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    Clinical Trial Results:
    A PHASE 1/2 OPEN-LABEL MULTICENTER STUDY OF AVADOMIDE (CC-122) IN COMBINATION WITH R-CHOP-21 FOR PREVIOUSLY UNTREATED POOR-RISK (IPI ≥ 3) DIFFUSE LARGE B-CELL LYMPHOMA

    Summary
    EudraCT number
    		 2016-003778-42
    Trial protocol
    		 ES   BE  
    Global end of trial date
    16 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 May 2022
    First version publication date
    07 May 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CC-122-DLBCL-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2020
    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 the study is to evaluate the safety and tolerability of avadomide (CC-122) in combination with R-CHOP-21 for first-line treatment of patients with poor-risk (IPI ≥ 3) diffuse large B-cell lymphoma (DLBCL) in order to identify an appropriate dose and schedule for further investigation in Phase 2. Phase 2: The primary objective of the Phase 2 portion of the study is to evaluate the rate of complete response when adding avadomide (CC-122) to the standard R-CHOP-21 regimen in first-line treatment of patients with poor-risk DLBCL
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    35
    EEA total number of subjects
    15
    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)
    15
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 35 Participants Enrolled

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1
    Arm description
    		 CC-122 1 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-122
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1mg

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    375mg/m²

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    750mg/m²

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    50mg/m²

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    1.4mg/m² (max 2.0mg total)

    Investigational medicinal product name
    Prednisone/Prednisolone
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    100mg

    Investigational medicinal product name
    Pegylated Granulocyte Colony-Stimulating Factor
    Investigational medicinal product code
    Other name
    Peg-G-CSF
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    NA

    Arm title
    		 Arm 2
    Arm description
    		 CC-122 2 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-122
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2mg

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    375mg/m²

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    750mg/m²

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    50mg/m²

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    1.4mg/m² (max 2.0mg total)

    Investigational medicinal product name
    Prednisone/Prednisolone
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    100mg

    Arm title
    		 Arm 3
    Arm description
    		 CC-122 3 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-122
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3mg

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    375mg/m²

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    750mg/m²

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    50mg/m²

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    1.4mg/m² (max 2.0mg total)

    Investigational medicinal product name
    Prednisone/Prednisolone
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    100mg

    Arm title
    		 Arm 4
    Arm description
    		 CC-122 3 mg, Days 1-5, Days 8-12, and Days 15-19 (3 weeks out of 3) + R-CHOP-21
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-122
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3mg

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    375mg/m²

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    750mg/m²

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    50mg/m²

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    1.4mg/m² (max 2.0mg total)

    Investigational medicinal product name
    Prednisone/Prednisolone
    Investigational medicinal product code
    Other name
    CHOP
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    100mg

    Number of subjects in period 1
    		Arm 1 Arm 2 Arm 3 Arm 4
    Started
    4
    11
    12
    8
    Completed
    4
    10
    11
    7
    Not completed
    0
    1
    1
    1
         Other Reasons
    -
    -
    1
    -
         Death
    -
    1
    -
    -
         Progressive Disease
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 CC-122 1 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21

    Reporting group title
    Arm 2
    Reporting group description
    		 CC-122 2 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21

    Reporting group title
    Arm 3
    Reporting group description
    		 CC-122 3 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21

    Reporting group title
    Arm 4
    Reporting group description
    		 CC-122 3 mg, Days 1-5, Days 8-12, and Days 15-19 (3 weeks out of 3) + R-CHOP-21

    Reporting group values
    		 Arm 1 Arm 2 Arm 3 Arm 4 Total
    Number of subjects
    		 4 11 12 8 35
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 3 4 4 4 15
        From 65-84 years
    		 1 7 8 4 20
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.3 ± 6.18 64.7 ± 8.56 62.6 ± 15.29 59.3 ± 13.81 -
    Gender Categorical
    Units: Subjects
        Female
    		 4 5 6 2 17
        Male
    		 0 6 6 6 18
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 0 0
        Black or African American
    		 0 0 2 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        White
    		 4 9 9 8 30
        Not Collected or Reported
    		 0 1 1 0 2
        Other
    		 0 1 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic of Latino
    		 0 1 0 2 3
        Not Hispanic or Latino
    		 3 10 11 6 30
        Not Reported
    		 1 0 1 0 2
        Unknown
    		 0 0 0 0 0
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Population

    Subject analysis set title
    DL/T Evaluable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    DLT Evaluable Population

    Subject analysis sets values
    		 Safety Population DL/T Evaluable
    Number of subjects
    35
    35
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    15
    15
        From 65-84 years
    20
    20
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    62.6 ± 12.00
    62.6 ± 12.0
    Gender Categorical
    Units: Subjects
        Female
    17
    17
        Male
    18
    18
    Race
    Units: Subjects
        American Indian or Alaska Native
    0
    0
        Asian
    0
    0
        Black or African American
    2
    2
        Native Hawaiian or Other Pacific Islander
    0
    0
        White
    30
    30
        Not Collected or Reported
    2
    2
        Other
    1
    1
    Ethnicity
    Units: Subjects
        Hispanic of Latino
    3
    3
        Not Hispanic or Latino
    30
    30
        Not Reported
    2
    2
        Unknown
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 CC-122 1 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21

    Reporting group title
    Arm 2
    Reporting group description
    		 CC-122 2 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21

    Reporting group title
    Arm 3
    Reporting group description
    		 CC-122 3 mg, Days 1-5 and Days 8-12 (2 weeks out of 3) + R-CHOP-21

    Reporting group title
    Arm 4
    Reporting group description
    		 CC-122 3 mg, Days 1-5, Days 8-12, and Days 15-19 (3 weeks out of 3) + R-CHOP-21

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Population

    Subject analysis set title
    DL/T Evaluable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    DLT Evaluable Population

    Primary: Rate of Dose Limiting Toxicities (DLTs)

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    End point title
    		 Rate of Dose Limiting Toxicities (DLTs) [1]
    End point description
    Dose limiting toxicity (DLT) is defined as an event related to CC-122 or its combination with R-CHOP-21 and meeting at least one of non-hematologic DLTs or Hematologic DLTs criteria.
    End point type
    Primary
    End point timeframe
    Up to six 21-day cycles
    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: Only summary analysis planned for this endpoint in Phase I.
    End point values
    		 Arm 1 Arm 2 Arm 3 Arm 4 DL/T Evaluable
    Number of subjects analysed
    4
    11
    12
    8
    35
    Units: Percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 60.2)
    18.2 (2.3 to 51.8)
    16.7 (2.1 to 48.4)
    25.0 (3.2 to 65.1)
    17.1 (6.6 to 33.6)
    No statistical analyses for this end point

    Primary: Complete Response Rate (CRR)

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    End point title
    		 Complete Response Rate (CRR) [2]
    End point description
    Complete response rate (CRR) is the percentage of participants experiencing positron emission tomography (PET)-negative complete response (CR); Score 1, 2, or 3a with or without a residual mass on 5PSb. Uptake at sites of initial involvement is no greater than surrounding normal tissue even if the tissue has high physiologic uptake.
    End point type
    Primary
    End point timeframe
    6-8 weeks after completion of treatment
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary analysis planned for this endpoint in Phase I.
    End point values
    		 Arm 1 Arm 2 Arm 3 Arm 4 Safety Population
    Number of subjects analysed
    4
    11
    12
    8
    35
    Units: Percentage of participants
        number (confidence interval 95%)
    75.0 (19.41 to 99.37)
    81.8 (48.22 to 97.72)
    91.7 (61.52 to 99.79)
    75.0 (34.91 to 96.81)
    82.9 (66.35 to 93.44)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    Objective response rate (ORR) is defined as the percentage of participants with partial response (PR); ≥ 50% decrease in sum of perpendicular diameters (SPD) of up to 6 target measurable nodes and extranodal sites or complete response (CR); Target nodes/nodal masses must regress to ≤ 1.5 cm in LDi.
    End point type
    Secondary
    End point timeframe
    After 4 and 6 treatment cycles, and at 6, 12, 18 and 24 months after enrollment
    End point values
    		 Arm 1 Arm 2 Arm 3 Arm 4 Safety Population
    Number of subjects analysed
    4
    11
    12
    8
    35
    Units: Percentage of participants
        number (confidence interval 95%)
    100.0 (39.76 to 100.00)
    81.8 (48.22 to 97.72)
    91.7 (61.52 to 99.79)
    87.5 (47.35 to 99.68)
    88.6 (73.26 to 96.80)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    Progression-free survival (PFS) is defined as the time from the start of treatment to the first documented disease progression or death due to any cause, whichever occurs first. Progression is defined per Lugano Classification criteria. 99999=NA
    End point type
    Secondary
    End point timeframe
    Up to 24 months after last subject is enrolled
    End point values
    		 Arm 1 Arm 2 Arm 3 Arm 4 Safety Population
    Number of subjects analysed
    4
    11
    12
    8
    35
    Units: Months
        median (confidence interval 95%)
    18.2 (5.09 to 99999)
    99999 (5.55 to 99999)
    99999 (99999 to 99999)
    99999 (0.76 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS)

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    End point title
    		 Event-Free Survival (EFS)
    End point description
    Event-free survival (EFS) is defined as the time from the first dosing date of any study drug to the first event of relapse or progression, unplanned re-treatment of lymphoma after initial immunochemotherapy, or death from any cause, whichever occurs first. 99999=NA
    End point type
    Secondary
    End point timeframe
    12 and 24 months after enrollment
    End point values
    		 Arm 1 Arm 2 Arm 3 Arm 4 Safety Population
    Number of subjects analysed
    4
    11
    12
    8
    35
    Units: Months
        median (confidence interval 95%)
    18.2 (5.09 to 99999)
    99999 (5.55 to 99999)
    99999 (99999 to 99999)
    99999 (0.76 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS) is defined as the time from the first dosing date to death from any cause. OS will be censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented. 99999=NA
    End point type
    Secondary
    End point timeframe
    24 months after enrollment (Cycle 1, Day 1)
    End point values
    		 Arm 1 Arm 2 Arm 3 Arm 4 Safety Population
    Number of subjects analysed
    4
    11
    12
    8
    35
    Units: Months
        median (confidence interval 95%)
    99999 (14.13 to 99999)
    99999 (9.23 to 99999)
    99999 (99999 to 99999)
    99999 (2.07 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    Number of Participants with any grade, grade 3-4, and grade 5 Treatment Emergent Adverse Events (TEAEs) including their attribution to treatment with investigational products
    End point type
    Secondary
    End point timeframe
    From first dose until 28 days post last dose
    End point values
    		 Arm 1 Arm 2 Arm 3 Arm 4 Safety Population
    Number of subjects analysed
    4
    11
    12
    8
    35
    Units: Participants
        Any Grade TEAE
    4
    11
    11
    8
    34
        Any Grade TEAE related to CC-122/R-CHOP
    4
    11
    11
    8
    34
        Grade 3-4 TEAE
    3
    9
    9
    7
    28
        Grade 3-4 TEAE related to CC-122/R-CHOP
    3
    9
    8
    6
    26
        Grade 5 TEAE
    0
    1
    0
    0
    1
        Grade 5 TEAE related to CC-122/R-CHOP
    0
    1
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and AEs are collected from first dose to 28 days post last dose Death is collected up from first patient first visit to last patient last visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 mg (Days 1-5 and Days 8-12 (5/7 days; 2 out of 3 weeks)

    Reporting group title
    Arm 4
    Reporting group description
    		 3 mg (Days 1-5, Days 8-12, and Days 15-19 (5/7 days; 3 out of 3 weeks)

    Reporting group title
    Arm 3
    Reporting group description
    		 3 mg (Days 1-5 and Days 8-12 (5/7 days; 2 out of weeks)

    Reporting group title
    Arm 2
    Reporting group description
    		 2 mg (Days 1-5 and Days 8-12 (5/7 days; 2 out of 3 weeks)

    Serious adverse events
    		 Arm 1 Arm 4 Arm 3 Arm 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 8 (37.50%)
    4 / 12 (33.33%)
    3 / 11 (27.27%)
         number of deaths (all causes)
    1
    1
    1
    2
         number of deaths resulting from adverse events
    0
    0
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Hepatic infection bacterial
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm 1 Arm 4 Arm 3 Arm 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    8 / 8 (100.00%)
    11 / 12 (91.67%)
    11 / 11 (100.00%)
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    3 / 12 (25.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    1
    Phlebitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    0
    1
    Chills
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Device related thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Early satiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 8 (25.00%)
    4 / 12 (33.33%)
    2 / 11 (18.18%)
         occurrences all number
    2
    2
    8
    2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    3 / 11 (27.27%)
         occurrences all number
    1
    1
    1
    4
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    3
    Performance status decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    3 / 11 (27.27%)
         occurrences all number
    1
    3
    1
    4
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    4
    1
    Dyspnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Emphysema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 8 (12.50%)
    3 / 12 (25.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    3
    1
    Epistaxis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pneumonitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Blood pressure decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Brain natriuretic peptide increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    3 / 12 (25.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    0
    5
    2
    Neutrophil count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Transaminases increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Troponin T increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    0
    2
    Troponin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    2
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural complication
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    2
    Atrial tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Cardiac failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
    3 / 11 (27.27%)
         occurrences all number
    0
    2
    2
    3
    Dysgeusia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    2
    2
    Drooling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 8 (37.50%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    3
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 8 (37.50%)
    3 / 12 (25.00%)
    7 / 11 (63.64%)
         occurrences all number
    0
    5
    3
    11
    Sudden onset of sleep
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 8 (50.00%)
    4 / 12 (33.33%)
    6 / 11 (54.55%)
         occurrences all number
    4
    4
    14
    19
    Febrile neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    5 / 12 (41.67%)
    3 / 11 (27.27%)
         occurrences all number
    0
    1
    11
    6
    Lymphopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
    3 / 11 (27.27%)
         occurrences all number
    1
    7
    2
    3
    Neutropenia
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 8 (50.00%)
    6 / 12 (50.00%)
    8 / 11 (72.73%)
         occurrences all number
    10
    9
    12
    14
    Thrombocytopenia
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 8 (0.00%)
    3 / 12 (25.00%)
    3 / 11 (27.27%)
         occurrences all number
    3
    0
    6
    5
    Thrombocytosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Anal fissure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ascites
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Colitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    2 / 4 (50.00%)
    5 / 8 (62.50%)
    5 / 12 (41.67%)
    3 / 11 (27.27%)
         occurrences all number
    2
    5
    5
    3
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    3 / 11 (27.27%)
         occurrences all number
    1
    1
    2
    3
    Dry mouth
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    2
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    2
    Flatulence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gingival swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    5 / 12 (41.67%)
    5 / 11 (45.45%)
         occurrences all number
    0
    0
    7
    5
    Oral pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    2 / 11 (18.18%)
         occurrences all number
    5
    0
    2
    2
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    2
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    3
    Erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    0
    2
    Nail discolouration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    2
    Rash erythematous
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    5
    0
    Skin induration
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin fissures
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    1
    1
    Muscular weakness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Diverticulitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Furuncle
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Herpes simplex
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oesophageal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    4
    1
    Oral fungal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Rhinovirus infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Streptococcal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Varicella zoster virus infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    2
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2017
    References to the generic drug name were deleted. This generic name was not yet approved outside the US and was not appropriate to reference in a multinational study. It was clarified that Grade 5 AEs would be tabulated and listed separately from Grade 3 or 4 AEs.
    12 Jun 2017
    The definition of DLT was updated according to feedback from the US Food and Drug Administration.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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