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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind Study of PF-06439535 Plus Paclitaxel-Carboplatin and Bevacizumab Plus Paclitaxel-Carboplatin for the First-Line Treatment of Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2014-003878-16
    Trial protocol
    		 SK   NL   CZ   DE   ES   PL   HU   GR   HR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    23 May 2018
    First version publication date
    23 May 2018
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    B7391003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    Interim
    Date of interim/final analysis
    13 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the confirmed objective response rate (ORR) by Week 19 following treatment with PF-06439535 in combination with paclitaxel and carboplatin to bevacizumab-EU plus paclitaxel and carboplatin in subjects who had not received previous treatment for advanced non-small cell lung cancer (NSCLC).
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Chile: 10
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Greece: 18
    Country: Number of subjects enrolled
    Hungary: 52
    Country: Number of subjects enrolled
    India: 30
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 19
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    Romania: 62
    Country: Number of subjects enrolled
    Russian Federation: 176
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Thailand: 15
    Country: Number of subjects enrolled
    Turkey: 32
    Country: Number of subjects enrolled
    Ukraine: 152
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    719
    EEA total number of subjects
    240
    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)
    456
    From 65 to 84 years
    261
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 719 subjects were enrolled in this study, and 5 of them didn't receive study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-06439535
    Arm description
    		 Subjects received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed in response to toxicity. Paclitaxel was administered before carboplatin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06439535
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    PF-06439535 was administered once at the start of each 21-day cycle via intravenous (IV) infusion. The initial dose level was 15 mg/kg and dose reduction was allowed in response to toxicity.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered once on Day 1 of each 21-day cycle via intravenous (IV) infusion after PF-06439535 administration. The initial dose level was 200 mg/m*2 and dose reduction was allowed in response to toxicity.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered once on Day 1 of each 21-day cycle via intravenous (IV) infusion after paclitaxel administration. The initial dose level was AUC 6 and dose reduction was allowed in response to toxicity.

    Arm title
    		 Bevacizumab-EU
    Arm description
    		 Subjects received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed in response to toxicity. Paclitaxel was administered before carboplatin.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab-EU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab-EU was administered once at the start of each 21-day cycle via intravenous (IV) infusion. The initial dose level was 15 mg/kg and dose reduction was allowed in response to toxicity.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered once on Day 1 of each 21-day cycle via intravenous (IV) infusion after paclitaxel administration. The initial dose level was AUC 6 and dose reduction was allowed in response to toxicity.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered once on Day 1 of each 21-day cycle via intravenous (IV) infusion after Bevacizumab-EU administration. The initial dose level was 200 mg/m*2 and dose reduction was allowed in response to toxicity.

    Number of subjects in period 1
    		PF-06439535 Bevacizumab-EU
    Started
    358
    361
    Received treatment
    356
    358
    Completed
    40
    39
    Not completed
    318
    322
         Adverse event, serious fatal
    109
    99
         Consent withdrawn by subject
    13
    10
         Study ongoing
    179
    194
         Randomized but did not receive treatment
    2
    3
         Global Deterioration Of Health Status
    -
    2
         Unspecified
    1
    1
         Lost to follow-up
    9
    11
         Objective Progression Or Relapse
    3
    -
         Protocol deviation
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-06439535
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed in response to toxicity. Paclitaxel was administered before carboplatin.

    Reporting group title
    Bevacizumab-EU
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed in response to toxicity. Paclitaxel was administered before carboplatin.

    Reporting group values
    		 PF-06439535 Bevacizumab-EU Total
    Number of subjects
    		 358 361 719
    Age, Customized
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age <37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days - 23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 217 239 456
        From 65-84 years
    		 139 122 261
        85 years and over
    		 2 0 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.7 ± 9.5 60.9 ± 8.9 -
    Sex/Gender, Customized
    Units: Subjects
        Female|
    		 121 131 252
        Male|
    		 237 230 467
    Race/Ethnicity, Customized
    Units: Subjects
        WHITE|
    		 319 319 638
        BLACK|
    		 3 1 4
        ASIAN|
    		 36 40 76
        OTHER|
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    PF-06439535
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed in response to toxicity. Paclitaxel was administered before carboplatin.

    Reporting group title
    Bevacizumab-EU
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed in response to toxicity. Paclitaxel was administered before carboplatin.

    Primary: Objective Response Rate (ORR) by Week 19

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    End point title
    		 Objective Response Rate (ORR) by Week 19
    End point description
    ORR refers to percentage of subjects who achieved complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A subject achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker levels above the normal limits.
    End point type
    Primary
    End point timeframe
    25 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    358
    361
    Units: percentage of subjects
        number (confidence interval 95%)
    45.3 (40.01 to 50.57)
    44.6 (39.40 to 49.89)
    Statistical analysis title
    		 PF-06439535 vs Bevacizumab-EU in Risk Difference
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.6531
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.608
         upper limit
    		 7.9082
    Notes
    [1] - Calculated based on 2-sided Miettinen and Nurminen method without strata for risk difference for confirmed response. EU equivalence margins (95% CI in -13% to 13%).
    Statistical analysis title
    		 Risk Ratio: PF-06439535 vs Bevacizumab-EU (95% CI)
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0146
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8628
         upper limit
    		 1.1933
    Notes
    [2] - Calculated based on 2-sided Miettinen and Nurminen method without strata for risk ratio for confirmed response. Japan equivalence margins (95% CI in 0.729 to 1.371).
    Statistical analysis title
    		 Risk Ratio: PF-06439535 vs Bevacizumab-EU (90% CI)
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0146
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8856
         upper limit
    		 1.1625
    Notes
    [3] - Calculated based on 2-sided Miettinen and Nurminen method without strata for risk ratio for confirmed response. US equivalence margins (90% CI in 0.73 to 1.37).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    25 weeks
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    PF-06439535
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed in response to toxicity. Paclitaxel was administered before carboplatin.

    Reporting group title
    Total
    Reporting group description
    		 This reporting group include all subjects who received at least 1 dose of study treatment from PF-06439535 and Bevacizumab-EU groups.

    Reporting group title
    Bevacizumab-EU
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed in response to toxicity. Paclitaxel was administered before carboplatin.

    Serious adverse events
    		 PF-06439535 Total Bevacizumab-EU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    78 / 356 (21.91%)
    152 / 714 (21.29%)
    74 / 358 (20.67%)
         number of deaths (all causes)
    25
    48
    23
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone cancer metastatic
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Vascular disorders
    Brachiocephalic vein thrombosis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Subgaleal haematoma
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 356 (1.12%)
    5 / 714 (0.70%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    3 / 5
    3 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 356 (0.56%)
    4 / 714 (0.56%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
    Disease progression
         subjects affected / exposed
    3 / 356 (0.84%)
    9 / 714 (1.26%)
    6 / 358 (1.68%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    0 / 4
    General physical health deterioration
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 356 (0.56%)
    3 / 714 (0.42%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 356 (0.84%)
    5 / 714 (0.70%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 356 (0.56%)
    3 / 714 (0.42%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 356 (0.56%)
    4 / 714 (0.56%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 5
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 356 (1.97%)
    9 / 714 (1.26%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    2 / 7
    4 / 9
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    3 / 356 (0.84%)
    6 / 714 (0.84%)
    3 / 358 (0.84%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 6
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    2 / 5
    1 / 3
    Pulmonary oedema
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
    Angina unstable
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 356 (0.00%)
    3 / 714 (0.42%)
    3 / 358 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Mononeuropathy
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 356 (0.56%)
    7 / 714 (0.98%)
    5 / 358 (1.40%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 356 (1.40%)
    12 / 714 (1.68%)
    7 / 358 (1.96%)
         occurrences causally related to treatment / all
    2 / 7
    3 / 14
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 356 (0.56%)
    2 / 714 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 356 (1.12%)
    10 / 714 (1.40%)
    6 / 358 (1.68%)
         occurrences causally related to treatment / all
    1 / 5
    6 / 13
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 356 (0.84%)
    6 / 714 (0.84%)
    3 / 358 (0.84%)
         occurrences causally related to treatment / all
    2 / 5
    4 / 8
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 356 (0.56%)
    4 / 714 (0.56%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 356 (0.00%)
    2 / 714 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    2 / 356 (0.56%)
    2 / 714 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 356 (0.00%)
    2 / 714 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal infection
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 356 (0.84%)
    3 / 714 (0.42%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 356 (0.28%)
    3 / 714 (0.42%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral fungal infection
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 356 (2.25%)
    14 / 714 (1.96%)
    6 / 358 (1.68%)
         occurrences causally related to treatment / all
    3 / 11
    3 / 17
    0 / 6
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 356 (0.56%)
    2 / 714 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 356 (0.00%)
    2 / 714 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 356 (0.28%)
    3 / 714 (0.42%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 356 (1.12%)
    4 / 714 (0.56%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PF-06439535 Total Bevacizumab-EU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    337 / 356 (94.66%)
    674 / 714 (94.40%)
    337 / 358 (94.13%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    49 / 356 (13.76%)
    86 / 714 (12.04%)
    37 / 358 (10.34%)
         occurrences all number
    81
    131
    50
    Aspartate aminotransferase increased
         subjects affected / exposed
    42 / 356 (11.80%)
    76 / 714 (10.64%)
    34 / 358 (9.50%)
         occurrences all number
    76
    130
    54
    Blood alkaline phosphatase increased
         subjects affected / exposed
    27 / 356 (7.58%)
    56 / 714 (7.84%)
    29 / 358 (8.10%)
         occurrences all number
    39
    81
    42
    Platelet count decreased
         subjects affected / exposed
    22 / 356 (6.18%)
    40 / 714 (5.60%)
    18 / 358 (5.03%)
         occurrences all number
    29
    65
    36
    Weight decreased
         subjects affected / exposed
    31 / 356 (8.71%)
    56 / 714 (7.84%)
    25 / 358 (6.98%)
         occurrences all number
    36
    68
    32
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    11 / 356 (3.09%)
    29 / 714 (4.06%)
    18 / 358 (5.03%)
         occurrences all number
    15
    36
    21
    Vascular disorders
    Hypertension
         subjects affected / exposed
    55 / 356 (15.45%)
    109 / 714 (15.27%)
    54 / 358 (15.08%)
         occurrences all number
    77
    178
    101
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 356 (7.87%)
    63 / 714 (8.82%)
    35 / 358 (9.78%)
         occurrences all number
    33
    75
    42
    Neuropathy peripheral
         subjects affected / exposed
    51 / 356 (14.33%)
    115 / 714 (16.11%)
    64 / 358 (17.88%)
         occurrences all number
    64
    150
    86
    Paraesthesia
         subjects affected / exposed
    40 / 356 (11.24%)
    71 / 714 (9.94%)
    31 / 358 (8.66%)
         occurrences all number
    61
    97
    36
    Peripheral sensory neuropathy
         subjects affected / exposed
    34 / 356 (9.55%)
    80 / 714 (11.20%)
    46 / 358 (12.85%)
         occurrences all number
    44
    114
    70
    Polyneuropathy
         subjects affected / exposed
    23 / 356 (6.46%)
    42 / 714 (5.88%)
    19 / 358 (5.31%)
         occurrences all number
    34
    56
    22
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    99 / 356 (27.81%)
    203 / 714 (28.43%)
    104 / 358 (29.05%)
         occurrences all number
    180
    371
    191
    Leukopenia
         subjects affected / exposed
    26 / 356 (7.30%)
    55 / 714 (7.70%)
    29 / 358 (8.10%)
         occurrences all number
    42
    94
    52
    Neutropenia
         subjects affected / exposed
    59 / 356 (16.57%)
    123 / 714 (17.23%)
    64 / 358 (17.88%)
         occurrences all number
    129
    260
    131
    Thrombocytopenia
         subjects affected / exposed
    54 / 356 (15.17%)
    118 / 714 (16.53%)
    64 / 358 (17.88%)
         occurrences all number
    115
    234
    119
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    43 / 356 (12.08%)
    83 / 714 (11.62%)
    40 / 358 (11.17%)
         occurrences all number
    75
    136
    61
    Fatigue
         subjects affected / exposed
    70 / 356 (19.66%)
    137 / 714 (19.19%)
    67 / 358 (18.72%)
         occurrences all number
    102
    184
    82
    Pyrexia
         subjects affected / exposed
    20 / 356 (5.62%)
    42 / 714 (5.88%)
    22 / 358 (6.15%)
         occurrences all number
    25
    59
    34
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    37 / 356 (10.39%)
    64 / 714 (8.96%)
    27 / 358 (7.54%)
         occurrences all number
    43
    79
    36
    Diarrhoea
         subjects affected / exposed
    44 / 356 (12.36%)
    90 / 714 (12.61%)
    46 / 358 (12.85%)
         occurrences all number
    55
    117
    62
    Nausea
         subjects affected / exposed
    70 / 356 (19.66%)
    136 / 714 (19.05%)
    66 / 358 (18.44%)
         occurrences all number
    110
    217
    107
    Vomiting
         subjects affected / exposed
    40 / 356 (11.24%)
    72 / 714 (10.08%)
    32 / 358 (8.94%)
         occurrences all number
    49
    85
    36
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    36 / 356 (10.11%)
    76 / 714 (10.64%)
    40 / 358 (11.17%)
         occurrences all number
    43
    91
    48
    Dyspnoea
         subjects affected / exposed
    29 / 356 (8.15%)
    59 / 714 (8.26%)
    30 / 358 (8.38%)
         occurrences all number
    34
    70
    36
    Epistaxis
         subjects affected / exposed
    39 / 356 (10.96%)
    69 / 714 (9.66%)
    30 / 358 (8.38%)
         occurrences all number
    48
    92
    44
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    166 / 356 (46.63%)
    330 / 714 (46.22%)
    164 / 358 (45.81%)
         occurrences all number
    215
    446
    231
    Rash
         subjects affected / exposed
    8 / 356 (2.25%)
    28 / 714 (3.92%)
    20 / 358 (5.59%)
         occurrences all number
    9
    36
    27
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    24 / 356 (6.74%)
    55 / 714 (7.70%)
    31 / 358 (8.66%)
         occurrences all number
    40
    102
    62
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    39 / 356 (10.96%)
    80 / 714 (11.20%)
    41 / 358 (11.45%)
         occurrences all number
    79
    148
    69
    Bone pain
         subjects affected / exposed
    25 / 356 (7.02%)
    47 / 714 (6.58%)
    22 / 358 (6.15%)
         occurrences all number
    58
    103
    45
    Myalgia
         subjects affected / exposed
    54 / 356 (15.17%)
    102 / 714 (14.29%)
    48 / 358 (13.41%)
         occurrences all number
    131
    237
    106
    Pain in extremity
         subjects affected / exposed
    15 / 356 (4.21%)
    38 / 714 (5.32%)
    23 / 358 (6.42%)
         occurrences all number
    23
    52
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    46 / 356 (12.92%)
    90 / 714 (12.61%)
    44 / 358 (12.29%)
         occurrences all number
    72
    135
    63

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2015
    Protocol was amended to incorporate feedback from investigators, regulatory agencies, and protocol template updates.
    10 Jun 2016
    For EU, primary analysis was changed to risk difference; inclusion and exclusion criteria were updated.

    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.
    This report reflects data collected up to Week 25, and will be updated within 12 months of study completion.
    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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