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    Clinical Trial Results:
    A Phase 1 Dose Escalation Study of MLN8237, an Aurora A Kinase Inhibitor, in Adult Patients With Nonhematological Malignancies, Followed by a Phase 2 of MLN8237 in Lung, Breast, Head and Neck, or Gastroesophageal Malignancies.

    Summary
    EudraCT number
    2008-006981-27
    Trial protocol
    CZ  
    Global end of trial date
    25 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C14007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01045421
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Millennium Pharmaceuticals, Inc
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, United States, 02139
    Public contact
    Drug Information Call Center, Millennium Pharmaceuticals, Inc, 001 5107402412, medical@mlnm.com
    Scientific contact
    Drug Information Call Center, Millennium Pharmaceuticals, Inc, 001 5107402412, medical@mlnm.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
    13 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 1: The primary objective of the phase 1 portion of this study is to assess the safety and tolerability of MLN8237, formulated as an enteric-coated tablet (ECT), on a 7-day dosing schedule for determining the recommended dose and schedule of MLN8237 to be used in phase 2. Phase 2: The primary objective of the phase 2 portion of this study is to estimate the antitumor activity of MLN8237 as measured by overall response rate (ORR) in patients with advanced, unresectable nonhematological malignancies (NSCLC, SCLC, adenocarcinoma of the breast, HNSCC, or adenocarcinoma of the esophagus/gastroesophageal junction or stomach).
    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 Feb 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 155
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Czech Republic: 69
    Country: Number of subjects enrolled
    France: 40
    Worldwide total number of subjects
    273
    EEA total number of subjects
    118
    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)
    180
    From 65 to 84 years
    92
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 42 investigative sites in France, Poland, the Czech Republic, and the United States from 16 February 2010 to 25 April 2014.

    Pre-assignment
    Screening details
    Subjects with a historical diagnosis of relapsed or refractory advanced nonhematological malignancies were enrolled in 1 of the 2 stages, Phase 1 (lead-in alisertib dose escalation stage) and Phase 2 (efficacy and safety assessment stage for alisertib dose determined in Phase 1).

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase 1: MLN8237 10 mg
    Arm description
    MLN8237 (alisertib) 10 milligram (mg), enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 10 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 1: MLN8237 20 mg
    Arm description
    MLN8237 (alisertib) 20 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 20 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 1: MLN8237 40 mg
    Arm description
    MLN8237 (alisertib) 40 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 40 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 40 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 1: MLN8237 50 mg
    Arm description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 1: MLN8237 60 mg
    Arm description
    MLN8237 (alisertib) 60 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 60 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 60 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 1: MLN8237 50 mg- Pancreatic Cancer
    Arm description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with pancreatic cancer during Phase 1 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 2: MLN8237 50 mg- Breast Cancer
    Arm description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with breast cancer during Phase 2 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 2: MLN8237 50 mg- Gastric Cancer
    Arm description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with gastric cancer during Phase 2 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 2: MLN8237 50 mg- HNSCC
    Arm description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with head and neck squamous cell carcinoma (HNSCC) during Phase 2 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 2: MLN8237 50 mg- NSCLC
    Arm description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with non-small cell lung cancer (NSCLC) during Phase 2 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Arm title
    Phase 2: MLN8237 50 mg- SCLC
    Arm description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with small cell lung cancer (SCLC) during Phase 2 portion of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN8237 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy.

    Number of subjects in period 1
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg Phase 1: MLN8237 60 mg Phase 1: MLN8237 50 mg- Pancreatic Cancer Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Started
    1
    3
    4
    12
    3
    1
    53
    55
    55
    26
    60
    Completed
    1
    3
    4
    11
    2
    1
    53
    50
    53
    23
    58
    Not completed
    0
    0
    0
    1
    1
    0
    0
    5
    2
    3
    2
         Death
    -
    -
    -
    -
    -
    -
    -
    1
    1
    2
    -
         Other
    -
    -
    -
    -
    -
    -
    -
    3
    -
    -
    1
         Progressive Disease
    -
    -
    -
    -
    1
    -
    -
    1
    1
    1
    1
         Consent withdrawn by subject
    -
    -
    -
    1
    -
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    Included all subjects enrolled in this study.

    Reporting group values
    Overall Trial Total
    Number of subjects
    273 273
    Age categorical
    Units: Subjects
        18-64 years
    180 180
        65-84 years
    92 92
        85 years and over
    1 1
    Gender categorical
    Units: Subjects
        Female
    117 117
        Male
    156 156
    Race/Ethnicity
    Units: Subjects
        Hispanic or Latino
    12 12
        Not Hispanic or Latino
    248 248
        Not reported
    13 13
    Race/Ethnicity
    Units: Subjects
        White
    249 249
        Black or African American
    15 15
        Asian
    4 4
        Chinese
    1 1
        Other
    1 1
        Not reported
    3 3
    Region of Enrollment
    Units: Subjects
        Czech Republic
    69 69
        France
    40 40
        Poland
    9 9
        United States
    155 155
    Disease stage at study entry
    Units: Subjects
        IA
    1 1
        II
    1 1
        III
    4 4
        IIIA
    3 3
        IIIB
    10 10
        IIIC
    1 1
        IV
    201 201
        IVA
    24 24
        IVB
    3 3
        IVC
    25 25
    Eastern Cooperative Oncology Group (ECOG) performance status
    ECOG performance status assesses a subject's physical ability on a 6-point scale: 0=fully active, able to carry on all predisease activities without restriction; 1=restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead.
    Units: Subjects
        0= Fully Active
    85 85
        1= Restricted Activity
    188 188
    Subject analysis sets

    Subject analysis set title
    Phase 1: MLN8237- All Subjects
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 10, 20, 30, 40, 50, or 60 mg enteric-coated tablets, orally, twice daily, for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects enrolled in dose-escalation or pancreatic cancer cohort during Phase 1 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- Breast Cancer
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with breast cancer during Phase 2 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- Gastric Cancer
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with gastric cancer during Phase 2 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- HNSCC
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with HNSCC during Phase 2 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- NSCLC
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with NSCLC during Phase 2 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- SCLC
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with SCLC during Phase 2 portion of the study.

    Subject analysis set title
    Phase 1: MLN8237 50 mg (Including Pancreatic Cancer)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study. Included subjects from dose-escalation cohort or pancreatic cancer cohort who received alisertib 50 mg twice daily.

    Subject analysis set title
    Phase 1: MLN8237 60 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 60 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.

    Subject analysis sets values
    Phase 1: MLN8237- All Subjects Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC Phase 1: MLN8237 50 mg (Including Pancreatic Cancer) Phase 1: MLN8237 60 mg
    Number of subjects
    24
    53
    55
    55
    26
    60
    13
    3
    Age categorical
    Units: Subjects
        18-64 years
    17
    37
    33
    38
    17
    38
        65-84 years
    7
    16
    21
    17
    9
    22
        85 years and over
    0
    0
    1
    0
    0
    0
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    9
    53
    12
    3
    12
    28
        Male
    15
    0
    43
    52
    14
    32
    Race/Ethnicity
    Units: Subjects
        Hispanic or Latino
    3
    4
    2
    1
    1
    1
        Not Hispanic or Latino
    19
    48
    49
    50
    25
    57
        Not reported
    2
    1
    4
    4
    0
    2
    Race/Ethnicity
    Units: Subjects
        White
    18
    49
    51
    53
    22
    56
        Black or African American
    3
    1
    3
    2
    2
    4
        Asian
    2
    1
    0
    0
    1
    0
        Chinese
    0
    0
    0
    0
    1
    0
        Other
    0
    1
    0
    0
    0
    0
        Not reported
    1
    1
    1
    0
    0
    0
    Region of Enrollment
    Units: Subjects
        Czech Republic
    0
    19
    20
    8
    7
    15
        France
    0
    10
    8
    11
    3
    8
        Poland
    0
    1
    0
    1
    0
    7
        United States
    24
    23
    27
    35
    16
    30
    Disease stage at study entry
    Units: Subjects
        IA
    1
    0
    0
    0
    0
    0
        II
    0
    0
    0
    1
    0
    0
        III
    1
    0
    1
    2
    0
    0
        IIIA
    1
    1
    0
    0
    0
    1
        IIIB
    0
    3
    0
    0
    5
    2
        IIIC
    0
    1
    0
    0
    0
    0
        IV
    19
    48
    54
    2
    21
    57
        IVA
    1
    0
    0
    23
    0
    0
        IVB
    1
    0
    0
    2
    0
    0
        IVC
    0
    0
    0
    25
    0
    0
    Eastern Cooperative Oncology Group (ECOG) performance status
    ECOG performance status assesses a subject's physical ability on a 6-point scale: 0=fully active, able to carry on all predisease activities without restriction; 1=restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead.
    Units: Subjects
        0= Fully Active
    4
    23
    21
    17
    7
    13
        1= Restricted Activity
    20
    30
    34
    38
    19
    47

    End points

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    End points reporting groups
    Reporting group title
    Phase 1: MLN8237 10 mg
    Reporting group description
    MLN8237 (alisertib) 10 milligram (mg), enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.

    Reporting group title
    Phase 1: MLN8237 20 mg
    Reporting group description
    MLN8237 (alisertib) 20 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.

    Reporting group title
    Phase 1: MLN8237 40 mg
    Reporting group description
    MLN8237 (alisertib) 40 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.

    Reporting group title
    Phase 1: MLN8237 50 mg
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.

    Reporting group title
    Phase 1: MLN8237 60 mg
    Reporting group description
    MLN8237 (alisertib) 60 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.

    Reporting group title
    Phase 1: MLN8237 50 mg- Pancreatic Cancer
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with pancreatic cancer during Phase 1 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- Breast Cancer
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with breast cancer during Phase 2 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- Gastric Cancer
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with gastric cancer during Phase 2 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- HNSCC
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with head and neck squamous cell carcinoma (HNSCC) during Phase 2 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- NSCLC
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with non-small cell lung cancer (NSCLC) during Phase 2 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- SCLC
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with small cell lung cancer (SCLC) during Phase 2 portion of the study.

    Subject analysis set title
    Phase 1: MLN8237- All Subjects
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 10, 20, 30, 40, 50, or 60 mg enteric-coated tablets, orally, twice daily, for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects enrolled in dose-escalation or pancreatic cancer cohort during Phase 1 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- Breast Cancer
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with breast cancer during Phase 2 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- Gastric Cancer
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with gastric cancer during Phase 2 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- HNSCC
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with HNSCC during Phase 2 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- NSCLC
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with NSCLC during Phase 2 portion of the study.

    Subject analysis set title
    Phase 2: MLN8237 50 mg- SCLC
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with SCLC during Phase 2 portion of the study.

    Subject analysis set title
    Phase 1: MLN8237 50 mg (Including Pancreatic Cancer)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study. Included subjects from dose-escalation cohort or pancreatic cancer cohort who received alisertib 50 mg twice daily.

    Subject analysis set title
    Phase 1: MLN8237 60 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    MLN8237 (alisertib) 60 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy during Phase 1 portion of the study.

    Primary: Phase 1: Number of Subjects With Dose-Limiting Toxicities (DLTs)

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    End point title
    Phase 1: Number of Subjects With Dose-Limiting Toxicities (DLTs) [1] [2]
    End point description
    Toxicity as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)v4.0.DLT=any of the following considered drug-related by investigator:Grade 4 (G4) neutropenia (absolute neutrophil count <500 cells/cubic meter [cells/mm^3]) for >7 days;G4 neutropenia with coincident fever;G4 thrombocytopenia for >7 days;Platelet count <10,000 cells/mm3;G3 thrombocytopenia, clinically significant bleeding;Delay in initiation of next cycle by >7 days due to treatment-related toxicity;>=G3 nonhematological toxicity except >=G3 nausea/emesis occurred in the absence of optimal antiemetic therapy;>=G3 diarrhea occurred in the absence of optimal supportive therapy with loperamide/comparable antidiarrheal;G3 fatigue for <1 week;Other G3 nonhematological toxicity that were safely,reliably controlled to <=G2 with treatment.DLT-Evaluable population:Phase 1 subjects who experienced DLT in Cycle 1/completed >=85% of planned alisertib doses,had sufficient follow-up data for DLT.
    End point type
    Primary
    End point timeframe
    Cycle 1 of Phase 1
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical comparison was not planned to be reported for this outcome.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: DLTs were planned to be analyzed for only the Phase 1 portion of the study.
    End point values
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg Phase 1: MLN8237 60 mg Phase 1: MLN8237 50 mg- Pancreatic Cancer
    Number of subjects analysed
    1
    3
    4
    12
    3
    1
    Units: subjects
    0
    0
    0
    2
    0
    0
    No statistical analyses for this end point

    Primary: Phase 2: Percentage of Subjects With Objective Response

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    End point title
    Phase 2: Percentage of Subjects With Objective Response [3] [4]
    End point description
    Percentage of subjects with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeter [mm]). No new lesions. PR was defined as greater than or equal to (>=) 30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Response-Evaluable population included all subjects with measurable disease who received at least 1 dose of alisertib and had at least 1 post-baseline response assessment.
    End point type
    Primary
    End point timeframe
    Baseline until complete response or partial response, assessed every 2 cycles up to end of study (up to 50 cycles)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical comparison was not planned to be reported for this outcome.
    [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: Tumor assessment was planned to be performed for only the Phase 2 portion of the study.
    End point values
    Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Number of subjects analysed
    49
    47
    45
    23
    48
    Units: percentage of subjects
        number (confidence interval 95%)
    18 (9 to 32)
    9 (2 to 20)
    9 (2 to 21)
    4 (0 to 22)
    21 (10 to 35)
    No statistical analyses for this end point

    Secondary: Phase 2: Progression-free Survival (PFS)

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    End point title
    Phase 2: Progression-free Survival (PFS) [5]
    End point description
    PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. Tumor progression as per RECIST 1.1 was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1or more new lesions is also considered progression. Safety population included all subjects who received any amount of alisertib.
    End point type
    Secondary
    End point timeframe
    Baseline until progressive disease, assessed every 2 cycles up to end of study (up to 50 cycles)
    Notes
    [5] - 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: Tumor assessment was planned to be performed for only the Phase 2 portion of the study.
    End point values
    Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Number of subjects analysed
    53
    55
    55
    26
    60
    Units: days
        median (confidence interval 95%)
    164 (78 to 239)
    49 (41 to 78)
    72 (43 to 96)
    92 (72 to 120)
    49 (42 to 96)
    No statistical analyses for this end point

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

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    End point title
    Phase 2: Time to Disease Progression (TTP) [6]
    End point description
    Time in days from start of study treatment to first documentation of objective tumor progression. Tumor progression as per RECIST 1.1 was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1or more new lesions is also considered progression. Safety population included all subjects who received any amount of alisertib.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression, assessed every 2 cycles up to end of study (up to 50 cycles)
    Notes
    [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: Tumor assessment was planned to be performed for only the Phase 2 portion of the study.
    End point values
    Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Number of subjects analysed
    53
    55
    55
    26
    60
    Units: days
        median (confidence interval 95%)
    164 (78 to 239)
    46 (40 to 86)
    72 (43 to 96)
    92 (74 to 144)
    78 (42 to 114)
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response (DOR)

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    End point title
    Phase 2: Duration of Response (DOR) [7]
    End point description
    Time in days from first documentation of objective tumor response to objective tumor progression/death due to any cancer. Duration of tumor response=(date of first documentation of objective tumor progression or death due to cancer minus date of first CR/PR that was subsequently confirmed plus 1).CR: complete disappearance of all target lesions, non-target disease, except nodal disease;all nodes decreased to normal; no new lesions.PR:>=30% decrease under baseline of sum of diameters of all target lesions; no unequivocal progression of non-target disease; no new lesions. Tumor progression: >=20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study; absolute increase of >=5 mm; appearance of >=1 new lesions is also considered progression. A subset of response-evaluable population who had objective tumor response. ‘+/-99999’ in median and 95% CI=not estimable as the 1 participant in the group was censored.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 50
    Notes
    [7] - 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: Tumor assessment was planned to be performed for only the Phase 2 portion of the study.
    End point values
    Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Number of subjects analysed
    9
    4
    4
    1
    10
    Units: days
        median (confidence interval 95%)
    169 (85 to 313)
    198 (146 to 501)
    79 (46 to 95)
    99999 (-99999 to 99999)
    125 (93 to 365)
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Subjects Reporting One or More Treatment-emergent Adverse Events and Serious Adverse Events

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    End point title
    Phase 2: Number of Subjects Reporting One or More Treatment-emergent Adverse Events and Serious Adverse Events [8]
    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. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. Safety population included all subjects who received any amount of alisertib.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after the last dose of study drug
    Notes
    [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: This secondary outcome was planned to be summarized only for Phase 2 portion of the study.
    End point values
    Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Number of subjects analysed
    53
    55
    55
    26
    60
    Units: subjects
        Adverse Events
    52
    52
    54
    26
    57
        Serious Adverse Events
    23
    30
    19
    8
    28
    No statistical analyses for this end point

    Secondary: Phase 1: Cmax- Maximum Observed Plasma Concentration for Alisertib

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    End point title
    Phase 1: Cmax- Maximum Observed Plasma Concentration for Alisertib [9]
    End point description
    Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Pharmacokinetic (PK)-Evaluable population included all subjects who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Days 1 and 7 assessment were available. '99999' in geometric coefficient of variation (CV) signifies not available. For Phase 1, MLN8237 10 mg group, geometric CV was not estimable as only 1 subject was evaluable for this group. In addition, geometric CV was not estimated if evaluable participants were less than 3, as per investigator's discretion.
    End point type
    Secondary
    End point timeframe
    Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours post-dose
    Notes
    [9] - 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: PK parameters were planned to be analyzed for only the Phase 1 portion of the study.
    End point values
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg (Including Pancreatic Cancer) Phase 1: MLN8237 60 mg
    Number of subjects analysed
    1
    3
    4
    13
    3
    Units: nanomole (nM)
    geometric mean (geometric coefficient of variation)
        Day 1 (n = 1, 3, 4, 13, 3)
    297 ± 99999
    602 ± 15
    949 ± 49
    1619 ± 39
    1696 ± 37
        Day 7 (n = 1, 3, 3, 12, 2)
    981 ± 99999
    1279 ± 35
    1830 ± 39
    2907 ± 49
    3027 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1: Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib

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    End point title
    Phase 1: Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib [10]
    End point description
    Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. PK-Evaluable population included all subjects who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Day 1 and Day 7 assessment were available. '99999' in full range signifies not available. Full range was not summarized if evaluable participants were less than 3, as per investigator's discretion.
    End point type
    Secondary
    End point timeframe
    Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
    Notes
    [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: PK parameters were planned to be analyzed for only the Phase 1 portion of the study.
    End point values
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg (Including Pancreatic Cancer) Phase 1: MLN8237 60 mg
    Number of subjects analysed
    1
    3
    4
    13
    3
    Units: hours
    median (full range (min-max))
        Day 1 (n = 1, 3, 4, 13, 3)
    2.9 (2.9 to 2.9)
    2 (2 to 2.9)
    3.2 (2.8 to 6)
    2.2 (1.7 to 11)
    6 (3 to 7.9)
        Day 7 (n = 1, 3, 3, 12, 2)
    3.1 (3.1 to 3.1)
    3 (1 to 6)
    3 (2 to 6)
    2.4 (0 to 8)
    2.8 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 1: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib

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    End point title
    Phase 1: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib [11]
    End point description
    Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval. PK-Evaluable population included all subjects who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Days 1 and 7 assessment were available. '99999' in geometric CV signifies not available. For Phase 1, MLN8237 10 mg group, geometric CV was not estimable as only 1 subject was evaluable for this group. In addition, geometric CV was not estimated if evaluable participants were less than 3, as per investigator's discretion.
    End point type
    Secondary
    End point timeframe
    Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
    Notes
    [11] - 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: PK parameters were planned to be analyzed for only the Phase 1 portion of the study.
    End point values
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg (Including Pancreatic Cancer) Phase 1: MLN8237 60 mg
    Number of subjects analysed
    1
    3
    4
    13
    3
    Units: nanomole*hour (nM*hr)
    geometric mean (geometric coefficient of variation)
        Day 1 (n = 1, 3, 4, 13, 3)
    2640 ± 99999
    3495 ± 19
    5015 ± 57
    10736 ± 48
    13932 ± 42
        Day 7 (n = 1, 3, 3, 11, 2)
    8660 ± 99999
    10184 ± 24
    13694 ± 59
    20867 ± 49
    28709 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1: Terminal Phase Elimination Half-life (T1/2) for Alisertib

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    End point title
    Phase 1: Terminal Phase Elimination Half-life (T1/2) for Alisertib [12]
    End point description
    Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. PK-Evaluable population included all subjects who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Day 7 assessment was available. '99999' in standard deviation signifies not available. For Phase 1, MLN8237 10 mg group, standard deviation was not estimable as only 1 subject was evaluable for this group. In addition, standard deviation was not estimated if evaluable participants were less than 3, as per investigator's discretion.
    End point type
    Secondary
    End point timeframe
    Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
    Notes
    [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: PK parameters were planned to be analyzed for only the Phase 1 portion of the study.
    End point values
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg (Including Pancreatic Cancer) Phase 1: MLN8237 60 mg
    Number of subjects analysed
    1
    3
    2
    9
    2
    Units: hours
        arithmetic mean (standard deviation)
    20.6 ± 99999
    16 ± 1.2
    19 ± 99999
    20.8 ± 10.3
    27.8 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1: Rac- Accumulation Ratio for Alisertib

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    End point title
    Phase 1: Rac- Accumulation Ratio for Alisertib [13]
    End point description
    Rac was estimated as a ratio of AUC (0-tau) at Day 7 and AUC (0-tau) at Day 1. Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.PK-Evaluable population included all subjects who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Days 1 and 7 assessment were available. '99999' in standard deviation signifies not available. For Phase 1, MLN8237 10 mg group, standard deviation was not estimable as only 1 subject was evaluable for this group. In addition, standard deviation was not estimated if evaluable participants were less than 3, as per investigator's discretion.
    End point type
    Secondary
    End point timeframe
    Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
    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: PK parameters were planned to be analyzed for only the Phase 1 portion of the study.
    End point values
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg (Including Pancreatic Cancer) Phase 1: MLN8237 60 mg
    Number of subjects analysed
    1
    3
    3
    11
    2
    Units: ratio
        arithmetic mean (standard deviation)
    3.3 ± 99999
    3 ± 1
    2.3 ± 0.4
    2.2 ± 0.9
    2.4 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1: Peak to Trough Ratio for Alisertib

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    End point title
    Phase 1: Peak to Trough Ratio for Alisertib [14]
    End point description
    Peak to trough ratio was estimated as a ratio of Cmax at Day 7 and the minimum observed plasma concentration (Ctrough) of alisertib at Day 7. Cmax is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Ctrough is the minimum plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. PK-Evaluable population included all subjects who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Days 1 and 7 assessment were available. '99999' in standard deviation signifies not available. For Phase 1, MLN8237 10 mg group, standard deviation was not estimable as only 1 subject was evaluable for this group. In addition, standard deviation was not estimated if evaluable participants were less than 3, as per investigator's discretion.
    End point type
    Secondary
    End point timeframe
    Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
    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: PK parameters were planned to be analyzed for only the Phase 1 portion of the study.
    End point values
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg (Including Pancreatic Cancer) Phase 1: MLN8237 60 mg
    Number of subjects analysed
    1
    3
    3
    11
    2
    Units: ratio
        arithmetic mean (standard deviation)
    1.7 ± 99999
    2.1 ± 0.7
    2.3 ± 1.4
    2.3 ± 0.8
    1.8 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1: Steady State Oral Clearance (CLss/F) for Alisertib

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    End point title
    Phase 1: Steady State Oral Clearance (CLss/F) for Alisertib [15]
    End point description
    CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-tau), expressed in liter per hour (L/hr). PK-Evaluable population included all subjects who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Day 7 assessment was available. '99999' in geometric CV signifies not available. For Phase 1, MLN8237 10 mg group, geometric CV was not estimable as only 1 subject was evaluable for this group. In addition, geometric CV was not estimated if evaluable participants were less than 3, as per investigator's discretion.
    End point type
    Secondary
    End point timeframe
    Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
    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: PK parameters were planned to be analyzed for only the Phase 1 portion of the study.
    End point values
    Phase 1: MLN8237 10 mg Phase 1: MLN8237 20 mg Phase 1: MLN8237 40 mg Phase 1: MLN8237 50 mg (Including Pancreatic Cancer) Phase 1: MLN8237 60 mg
    Number of subjects analysed
    1
    3
    3
    11
    2
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    2.2 ± 99999
    3.8 ± 22
    5.6 ± 72
    4.6 ± 39
    4 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 2: Relationship Between Clinical Response and Molecular Markers of Response

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    End point title
    Phase 2: Relationship Between Clinical Response and Molecular Markers of Response [16]
    End point description
    End point type
    Secondary
    End point timeframe
    12 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: This outcome was planned to be performed for only the Phase 2 portion of the study.
    End point values
    Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    Units: subjects
    Notes
    [17] - This endpoint was not analyzed.
    [18] - This endpoint was not analyzed.
    [19] - This endpoint was not analyzed.
    [20] - This endpoint was not analyzed.
    [21] - This endpoint was not analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug
    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. Dictionary version was not captured, hence 0.0 is mentioned here.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    0.0
    Reporting groups
    Reporting group title
    Phase 1: MLN8237- Dose Escalation
    Reporting group description
    MLN8237 (alisertib) 10, 20, 30, 40, 50, or 60 mg enteric-coated tablets, orally, twice daily, for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects enrolled in dose escalation cohort during Phase 1 portion of the study.

    Reporting group title
    Phase 1: MLN8237 50 mg- Pancreatic Cancer
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with pancreatic cancer during Phase 1 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- Breast Cancer
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with breast cancer during Phase 2 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- Gastric Cancer
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with gastric cancer during Phase 2 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- HNSCC
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with HNSCC during Phase 2 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- NSCLC
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with NSCLC during Phase 2 portion of the study.

    Reporting group title
    Phase 2: MLN8237 50 mg- SCLC
    Reporting group description
    MLN8237 (alisertib) 50 mg, enteric-coated tablets, orally, twice daily for 7 days followed by 14 days of rest period in 21-day treatment cycles for a maximum of 24 months, or until progressive disease, unacceptable treatment-related toxicity, or initiation of a different anticancer therapy in subjects with SCLC during Phase 2 portion of the study.

    Serious adverse events
    Phase 1: MLN8237- Dose Escalation Phase 1: MLN8237 50 mg- Pancreatic Cancer Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 23 (56.52%)
    1 / 1 (100.00%)
    23 / 53 (43.40%)
    30 / 55 (54.55%)
    19 / 55 (34.55%)
    8 / 26 (30.77%)
    28 / 60 (46.67%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal cancer
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Malignant pleural effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal cancer metastatic
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    2 / 55 (3.64%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 1 (100.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer stage unspecified
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    4 / 60 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    Tumour ulceration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oesophageal ulcer
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    2 / 53 (3.77%)
    2 / 55 (3.64%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    1 / 2
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    3 / 55 (5.45%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
    Fatigue
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    2 / 55 (3.64%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arterial injury
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Haemoptysis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    2 / 55 (3.64%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    2 / 53 (3.77%)
    4 / 55 (7.27%)
    1 / 55 (1.82%)
    3 / 26 (11.54%)
    5 / 60 (8.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    2 / 3
    2 / 5
    1 / 2
    2 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 1 (0.00%)
    2 / 53 (3.77%)
    2 / 55 (3.64%)
    2 / 55 (3.64%)
    0 / 26 (0.00%)
    4 / 60 (6.67%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    2 / 2
    2 / 2
    2 / 2
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 1 (100.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 1 (100.00%)
    2 / 53 (3.77%)
    2 / 55 (3.64%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    2 / 2
    2 / 2
    1 / 1
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sedation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    2 / 55 (3.64%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Keratitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    3 / 53 (5.66%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    2 / 55 (3.64%)
    2 / 55 (3.64%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    2 / 2
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    3 / 55 (5.45%)
    2 / 55 (3.64%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecal incontinence
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    2 / 55 (3.64%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ascites
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    2 / 55 (3.64%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 1 (100.00%)
    2 / 53 (3.77%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 1 (100.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute generalised exanthematous pustulosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal disorder
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    2 / 55 (3.64%)
    0 / 55 (0.00%)
    2 / 26 (7.69%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    0 / 0
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 1 (100.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    1 / 26 (3.85%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    3 / 53 (5.66%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 53 (1.89%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    2 / 53 (3.77%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Phase 1: MLN8237- Dose Escalation Phase 1: MLN8237 50 mg- Pancreatic Cancer Phase 2: MLN8237 50 mg- Breast Cancer Phase 2: MLN8237 50 mg- Gastric Cancer Phase 2: MLN8237 50 mg- HNSCC Phase 2: MLN8237 50 mg- NSCLC Phase 2: MLN8237 50 mg- SCLC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    1 / 1 (100.00%)
    52 / 53 (98.11%)
    52 / 55 (94.55%)
    54 / 55 (98.18%)
    26 / 26 (100.00%)
    55 / 60 (91.67%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    2 / 53 (3.77%)
    1 / 55 (1.82%)
    1 / 55 (1.82%)
    2 / 26 (7.69%)
    8 / 60 (13.33%)
         occurrences all number
    0
    0
    9
    3
    1
    3
    18
    Weight decreased
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 1 (0.00%)
    5 / 53 (9.43%)
    2 / 55 (3.64%)
    6 / 55 (10.91%)
    2 / 26 (7.69%)
    5 / 60 (8.33%)
         occurrences all number
    3
    0
    6
    2
    7
    4
    8
    White blood cell count decreased
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 1 (0.00%)
    5 / 53 (9.43%)
    4 / 55 (7.27%)
    4 / 55 (7.27%)
    1 / 26 (3.85%)
    10 / 60 (16.67%)
         occurrences all number
    8
    0
    7
    8
    6
    1
    32
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 1 (0.00%)
    9 / 53 (16.98%)
    1 / 55 (1.82%)
    10 / 55 (18.18%)
    3 / 26 (11.54%)
    5 / 60 (8.33%)
         occurrences all number
    4
    0
    11
    1
    10
    3
    6
    Dyspnoea
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    11 / 53 (20.75%)
    9 / 55 (16.36%)
    9 / 55 (16.36%)
    3 / 26 (11.54%)
    9 / 60 (15.00%)
         occurrences all number
    2
    0
    15
    11
    13
    4
    9
    Oropharyngeal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    3 / 53 (5.66%)
    2 / 55 (3.64%)
    2 / 55 (3.64%)
    1 / 26 (3.85%)
    5 / 60 (8.33%)
         occurrences all number
    1
    0
    3
    2
    3
    1
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 1 (100.00%)
    20 / 53 (37.74%)
    37 / 55 (67.27%)
    24 / 55 (43.64%)
    13 / 26 (50.00%)
    16 / 60 (26.67%)
         occurrences all number
    6
    2
    35
    25
    28
    22
    22
    Leukopenia
         subjects affected / exposed
    8 / 23 (34.78%)
    0 / 1 (0.00%)
    18 / 53 (33.96%)
    8 / 55 (14.55%)
    14 / 55 (25.45%)
    7 / 26 (26.92%)
    2 / 60 (3.33%)
         occurrences all number
    13
    0
    76
    19
    30
    14
    2
    Neutropenia
         subjects affected / exposed
    10 / 23 (43.48%)
    0 / 1 (0.00%)
    31 / 53 (58.49%)
    23 / 55 (41.82%)
    25 / 55 (45.45%)
    15 / 26 (57.69%)
    21 / 60 (35.00%)
         occurrences all number
    17
    0
    159
    64
    55
    32
    50
    Thrombocytopenia
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 1 (100.00%)
    11 / 53 (20.75%)
    14 / 55 (25.45%)
    7 / 55 (12.73%)
    6 / 26 (23.08%)
    11 / 60 (18.33%)
         occurrences all number
    6
    1
    19
    27
    14
    9
    17
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    3 / 53 (5.66%)
    2 / 55 (3.64%)
    6 / 55 (10.91%)
    5 / 26 (19.23%)
    7 / 60 (11.67%)
         occurrences all number
    2
    0
    7
    2
    7
    5
    8
    Headache
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    11 / 53 (20.75%)
    1 / 55 (1.82%)
    6 / 55 (10.91%)
    4 / 26 (15.38%)
    9 / 60 (15.00%)
         occurrences all number
    2
    0
    16
    1
    8
    5
    11
    Somnolence
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    15 / 53 (28.30%)
    8 / 55 (14.55%)
    11 / 55 (20.00%)
    3 / 26 (11.54%)
    9 / 60 (15.00%)
         occurrences all number
    0
    0
    30
    10
    16
    3
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    3 / 53 (5.66%)
    4 / 55 (7.27%)
    5 / 55 (9.09%)
    3 / 26 (11.54%)
    5 / 60 (8.33%)
         occurrences all number
    0
    0
    3
    4
    6
    3
    5
    Fatigue
         subjects affected / exposed
    13 / 23 (56.52%)
    1 / 1 (100.00%)
    29 / 53 (54.72%)
    24 / 55 (43.64%)
    26 / 55 (47.27%)
    15 / 26 (57.69%)
    27 / 60 (45.00%)
         occurrences all number
    20
    1
    56
    33
    37
    15
    28
    Oedema peripheral
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 1 (0.00%)
    9 / 53 (16.98%)
    11 / 55 (20.00%)
    2 / 55 (3.64%)
    3 / 26 (11.54%)
    4 / 60 (6.67%)
         occurrences all number
    3
    0
    12
    13
    2
    3
    5
    Pyrexia
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 1 (0.00%)
    5 / 53 (9.43%)
    13 / 55 (23.64%)
    11 / 55 (20.00%)
    3 / 26 (11.54%)
    4 / 60 (6.67%)
         occurrences all number
    4
    0
    7
    14
    14
    3
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    3 / 53 (5.66%)
    5 / 55 (9.09%)
    2 / 55 (3.64%)
    0 / 26 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    1
    0
    3
    5
    2
    0
    3
    Confusional state
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    3 / 53 (5.66%)
    1 / 55 (1.82%)
    2 / 55 (3.64%)
    1 / 26 (3.85%)
    6 / 60 (10.00%)
         occurrences all number
    4
    0
    5
    1
    2
    1
    6
    Insomnia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    6 / 53 (11.32%)
    7 / 55 (12.73%)
    6 / 55 (10.91%)
    3 / 26 (11.54%)
    7 / 60 (11.67%)
         occurrences all number
    1
    0
    9
    7
    6
    3
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 1 (0.00%)
    9 / 53 (16.98%)
    3 / 55 (5.45%)
    3 / 55 (5.45%)
    1 / 26 (3.85%)
    2 / 60 (3.33%)
         occurrences all number
    4
    0
    14
    6
    3
    1
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    2 / 53 (3.77%)
    6 / 55 (10.91%)
    1 / 55 (1.82%)
    1 / 26 (3.85%)
    3 / 60 (5.00%)
         occurrences all number
    2
    0
    3
    9
    1
    2
    4
    Aphthous stomatitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    4 / 53 (7.55%)
    6 / 55 (10.91%)
    3 / 55 (5.45%)
    0 / 26 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    5
    7
    3
    0
    0
    Constipation
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    9 / 53 (16.98%)
    11 / 55 (20.00%)
    9 / 55 (16.36%)
    5 / 26 (19.23%)
    5 / 60 (8.33%)
         occurrences all number
    2
    0
    12
    14
    10
    6
    7
    Diarrhoea
         subjects affected / exposed
    10 / 23 (43.48%)
    0 / 1 (0.00%)
    27 / 53 (50.94%)
    21 / 55 (38.18%)
    15 / 55 (27.27%)
    9 / 26 (34.62%)
    17 / 60 (28.33%)
         occurrences all number
    19
    0
    58
    30
    25
    13
    31
    Nausea
         subjects affected / exposed
    11 / 23 (47.83%)
    0 / 1 (0.00%)
    15 / 53 (28.30%)
    18 / 55 (32.73%)
    14 / 55 (25.45%)
    12 / 26 (46.15%)
    18 / 60 (30.00%)
         occurrences all number
    16
    0
    34
    26
    18
    17
    20
    Stomatitis
         subjects affected / exposed
    9 / 23 (39.13%)
    0 / 1 (0.00%)
    24 / 53 (45.28%)
    11 / 55 (20.00%)
    14 / 55 (25.45%)
    4 / 26 (15.38%)
    12 / 60 (20.00%)
         occurrences all number
    16
    0
    43
    14
    18
    7
    12
    Vomiting
         subjects affected / exposed
    8 / 23 (34.78%)
    1 / 1 (100.00%)
    11 / 53 (20.75%)
    16 / 55 (29.09%)
    13 / 55 (23.64%)
    6 / 26 (23.08%)
    10 / 60 (16.67%)
         occurrences all number
    9
    1
    20
    27
    24
    18
    12
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 23 (43.48%)
    0 / 1 (0.00%)
    26 / 53 (49.06%)
    21 / 55 (38.18%)
    24 / 55 (43.64%)
    11 / 26 (42.31%)
    16 / 60 (26.67%)
         occurrences all number
    10
    0
    37
    26
    29
    12
    18
    Dry skin
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    5 / 53 (9.43%)
    2 / 55 (3.64%)
    4 / 55 (7.27%)
    2 / 26 (7.69%)
    5 / 60 (8.33%)
         occurrences all number
    0
    0
    7
    2
    5
    2
    7
    Pruritus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    6 / 53 (11.32%)
    6 / 55 (10.91%)
    2 / 55 (3.64%)
    1 / 26 (3.85%)
    7 / 60 (11.67%)
         occurrences all number
    0
    0
    6
    6
    3
    2
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    6 / 53 (11.32%)
    4 / 55 (7.27%)
    4 / 55 (7.27%)
    4 / 26 (15.38%)
    4 / 60 (6.67%)
         occurrences all number
    0
    0
    9
    4
    4
    4
    5
    Back pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    7 / 53 (13.21%)
    6 / 55 (10.91%)
    4 / 55 (7.27%)
    3 / 26 (11.54%)
    5 / 60 (8.33%)
         occurrences all number
    2
    0
    10
    6
    4
    3
    5
    Musculoskeletal pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    4 / 53 (7.55%)
    0 / 55 (0.00%)
    5 / 55 (9.09%)
    3 / 26 (11.54%)
    3 / 60 (5.00%)
         occurrences all number
    2
    0
    4
    0
    5
    3
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 23 (56.52%)
    0 / 1 (0.00%)
    13 / 53 (24.53%)
    15 / 55 (27.27%)
    12 / 55 (21.82%)
    5 / 26 (19.23%)
    18 / 60 (30.00%)
         occurrences all number
    16
    0
    17
    19
    15
    10
    22
    Dehydration
         subjects affected / exposed
    6 / 23 (26.09%)
    0 / 1 (0.00%)
    7 / 53 (13.21%)
    3 / 55 (5.45%)
    2 / 55 (3.64%)
    3 / 26 (11.54%)
    4 / 60 (6.67%)
         occurrences all number
    6
    0
    7
    3
    2
    5
    4
    Hypokalaemia
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 1 (100.00%)
    5 / 53 (9.43%)
    4 / 55 (7.27%)
    2 / 55 (3.64%)
    2 / 26 (7.69%)
    4 / 60 (6.67%)
         occurrences all number
    2
    2
    6
    6
    2
    2
    6
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    5 / 23 (21.74%)
    0 / 1 (0.00%)
    5 / 53 (9.43%)
    2 / 55 (3.64%)
    3 / 55 (5.45%)
    0 / 26 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    5
    0
    7
    2
    3
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Apr 2010
    1. Clarified that if treatment was delayed for more than 2 weeks (that is, a rest period of more than 28 days) because of incomplete recovery from treatment-related toxicity, the patient was to be removed from the study. 2. Changed the reporting period for nonserious AEs from “through 30 days after the last dose of study drug” to “through 30 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first.”
    07 Jul 2010
    1. Remove the originally planned 14-day (28-day cycle) dosing schedule in phase 1, and to revise the Schedule of Events for phases 1 and 2 to reflect a 7-day dosing schedule in a 21-day cycle. 2. Enrollment in the phase 1 pancreatic cancer cohort was discontinued approximately 8 months after enrollment was opened because of slow subject accrual.

    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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