
    7
    1
    3
    Hyperglycaemia
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 64 (7.81%)
    2 / 64 (3.13%)
         occurrences all number
    6
    7
    2
    Hypokalaemia
         subjects affected / exposed
    8 / 60 (13.33%)
    12 / 64 (18.75%)
    7 / 64 (10.94%)
         occurrences all number
    10
    21
    11
    Hypomagnesaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    12 / 64 (18.75%)
    5 / 64 (7.81%)
         occurrences all number
    1
    13
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Feb 2014
    The main changes in Amendment 1 were based on recommendations from the Scientific Steering Committee, Institutional Review Boards and Ethics Committees, and Principal Investigators. They included modification to the requirement for mandatory participation in biomarker studies, changes to inclusion/exclusion criteria, and management of toxicities by allowing subjects to continue in the study on monotherapy. - Biomarker collection was updated to optional participation. - Changes to inclusion/exclusion criteria were: o Disease free interval for patients that received neoadjuvant or adjuvant therapy prior to study entry was defined depending on the regimen previously received. o The time permitted for the administration of bone targeted therapies was expanded to any time during the screening and treatment periods, since an impact on outcomes had not been proven in this patient population. o Changes permitted the administration of warfarin, as well as other anticoagulation therapies, during the trial. The 7-day wash-out period for anticoagulants prior to randomization was also eliminated. These changes were supported by the absence of clinical evidence contraindicating the use of anticoagulants during nab-paclitaxel treatment. - Toxicity management was updated to allow monotherapy in the case when hypersensitivity or other toxicity specifically related to one of the drugs demanded discontinuation, and there was potential benefit to maintaining treatment with the second component of the particular doublet. 
    01 Jul 2015
    Included DMC conclusions and recommendations. - Changed event-driven analyses to time-driven. A final Phase 2 analysis was to be conducted approximately 12 months after the last subject had been randomized. - Length of study was updated to reflect approximately 80 months, with a Phase 2 enrollment of 24 months and a Phase 2 follow-up of 12 months. - Sample size was reduced from 240 subjects (80 per treatment arm) to approximately 180 subjects (60 per treatment arm) to reflect the number of subjects randomized at the time of the decision to stop enrollment per DMC recommendations. - Clarified exploratory endpoints and objectives. Time to death was determined by the secondary objective and the secondary endpoint of overall survival. Exploratory objectives and endpoints of time to second line therapy or death were clarified to time to second line therapy. - With the identification of nab-paclitaxel plus carboplatin as the experimental treatment arm for further investigation, all references to a Phase 3 treatment of nab-paclitaxel plus gemcitabine were removed.

    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 changes in the treatment landscape since the trial initiation, including the initiation of trials with immunotherapy drugs, successful enrollment of the Phase 3 part was considered unlikely and was not conducted; no safety signals were raised.
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    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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