Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   36348   clinical trials with a EudraCT protocol, of which   5989   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Randomized Phase 2 Study of MLN8237, an Aurora A Kinase Inhibitor, Plus Weekly Paclitaxel or Weekly Paclitaxel Alone in Patients with Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer, Preceded by a Phase 1 Portion in Patients with Ovarian or Breast Cancer

    Summary
    EudraCT number
    2009-011428-79
    Trial protocol
    PL  
    Global end of trial date
    19 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Mar 2018
    First version publication date
    11 Mar 2018
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    C14008
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01091428
    WHO universal trial number (UTN)
    U1111-1191-6584
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.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
    19 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to evaluate MLN8237 in combination with weekly paclitaxel in adult female subjects with advanced breast cancer (Phase 1 portion only) and recurrent ovarian cancer (both Phase 1 and Phase 2 portions).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Apr 2010
    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
    United States: 142
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Poland: 18
    Worldwide total number of subjects
    191
    EEA total number of subjects
    49
    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)
    131
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Subjects took part in the study at 33 investigative sites in France, Poland and the United States from 16 April 2010 to 19 July 2017. Data cutoff for the primary analysis was 12 August 2014.

    Pre-assignment
    Screening details
    Subjects with a diagnosis of ovarian cancer or breast cancer were enrolled equally in a dose escalation study to determine the recommended Phase 2 dose. In Phase 2 subjects were randomized equally to receive alisertib 40 mg BID + paclitaxel 60 mg/m^2 or single-agent paclitaxel 80 mg/m^2.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Alisertib (Phase 1 - Ovarian Cancer)
    Arm description
    Subjects with ovarian cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Alisertib
    Investigational medicinal product code
    Other name
    MLN8237
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alisertib Tablets

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel Intravenous Infusion

    Arm title
    Alisertib (Phase 1 - Breast Cancer)
    Arm description
    Subjects with breast cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Alisertib
    Investigational medicinal product code
    Other name
    MLN8237
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alisertib Tablets

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel Intravenous Infusion

    Arm title
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)
    Arm description
    Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Alisertib
    Investigational medicinal product code
    Other name
    MLN8237
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alisertib Tablets

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel intravenous Infusion

    Arm title
    Paclitaxel 80 mg/m^2 (Phase 2)
    Arm description
    Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel Intravenous Infusion

    Number of subjects in period 1
    Alisertib (Phase 1 - Ovarian Cancer) Alisertib (Phase 1 - Breast Cancer) Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Started
    38
    11
    73
    69
    Completed
    0
    0
    0
    0
    Not completed
    38
    11
    73
    69
         Unsatisfactory Therapeutic Response
    -
    -
    1
    1
         Symptomatic Deterioration
    3
    2
    1
    6
         Single-Patient IND
    2
    -
    -
    -
         Adverse event, non-fatal
    2
    -
    12
    5
         Progressive Disease
    24
    8
    44
    46
         Consent withdrawn by subject
    7
    -
    9
    8
         Physician Decision
    -
    -
    2
    -
         Reason not specified
    -
    1
    4
    3

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Alisertib (Phase 1 - Ovarian Cancer)
    Reporting group description
    Subjects with ovarian cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

    Reporting group title
    Alisertib (Phase 1 - Breast Cancer)
    Reporting group description
    Subjects with breast cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

    Reporting group title
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)
    Reporting group description
    Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

    Reporting group title
    Paclitaxel 80 mg/m^2 (Phase 2)
    Reporting group description
    Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

    Reporting group values
    Alisertib (Phase 1 - Ovarian Cancer) Alisertib (Phase 1 - Breast Cancer) Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2) Total
    Number of subjects
    38 11 73 69 191
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    55.8 ± 10.29 58.6 ± 10.06 61.0 ± 11.60 60.8 ± 8.41 -
    Gender, Male/Female
    Units: Subjects
        Female
    38 11 73 69 191
        Male
    0 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    4 0 1 4 9
        Not Hispanic or Latino
    34 10 64 62 170
        Not Reported
    0 1 7 3 11
        Missing
    0 0 1 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        White
    34 11 66 55 166
        Black or African American
    3 0 2 6 11
        Asian
    1 0 1 2 4
        American Indian or Alaskan Native
    0 0 0 2 2
        Other
    0 0 1 1 2
        Not Reported
    0 0 2 3 5
        Missing
    0 0 1 0 1
    Region of Enrollment
    Units: Subjects
        United States
    38 11 48 45 142
        Poland
    0 0 10 8 18
        France
    0 0 15 16 31
    Height
    Units: cm
        arithmetic mean (standard deviation)
    164.2 ± 6.41 164.5 ± 6.38 162.4 ± 7.02 161.9 ± 7.30 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    75.86 ± 16.41 76.29 ± 7.29 70.42 ± 14.78 72.50 ± 18.71 -
    Body Surface Area
    Body Surface Area (m^2) = square root [height (cm) x weight (kg) / 3600].
    Units: m^2
        arithmetic mean (standard deviation)
    1.850 ± 0.21 1.865 ± 0.10 1.776 ± 0.20 1.794 ± 0.24 -

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Alisertib (Phase 1 - Ovarian Cancer)
    Reporting group description
    Subjects with ovarian cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

    Reporting group title
    Alisertib (Phase 1 - Breast Cancer)
    Reporting group description
    Subjects with breast cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

    Reporting group title
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)
    Reporting group description
    Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

    Reporting group title
    Paclitaxel 80 mg/m^2 (Phase 2)
    Reporting group description
    Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

    Subject analysis set title
    Alisertib + Paclitaxel (Phase 1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects with ovarian cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

    Subject analysis set title
    Alisertib + Paclitaxel
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

    Subject analysis set title
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alisertib (MLN8237) 10 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

    Subject analysis set title
    Alisertib 20 mg BID + Paclitaxel 80 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alisertib 20 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

    Subject analysis set title
    Alisertib 20 mg BID + Paclitaxel 60 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alisertib 20 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

    Subject analysis set title
    Alisertib 30 mg BID + Paclitaxel 60 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alisertib 30 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase

    Subject analysis set title
    Alisertib 40 mg BID + Paclitaxel 60 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alisertib 10 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

    Subject analysis set title
    Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alisertib 10 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1

    Subject analysis set title
    Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 (Phase 2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

    Primary: Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination with Paclitaxel

    Close Top of page
    End point title
    Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination with Paclitaxel [1]
    End point description
    MTD: Dose range at which ≤1 of 6 evaluable subjects experience dose limiting toxicities (DLT). DLT evaluated a/c to National Cancer Institute's Common Terminology Criteria for Adverse v4.02 & as any of events: 1.Grade 4 neutropenia & thrombocytopenia lasting ≥7 consecutive days; 2.Grade 4 neutropenia with fever/infection; 3.Platelet count <10,000/mm^3; 4.Grade 3 thrombocytopenia with bleeding; 5.Any other ≥Grade3 nonhematologic toxicity, with exceptions: ≥Grade3 nausea/emesis, ≥Grade3 diarrhoea, Grade3 fatigue, Grade3 nonhematological toxicity that is controlled to ≤Grade 2 with appropriate treatment; 6.Other alisertib-related nonhematologic toxicities ≥Grade2 that, in investigator opinion, required a dose reduction/discontinuation of therapy with alisertib. DLT-Evaluable Population: all subjects in phase 1 who experienced DLT during Cycle 1/completed treatment with 15 of planned 18 doses of alisertib & 2 of planned 3 doses of paclitaxel in Cycle 1 & had sufficient follow-up data.
    End point type
    Primary
    End point timeframe
    Cycle 1 (Up to 28 days)
    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 analyses are reported for this endpoint.
    End point values
    Alisertib + Paclitaxel (Phase 1)
    Number of subjects analysed
    49
    Units: mg
    40
    No statistical analyses for this end point

    Primary: Phase 1: MTD and RP2D for Paclitaxel in Combination with Alisertib

    Close Top of page
    End point title
    Phase 1: MTD and RP2D for Paclitaxel in Combination with Alisertib [2]
    End point description
    The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable subjects experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1). DLT-Evaluable Population was defined as all subjects in the phase 1 who either experienced DLT during Cycle 1 or completed treatment with at least 15 of the planned 18 doses of alisertib and 2 of the planned 3 doses of paclitaxel in Cycle 1 and had sufficient follow-up data.
    End point type
    Primary
    End point timeframe
    Cycle 1 (Up to 28 days)
    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 analyses are reported for this endpoint.
    End point values
    Alisertib + Paclitaxel
    Number of subjects analysed
    49
    Units: mg/m^2
    60
    No statistical analyses for this end point

    Primary: Phase 1: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Close Top of page
    End point title
    Phase 1: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) [3] [4]
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Safety population was defined as all subjects who received at least 1 dose of any study drug.
    End point type
    Primary
    End point timeframe
    First dose to 30 days past last dose (Up to 36 Months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib (Phase 1 - Ovarian Cancer) Alisertib (Phase 1 - Breast Cancer)
    Number of subjects analysed
    38
    11
    Units: subjects
        AEs
    38
    11
        SAEs
    13
    2
    No statistical analyses for this end point

    Primary: Phase 1: Number of Subjects with Clinically Significant Laboratory Values

    Close Top of page
    End point title
    Phase 1: Number of Subjects with Clinically Significant Laboratory Values [5] [6]
    End point description
    Abnormal clinical laboratory values (serum chemistry, hematology and urinalysis) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. Safety population was defined as all subjects who received at least 1 dose of any study drug.
    End point type
    Primary
    End point timeframe
    First dose to 30 days past last dose (Up to 36 Months)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib (Phase 1 - Ovarian Cancer) Alisertib (Phase 1 - Breast Cancer)
    Number of subjects analysed
    38
    11
    Units: subjects
        Neutrophil count decreased
    3
    0
        White blood cell count decreased
    1
    1
        Aspartate aminotransferase increased
    3
    1
        Alanine aminotransferase increased
    2
    0
        Ammonia increased
    1
    0
        Transaminases increased
    1
    0
        Blood alkaline phosphatase increased
    1
    1
        High density lipoprotein decreased
    1
    0
        Urine output decreased
    1
    0
        Granulocyte count decreased
    0
    1
    No statistical analyses for this end point

    Primary: Phase 1: Number of Subjects with Clinically Significant Vital Sign Findings

    Close Top of page
    End point title
    Phase 1: Number of Subjects with Clinically Significant Vital Sign Findings [7] [8]
    End point description
    Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study. Safety population was defined as all subjects who received at least 1 dose of any study drug.
    End point type
    Primary
    End point timeframe
    First dose to 30 days past last dose (Up to 36 Months)
    Notes
    [7] - 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 analyses are reported for this endpoint.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib (Phase 1 - Ovarian Cancer) Alisertib (Phase 1 - Breast Cancer)
    Number of subjects analysed
    38
    11
    Units: subjects
        Pyrexia
    8
    5
        Heart rate irregular
    1
    0
        Blood pressure increased
    0
    1
        Weight decreased
    3
    0
    No statistical analyses for this end point

    Primary: Phase 1: Number of Subjects with Hypersensitivity and Neurotoxicity

    Close Top of page
    End point title
    Phase 1: Number of Subjects with Hypersensitivity and Neurotoxicity [9] [10]
    End point description
    Safety population was defined as all subjects who received at least 1 dose of any study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to Month 36
    Notes
    [9] - 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 analyses are reported for this endpoint.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib (Phase 1 - Ovarian Cancer) Alisertib (Phase 1 - Breast Cancer)
    Number of subjects analysed
    38
    11
    Units: subjects
        Hypersensitivity|
    1
    0
        Neurotoxicity|
    0
    0
    No statistical analyses for this end point

    Primary: Phase 2: Progression-Free Survival (PFS)

    Close Top of page
    End point title
    Phase 2: Progression-Free Survival (PFS) [11] [12]
    End point description
    PFS is defined as the time from the date randomization for Phase 2 subjects to the date of first documented progressive disease (PD) or death as assessed by the investigator using both RECIST 1.1 criteria and CA-125 criteria. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease or CA-125 criteria with elevated (>70 units/mL) levels on 2 occasions. CA 125 progression for subjects with normal CA 125 levels is defined as a CA 125 level >2 times the upper limit of normal and for subjects with elevated values during the trial, is defined as a CA 125 level greater than 2 times the nadir value of CA 125. The modified intent-to-treat (mITT) population was defined as all subjects who were randomized and received at least 1 dose of any study drug. For a subject that has not progressed and has not died or has started the alternate therapy, PFS is censored at the last response assessment that is stable disease (SD) or better.
    End point type
    Primary
    End point timeframe
    At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)
    Notes
    [11] - 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 analyses are reported for this endpoint.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Number of subjects analysed
    73
    69
    Units: days
        median (confidence interval 80%)
    204 (175 to 230)
    142 (117 to 148)
    No statistical analyses for this end point

    Secondary: Phase 1: Combined Best Overall Response Rate (ORR) in Subjects with Recurrent Ovarian Cancer or Breast Cancer

    Close Top of page
    End point title
    Phase 1: Combined Best Overall Response Rate (ORR) in Subjects with Recurrent Ovarian Cancer or Breast Cancer [13]
    End point description
    Combined objective response rate: Percentage of subjects with Complete Response (CR)+Partial Response (PR) as assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 or response by Cancer antigen (CA) 125 criteria. According to RECIST: CR-disappearance of all target lesions & PR- 30% decrease in sum of longest diameter of target lesions. CA-125 response criteria: 50% decrease from 2 initially elevated samples; sample demonstrating 50% decrease must be confirmed by a fourth sample 28 days later (total of 4 samples required) or serial decrease of >75% over 3 samples; third sample was obtained 28 days after second (total of 3 samples required). Response evaluable population: Subjects who were randomized & had measurable disease according to RECIST or assessable disease by CA-125 criteria, who received at least 1 dose of any study drug & who had at least 1 available post-Baseline response assessment as per either RECIST or CA-125 criteria.
    End point type
    Secondary
    End point timeframe
    At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib (Phase 1 - Ovarian Cancer) Alisertib (Phase 1 - Breast Cancer)
    Number of subjects analysed
    38
    11
    Units: percentage of subjects
        number (confidence interval 80%)
    47 (36 to 59)
    55 (32 to 76)
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Concentration for Alisertib in Phase 1

    Close Top of page
    End point title
    Cmax: Maximum Observed Concentration for Alisertib in Phase 1
    End point description
    Pharmacokinetic (PK) analysis set for alisertib was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: nM
    arithmetic mean (standard deviation)
        Cycle1 (Day1)
    428.7 ± 189.59
    766.8 ± 312.10
    900.00 ± 392.17
    1365.3 ± 466.51
    1398.7 ± 607.70
    1960.0 ± 515.65
        Cycle1 (Day3)
    594.3 ± 228.46
    1042.3 ± 280.95
    871.3 ± 268.23
    1708.5 ± 820.54
    2493.4 ± 955.31
    4456.7 ± 947.33
    No statistical analyses for this end point

    Secondary: Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1

    Close Top of page
    End point title
    Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1
    End point description
    PK analysis set for alisertib was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: hour
    median (full range (min-max))
        Cycle 1, Day 1
    3.0 (1 to 5)
    3.1 (2 to 4)
    2.6 (2 to 3)
    2.5 (2 to 9)
    3.0 (2 to 9)
    2.0 (2 to 9)
        Cycle 1, Day 3
    2.2 (0 to 5)
    3.0 (1 to 3)
    3.5 (2 to 5)
    2.0 (1 to 4)
    2.0 (1 to 9)
    2.0 (2 to 3)
    No statistical analyses for this end point

    Secondary: AUC(tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1

    Close Top of page
    End point title
    AUC(tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1
    End point description
    PK analysis set for alisertib was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: nM*hour
    arithmetic mean (standard deviation)
        Cycle 1, Day 1
    2519.3 ± 937.52
    5175.0 ± 1766.11
    5610.0 ± 2105.42
    8581.7 ± 3225.64
    9594.0 ± 4600.42
    14666.7 ± 3707.20
        Cycle 1, Day3
    3966.7 ± 1112.11
    7745.0 ± 2233.91
    6155.0 ± 1737.69
    12478.3 ± 6013.93
    17557.3 ± 7856.30
    35500.0 ± 12842.12
    No statistical analyses for this end point

    Secondary: AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1

    Close Top of page
    End point title
    AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1
    End point description
    PK analysis set for alisertib was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: nM*hour
    arithmetic mean (standard deviation)
        Cycle 1, Day 1
    2519.3 ± 937.52
    5175.0 ± 1766.11
    5610.0 ± 2105.42
    8581.7 ± 3225.64
    9594.0 ± 4600.42
    14666.7 ± 3707.20
        Cycle 1, Day 3
    3966.7 ± 1112.11
    7745.0 ± 2233.91
    6155.0 ± 1737.69
    12478.3 ± 6013.93
    17557.3 ± 7856.30
    35500.0 ± 12842.12
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1

    Close Top of page
    End point title
    Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1
    End point description
    PK analysis set for paclitaxel was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration-time data to permit noncompartmental PK analysis. Number analyzed is the number of subjects with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: ng/mL*hr
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=15,6,4,5,15,3)
    3097.3 ± 1114.51
    3120.0 ± 447.75
    2117.5 ± 745.54
    2448.0 ± 988.65
    1917.3 ± 528.32
    1338.7 ± 617.94
        Cycle 2, Day 1 (n=13,6,3,6,13,2)
    2654.6 ± 696.45
    3231.7 ± 615.64
    1733.3 ± 541.97
    2478.3 ± 878.39
    1492.7 ± 558.14
    1750.0 ± 183.85
    No statistical analyses for this end point

    Secondary: AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1

    Close Top of page
    End point title
    AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1
    End point description
    PK analysis set for paclitaxel was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration-time data to permit noncompartmental PK analysis. Number analyzed is the number of subjects with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: ng/mL*hr
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=13,6,4,5,15,3)
    4437.7 ± 1053.87
    4825.0 ± 735.17
    3355.0 ± 865.89
    3366.0 ± 1139.25
    2652.7 ± 651.32
    2190.0 ± 387.43
        Cycle 2, Day 1 (n=12,6,3,5,13,2)
    4061.7 ± 1298.86
    5301.7 ± 1183.31
    2660.0 ± 307.90
    3056.0 ± 812.67
    2231.5 ± 604.76
    2460.0 ± 14.14
    No statistical analyses for this end point

    Secondary: AUC0-∞: Area under the Concentration-Time Curve from Time 0 to Infinity, Calculated using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

    Close Top of page
    End point title
    AUC0-∞: Area under the Concentration-Time Curve from Time 0 to Infinity, Calculated using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1
    End point description
    PK analysis set for paclitaxel was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration-time data to permit noncompartmental PK analysis. Number analyzed is the number of subjects with evaluable data at the specified time-point. Here, 99999 indicates that data was not collected as no subject was evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: ng/mL*hr
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=9,5,3,4,11,2)
    5317.8 ± 1052.40
    5238.0 ± 812.26
    3860.0 ± 824.20
    3375.0 ± 1130.56
    3175.5 ± 933.10
    2535.0 ± 657.61
        Cycle 2, Day 1 (n=11,5,2,4,10,0)
    4606.4 ± 1391.35
    5584.0 ± 1367.51
    3185.0 ± 176.78
    3415.0 ± 1010.82
    2680.0 ± 607.22
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: t½: Terminal Half-Life for Paclitaxel in Phase 1

    Close Top of page
    End point title
    t½: Terminal Half-Life for Paclitaxel in Phase 1
    End point description
    PK analysis set for paclitaxel was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration-time data to permit noncompartmental PK analysis. Number analyzed is the number of subjects with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: hour
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=11,5,3,5,11,2)
    17.2 ± 4.20
    17.5 ± 1.87
    17.3 ± 4.16
    13.9 ± 4.68
    16.8 ± 6.83
    18.4 ± 8.70
        Cycle 2, Day 1 (n=12,5,2,4,10,2)
    17.0 ± 3.63
    16.2 ± 5.05
    17.3 ± 5.23
    16.5 ± 4.32
    13.3 ± 5.59
    14.6 ± 2.19
    No statistical analyses for this end point

    Secondary: CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

    Close Top of page
    End point title
    CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1
    End point description
    PK analysis set for paclitaxel was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration-time data to permit noncompartmental PK analysis. Number analyzed is the number of subjects with evaluable data at the specified time-point. Here, 99999 indicates that data was not collected as no subject was evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: liter per hour
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=9,5,3,4,11,2)
    29.756 ± 6.8175
    28.220 ± 5.1804
    26.800 ± 7.5386
    40.950 ± 17.5268
    38.055 ± 13.7095
    38.950 ± 11.2430
        Cycle 2, Day 1 (n=11,5,2,4,10,0)
    35.827 ± 10.4005
    28.240 ± 7.3748
    33.900 ± 5.2326
    34.250 ± 8.2614
    42.440 ± 10.4296
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1

    Close Top of page
    End point title
    Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1
    End point description
    PK analysis set for paclitaxel was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration-time data to permit noncompartmental PK analysis. Number analyzed is the number of subjects with evaluable data at the specified time-point. Here, 99999 indicates that data was not collected as no subject was evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: liter
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=9,5,3,4,11,2)
    313.444 ± 118.6593
    310.800 ± 86.9235
    330.000 ± 208.8851
    357.000 ± 158.1834
    433.909 ± 179.7757
    460.500 ± 103.9447
        Cycle 2, Day 1 (n=11,5,2,4,10,0)
    391.364 ± 64.3137
    283.200 ± 121.1123
    413.500 ± 242.5376
    377.000 ± 118.9650
    372.600 ± 180.7332
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1

    Close Top of page
    End point title
    Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1
    End point description
    PK analysis set for paclitaxel was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration-time data to permit noncompartmental PK analysis. Number analyzed is the number of subjects with evaluable data at the specified time-point. Here, 99999 indicates that data was not collected as no subject was evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
    End point values
    Alisertib 10 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 80 mg/m^2 Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
    Number of subjects analysed
    15
    6
    4
    6
    15
    3
    Units: liter
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=9,5,3,4,11,2)
    705.000 ± 179.0223
    721.600 ± 203.8021
    694.000 ± 352.1534
    850.500 ± 291.0401
    872.727 ± 328.6202
    956.500 ± 188.7975
        Cycle 2, Day 1 (n=11,5,2,4,10,0)
    829.364 ± 156.6060
    663.200 ± 321.3070
    865.500 ± 388.2016
    777.250 ± 103.7027
    733.000 ± 208.4898
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 2: Combined Best Overall Response Rate (ORR)

    Close Top of page
    End point title
    Phase 2: Combined Best Overall Response Rate (ORR) [14]
    End point description
    Combined objective response rate: Percentage of subjects with CR+ PR as assessed by the investigator according to RECIST criteria 1.1 or response by CA-125 criteria. According to RECIST: CR- the disappearance of all target lesions and PR- 30% decrease in the sum of the longest diameter of target lesions. CA-125 response criteria is defined as either: A 50% decrease from 2 initially elevated samples; the sample demonstrating the 50% decrease must have been confirmed by a fourth sample 28 days later (a total of 4 samples required) or A serial decrease of >75% over 3 samples; the third sample was to be obtained 28 days after the second (a total of 3 samples required). Response evaluable population was defined as all subjects who were randomized and had measurable disease according to RECIST or assessable disease by CA-125 criteria, who received at least 1 dose of any study drug, and who had at least 1 available post-Baseline response assessment as per either RECIST or CA-125 criteria.
    End point type
    Secondary
    End point timeframe
    At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Number of subjects analysed
    67
    64
    Units: percentage of subjects
        number (confidence interval 80%)
    60 (51 to 68)
    52 (43 to 60)
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response (DOR)

    Close Top of page
    End point title
    Phase 2: Duration of Response (DOR) [15]
    End point description
    DOR: Time from date of first documentation of response to date of first documentation of PD or last response assessment i.e. stable disease (SD) or better for subject who started alternate therapy without progression. PD: 20% increase in sum of longest diameter of target lesions for measurable neoplastic disease or per CA-125 criteria with elevated (>70 units/mL) levels on 2 occasions. CA-125 progression for subjects with normal CA-125 levels: CA-125 level >2 times upper limit of normal and for subjects with elevated values during trial: CA-125 level >2 times nadir value of CA-125. A responder that did not experience disease progression is censored at last response assessment i.e. SD. Response evaluable population: subjects who were randomized and had measurable disease according to RECIST 1.1 or assessable disease by CA-125 criteria, who received 1 dose of study drug, and who had 1 available post-Baseline response assessment per RECIST 1.1 or CA-125 criteria, who were responders.
    End point type
    Secondary
    End point timeframe
    Up to data-cut off: 12 August 2014 (approximately 24 months)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Number of subjects analysed
    40
    33
    Units: days
        median (confidence interval 80%)
    201 (181 to 218)
    169 (120 to 231)
    No statistical analyses for this end point

    Secondary: Phase 2: Time to Disease Progression (TTP)

    Close Top of page
    End point title
    Phase 2: Time to Disease Progression (TTP) [16]
    End point description
    TTP was defined as the time from the date of randomization to the date of first documentation of PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease or per CA-125 criteria with elevated (>70 units/mL) levels on 2 occasions. CA 125 progression for subjects with normal CA 125 levels is defined as a CA 125 level >2 times the upper limit of normal and for subjects with elevated values during the trial, is defined as a CA 125 level greater than 2 times the nadir value of CA 125. mITT Population was defined as all subjects who were randomized and received at least 1 dose of any study drug. For a subject that has not progressed, TTP is censored at the last response assessment that is SD or better.
    End point type
    Secondary
    End point timeframe
    Up to data-cut off: 12 August 2014 (approximately 24 months)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Number of subjects analysed
    73
    69
    Units: days
        median (confidence interval 80%)
    204 (175 to 232)
    142 (117 to 161)
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival (OS)

    Close Top of page
    End point title
    Phase 2: Overall Survival (OS) [17]
    End point description
    OS was defined as the time form the date of the randomization to the date of death. mITT Population was defined as all subjects who were randomized and received at least 1 dose of any study drug. For a subject that is alive, OS will be censored at the last known date. Here, 99999 indicates that Median, upper and lower limits of CI were not reached due to low number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to data-cut off: 12 August 2014 (approximately 24 months)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Number of subjects analysed
    73
    69
    Units: days
        median (confidence interval 80%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Close Top of page
    End point title
    Phase 2: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) [18]
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Safety population was defined as all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    First dose to 30 days past last dose (Up to 27 Months)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Number of subjects analysed
    73
    69
    Units: subjects
        AEs
    73
    66
        SAEs
    30
    19
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Subjects With Clinically Significant Laboratory Values

    Close Top of page
    End point title
    Phase 2: Number of Subjects With Clinically Significant Laboratory Values [19]
    End point description
    Abnormal clinical laboratory values (serum chemistry, hematology, and urinalysis) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. Safety population was defined as all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    First dose to 30 days past last dose (Up to 27 Months)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Paclitaxel 80 mg/m^2 (Phase 2) Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 (Phase 2)
    Number of subjects analysed
    69
    73
    Units: subjects
        Neutrophil count decreased
    4
    14
        White blood cell count decreased
    1
    6
        Lymphocyte count decreased
    1
    1
        Aspartate aminotransferase increased
    3
    1
        Alanine aminotransferase increased
    4
    1
        Gamma-glutamyltransferase increased
    1
    0
        Blood alkaline phosphatase increased
    2
    2
        Haemoglobin decreased
    1
    3
        Blood magnesium decreased
    3
    0
        Blood creatinine increased
    2
    1
        Platelet count decreased
    0
    2
        International normalised ratio increased
    0
    1
        Blood albumin decreased
    0
    1
        Troponin T increased
    1
    0
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Subjects with Clinically Significant Vital Sign Findings

    Close Top of page
    End point title
    Phase 2: Number of Subjects with Clinically Significant Vital Sign Findings [20]
    End point description
    Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study. Safety population was defined as all subjects who received at least 1 dose of any study drug.
    End point type
    Secondary
    End point timeframe
    First dose to 30 days past last dose (Up to 27 Months)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable to this Endpoint.
    End point values
    Paclitaxel 80 mg/m^2 (Phase 2) Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 (Phase 2)
    Number of subjects analysed
    69
    73
    Units: Subjects
        Pyrexia
    8
    15
        Heart rate increased
    0
    1
        Blood pressure increased
    0
    1
        Weight decreased
    2
    8
    No statistical analyses for this end point

    Other pre-specified: Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes

    Close Top of page
    End point title
    Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes
    End point description
    This Outcome Measure was originally registered as a Secondary but this Outcome Measure was Exploratory and no data was collected.
    End point type
    Other pre-specified
    End point timeframe
    Up to 24 Months
    End point values
    Alisertib + Paclitaxel (Phase 1)
    Number of subjects analysed
    0 [21]
    Units: levels
        arithmetic mean (standard deviation)
    ±
    Notes
    [21] - This endpoint was registered as a Secondary but this was Exploratory and no data was collected.
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Phase 1: First dose to 30 days past last dose (Up to 36 Months); Phase 2: First dose to 30 days past last dose (Up to 27 Months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the subject or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Alisertib (Phase 1 - Ovarian cancer)
    Reporting group description
    Alisertib (MLN8237) 10 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

    Reporting group title
    Alisertib (Phase 1 - Breast cancer)
    Reporting group description
    Alisertib 20 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

    Reporting group title
    Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)
    Reporting group description
    Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

    Reporting group title
    Paclitaxel 80 mg/m^2 (Phase 2)
    Reporting group description
    Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

    Serious adverse events
    Alisertib (Phase 1 - Ovarian cancer) Alisertib (Phase 1 - Breast cancer) Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 38 (34.21%)
    2 / 11 (18.18%)
    30 / 73 (41.10%)
    19 / 69 (27.54%)
         number of deaths (all causes)
    0
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    3 / 73 (4.11%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Vascular access complication
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    6 / 38 (15.79%)
    0 / 11 (0.00%)
    9 / 73 (12.33%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    6 / 9
    0 / 0
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    6 / 73 (8.22%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    6 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    3 / 73 (4.11%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    4 / 73 (5.48%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
    Additional description: One treatment-emergent death occurred during treatment with alisertib and paclitaxel and was not related.
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia obstructive
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ascites
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postrenal failure
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Paraneoplastic dermatomyositis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    4 / 73 (5.48%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    3 / 73 (4.11%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    Additional description: One treatment-emergent death occurred during treatment with paclitaxel and was not related.
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Alisertib (Phase 1 - Ovarian cancer) Alisertib (Phase 1 - Breast cancer) Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) Paclitaxel 80 mg/m^2 (Phase 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 38 (100.00%)
    11 / 11 (100.00%)
    73 / 73 (100.00%)
    64 / 69 (92.75%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    3 / 73 (4.11%)
    1 / 69 (1.45%)
         occurrences all number
    2
    1
    5
    2
    Hot flush
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    2 / 69 (2.90%)
         occurrences all number
    4
    0
    1
    3
    Hypotension
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    4 / 73 (5.48%)
    2 / 69 (2.90%)
         occurrences all number
    0
    0
    5
    2
    Deep vein thrombosis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    1
    1
    1
    1
    Lymphoedema
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Blood pressure fluctuation
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Superior vena cava stenosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    3
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    26 / 38 (68.42%)
    8 / 11 (72.73%)
    43 / 73 (58.90%)
    31 / 69 (44.93%)
         occurrences all number
    29
    10
    82
    37
    Oedema peripheral
         subjects affected / exposed
    15 / 38 (39.47%)
    3 / 11 (27.27%)
    12 / 73 (16.44%)
    18 / 69 (26.09%)
         occurrences all number
    24
    3
    15
    25
    Pyrexia
         subjects affected / exposed
    8 / 38 (21.05%)
    4 / 11 (36.36%)
    13 / 73 (17.81%)
    7 / 69 (10.14%)
         occurrences all number
    11
    7
    18
    10
    Asthenia
         subjects affected / exposed
    5 / 38 (13.16%)
    2 / 11 (18.18%)
    10 / 73 (13.70%)
    8 / 69 (11.59%)
         occurrences all number
    6
    2
    20
    11
    Chills
         subjects affected / exposed
    10 / 38 (26.32%)
    0 / 11 (0.00%)
    6 / 73 (8.22%)
    0 / 69 (0.00%)
         occurrences all number
    12
    0
    6
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 11 (18.18%)
    3 / 73 (4.11%)
    0 / 69 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Catheter site pain
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences all number
    5
    0
    2
    1
    Peripheral swelling
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences all number
    3
    0
    4
    1
    Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    2
    0
    1
    1
    Chest discomfort
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Early satiety
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 38 (15.79%)
    2 / 11 (18.18%)
    8 / 73 (10.96%)
    7 / 69 (10.14%)
         occurrences all number
    6
    2
    8
    8
    Anxiety
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    11 / 73 (15.07%)
    7 / 69 (10.14%)
         occurrences all number
    3
    1
    11
    9
    Depression
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 11 (9.09%)
    6 / 73 (8.22%)
    4 / 69 (5.80%)
         occurrences all number
    4
    1
    7
    4
    Aggression
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    2 / 69 (2.90%)
         occurrences all number
    4
    0
    0
    2
    Genital discomfort
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Vulvovaginal pain
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Cystocele
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    8 / 38 (21.05%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    3 / 69 (4.35%)
         occurrences all number
    14
    0
    1
    3
    Limb injury
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Fibula fracture
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    13 / 73 (17.81%)
    4 / 69 (5.80%)
         occurrences all number
    4
    0
    22
    5
    Weight decreased
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    8 / 73 (10.96%)
    2 / 69 (2.90%)
         occurrences all number
    3
    0
    11
    2
    White blood cell count decreased
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    6 / 73 (8.22%)
    1 / 69 (1.45%)
         occurrences all number
    2
    6
    14
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    3 / 69 (4.35%)
         occurrences all number
    3
    2
    2
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    4 / 69 (5.80%)
         occurrences all number
    3
    0
    2
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    2 / 69 (2.90%)
         occurrences all number
    1
    2
    3
    3
    Blood pressure increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cardiac murmur
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Granulocyte count decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    5 / 38 (13.16%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    2 / 69 (2.90%)
         occurrences all number
    5
    1
    1
    2
    Palpitations
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    5
    0
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    24 / 38 (63.16%)
    10 / 11 (90.91%)
    52 / 73 (71.23%)
    10 / 69 (14.49%)
         occurrences all number
    100
    58
    179
    17
    Anaemia
         subjects affected / exposed
    22 / 38 (57.89%)
    7 / 11 (63.64%)
    33 / 73 (45.21%)
    20 / 69 (28.99%)
         occurrences all number
    37
    13
    61
    36
    Leukopenia
         subjects affected / exposed
    20 / 38 (52.63%)
    8 / 11 (72.73%)
    11 / 73 (15.07%)
    3 / 69 (4.35%)
         occurrences all number
    47
    32
    27
    6
    Thrombocytopenia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 11 (18.18%)
    4 / 73 (5.48%)
    1 / 69 (1.45%)
         occurrences all number
    0
    17
    7
    2
    Granulocytopenia
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    4
    4
    0
    1
    Febrile neutropenia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 38 (28.95%)
    3 / 11 (27.27%)
    17 / 73 (23.29%)
    4 / 69 (5.80%)
         occurrences all number
    13
    3
    20
    4
    Dyspnoea
         subjects affected / exposed
    10 / 38 (26.32%)
    3 / 11 (27.27%)
    9 / 73 (12.33%)
    11 / 69 (15.94%)
         occurrences all number
    11
    3
    10
    19
    Epistaxis
         subjects affected / exposed
    7 / 38 (18.42%)
    1 / 11 (9.09%)
    6 / 73 (8.22%)
    7 / 69 (10.14%)
         occurrences all number
    11
    1
    6
    11
    Oropharyngeal pain
         subjects affected / exposed
    10 / 38 (26.32%)
    1 / 11 (9.09%)
    6 / 73 (8.22%)
    2 / 69 (2.90%)
         occurrences all number
    12
    1
    7
    2
    Nasal congestion
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 11 (9.09%)
    3 / 73 (4.11%)
    0 / 69 (0.00%)
         occurrences all number
    5
    1
    5
    0
    Rhinorrhoea
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    0 / 69 (0.00%)
         occurrences all number
    4
    1
    2
    0
    Pleural effusion
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences all number
    2
    2
    2
    1
    Dysphonia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    2
    0
    1
    1
    Rhinitis allergic
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    3
    0
    0
    2
    Hypoxia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    1
    1
    0
    1
    Throat irritation
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Sinus disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    8 / 38 (21.05%)
    4 / 11 (36.36%)
    12 / 73 (16.44%)
    13 / 69 (18.84%)
         occurrences all number
    8
    4
    15
    16
    Headache
         subjects affected / exposed
    6 / 38 (15.79%)
    1 / 11 (9.09%)
    8 / 73 (10.96%)
    13 / 69 (18.84%)
         occurrences all number
    9
    1
    11
    22
    Dizziness
         subjects affected / exposed
    8 / 38 (21.05%)
    0 / 11 (0.00%)
    10 / 73 (13.70%)
    6 / 69 (8.70%)
         occurrences all number
    14
    0
    16
    9
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 11 (18.18%)
    9 / 73 (12.33%)
    8 / 69 (11.59%)
         occurrences all number
    4
    2
    9
    9
    Dysgeusia
         subjects affected / exposed
    7 / 38 (18.42%)
    0 / 11 (0.00%)
    4 / 73 (5.48%)
    5 / 69 (7.25%)
         occurrences all number
    9
    0
    4
    6
    Somnolence
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    7 / 73 (9.59%)
    0 / 69 (0.00%)
         occurrences all number
    3
    1
    9
    0
    Paraesthesia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    5 / 69 (7.25%)
         occurrences all number
    2
    0
    1
    8
    Restless legs syndrome
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    3 / 73 (4.11%)
    2 / 69 (2.90%)
         occurrences all number
    3
    0
    3
    2
    Memory impairment
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    2 / 69 (2.90%)
         occurrences all number
    2
    0
    1
    2
    Amnesia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    1
    1
    1
    1
    Hyperaesthesia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Tremor
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    2
    0
    1
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 11 (18.18%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    5
    2
    1
    1
    Lacrimation increased
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 11 (18.18%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences all number
    2
    2
    2
    1
    Visual impairment
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Cataract
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Eye pruritus
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    2
    0
    1
    1
    Vision blurred
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    4
    0
    1
    1
    Vitreous floaters
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Meibomian gland dysfunction
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    3 / 73 (4.11%)
    1 / 69 (1.45%)
         occurrences all number
    4
    0
    3
    1
    Ear congestion
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    0
    1
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    27 / 38 (71.05%)
    8 / 11 (72.73%)
    46 / 73 (63.01%)
    15 / 69 (21.74%)
         occurrences all number
    49
    11
    96
    19
    Nausea
         subjects affected / exposed
    23 / 38 (60.53%)
    5 / 11 (45.45%)
    32 / 73 (43.84%)
    32 / 69 (46.38%)
         occurrences all number
    33
    6
    54
    46
    Stomatitis
         subjects affected / exposed
    15 / 38 (39.47%)
    8 / 11 (72.73%)
    46 / 73 (63.01%)
    6 / 69 (8.70%)
         occurrences all number
    32
    10
    91
    8
    Constipation
         subjects affected / exposed
    15 / 38 (39.47%)
    3 / 11 (27.27%)
    26 / 73 (35.62%)
    17 / 69 (24.64%)
         occurrences all number
    22
    4
    33
    23
    Abdominal pain
         subjects affected / exposed
    12 / 38 (31.58%)
    3 / 11 (27.27%)
    21 / 73 (28.77%)
    20 / 69 (28.99%)
         occurrences all number
    19
    3
    39
    26
    Vomiting
         subjects affected / exposed
    13 / 38 (34.21%)
    4 / 11 (36.36%)
    20 / 73 (27.40%)
    18 / 69 (26.09%)
         occurrences all number
    42
    4
    31
    25
    Abdominal pain upper
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    11 / 73 (15.07%)
    4 / 69 (5.80%)
         occurrences all number
    5
    1
    12
    6
    Dyspepsia
         subjects affected / exposed
    5 / 38 (13.16%)
    1 / 11 (9.09%)
    9 / 73 (12.33%)
    3 / 69 (4.35%)
         occurrences all number
    5
    1
    12
    3
    Abdominal distension
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 11 (18.18%)
    9 / 73 (12.33%)
    4 / 69 (5.80%)
         occurrences all number
    2
    2
    10
    4
    Ascites
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    8 / 73 (10.96%)
    5 / 69 (7.25%)
         occurrences all number
    3
    1
    11
    7
    Haemorrhoids
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 11 (0.00%)
    9 / 73 (12.33%)
    2 / 69 (2.90%)
         occurrences all number
    4
    0
    10
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 11 (0.00%)
    6 / 73 (8.22%)
    4 / 69 (5.80%)
         occurrences all number
    4
    0
    7
    5
    Oral pain
         subjects affected / exposed
    5 / 38 (13.16%)
    0 / 11 (0.00%)
    6 / 73 (8.22%)
    0 / 69 (0.00%)
         occurrences all number
    6
    0
    6
    0
    Dry mouth
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 11 (18.18%)
    1 / 73 (1.37%)
    3 / 69 (4.35%)
         occurrences all number
    3
    2
    1
    3
    Abdominal discomfort
         subjects affected / exposed
    5 / 38 (13.16%)
    2 / 11 (18.18%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    6
    2
    1
    0
    Flatulence
         subjects affected / exposed
    6 / 38 (15.79%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    9
    3
    1
    0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    5 / 73 (6.85%)
    2 / 69 (2.90%)
         occurrences all number
    0
    0
    9
    2
    Dysphagia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    4 / 73 (5.48%)
    1 / 69 (1.45%)
         occurrences all number
    1
    1
    6
    2
    Toothache
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    2 / 69 (2.90%)
         occurrences all number
    2
    0
    2
    4
    Rectal haemorrhage
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Abdominal pain lower
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    4
    0
    0
    1
    Tongue ulceration
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 11 (18.18%)
    3 / 73 (4.11%)
    5 / 69 (7.25%)
         occurrences all number
    1
    2
    3
    5
    Dysuria
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    4 / 73 (5.48%)
    3 / 69 (4.35%)
         occurrences all number
    2
    1
    12
    9
    Pollakiuria
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    3 / 73 (4.11%)
    1 / 69 (1.45%)
         occurrences all number
    2
    1
    3
    1
    Bladder spasm
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Acute kidney injury
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Renal failure
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Cystitis noninfective
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    26 / 38 (68.42%)
    5 / 11 (45.45%)
    28 / 73 (38.36%)
    22 / 69 (31.88%)
         occurrences all number
    29
    6
    36
    24
    Rash
         subjects affected / exposed
    8 / 38 (21.05%)
    2 / 11 (18.18%)
    5 / 73 (6.85%)
    2 / 69 (2.90%)
         occurrences all number
    9
    2
    5
    2
    Dry skin
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 11 (9.09%)
    5 / 73 (6.85%)
    2 / 69 (2.90%)
         occurrences all number
    4
    1
    5
    2
    Pruritus
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 11 (0.00%)
    5 / 73 (6.85%)
    2 / 69 (2.90%)
         occurrences all number
    5
    0
    5
    4
    Erythema
         subjects affected / exposed
    5 / 38 (13.16%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    2 / 69 (2.90%)
         occurrences all number
    6
    1
    2
    4
    Nail disorder
         subjects affected / exposed
    4 / 38 (10.53%)
    3 / 11 (27.27%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    4
    3
    1
    0
    Onycholysis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    3 / 69 (4.35%)
         occurrences all number
    2
    0
    2
    3
    Skin lesion
         subjects affected / exposed
    6 / 38 (15.79%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    12
    0
    3
    0
    Skin exfoliation
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Pruritus generalised
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Rash macular
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    2
    0
    4
    1
    Rash pruritic
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Nail discolouration
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Rash erythematous
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Skin ulcer
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    10
    0
    0
    0
    Solar dermatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    10 / 38 (26.32%)
    2 / 11 (18.18%)
    9 / 73 (12.33%)
    9 / 69 (13.04%)
         occurrences all number
    15
    7
    11
    13
    Arthralgia
         subjects affected / exposed
    11 / 38 (28.95%)
    3 / 11 (27.27%)
    7 / 73 (9.59%)
    6 / 69 (8.70%)
         occurrences all number
    18
    3
    9
    9
    Pain in extremity
         subjects affected / exposed
    7 / 38 (18.42%)
    1 / 11 (9.09%)
    8 / 73 (10.96%)
    5 / 69 (7.25%)
         occurrences all number
    14
    1
    9
    6
    Muscle spasms
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    4 / 73 (5.48%)
    7 / 69 (10.14%)
         occurrences all number
    7
    0
    4
    9
    Back pain
         subjects affected / exposed
    5 / 38 (13.16%)
    1 / 11 (9.09%)
    4 / 73 (5.48%)
    3 / 69 (4.35%)
         occurrences all number
    10
    1
    4
    3
    Musculoskeletal pain
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    3 / 73 (4.11%)
    2 / 69 (2.90%)
         occurrences all number
    2
    1
    5
    2
    Neck pain
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    4 / 73 (5.48%)
    1 / 69 (1.45%)
         occurrences all number
    4
    0
    5
    1
    Muscular weakness
         subjects affected / exposed
    6 / 38 (15.79%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    9
    0
    0
    3
    Flank pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    3 / 69 (4.35%)
         occurrences all number
    2
    0
    1
    3
    Bone pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences all number
    2
    0
    4
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Pain in jaw
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    8
    0
    0
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 38 (31.58%)
    2 / 11 (18.18%)
    15 / 73 (20.55%)
    8 / 69 (11.59%)
         occurrences all number
    17
    2
    18
    11
    Hypokalaemia
         subjects affected / exposed
    6 / 38 (15.79%)
    4 / 11 (36.36%)
    13 / 73 (17.81%)
    4 / 69 (5.80%)
         occurrences all number
    8
    5
    27
    5
    Hypomagnesaemia
         subjects affected / exposed
    8 / 38 (21.05%)
    3 / 11 (27.27%)
    8 / 73 (10.96%)
    7 / 69 (10.14%)
         occurrences all number
    16
    3
    9
    8
    Dehydration
         subjects affected / exposed
    7 / 38 (18.42%)
    0 / 11 (0.00%)
    8 / 73 (10.96%)
    3 / 69 (4.35%)
         occurrences all number
    8
    0
    9
    4
    Hyperglycaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    2 / 69 (2.90%)
         occurrences all number
    3
    3
    2
    3
    Hyponatraemia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    4 / 73 (5.48%)
    1 / 69 (1.45%)
         occurrences all number
    1
    1
    4
    1
    Hypophosphataemia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    3 / 73 (4.11%)
    0 / 69 (0.00%)
         occurrences all number
    3
    1
    3
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    2 / 69 (2.90%)
         occurrences all number
    0
    1
    0
    3
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    4
    0
    2
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    11 / 38 (28.95%)
    4 / 11 (36.36%)
    11 / 73 (15.07%)
    4 / 69 (5.80%)
         occurrences all number
    29
    8
    20
    7
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 38 (28.95%)
    4 / 11 (36.36%)
    3 / 73 (4.11%)
    4 / 69 (5.80%)
         occurrences all number
    24
    4
    4
    5
    Sinusitis
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 11 (27.27%)
    1 / 73 (1.37%)
    2 / 69 (2.90%)
         occurrences all number
    10
    3
    1
    2
    Oral candidiasis
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences all number
    4
    0
    2
    1
    Oral herpes
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    2 / 73 (2.74%)
    2 / 69 (2.90%)
         occurrences all number
    4
    0
    2
    2
    Bronchitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    3 / 73 (4.11%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Folliculitis
         subjects affected / exposed
    5 / 38 (13.16%)
    0 / 11 (0.00%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    4 / 73 (5.48%)
    0 / 69 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Cellulitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 73 (1.37%)
    1 / 69 (1.45%)
         occurrences all number
    5
    0
    1
    1
    Influenza
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    2 / 73 (2.74%)
    1 / 69 (1.45%)
         occurrences all number
    0
    1
    2
    1
    Localised infection
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    1 / 73 (1.37%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Catheter site cellulitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin candida
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 73 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2009
    • Changed the study drug from the powder-in-capsule (PIC) to the enteric coated tablet (ECT) formulation • Modified the alisertib dosing schedule from consecutive daily dosing to intermittent dosing • Increase the sample size in phase 1 from 20 to 30, and to decrease the number of study centers in phase 2 from 50 to 30 • Increased the duration of the phase 1 portion from 18 to 22 months, including an increase in the duration of the enrollment period from 6 to 10 months
    15 Nov 2010
    • Specified that subjects in the phase 1 portion could be followed until 110 progression-free survival (PFS) events were achieved in phase 2 • Added antineoplastic therapy as a reason to discontinue treatment with alisertib, paclitaxel, or combination therapy (alisertib + paclitaxel) • Allowed continued protocol treatment up to 24 months
    30 Nov 2010
    • Allowed subjects that could have been maintained on study treatment after disease progression (PD) in selected circumstances and to define the criteria for withdrawing subjects from study treatment
    27 Apr 2012
    • Provided the RP2D for the combination arm in phase 2 as determined from the phase 1 portion of the study

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA