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    Clinical Trial Results:
    Phase II multicenter randomized, double blind, placebo controlled study assessing the efficacy of buparlisib (BKM120) plus paclitaxel vs. placebo plus paclitaxel in patients with platinum pre-treated recurrent or metastatic head and neck squamous cell carcinoma

    Summary
    EudraCT number
    		 2013-000744-26
    Trial protocol
    		 HU   ES   IT   GB   DE   IE   PL   FR  
    Global end of trial date
    30 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Apr 2018
    First version publication date
    15 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBKM120H2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01852292
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.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
    30 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To estimate the efficacy of buparlisib in combination with paclitaxel in terms of progression-free survival (PFS) according to local radiological assessment and Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2013
    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: 2
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    India: 14
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 11
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    Thailand: 8
    Worldwide total number of subjects
    158
    EEA total number of subjects
    76
    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)
    117
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Planned: 150; Analyzed: 158. Patients were randomized to receive treatment with buparlisib 100 mg daily (n=79) or placebo (n=79) in combination with paclitaxel.

    Pre-assignment
    Screening details
    		 One hundred and fifty-eight patients were randomized in a 1:1 ratio to treatment with buparlisib plus paclitaxel or placebo plus paclitaxel, with stratification according to number of prior lines of treatment in the recurrent/metastatic setting (1 vs.2) and the region of Investigator site (North America vs. Rest of the World).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Buparlisib + Paclitaxel
    Arm description
    		 Patients who were randomized to this arm on a 1:1 randomization, took buparlisib 100 mg daily and paclitaxel 80 mg/m^2 weekly.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Buparlisib was supplied as 10-mg, and 50-mg hard gelatin capsules. Buparlisib was administered orally once daily on a continuous dosing schedule starting on Day 1.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered weekly (Days 1, 8, 15 and 22 of a 28-day cycle) as an intravenous infusion at a dose of 80 mg/m^2 on a continuous dosing schedule.

    Arm title
    		 Buparlisib matching placebo + Paclitaxel
    Arm description
    		 Patients who were randomized to this arm on a 1:1 randomization, took buparlisib matching placebo 100 mg daily and paclitaxel 80 mg/m^2 weekly.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Buparlisib matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Buparlisib matching placebo was supplied as 10-mg, and 50-mg hard gelatin capsules. Buparlisib matching placebo was administered orally once daily on a continuous dosing schedule starting on Day 1.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered weekly (Days 1, 8, 15 and 22 of a 28-day cycle) as an intravenous infusion at a dose of 80 mg/m^2 on a continuous dosing schedule.

    Number of subjects in period 1
    		Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Started
    79
    79
    Completed
    0
    0
    Not completed
    79
    79
         Adverse event, serious fatal
    9
    8
         Physician decision
    6
    2
         Study terminated by Sponsor
    -
    1
         Adverse event, non-fatal
    8
    11
         Non-compliance with study treatment
    1
    -
         Patient/guardian decision
    8
    4
         Progressive disease
    42
    52
         Untreated - did not receive study drug
    3
    1
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Buparlisib + Paclitaxel
    Reporting group description
    		 Patients who were randomized to this arm on a 1:1 randomization, took buparlisib 100 mg daily and paclitaxel 80 mg/m^2 weekly.

    Reporting group title
    Buparlisib matching placebo + Paclitaxel
    Reporting group description
    		 Patients who were randomized to this arm on a 1:1 randomization, took buparlisib matching placebo 100 mg daily and paclitaxel 80 mg/m^2 weekly.

    Reporting group values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel Total
    Number of subjects
    		 79 79 158
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 59 58 117
        From 65-84 years
    		 20 21 41
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.0 ± 9.44 58.2 ± 9.44 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 14 11 25
        Male
    		 65 68 133
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino|
    		 3 0 3
        East Asian|
    		 12 9 21
        Southeast Asian|
    		 4 9 13
        South Asian|
    		 6 5 11
        Russian|
    		 7 4 11
        Mixed ethnicity|
    		 1 2 3
        Not reported|
    		 13 10 23
        Unknown|
    		 3 6 9
        Other|
    		 30 34 64

    End points

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    End points reporting groups
    Reporting group title
    Buparlisib + Paclitaxel
    Reporting group description
    		 Patients who were randomized to this arm on a 1:1 randomization, took buparlisib 100 mg daily and paclitaxel 80 mg/m^2 weekly.

    Reporting group title
    Buparlisib matching placebo + Paclitaxel
    Reporting group description
    		 Patients who were randomized to this arm on a 1:1 randomization, took buparlisib matching placebo 100 mg daily and paclitaxel 80 mg/m^2 weekly.

    Primary: Progression Free Survival (PFS) per Investigator assessment

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    End point title
    		 Progression Free Survival (PFS) per Investigator assessment
    End point description
    PFS was defined as the time from the date of randomization to the date of the event, defined as the first radiologically documented disease progression per RECIST v 1.1 or death due to any cause. If a patient has not progressed or died at the analysis cut-off date or when the patient receives further anti-neoplastic therapy, PFS was censored on the date of the last adequate tumor assessment before the earlier of the cut-off date or start of the further anti-neoplastic therapy date.
    End point type
    Primary
    End point timeframe
    4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years
    End point values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Number of subjects analysed
    79
    79
    Units: months
        median (confidence interval 95%)
    4.63 (3.52 to 5.32)
    3.45 (2.17 to 3.71)
    Statistical analysis title
    		 Analysis of Double Criteria for PFS
    Comparison groups
    Buparlisib + Paclitaxel v Buparlisib matching placebo + Paclitaxel
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.646
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.94
    Notes
    [1] - Double Criteria for PFS

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS) was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years
    End point values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Number of subjects analysed
    79
    79
    Units: months
        median (confidence interval 95%)
    10.41 (7.29 to 12.78)
    6.54 (5.26 to 8.77)
    Statistical analysis title
    		 Analysis of Double Criteria for Overall survival
    Comparison groups
    Buparlisib + Paclitaxel v Buparlisib matching placebo + Paclitaxel
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.04
    Notes
    [2] - Double criteria for OS

    Secondary: Overall Response Rate (ORR) as per local radiological assessment

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    End point title
    		 Overall Response Rate (ORR) as per local radiological assessment
    End point description
    ORR: Percentage of patients with best overall response of complete response (CR) or partial response (PR) according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years
    End point values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Number of subjects analysed
    79
    79
    Units: Percentage of participants
        median (confidence interval 95%)
    39.2 (28.4 to 50.9)
    13.9 (7.2 to 23.5)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) as per local radiological assessment

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    End point title
    		 Time to Response (TTR) as per local radiological assessment
    End point description
    TTR is the time from date of randomization until first documented response (CR or PR, which has to be confirmed subsequently) according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years
    End point values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Number of subjects analysed
    79 [3]
    79 [4]
    Units: months
        median (full range (min-max))
    1.02 (0.8 to 9.2)
    0.99 (0.8 to 5.1)
    Notes
    [3] - n for responders = 31
    [4] - n for responders = 11
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) as per local radiological assessment

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    End point title
    		 Disease Control Rate (DCR) as per local radiological assessment
    End point description
    DCR is the the proportion of patients with a best overall response of CR, PR or stable disease (SD), according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years
    End point values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Number of subjects analysed
    79
    79
    Units: Percentage of participants
        number (confidence interval 95%)
    72.2 (60.9 to 81.7)
    69.6 (58.2 to 79.5)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) as per local investigator

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    End point title
    		 Duration of Response (DoR) as per local investigator
    End point description
    DoR is the time from the date of the first documented response (CR or PR, which had to be confirmed subsequently) to the date of the first radiologically documented disease progression or death due to disease according to RECIST v1.1 .
    End point type
    Secondary
    End point timeframe
    4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years
    End point values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Number of subjects analysed
    79 [5]
    79 [6]
    Units: months
        median (full range (min-max))
    3.06 (2.1 to 9.6)
    4.17 (2.7 to 5.6)
    Notes
    [5] - n for responders = 17
    [6] - n for responders = 4
    No statistical analyses for this end point

    Secondary: Health-related quality of life (HRQoL):Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30

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    End point title
    		 Health-related quality of life (HRQoL):Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30
    End point description
    A summary of EORTC-QLQ-C30 scores by time window. Time to deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive Deterioration in global health status and symptoms was defined as a decrease in the subscale score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study. If a patient had not had an event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last quality of life (QoL) evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks starting from cycle 2 day 15 up to 3.5 years
    End point values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Number of subjects analysed
    79
    79
    Units: months
        median (confidence interval 95%)
    3.0 (1.6 to 4.9)
    3.5 (2.1 to 4.3)
    No statistical analyses for this end point

    Secondary: Health-related quality of life (HRQoL):Time to 10% definitive deterioration in the head and neck cancer symptoms scales for pain, speech problems, swallowing and sense problems per EORTC-QLQ-HN35

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    End point title
    		 Health-related quality of life (HRQoL):Time to 10% definitive deterioration in the head and neck cancer symptoms scales for pain, speech problems, swallowing and sense problems per EORTC-QLQ-HN35
    End point description
    A summary of EORTC-QLQ-HN35 scores by time window. Time to deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive Deterioration in global health status and symptoms was defined as an increase in the subscale score of at least 10% compared to baseline, with no later decrease above this threshold observed during the course of the study. If a patient had not had an event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last quality of life (QoL) evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks starting from cycle 2 day 15 up to 3.5 years
    End point values
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Number of subjects analysed
    79
    79
    Units: Months
    median (confidence interval 95%)
        Pain Subscale|
    5.8 (4.2 to 7.3)
    5.3 (3.2 to 6.8)
        Speech problems|
    5.6 (4.1 to 6.9)
    4.2 (2.2 to 5.4)
        Swallowing|
    5.1 (3.7 to 7.2)
    4.6 (2.8 to 6.7)
        Sense Problems|
    5.1 (3.1 to 7.3)
    4.6 (2.9 to 6.5)
    No statistical analyses for this end point

    Secondary: Plasma Concentration-time profiles of BKM120 Pharmacokinetics (PK) for AUC0-24 and AUClast

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    End point title
    		 Plasma Concentration-time profiles of BKM120 Pharmacokinetics (PK) for AUC0-24 and AUClast [7]
    End point description
    To characterize the pharmacokinetics of buparlisib given in combination with paclitaxel for AUC0-24 and AUClast. At a 100 mg QD dose these primary PK parameters were determined for buparlisib.
    End point type
    Secondary
    End point timeframe
    6 Full PK samples over 24hrs at Day 15 of Cycle 1 (steady state)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical analysis planned for this endpoint.
    End point values
    		 Buparlisib + Paclitaxel
    Number of subjects analysed
    79 [8]
    Units: ng*hr/mL
    median (full range (min-max))
        AUC0-24|
    25628.56 (13651.75 to 33375.10)
        AUClast|
    25734.33 (13651.75 to 33306.37)
    Notes
    [8] - n = 4
    No statistical analyses for this end point

    Secondary: Plasma Concentration-time profiles of BKM120 Pharmacokinetics (PK) for Cmax

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    End point title
    		 Plasma Concentration-time profiles of BKM120 Pharmacokinetics (PK) for Cmax [9]
    End point description
    To characterize the pharmacokinetics of buparlisib given in combination with paclitaxel for Cmax.
    End point type
    Secondary
    End point timeframe
    At a 100 mg QD dose this primary PK parameter was determined for buparlisib.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical analysis planned for this endpoint.
    End point values
    		 Buparlisib + Paclitaxel
    Number of subjects analysed
    79 [10]
    Units: ng/mL
        median (full range (min-max))
    1775.00 (834.00 to 2180.00)
    Notes
    [10] - n = 4
    No statistical analyses for this end point

    Secondary: Plasma Concentration-time profiles of BKM120 Pharmacokinetics (PK) for Tmax

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    End point title
    		 Plasma Concentration-time profiles of BKM120 Pharmacokinetics (PK) for Tmax [11]
    End point description
    To characterize the pharmacokinetics of buparlisib given in combination with paclitaxel for Tmax.
    End point type
    Secondary
    End point timeframe
    At a 100 mg QD dose this primary PK parameter was determined for buparlisib.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical analysis planned for this endpoint.
    End point values
    		 Buparlisib + Paclitaxel
    Number of subjects analysed
    79 [12]
    Units: hour (hr)
        median (full range (min-max))
    2.42 (1.00 to 4.00)
    Notes
    [12] - n = 4
    No statistical analyses for this end point

    Secondary: Plasma Concentration-time profiles of BKM120 Pharmacokinetics (PK) for CL/F

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    End point title
    		 Plasma Concentration-time profiles of BKM120 Pharmacokinetics (PK) for CL/F [13]
    End point description
    To characterize the pharmacokinetics of buparlisib given in combination with paclitaxel for CL/F.
    End point type
    Secondary
    End point timeframe
    At a 100 mg QD dose this primary PK parameter was determined for buparlisib.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical analysis planned for this endpoint.
    End point values
    		 Buparlisib + Paclitaxel
    Number of subjects analysed
    79 [14]
    Units: L/hr
        median (full range (min-max))
    4.14 (3.00 to 7.33)
    Notes
    [14] - n = 4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 3.5 yrs.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Buparlisib + Paclitaxel
    Reporting group description
    		 Patients who were randomized to this arm on a 1:1 randomization, took buparlisib 100 mg daily and paclitaxel 80 mg/m^2 weekly.

    Reporting group title
    Buparlisib matching placebo + Paclitaxel
    Reporting group description
    		 Patients who were randomized to this arm on a 1:1 randomization, took buparlisib matching placebo 100 mg daily and paclitaxel 80 mg/m^2 weekly.

    Serious adverse events
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 76 (56.58%)
    37 / 78 (47.44%)
         number of deaths (all causes)
    16
    17
         number of deaths resulting from adverse events
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour haemorrhage
         subjects affected / exposed
    3 / 76 (3.95%)
    5 / 78 (6.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Tumour invasion
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial rupture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 78 (5.13%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    General physical health deterioration
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Haemoptysis
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper airway obstruction
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device connection issue
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural discharge
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Sinus bradycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 76 (3.95%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Aorto-oesophageal fistula
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral cavity fistula
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall abscess
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung abscess
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lung infection
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 76 (7.89%)
    6 / 78 (7.69%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Post procedural infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 76 (1.32%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Decreased appetite
         subjects affected / exposed
    3 / 76 (3.95%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Buparlisib + Paclitaxel Buparlisib matching placebo + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 76 (100.00%)
    75 / 78 (96.15%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 78 (2.56%)
         occurrences all number
    5
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 76 (14.47%)
    6 / 78 (7.69%)
         occurrences all number
    13
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    20 / 76 (26.32%)
    15 / 78 (19.23%)
         occurrences all number
    27
    19
    Face oedema
         subjects affected / exposed
    2 / 76 (2.63%)
    4 / 78 (5.13%)
         occurrences all number
    2
    4
    Fatigue
         subjects affected / exposed
    31 / 76 (40.79%)
    16 / 78 (20.51%)
         occurrences all number
    45
    19
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 76 (2.63%)
    4 / 78 (5.13%)
         occurrences all number
    2
    4
    Oedema peripheral
         subjects affected / exposed
    5 / 76 (6.58%)
    10 / 78 (12.82%)
         occurrences all number
    5
    12
    Pyrexia
         subjects affected / exposed
    12 / 76 (15.79%)
    16 / 78 (20.51%)
         occurrences all number
    16
    23
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 78 (5.13%)
         occurrences all number
    1
    4
    Cough
         subjects affected / exposed
    17 / 76 (22.37%)
    18 / 78 (23.08%)
         occurrences all number
    18
    20
    Dysphonia
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 78 (5.13%)
         occurrences all number
    3
    4
    Dyspnoea
         subjects affected / exposed
    8 / 76 (10.53%)
    13 / 78 (16.67%)
         occurrences all number
    10
    17
    Epistaxis
         subjects affected / exposed
    7 / 76 (9.21%)
    4 / 78 (5.13%)
         occurrences all number
    7
    5
    Haemoptysis
         subjects affected / exposed
    1 / 76 (1.32%)
    7 / 78 (8.97%)
         occurrences all number
    1
    7
    Hiccups
         subjects affected / exposed
    5 / 76 (6.58%)
    3 / 78 (3.85%)
         occurrences all number
    9
    3
    Oropharyngeal pain
         subjects affected / exposed
    5 / 76 (6.58%)
    6 / 78 (7.69%)
         occurrences all number
    5
    6
    Pneumonitis
         subjects affected / exposed
    4 / 76 (5.26%)
    3 / 78 (3.85%)
         occurrences all number
    4
    3
    Productive cough
         subjects affected / exposed
    4 / 76 (5.26%)
    3 / 78 (3.85%)
         occurrences all number
    5
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    13 / 76 (17.11%)
    9 / 78 (11.54%)
         occurrences all number
    17
    10
    Depression
         subjects affected / exposed
    13 / 76 (17.11%)
    7 / 78 (8.97%)
         occurrences all number
    16
    7
    Insomnia
         subjects affected / exposed
    10 / 76 (13.16%)
    6 / 78 (7.69%)
         occurrences all number
    13
    6
    Mood altered
         subjects affected / exposed
    4 / 76 (5.26%)
    5 / 78 (6.41%)
         occurrences all number
    4
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 76 (7.89%)
    4 / 78 (5.13%)
         occurrences all number
    6
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 76 (7.89%)
    7 / 78 (8.97%)
         occurrences all number
    8
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 76 (7.89%)
    1 / 78 (1.28%)
         occurrences all number
    6
    1
    Blood creatinine increased
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 78 (1.28%)
         occurrences all number
    6
    1
    Blood glucose increased
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 78 (5.13%)
         occurrences all number
    4
    5
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    5 / 76 (6.58%)
    5 / 78 (6.41%)
         occurrences all number
    5
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 76 (10.53%)
    7 / 78 (8.97%)
         occurrences all number
    9
    8
    Neutrophil count decreased
         subjects affected / exposed
    5 / 76 (6.58%)
    4 / 78 (5.13%)
         occurrences all number
    5
    7
    Weight decreased
         subjects affected / exposed
    19 / 76 (25.00%)
    9 / 78 (11.54%)
         occurrences all number
    27
    11
    White blood cell count decreased
         subjects affected / exposed
    7 / 76 (9.21%)
    3 / 78 (3.85%)
         occurrences all number
    18
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 76 (7.89%)
    6 / 78 (7.69%)
         occurrences all number
    6
    7
    Dysgeusia
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 78 (1.28%)
         occurrences all number
    4
    1
    Headache
         subjects affected / exposed
    14 / 76 (18.42%)
    6 / 78 (7.69%)
         occurrences all number
    17
    6
    Neuropathy peripheral
         subjects affected / exposed
    6 / 76 (7.89%)
    18 / 78 (23.08%)
         occurrences all number
    7
    21
    Paraesthesia
         subjects affected / exposed
    8 / 76 (10.53%)
    9 / 78 (11.54%)
         occurrences all number
    11
    12
    Peripheral sensory neuropathy
         subjects affected / exposed
    6 / 76 (7.89%)
    3 / 78 (3.85%)
         occurrences all number
    6
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    29 / 76 (38.16%)
    32 / 78 (41.03%)
         occurrences all number
    39
    42
    Leukopenia
         subjects affected / exposed
    7 / 76 (9.21%)
    13 / 78 (16.67%)
         occurrences all number
    15
    28
    Neutropenia
         subjects affected / exposed
    23 / 76 (30.26%)
    10 / 78 (12.82%)
         occurrences all number
    49
    21
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 76 (9.21%)
    2 / 78 (2.56%)
         occurrences all number
    7
    2
    Constipation
         subjects affected / exposed
    14 / 76 (18.42%)
    8 / 78 (10.26%)
         occurrences all number
    15
    9
    Diarrhoea
         subjects affected / exposed
    26 / 76 (34.21%)
    13 / 78 (16.67%)
         occurrences all number
    50
    23
    Dyspepsia
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 78 (2.56%)
         occurrences all number
    4
    2
    Dysphagia
         subjects affected / exposed
    9 / 76 (11.84%)
    5 / 78 (6.41%)
         occurrences all number
    10
    5
    Nausea
         subjects affected / exposed
    19 / 76 (25.00%)
    13 / 78 (16.67%)
         occurrences all number
    22
    19
    Odynophagia
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 78 (1.28%)
         occurrences all number
    5
    1
    Oral pain
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 78 (1.28%)
         occurrences all number
    4
    1
    Stomatitis
         subjects affected / exposed
    23 / 76 (30.26%)
    10 / 78 (12.82%)
         occurrences all number
    30
    13
    Vomiting
         subjects affected / exposed
    19 / 76 (25.00%)
    11 / 78 (14.10%)
         occurrences all number
    25
    15
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    24 / 76 (31.58%)
    15 / 78 (19.23%)
         occurrences all number
    25
    15
    Dry skin
         subjects affected / exposed
    8 / 76 (10.53%)
    2 / 78 (2.56%)
         occurrences all number
    8
    2
    Dermatitis acneiform
         subjects affected / exposed
    5 / 76 (6.58%)
    1 / 78 (1.28%)
         occurrences all number
    9
    1
    Erythema
         subjects affected / exposed
    8 / 76 (10.53%)
    2 / 78 (2.56%)
         occurrences all number
    8
    3
    Onycholysis
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    0
    4
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 78 (0.00%)
         occurrences all number
    4
    0
    Pruritus
         subjects affected / exposed
    8 / 76 (10.53%)
    3 / 78 (3.85%)
         occurrences all number
    10
    4
    Rash
         subjects affected / exposed
    14 / 76 (18.42%)
    11 / 78 (14.10%)
         occurrences all number
    18
    14
    Rash maculo-papular
         subjects affected / exposed
    5 / 76 (6.58%)
    3 / 78 (3.85%)
         occurrences all number
    8
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 76 (0.00%)
    6 / 78 (7.69%)
         occurrences all number
    0
    7
    Muscle spasms
         subjects affected / exposed
    4 / 76 (5.26%)
    3 / 78 (3.85%)
         occurrences all number
    4
    3
    Muscular weakness
         subjects affected / exposed
    0 / 76 (0.00%)
    5 / 78 (6.41%)
         occurrences all number
    0
    5
    Musculoskeletal pain
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 78 (2.56%)
         occurrences all number
    5
    2
    Myalgia
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 78 (1.28%)
         occurrences all number
    4
    2
    Neck pain
         subjects affected / exposed
    6 / 76 (7.89%)
    7 / 78 (8.97%)
         occurrences all number
    7
    7
    Pain in extremity
         subjects affected / exposed
    1 / 76 (1.32%)
    5 / 78 (6.41%)
         occurrences all number
    1
    5
    Pain in jaw
         subjects affected / exposed
    5 / 76 (6.58%)
    1 / 78 (1.28%)
         occurrences all number
    5
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 76 (5.26%)
    4 / 78 (5.13%)
         occurrences all number
    5
    4
    Pneumonia
         subjects affected / exposed
    2 / 76 (2.63%)
    6 / 78 (7.69%)
         occurrences all number
    2
    6
    Respiratory tract infection
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 78 (2.56%)
         occurrences all number
    5
    4
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 78 (5.13%)
         occurrences all number
    1
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 76 (30.26%)
    14 / 78 (17.95%)
         occurrences all number
    34
    15
    Hyperglycaemia
         subjects affected / exposed
    47 / 76 (61.84%)
    27 / 78 (34.62%)
         occurrences all number
    95
    46
    Hyperkalaemia
         subjects affected / exposed
    2 / 76 (2.63%)
    8 / 78 (10.26%)
         occurrences all number
    2
    10
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 76 (5.26%)
    3 / 78 (3.85%)
         occurrences all number
    5
    3
    Hypocalcaemia
         subjects affected / exposed
    5 / 76 (6.58%)
    4 / 78 (5.13%)
         occurrences all number
    7
    5
    Hypokalaemia
         subjects affected / exposed
    7 / 76 (9.21%)
    3 / 78 (3.85%)
         occurrences all number
    9
    3
    Hypomagnesaemia
         subjects affected / exposed
    4 / 76 (5.26%)
    6 / 78 (7.69%)
         occurrences all number
    12
    7
    Hyponatraemia
         subjects affected / exposed
    5 / 76 (6.58%)
    6 / 78 (7.69%)
         occurrences all number
    8
    8
    Hypophosphataemia
         subjects affected / exposed
    3 / 76 (3.95%)
    5 / 78 (6.41%)
         occurrences all number
    3
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2013
    Amendment 1 introduced the following changes: • Added pharmacokinetics (PK) sampling collection in a subset of patients in order to characterize the PK of buparlisib given in combination with paclitaxel. Aim: to assess if patients treated with buparlisib are exposed to the drug within the targeted range. The inclusion of this assessment was based on findings that emerged from Study CBEZ235A2118, which investigated the use of the same combination. The collection of additional PK data was to provide more information in support of this study indication and also to obtain a more robust population PK model based on several indications currently in clinical development using the same regimen. Objectives and statistical plan were updated accordingly. • Reduced the amount of tumor tissue required at Baseline for HPV and PI3K pathway determination Novartis had adopted the use of a more sensitive platform requiring smaller amount of DNA compared to the one previously used. The list of biomarkers being assessed was not changed. •Allowed confirmation of an adequate amount of tumor tissue for enrollment by central or local pathologist in order to accelerate the turnaround time for eligibility decision making process and eventually to start the study treatment earlier. • Mild and asymptomatic transaminase elevations at Baseline are a common finding in this patient population even in the absence of liver metastasis (e.g. related to concomitant medications, prior treatment/surgery, underlying disease, fatty liver, etc.). Therefore, the upper limit for aspartate aminotransferase (AST)/alanine aminotransferase (ALT) in patients without liver metastases was slightly increased to allow 1.5x upper limit of normal (ULN) for study inclusion. The ULN for bilirubin remained unchanged
    02 Jul 2015
    Amendment 2 issued when recruitment was 100% complete, introduced the following change(s): • Provided additional guidance to Investigators regarding management of liver toxicities: o Clarification of the management of AST or ALT side effects o New section added “Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) in patients receiving buparlisib/placebo” including detailed liver event follow-up assessments and close monitoring measures • Addition of hepatotoxicity follow-up testing/procedures • Clarification provided in the data analysis to reflect the change in wording for number of events needed for final PFS and final OS analyses • Update of the clinical background section on liver toxicity to align with the protocol amendment rationale. • Clarification of laboratory parameters collection plan and viral hepatitis testing. • Clarification of the wording for the number of PFS events required for the PFS analysis and for the number of deaths to be observed for the planned final Overall Survival analyses.
    30 Aug 2016
    The main purposes of this protocol amendment 3 were to: • Provide a clarification on the measures to follow when a patient exhibits suicidal ideation regardless of the response to question 9 of the Patient Health Questionnaire-9 (PHQ-9) questionnaire (as has been described in the BKM120 Investigator’s Brochure Ed. 8.0). • Unblind patients’ treatment considering that all planned analyses (final PFS analysis & final OS analysis) have been completed. The study was to be closed after LPLV. • Reduce assessment schedule for patients still on study treatment. Tumor assessment will be performed per local clinical practices & safety evaluation will be done per revised visit schedule. • For patients who are still on study treatment & are considered benefiting from study drug (s), study treatment will continue to be provided on or off this study. Treatment for these patients can also be managed according to local clinical practices per Investigator discretion.

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

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