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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-Controlled, Phase 2 Clinical Trial of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC)

    Summary
    EudraCT number
    		 2013-003713-18
    Trial protocol
    		 BE   HU   CZ   ES   DE   IT   PL  
    Global end of trial date
    10 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

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    Trial identification
    Sponsor protocol code
    C14018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02038647
    WHO universal trial number (UTN)
    		 U1111-1154-9805
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Medical Director, Takeda, +1877 8253327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Takeda, +1877 8253327, 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
    10 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 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 determine if the combination treatment can improve progression free survival (defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first) when compared with placebo + paclitaxel.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 May 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 70
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 31
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Spain: 17
    Worldwide total number of subjects
    178
    EEA total number of subjects
    96
    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)
    107
    From 65 to 84 years
    70
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 54 investigative sites in the United States, Canada, European Union (Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland and Spain) from 12 May 2014 to 10 July 2017. Data cutoff for the primary analysis was 3 January 2016.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of Small Cell Lung Cancer (SCLC) were enrolled in 1 of 2 treatment groups: alisertib + paclitaxel or placebo + paclitaxel arm group.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alisertib + Paclitaxel
    Arm description
    		 Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alisertib
    Investigational medicinal product code
    MLN8237
    Other name
    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
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel IV

    Arm title
    		 Placebo + Paclitaxel
    Arm description
    		 Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Alisertib Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alisertib placebo-matching tablets

    Number of subjects in period 1
    		Alisertib + Paclitaxel Placebo + Paclitaxel
    Started
    89
    89
    Completed
    0
    0
    Not completed
    89
    89
         Consent withdrawn by subject
    5
    2
         Not Reported
    -
    1
         Adverse event, non-fatal
    18
    10
         Ongoing at Datacut
    9
    10
         Progressive Disease
    50
    59
         Symptomatic Deterioration
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alisertib + Paclitaxel
    Reporting group description
    		 Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).

    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).

    Reporting group values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel Total
    Number of subjects
    		 89 89 178
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.8 ± 8.55 63.4 ± 8.56 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 38 39 77
        Male
    		 51 50 101
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 2 3 5
        Not Hispanic or Latino
    		 81 84 165
        Unknown or Not Reported
    		 6 1 7
        Missing
    		 0 1 1
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 83 83 166
        Black or African American
    		 3 2 5
        Not reported|
    		 2 2 4
        Asian
    		 1 0 1
        Other
    		 0 1 1
        Missing
    		 0 1 1
    Region of Enrollment
    Units: Subjects
        Belgium|
    		 8 8 16
        Czech Republic|
    		 6 5 11
        France|
    		 7 5 12
        Germany|
    		 2 1 3
        Hungary|
    		 16 15 31
        Italy|
    		 2 0 2
        Poland|
    		 1 3 4
        Spain|
    		 6 11 17
        Canada|
    		 6 6 12
        United States|
    		 35 35 70
    Height
    Data is available only for 86 and 87 participants respectively.
    Units: cm
        arithmetic mean (standard deviation)
    		 169.5 ± 10.43 168.8 ± 9.52 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 78.47 ± 20.561 75.26 ± 17.602 -
    Body Surface Area
    Body surface area=square root of (height [cm]*weight [kg]/3600). Data is available only for 86 and 87 participants respectively.
    Units: m^2
        arithmetic mean (standard deviation)
    		 1.911 ± 0.2829 1.872 ± 0.2433 -

    End points

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    End points reporting groups
    Reporting group title
    Alisertib + Paclitaxel
    Reporting group description
    		 Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).

    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).

    Primary: Progression-Free Survival (PFS) as determined by Investigator, analyzed using FDA Guidelines

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    End point title
    		 Progression-Free Survival (PFS) as determined by Investigator, analyzed using FDA Guidelines
    End point description
    PFS is defined as time in days from start of study treatment to first documentation of objective tumor progression based on Investigator's assessment or up to death due to any cause, whichever occurs first based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Progressive disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Primary
    End point timeframe
    Every cycle for first 6 months and then every 2 months until disease progression or death or up to data cut-off: 03 January 2016 (approximately 22 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    89
    89
    Units: days
        median (confidence interval 95%)
    101 (80 to 113)
    66 (53 to 83)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alisertib + Paclitaxel v Placebo + Paclitaxel
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.113 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.557
         upper limit
    		 1.067
    Notes
    [1] - P-value tests the hypothesis of equal event times in both treatment arms obtained using the Log-rank test stratified by disease subtype as sensitive versus resistant/refractory and the presence of brain metastases.

    Secondary: Percentage of Participants who Experience at least one Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants who Experience at least one Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with treatment. An AE can be any unfavorable and unintended sign (eg, clinically significant abnormal laboratory finding), symptom, or disease temporally associated with use of drug, whether or not it is considered related to drug. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) is any experience that suggests 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 congenital anomaly/birth defect or is medically significant per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
    End point type
    Secondary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication: data cut-off 03 January 2016 (Up to 10.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    87
    89
    Units: percentage of participants
        TEAEs|
    99
    96
        SAEs|
    44
    31
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time in days from the date of randomization to the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    Contact every 2 months after EOT/disease progression until the sooner of death, study closure, or 14 months after the last participant was randomized up to data cut-off: 3 January 2016 (approximately 22 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    89
    89
    Units: days
        median (confidence interval 95%)
    186 (150 to 219)
    165 (128 to 183)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alisertib + Paclitaxel v Placebo + Paclitaxel
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.714 [2]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.652
         upper limit
    		 1.341
    Notes
    [2] - P-value tests the hypothesis of equal event times in both treatment arms obtained using the Log-rank test stratified by disease subtype as sensitive versus resistant/refractory and the presence of brain metastases.

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR is defined as the percentage of participants who achieved CR or partial response (PR) as best response based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    89
    89
    Units: percentage of participants
        number (confidence interval 95%)
    22 (14 to 33)
    18 (11 to 28)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alisertib + Paclitaxel v Placebo + Paclitaxel
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.406 [3]
    Method
    		 Weighted Cochran-Mantel-Haenszel test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.55
    Notes
    [3] - Stratification factors were disease subtypes (sensitive versus resistant/refractory), the presence of brain metastases and region.

    Secondary: Complete Response Rate (CRR)

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    End point title
    		 Complete Response Rate (CRR)
    End point description
    CRR is defined as the percentage of participants who achieved CR as best response and based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    89
    89
    Units: percentage of participants
        number (confidence interval 95%)
    1 (1 to 6)
    0 (0 to 0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alisertib + Paclitaxel v Placebo + Paclitaxel
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.283 [4]
    Method
    		 Weighted Cochran-Mantel-Haenszel test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 9999.99
    Notes
    [4] - Stratification factors were disease subtypes (sensitive versus resistant/refractory), the presence of brain metastases and region.

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR was defined as the percentage of participants who achieved CR, PR, or SD (when SD was a minimum of 8 weeks in duration). Duration of SD was defined as the time from the date of randomization to the date of first documentation of disease progression for participants who achieved SD as their best overall response. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    89
    89
    Units: percentage of participants
        number (confidence interval 95%)
    58 (47 to 69)
    46 (35 to 57)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alisertib + Paclitaxel v Placebo + Paclitaxel
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.077 [5]
    Method
    		 Weighted Cochran-Mantel-Haenszel test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.08
    Notes
    [5] - Stratification factors were disease subtypes (sensitive versus resistant/refractory), the presence of brain metastases and region.

    Secondary: Duration of response (DOR)

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    End point title
    		 Duration of response (DOR)
    End point description
    DOR was defined as the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders. PR was defined as ≥ 30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    From first documented response until disease progression until data cut-off 03 January 2016 (approximately 9.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    20
    16
    Units: days
        median (confidence interval 95%)
    96 (84 to 141)
    85 (58 to 177)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5

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    End point title
    		 Change from Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5
    End point description
    European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions use 7-point scale (1=very poor – 7=Excellent). Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the quality of life (QL) of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology. The change between (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) score collected at Cycle 5 relative to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 5 (approximately 4.6 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    20
    15
    Units: score on a scale
    least squares mean (standard error)
        Change at Cycle 5, QLQ-LC-13 Cough Scale|
    -10.94 ± 3.07
    8.07 ± 6.04
        Change at Cycle 5, QLQ-C30 Dyspnea Scale|
    -3.48 ± 4.25
    -1.09 ± 2.92
        Change at Cycle 5, QLQ-C30 Pain Scale|
    -4.82 ± 4.86
    -4.88 ± 5.16
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Symptom Relief

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    End point title
    		 Percentage of Participants Experiencing Symptom Relief
    End point description
    Percentage of participants experiencing symptom relief, including coughing relief, dyspnea relief, and pain relief. Coughing relief is defined as a decrease from baseline ≥ 10 in QLQ-LC13 cough scale/item score. Dyspnea relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 dyspnea scale/item score. Pain relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales, 1 global health status scale, 3 symptom scales, 6 single items. Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the QL of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    89
    89
    Units: percentage of participants
    number (confidence interval 95%)
        Coughing Relief|
    28 (19 to 39)
    24 (15 to 34)
        Dyspnea Relief|
    31 (22 to 42)
    16 (9 to 25)
        Pain Relief|
    39 (29 to 50)
    36 (26 to 47)
    No statistical analyses for this end point

    Secondary: Time to Symptom Relief

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    End point title
    		 Time to Symptom Relief
    End point description
    Time to symptom (coughing/dyspnea/pain) relief was defined as the time from the date of randomization to the date of first detection of coughing/dyspnea/pain relief, respectively. Here, 9999=Not Estimable as median was not reached due to low number of participants with events and 99999= Not Estimable as upper limit of CI was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    89
    89
    Units: months
    median (confidence interval 95%)
        Time to Coughing Relief|
    9999 (7.6 to 9999)
    9999 (9999 to 9999)
        Time to Dyspnea Relief|
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Time to Pain Relief|
    3.0 (1.9 to 99999)
    3.7 (1.1 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Symptom Progression

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    End point title
    		 Time to Symptom Progression
    End point description
    Time to coughing/dyspnea/pain progression (prg) was time from the date of randomization to first detection of prg.Coughing prg was rise from baseline≥10 in QLQ-LC13 cough scale (scl) score.Dyspnea prg was rise from baseline≥10 in QLQ-C30 dyspnea scl score.Pain prg was rise from baseline≥10 in QLQ-C30 pain scl score.EORTC QLQ-C30 is 30-item questionnaire with 5 functional scls (physical,role,emotional,cognitive,social),1global health status scl,3symptom (symp)scls(fatigue,nausea,vomiting,pain),6single items(dyspnea,insomnia,appetite loss,constipation,diarrhea,financial difficulties).The QLQ-LC13 is 13-item scl for rate treatment-specific symps in lung cancer.Total Score= 0-100 scl; for 5 functional and global quality-of-life scl,higher score=better level of functioning and same for symps scl.Here, 9999=Not Estimable (NE) as median was not reached due to low number of participants with events,99999= NE as upper limit of CI was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    89
    89
    Units: months
    median (confidence interval 95%)
        Time to Coughing Progression|
    9999 (9999 to 9999)
    2.8 (2.2 to 6.3)
        Time to Dyspnea Progression|
    3.7 (1.9 to 99999)
    4.6 (1.9 to 6.3)
        Time to Pain Progression|
    2.9 (2.1 to 99999)
    2.8 (1.9 to 99999)
    No statistical analyses for this end point

    Secondary: Observed Plasma Concentration for Alisertib and Paclitaxel

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    End point title
    		 Observed Plasma Concentration for Alisertib and Paclitaxel
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose and at multiple timepoints (up to 11 hours) post-dose; Day 8, 2 hours post-dose; Day 15, 1 hour pre-dose
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: nM
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [6] - Less PK sampling planned for alisertib PK,exposure-response analysis not done due to program status
    [7] - Less PK sampling planned for alisertib PK,exposure-response analysis not done due to program status
    No statistical analyses for this end point

    Secondary: Health Related Quality of Life (HRQOL )

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    End point title
    		 Health Related Quality of Life (HRQOL )
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [8] - Due to change in planned analysis, data was not analyzed for this outcome measure.
    [9] - Due to change in planned analysis, data was not analyzed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Biomarker Correlative Studies including Circulating Tumor Cells and Circulating DNA Assessments

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    End point title
    		 Biomarker Correlative Studies including Circulating Tumor Cells and Circulating DNA Assessments
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 cycle 1 in a 28-day cycle
    End point values
    		 Alisertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: percentage of participants
        number (not applicable)
    Notes
    [10] - Due to change in planned analysis, data was not analyzed for this outcome measure.
    [11] - Due to change in planned analysis, data was not analyzed for this outcome measure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days)
    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 participant 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
    15.0
    Reporting groups
    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).

    Reporting group title
    Alisertib + Paclitaxel
    Reporting group description
    		 Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).

    Serious adverse events
    		 Placebo + Paclitaxel Alisertib + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 89 (33.71%)
    39 / 87 (44.83%)
         number of deaths (all causes)
    11
    12
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Small cell lung cancer
    Additional description: Four treatment-emergent deaths occurred during treatment in Placebo + Paclitaxel arm group and are not related with study drug.
         subjects affected / exposed
    6 / 89 (6.74%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
    Additional description: Two treatment-emergent deaths occurred during treatment in Alisertib+ Paclitaxel arm group and are not related with study drug.
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Glioblastoma
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic thrombosis
    Additional description: One treatment-emergent death occurred during treatment in Alisertib + Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Embolism
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
    Additional description: One treatment-emergent death occurred during treatment in Placebo + Paclitaxel arm group and two treatment-emergent deaths occurred during treatment in Alisertib + Paclitaxel arm group and are not related with study drug.
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 87 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Fatigue
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
    Additional description: Two treatment-emergent death occurred during treatment in Alisertib+ Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    0 / 89 (0.00%)
    3 / 87 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute respiratory failure
    Additional description: One treatment-emergent death occurred during treatment in Placebo + Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
    Additional description: One treatment-emergent death occurred during treatment in Placebo + Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
    Additional description: One treatment-emergent death occurred during treatment in Alisertib + Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
    Additional description: One treatment-emergent death occurred during treatment in Alisertib + Paclitaxel arm group and is related with study drug.
         subjects affected / exposed
    0 / 89 (0.00%)
    9 / 87 (10.34%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 12
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenia
         subjects affected / exposed
    0 / 89 (0.00%)
    5 / 87 (5.75%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
    Additional description: One treatment-emergent death occurred during treatment in Placebo + Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 89 (0.00%)
    5 / 87 (5.75%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 89 (1.12%)
    4 / 87 (4.60%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Neutropenic sepsis
    Additional description: One treatment-emergent death occurred during treatment in Alisertib + Paclitaxel arm group and is related with study drug.
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bacteraemia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    Additional description: One treatment-emergent death occurred during treatment in Alisertib + Paclitaxel arm group and is related with study drug.
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Septic shock
    Additional description: One treatment-emergent death occurred during treatment in Alisertib + Paclitaxel arm group and is related with study drug.
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia
    Additional description: One treatment-emergent death occurred during treatment in Placebo + Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 87 (3.45%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
    Additional description: One treatment-emergent death occurred during treatment in Placebo + Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: One treatment-emergent death occurred during treatment in Placebo + Paclitaxel arm group and is not related with study drug.
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Paclitaxel Alisertib + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 89 (89.89%)
    85 / 87 (97.70%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 89 (12.36%)
    5 / 87 (5.75%)
         occurrences all number
    13
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    28 / 89 (31.46%)
    38 / 87 (43.68%)
         occurrences all number
    35
    52
    Asthenia
         subjects affected / exposed
    11 / 89 (12.36%)
    14 / 87 (16.09%)
         occurrences all number
    16
    32
    Oedema peripheral
         subjects affected / exposed
    10 / 89 (11.24%)
    6 / 87 (6.90%)
         occurrences all number
    14
    7
    Pyrexia
         subjects affected / exposed
    6 / 89 (6.74%)
    8 / 87 (9.20%)
         occurrences all number
    7
    8
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 87 (4.60%)
         occurrences all number
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    19 / 89 (21.35%)
    21 / 87 (24.14%)
         occurrences all number
    22
    23
    Cough
         subjects affected / exposed
    17 / 89 (19.10%)
    17 / 87 (19.54%)
         occurrences all number
    18
    19
    Productive cough
         subjects affected / exposed
    9 / 89 (10.11%)
    4 / 87 (4.60%)
         occurrences all number
    12
    4
    Epistaxis
         subjects affected / exposed
    7 / 89 (7.87%)
    3 / 87 (3.45%)
         occurrences all number
    10
    3
    Dysphonia
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 87 (5.75%)
         occurrences all number
    3
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 89 (7.87%)
    7 / 87 (8.05%)
         occurrences all number
    8
    7
    Confusional state
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 87 (2.30%)
         occurrences all number
    5
    2
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    4 / 89 (4.49%)
    14 / 87 (16.09%)
         occurrences all number
    4
    28
    Weight decreased
         subjects affected / exposed
    5 / 89 (5.62%)
    13 / 87 (14.94%)
         occurrences all number
    7
    18
    White blood cell count decreased
         subjects affected / exposed
    1 / 89 (1.12%)
    12 / 87 (13.79%)
         occurrences all number
    4
    20
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 87 (5.75%)
         occurrences all number
    4
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 89 (10.11%)
    15 / 87 (17.24%)
         occurrences all number
    14
    17
    Headache
         subjects affected / exposed
    6 / 89 (6.74%)
    9 / 87 (10.34%)
         occurrences all number
    7
    9
    Neuropathy peripheral
         subjects affected / exposed
    7 / 89 (7.87%)
    8 / 87 (9.20%)
         occurrences all number
    10
    10
    Paraesthesia
         subjects affected / exposed
    6 / 89 (6.74%)
    4 / 87 (4.60%)
         occurrences all number
    9
    5
    Hypoaesthesia
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 87 (4.60%)
         occurrences all number
    6
    5
    Somnolence
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 87 (5.75%)
         occurrences all number
    3
    6
    Dysgeusia
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 87 (2.30%)
         occurrences all number
    5
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 89 (20.22%)
    38 / 87 (43.68%)
         occurrences all number
    23
    55
    Neutropenia
         subjects affected / exposed
    7 / 89 (7.87%)
    41 / 87 (47.13%)
         occurrences all number
    11
    89
    Leukopenia
         subjects affected / exposed
    5 / 89 (5.62%)
    12 / 87 (13.79%)
         occurrences all number
    8
    18
    Thrombocytopenia
         subjects affected / exposed
    3 / 89 (3.37%)
    7 / 87 (8.05%)
         occurrences all number
    3
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    18 / 89 (20.22%)
    48 / 87 (55.17%)
         occurrences all number
    32
    104
    Nausea
         subjects affected / exposed
    30 / 89 (33.71%)
    30 / 87 (34.48%)
         occurrences all number
    38
    43
    Vomiting
         subjects affected / exposed
    19 / 89 (21.35%)
    28 / 87 (32.18%)
         occurrences all number
    27
    45
    Stomatitis
         subjects affected / exposed
    6 / 89 (6.74%)
    27 / 87 (31.03%)
         occurrences all number
    7
    49
    Constipation
         subjects affected / exposed
    21 / 89 (23.60%)
    8 / 87 (9.20%)
         occurrences all number
    25
    11
    Abdominal pain
         subjects affected / exposed
    3 / 89 (3.37%)
    12 / 87 (13.79%)
         occurrences all number
    4
    13
    Abdominal pain upper
         subjects affected / exposed
    6 / 89 (6.74%)
    7 / 87 (8.05%)
         occurrences all number
    6
    9
    Dyspepsia
         subjects affected / exposed
    4 / 89 (4.49%)
    8 / 87 (9.20%)
         occurrences all number
    4
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 89 (5.62%)
    5 / 87 (5.75%)
         occurrences all number
    5
    7
    Dysphagia
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 87 (5.75%)
         occurrences all number
    3
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 89 (5.62%)
    14 / 87 (16.09%)
         occurrences all number
    5
    15
    Rash maculo-papular
         subjects affected / exposed
    6 / 89 (6.74%)
    0 / 87 (0.00%)
         occurrences all number
    10
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 89 (5.62%)
    9 / 87 (10.34%)
         occurrences all number
    10
    12
    Muscular weakness
         subjects affected / exposed
    6 / 89 (6.74%)
    6 / 87 (6.90%)
         occurrences all number
    11
    6
    Back pain
         subjects affected / exposed
    6 / 89 (6.74%)
    5 / 87 (5.75%)
         occurrences all number
    9
    8
    Musculoskeletal pain
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 87 (4.60%)
         occurrences all number
    5
    4
    Pain in extremity
         subjects affected / exposed
    5 / 89 (5.62%)
    3 / 87 (3.45%)
         occurrences all number
    7
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    6 / 89 (6.74%)
    0 / 87 (0.00%)
         occurrences all number
    8
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 87 (2.30%)
         occurrences all number
    5
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 89 (21.35%)
    29 / 87 (33.33%)
         occurrences all number
    26
    36
    Hypokalaemia
         subjects affected / exposed
    6 / 89 (6.74%)
    10 / 87 (11.49%)
         occurrences all number
    7
    12
    Dehydration
         subjects affected / exposed
    4 / 89 (4.49%)
    7 / 87 (8.05%)
         occurrences all number
    5
    8
    Hypomagnesaemia
         subjects affected / exposed
    6 / 89 (6.74%)
    5 / 87 (5.75%)
         occurrences all number
    10
    5
    Hypocalcaemia
         subjects affected / exposed
    1 / 89 (1.12%)
    7 / 87 (8.05%)
         occurrences all number
    1
    7
    Hyperglycaemia
         subjects affected / exposed
    1 / 89 (1.12%)
    5 / 87 (5.75%)
         occurrences all number
    1
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2014
    The key purposes of Amendment 1 were to: • Modify and clarify the dose modification rules when managing hematologic or non-hematologic toxicities. • Remove the restrictions for 5-hydroxytryptamine 3 receptor antagonists. • Indicate that the dose could be reduced, if indicated, for participants who experienced sedation. • Increase the approximate number of study sites to be used in the study. • Add inclusion criterion 7 to allow participants requiring full systemic anticoagulation. • Modify inclusion criterion 12 regarding suitable venous access to remove reference to comparator arm. • Modify exclusion criterion 3 regarding prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent. • Modify exclusion criterion 12 regarding diagnosis with another malignancy before the first dose of study drug. • Modify exclusion criterion 16 regarding infection to provide further definition. • Update language regarding the use of prophylactic antiemetic agents. • Update medical history to include disease stage and smoking history. • Update the extent of disease evaluation to include brain magnetic resonance imaging (MRI) with intravenous (IV) contrast (preferred) or computed tomography (CT) scan with IV contrast to be completed within 28 days before receiving the first dose of alisertib/placebo, irrespective of symptoms.
    23 Jan 2015
    The key purposes of Amendment 2 were to: •Clarify the definition of patient response to first-line chemotherapy. •Provide dose adjustment guidance for management of oral mucositis. •Add strong and moderate cytochrome P450 3A4 (CYP3A) inhibitors to list of excluded concomitant medications. •Remove collection of blood sample for profiling deoxyribonucleic acid (DNA) from circulating tumor cell (CTC), clarify that ctDNA samples would be used for biomarker assessment, and add blood sample collection for genomic DNA genetic characterization. •Remove “legal representative” as a potential party who may provide informed consent on behalf of participant. •Add text regarding requirement for treatment-specific pregnancy prevention guidelines for paclitaxel. •Update exclusion criterion restricting proton pump inhibitor (PPI) use to within 5 days prior to the first dose of study drug to maintain consistency in the restriction across alisertib clinical trials. •Update exclusion criteria regarding cardiovascular conditions and thromboembolic events. •Update exclusion criterion to exclude patients who had radiation therapy within the 2 weeks before study enrollment and had not fully recovered to stable clinical status. •Remove redundant information regarding the continuation of patients on study treatment following completion of the trial. •Remove the restriction of a maximum dose of diphenhydramine that was permitted for use as a premedication for paclitaxel-associated reactions. •Correct a typographical error in the dose modification rules regarding a repeat occurrence of hematologic toxicity after dosing for Arm A to indicate that alisertib dosing should remain the same for Days 1-3 and 8-10. •Indicate that patients were permitted to continue receiving study drug in cases where treatment assignment was inadvertently revealed. •Add collection of sparse paclitaxel pharmacokinetic (PK) samples to contribute to population PK analysis, and clarify timing of PK measurements.

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

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