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    Clinical Trial Results:
    A phase Ib/II multi-center, open-label, dose escalation study of LGX818 and cetuximab or LGX818, BYL719, and cetuximab in patients with BRAF mutant metastatic colorectal cancer

    Summary
    EudraCT number
    		 2012-002138-35
    Trial protocol
    		 ES   DE   NL   IT   NO   BE  
    Global end of trial date
    12 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Feb 2020
    First version publication date
    21 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLGX818X2103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01719380
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Array BioPharma Inc.
    Sponsor organisation address
    3200 Walnut Street, Boulder, United States, 80301
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., Array BioPharma Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., Array BioPharma Inc., +1 18007181021, 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
    Final
    Date of interim/final analysis
    12 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase Ib: To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of encorafenib in combination with cetuximab ± alpelisib Phase II: To compare the efficacy of the dual (encorafenib, cetuximab) and triple (encorafenib, alpelisib, cetuximab) combinations Secondary objective (Phase 1b and Phase 2): To characterize the safety and tolerability of encorafenib in combination with cetuximab ± alpelisib
    Protection of trial subjects
    Before each subject was admitted to the clinical study, informed consent was to be obtained from the subject (or his/her legally authorized representative) according to the regulatory and legal requirements of the participating country. The informed consent form (ICF) was to be dated and retained by the investigator as part of the clinical study records. The investigator was not to undertake any investigation specifically required for the clinical study until valid consent was obtained. The date consent was obtained was to be documented in the electronic case report form (eCRF). Each subject was to receive a fully signed copy of each consent form that he/she signed for the clinical study.
    Background therapy
    		 Pre-medications for routine cetuximab infusions must have been used in accordance with the label and with the national and/or institutional standards. Following cetuximab label instructions, medications such as corticosteroids and anti-histamines was administered at the discretion of the Investigator to treat an existing infusion reaction, or as pre-medication for a patient who had previously experienced an infusion reaction. Concomitant therapy used from the time the subject signed the ICF through the study treatment period was recorded in the eCRF, including medications required for treatment of any AEs or SAEs. The medication name, dosage, date, and indication for use was recorded.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 41
    Country: Number of subjects enrolled
    Norway: 12
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    United States: 37
    Worldwide total number of subjects
    156
    EEA total number of subjects
    80
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    107
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible subjects for this study were those who had BRAF-mutant mCRC and whose disease had progressed despite previous antineoplastic therapy or for whom no further effective standard therapy was available. For Phase 1b, subjects who were chemo-naïve were eligible if other standard therapy was not considered effective.

    Pre-assignment
    Screening details
    		 All screening assessments were completed within 14 days before the first dose for phase Ib and before randomization for phase II, with the exception of the baseline imaging assessments (≤ 21 days), dermatologic evaluations (≤ 21 days), and the determination of the BRAF and KRAS mutational status.

    Period 1
    Period 1 title
    Phase 1b
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label phase I dose escalation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dual (Encorafenib+Cetuximab)
    Arm description
    		 Treatment assignment of subjects in each cohort in the dose escalation part was coordinated by the sponsor with allocation forms. The starting dose for the dual combination study drugs was 100 mg QD for Encorafenib and 400 mg/m² initial dose (cycle 1 day 1) and 250 mg/m² subsequent weekly doses as an intravenous infusion for Cetuximab. The following dual combinations were used Encorafenib 100 mg QD + Cetuximab; Encorafenib 200 mg (QD) + Cetuximab; Encorafenib 400 mg (QD) + Cetuximab; Encorafenib 450 mg (QD) + Cetuximab 400 mg/m² QW as intravenous infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    LGX818
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Encorafenib 25 mg, 50 mg, and 100 mg capsules for oral administration once daily (QD).

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab initial administered dose (Cycle 1 Day 1) was 400 mg/m2 as a 120-minute intravenous infusion followed by 250 mg/m2 weekly dose infused over 60 minutes. The infusion rate was not exceed 10 mg/min.

    Arm title
    		 Triple (Encorafenib+Alpelisib+Cetuximab)
    Arm description
    		 Treatment assignment of subjects in each cohort in the dose escalation part was coordinated by the sponsor with allocation forms. The following triple combinations were used: Encorafenib 200 mg + Alpelisib 100 mg (QD) + Cetuximab; Encorafenib 200 mg + Alpelisib 200 mg (QD) + Cetuximab; Encorafenib 200 mg + Alpelisib 300 mg (QD) + Cetuximab; Encorafenib 300 mg + Alpelisib 200 mg (QD) + Cetuximab (MTD/RP2D of dual) as intravenous infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alpelisib
    Investigational medicinal product code
    BYL719
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alpelisib 50 mg and 200 mg tablets for oral administration QD.

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    LGX818
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Encorafenib 25 mg, 50 mg, and 100 mg capsules for oral administration once daily (QD).

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab initial administered dose (Cycle 1 Day 1) was 400 mg/m2 as a 120-minute intravenous infusion followed by 250 mg/m2 weekly dose infused over 60 minutes. The infusion rate was not exceed 10 mg/min.

    Number of subjects in period 1
    		Dual (Encorafenib+Cetuximab) Triple (Encorafenib+Alpelisib+Cetuximab)
    Started
    26
    28
    Completed
    50
    52
    Not completed
    26
    28
         All subjects from Period 1 have discontinued
    26
    28
    Joined
    50
    52
         New patients enrolled in phase 2 analysis
    50
    52
    Period 2
    Period 2 title
    Phase 2
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study. Randomization was used in Phase 2 to ensure that treatment assignment was unbiased. Patients were assigned to one of the 2 treatment arms in a ratio of 1:1.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dual (Encorafenib+Cetuximab)
    Arm description
    		 Encorafenib 200 mg QD + Cetuximab 400 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 QW.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    LGX818
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Encorafenib 25 mg, 50 mg, and 100 mg capsules for oral administration once daily (QD).

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab initial administered dose (Cycle 1 Day 1) was 400 mg/m2 as a 120-minute intravenous infusion followed by 250 mg/m2 weekly dose infused over 60 minutes. The infusion rate was not exceed 10 mg/min.

    Arm title
    		 Triple (Encorafenib+Alpelisib+Cetuximab)
    Arm description
    		 Encorafenib 200 mg QD + Alpelisib 300 mg QD + Cetuximab 400 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 QW
    Arm type
    		 Experimental

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    LGX818
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Encorafenib 25 mg, 50 mg, and 100 mg capsules for oral administration once daily (QD).

    Investigational medicinal product name
    Alpelisib
    Investigational medicinal product code
    BYL719
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alpelisib 50 mg and 200 mg tablets for oral administration QD.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab initial administered dose (Cycle 1 Day 1) was 400 mg/m2 as a 120-minute intravenous infusion followed by 250 mg/m2 weekly dose infused over 60 minutes. The infusion rate was not exceed 10 mg/min.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The main results are based on Period 2, that is why Period 2 is taken as Baseline period. The design of Phase 1b dose-escalation part (Period 1) of the study was to determine the MTD and/or RP2D of Encorafenib in combination with Cetuximab (dual combination) and the MTD and/or RP2D of Encorafenib in combination with Alpelisib and Cetuximab (triple combination). Randomized Phase (Period 2) was designed to assess clinical efficacy and to characterize the safety of the drug combinations.
    Number of subjects in period 2 [2]
    		Dual (Encorafenib+Cetuximab) Triple (Encorafenib+Alpelisib+Cetuximab)
    Started
    50
    52
    Completed
    0
    1
    Not completed
    50
    51
         Adverse event, serious fatal
    3
    3
         Physician decision
    1
    1
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    4
    3
         Lack of efficacy
    40
    42
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 156 subjects were enrolled in the study (54 subjects in Phase 1b and 102 subjects in Phase 2). Efficacy and safety data for Full Analysis Set and Safety Set included 102 randomized subjects. Data for Incidence of dose-limiting toxicities for phase 1b (54 subjects) was provided as primary endpoint.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dual (Encorafenib+Cetuximab)
    Reporting group description
    		 Encorafenib 200 mg QD + Cetuximab 400 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 QW.

    Reporting group title
    Triple (Encorafenib+Alpelisib+Cetuximab)
    Reporting group description
    		 Encorafenib 200 mg QD + Alpelisib 300 mg QD + Cetuximab 400 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 QW

    Reporting group values
    		 Dual (Encorafenib+Cetuximab) Triple (Encorafenib+Alpelisib+Cetuximab) Total
    Number of subjects
    		 50 52 102
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 32 38 70
        From 65-84 years
    		 18 14 32
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 49.5 (20 to 79) 52.5 (29 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 36 27 63
        Male
    		 14 25 39
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis set (FAS) - comprised all randomized patients in Phase 2.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set included all subjects from the FAS who received at least one dose of Encorafenib, Alpelisib or Cetuximab and had at least one valid post-baseline safety assessment.

    Subject analysis sets values
    		 Full Analysis Set Safety Set
    Number of subjects
    102
    102
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    70
    70
        From 65-84 years
    32
    32
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    49.5 (20 to 79)
    52.5 (29 to 76)
    Gender categorical
    Units: Subjects
        Female
    63
    63
        Male
    39
    39

    End points

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    End points reporting groups
    Reporting group title
    Dual (Encorafenib+Cetuximab)
    Reporting group description
    		 Treatment assignment of subjects in each cohort in the dose escalation part was coordinated by the sponsor with allocation forms. The starting dose for the dual combination study drugs was 100 mg QD for Encorafenib and 400 mg/m² initial dose (cycle 1 day 1) and 250 mg/m² subsequent weekly doses as an intravenous infusion for Cetuximab. The following dual combinations were used Encorafenib 100 mg QD + Cetuximab; Encorafenib 200 mg (QD) + Cetuximab; Encorafenib 400 mg (QD) + Cetuximab; Encorafenib 450 mg (QD) + Cetuximab 400 mg/m² QW as intravenous infusion.

    Reporting group title
    Triple (Encorafenib+Alpelisib+Cetuximab)
    Reporting group description
    		 Treatment assignment of subjects in each cohort in the dose escalation part was coordinated by the sponsor with allocation forms. The following triple combinations were used: Encorafenib 200 mg + Alpelisib 100 mg (QD) + Cetuximab; Encorafenib 200 mg + Alpelisib 200 mg (QD) + Cetuximab; Encorafenib 200 mg + Alpelisib 300 mg (QD) + Cetuximab; Encorafenib 300 mg + Alpelisib 200 mg (QD) + Cetuximab (MTD/RP2D of dual) as intravenous infusion.
    Reporting group title
    Dual (Encorafenib+Cetuximab)
    Reporting group description
    		 Encorafenib 200 mg QD + Cetuximab 400 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 QW.

    Reporting group title
    Triple (Encorafenib+Alpelisib+Cetuximab)
    Reporting group description
    		 Encorafenib 200 mg QD + Alpelisib 300 mg QD + Cetuximab 400 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 QW

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis set (FAS) - comprised all randomized patients in Phase 2.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set included all subjects from the FAS who received at least one dose of Encorafenib, Alpelisib or Cetuximab and had at least one valid post-baseline safety assessment.

    Primary: Incidence of dose-limiting toxicities

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    End point title
    		 Incidence of dose-limiting toxicities [1]
    End point description
    In Phase 1b, estimation of the MTD of both the dual and triple combination treatments was based on the incidence of dose-limiting toxicity (DLT) in Cycle 1 for patients in the Dose-determining Set. Incidence of serious adverse events were provided for all product strengths in dual (LGX818 + Cetuximab) and triple (LGX818 + BYL719 + Cetuximab) combinations for subjects who participated in Phase 1b.
    End point type
    Primary
    End point timeframe
    Incidence of dose-limiting toxicities (DLTs) were defined from date of taking of first dose of study drug until receipt of at least 21 out of 28 planned daily oral doses in Cycle 1 of treatment.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There is no statistical analysis for the end point.
    End point values
    		 Dual (Encorafenib+Cetuximab) Triple (Encorafenib+Alpelisib+Cetuximab)
    Number of subjects analysed
    26
    28
    Units: Incidence of serious adverse events
        Incidence of SAEs in LGX818 100 mg+Cetuximab
    2
    0
        Incidence of SAEs in LGX818 200 mg+Cetuximab
    13
    0
        Incidence of SAEs in LGX818 400 mg+Cetuximab
    14
    0
        Incidence of SAEs in LGX818 450 mg+Cetuximab
    20
    0
        Incidence of SAEs in LGX818 200 mg+BYL719 100 mg+C
    0
    2
        Incidence of SAEs in LGX818 200 mg+BYL719 200 mg+C
    0
    16
        Incidence of SAEs in LGX818 200 mg+BYL719 300 mg+C
    0
    9
        Incidence of SAEs in LGX818 300 mg+BYL719 200 mg+C
    0
    8
    No statistical analyses for this end point

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    The primary efficacy endpoint in Phase 2 was the comparison of the PFS between the dual combination MTD/RP2D and triple combination MTD/RP2D. PFS values were based on Kaplan-Meier estimates. This corresponded to an estimated 19.0% risk reduction in disease progression or death for subjects treated with the triple combination compared to those treated with the dual combination.
    End point type
    Primary
    End point timeframe
    Progression-free survival (PFS) was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause.
    End point values
    		 Dual (Encorafenib+Cetuximab) Triple (Encorafenib+Alpelisib+Cetuximab)
    Number of subjects analysed
    50
    52
    Units: months
    median (confidence interval 95%)
        2 months
    87.5 (74.3 to 94.2)
    82.6 (69.2 to 90.5)
        4 months
    53.1 (37.9 to 66.1)
    64.1 (49.1 to 75.7)
        6 months
    28.5 (15.9 to 42.4)
    38.9 (25.3 to 52.2)
        8 months
    18.1 (8.2 to 31.2)
    32.4 (19.8 to 45.7)
        10 months
    12.9 (4.8 to 25.2)
    27.9 (16.1 to 41.1)
        12 months
    12.9 (4.8 to 25.2)
    25.6 (14.2 to 38.6)
        14 months
    7.8 (2.0 to 18.7)
    11.6 (4.3 to 22.9)
        16 months
    7.8 (2.0 to 18.7)
    9.3 (3.0 to 20.0)
        18 months
    7.8 (2.0 to 18.7)
    7.0 (1.8 to 17.0)
    Statistical analysis title
    		 Statistical Analysis Plan
    Statistical analysis description
    Statistical Analysis provided Kaplan-Meier plot for progression-free survival. Hazard ratio of dual combination was 4.2 (3.0, 5.1) and for triple combination was 4.9 (4.0, 7.0). P-value: statistical significance (one-sided) at the alpha 0.05 level. This corresponded to an estimated 19.0% risk reduction in disease progression or death for subjects treated with the triple combination compared to those treated with the dual combination
    Comparison groups
    Dual (Encorafenib+Cetuximab) v Triple (Encorafenib+Alpelisib+Cetuximab)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1645 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.532
         upper limit
    		 1.234
    Notes
    [2] - one-sided log rank test p = 0.1645

    Secondary: Duration of Exposure

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    End point title
    		 Duration of Exposure
    End point description
    Duration of exposure was defined as: date of last exposure to study treatment - date of first administration of study treatment +1. There were no on-treatment patient deaths or AEs leading to discontinuation of study treatment reported between the primary CSR data cutoff date and the last patient assessment.
    End point type
    Secondary
    End point timeframe
    Inclusion of explosure of data from date of randomization until date of last patient assessment.
    End point values
    		 Dual (Encorafenib+Cetuximab) Triple (Encorafenib+Alpelisib+Cetuximab)
    Number of subjects analysed
    50
    52
    Units: weeks
        median (full range (min-max))
    17.79 (1.1 to 228.1)
    22.14 (0.3 to 161.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for adverse event reporting is from start of treatment within 30 days of the last study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Dual combination
    Reporting group description
    		 Encorafenib 200 mg QD + Cetuximab 400 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 QW

    Reporting group title
    Triple combination
    Reporting group description
    		 Encorafenib 200 mg QD + Alpelisib 300 mg QD + Cetuximab 400 mg/m2 on Cycle 1 Day 1 and 250 mg/m2 QW

    Serious adverse events
    		 Dual combination Triple combination
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 50 (52.00%)
    33 / 52 (63.46%)
         number of deaths (all causes)
    7
    9
         number of deaths resulting from adverse events
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Eye naevus
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    Thrombosis in device
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (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 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Refractoriness to platelet transfusion
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 52 (9.62%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal fistula
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         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
    Arthralgia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site abscess
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dual combination Triple combination
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    52 / 52 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 52 (0.00%)
         occurrences all number
    5
    0
    Melanocytic naevus
         subjects affected / exposed
    1 / 50 (2.00%)
    6 / 52 (11.54%)
         occurrences all number
    1
    6
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 52 (3.85%)
         occurrences all number
    4
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    25 / 50 (50.00%)
    27 / 52 (51.92%)
         occurrences all number
    25
    27
    Pyrexia
         subjects affected / exposed
    12 / 50 (24.00%)
    11 / 52 (21.15%)
         occurrences all number
    12
    11
    Oedema peripheral
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 52 (9.62%)
         occurrences all number
    5
    5
    Pain
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 52 (0.00%)
         occurrences all number
    4
    0
    Malaise
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 52 (5.77%)
         occurrences all number
    3
    3
    Influenza like illness
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Asthenia
         subjects affected / exposed
    0 / 50 (0.00%)
    8 / 52 (15.38%)
         occurrences all number
    0
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 50 (16.00%)
    7 / 52 (13.46%)
         occurrences all number
    8
    7
    Dyspnoea
         subjects affected / exposed
    8 / 50 (16.00%)
    3 / 52 (5.77%)
         occurrences all number
    8
    3
    Oropharyngeal pain
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 52 (0.00%)
         occurrences all number
    4
    0
    Epistaxis
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 52 (3.85%)
         occurrences all number
    3
    2
    Dysphonia
         subjects affected / exposed
    2 / 50 (4.00%)
    7 / 52 (13.46%)
         occurrences all number
    2
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 50 (16.00%)
    8 / 52 (15.38%)
         occurrences all number
    8
    8
    Anxiety
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 52 (3.85%)
         occurrences all number
    5
    2
    Investigations
    Lipase increased
         subjects affected / exposed
    17 / 50 (34.00%)
    7 / 52 (13.46%)
         occurrences all number
    17
    7
    Weight decreased
         subjects affected / exposed
    10 / 50 (20.00%)
    19 / 52 (36.54%)
         occurrences all number
    10
    19
    Amylase increased
         subjects affected / exposed
    7 / 50 (14.00%)
    3 / 52 (5.77%)
         occurrences all number
    7
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 52 (9.62%)
         occurrences all number
    5
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 50 (10.00%)
    4 / 52 (7.69%)
         occurrences all number
    5
    4
    Neutrophil count decreased
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 52 (0.00%)
         occurrences all number
    4
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Blood bilirubin increased
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 52 (9.62%)
         occurrences all number
    1
    5
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 52 (7.69%)
         occurrences all number
    0
    4
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 52 (3.85%)
         occurrences all number
    5
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 50 (34.00%)
    13 / 52 (25.00%)
         occurrences all number
    17
    13
    Dizziness
         subjects affected / exposed
    6 / 50 (12.00%)
    4 / 52 (7.69%)
         occurrences all number
    6
    4
    Dysgeusia
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 52 (13.46%)
         occurrences all number
    4
    7
    Paraesthesia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 52 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 50 (16.00%)
    12 / 52 (23.08%)
         occurrences all number
    8
    12
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 52 (7.69%)
         occurrences all number
    3
    4
    Cataract
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Vision blurred
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    23 / 50 (46.00%)
    30 / 52 (57.69%)
         occurrences all number
    23
    30
    Vomiting
         subjects affected / exposed
    18 / 50 (36.00%)
    25 / 52 (48.08%)
         occurrences all number
    18
    25
    Abdomina pain
         subjects affected / exposed
    17 / 50 (34.00%)
    21 / 52 (40.38%)
         occurrences all number
    17
    21
    Constipation
         subjects affected / exposed
    14 / 50 (28.00%)
    6 / 52 (11.54%)
         occurrences all number
    14
    6
    Diarrhoea
         subjects affected / exposed
    14 / 50 (28.00%)
    29 / 52 (55.77%)
         occurrences all number
    14
    29
    Abdominal pain upper
         subjects affected / exposed
    5 / 50 (10.00%)
    4 / 52 (7.69%)
         occurrences all number
    5
    4
    Stomatitis
         subjects affected / exposed
    5 / 50 (10.00%)
    18 / 52 (34.62%)
         occurrences all number
    5
    18
    Dyspepsia
         subjects affected / exposed
    4 / 50 (8.00%)
    8 / 52 (15.38%)
         occurrences all number
    4
    8
    Ascites
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 52 (5.77%)
         occurrences all number
    3
    3
    Dry mouth
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Flatulence
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    9 / 50 (18.00%)
    12 / 52 (23.08%)
         occurrences all number
    9
    12
    Dry skin
         subjects affected / exposed
    9 / 50 (18.00%)
    15 / 52 (28.85%)
         occurrences all number
    9
    15
    Rash
         subjects affected / exposed
    9 / 50 (18.00%)
    18 / 52 (34.62%)
         occurrences all number
    9
    18
    Pruritus
         subjects affected / exposed
    7 / 50 (14.00%)
    9 / 52 (17.31%)
         occurrences all number
    7
    9
    Acne
         subjects affected / exposed
    6 / 50 (12.00%)
    4 / 52 (7.69%)
         occurrences all number
    6
    4
    Skin fissures
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 52 (9.62%)
         occurrences all number
    5
    5
    Alopecia
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 52 (7.69%)
         occurrences all number
    3
    4
    Erythema
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Skin hyperpigmentation
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 52 (7.69%)
         occurrences all number
    3
    4
    Hyperkeratosis
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Pruritus generalised
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Rash maculo-papular
         subjects affected / exposed
    2 / 50 (4.00%)
    11 / 52 (21.15%)
         occurrences all number
    2
    11
    Actinic keratosis
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Erythema multiforme
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 50 (38.00%)
    15 / 52 (28.85%)
         occurrences all number
    19
    15
    Back pain
         subjects affected / exposed
    12 / 50 (24.00%)
    10 / 52 (19.23%)
         occurrences all number
    12
    10
    Myalgia
         subjects affected / exposed
    8 / 50 (16.00%)
    12 / 52 (23.08%)
         occurrences all number
    8
    12
    Pain in extremity
         subjects affected / exposed
    8 / 50 (16.00%)
    9 / 52 (17.31%)
         occurrences all number
    8
    9
    Musculoskeletal pain
         subjects affected / exposed
    4 / 50 (8.00%)
    9 / 52 (17.31%)
         occurrences all number
    4
    9
    Muscle spasms
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 52 (9.62%)
         occurrences all number
    2
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Bone pain
         subjects affected / exposed
    0 / 50 (0.00%)
    6 / 52 (11.54%)
         occurrences all number
    0
    6
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 52 (11.54%)
         occurrences all number
    3
    6
    Gastroenteritis
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Paronychia
         subjects affected / exposed
    1 / 50 (2.00%)
    7 / 52 (13.46%)
         occurrences all number
    1
    7
    Rash pustular
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Cystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 52 (7.69%)
         occurrences all number
    0
    4
    Nail infection
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Tooth infection
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 50 (32.00%)
    19 / 52 (36.54%)
         occurrences all number
    16
    19
    Hypokalaemia
         subjects affected / exposed
    6 / 50 (12.00%)
    10 / 52 (19.23%)
         occurrences all number
    6
    10
    Hyperglycaemia
         subjects affected / exposed
    5 / 50 (10.00%)
    18 / 52 (34.62%)
         occurrences all number
    5
    18
    Hypomagnesaemia
         subjects affected / exposed
    4 / 50 (8.00%)
    11 / 52 (21.15%)
         occurrences all number
    4
    11
    Hyponatraemia
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Hypophosphataemia
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 52 (13.46%)
         occurrences all number
    3
    7
    Dehydration
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 52 (7.69%)
         occurrences all number
    2
    4
    Hypocalcaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jul 2013
    Amendment 1 (date 03 July 2013) - The main purpose of this amendment was to introduce enhanced safety monitoring and risk assessment to mitigate any potential development of TLS in patients. This safety monitoring was implemented for all patients enrolled in this study. In addition, collection of overall survival data was added to the phase 1b dose escalation portion of the study as a secondary endpoint to have some initial understanding of long term benefit of patients treated at dual (LGX818 plus cetuximab) and triple (LGX818 plus cetuximab plus BYL719) combination. Lastly, the protocol was amended to allow that doses higher than LGX818 single agent MTD could be explored in combination with cetuximab and/or BYL719.
    24 Oct 2013
    Amendment 2 (date 24 October 2013) - The main purpose of this amendment was to further clarify the patient population for this study as preliminary study data suggested that patients with Braf mutations other than V600 E had benefit from the study treatment. In addition, DLT criteria was updated to clarify that any Tumor Lysis Syndrome CTCAE Grade ≥4 (Life-threatening TLS) was considered a DLT regardless whether protocol mandated monitoring was implemented. Inclusion/exclusion criteria was changed to include patients with Braf mutations other than V600, to evaluate early efficacy signals in this population. Patients with elevated blood glucose values, or with a diagnosis of diabetes mellitus, were excluded from protocol participation as BYL719 causes hyperglycemia. However, both LGX818 and cetuximab did not cause blood glucose elevation and given that patients with V600 Braf mutations in metastatic colorectal carcinoma were rare, patients with glucose elevation considered for LGX818 and cetuximab dual combination treatment was not be excluded in the phase 1 dose escalation portion of the study. This amendment introduced the monitoring of tumor markers CEA and CA19-9 during treatment. Intra-patient dose escalation to the recommended phase 2 dose was permitted with this amendment. All radiological assessments obtained for patients was centrally collected and centrally reviewed for confirmation of efficacy.
    16 Dec 2013
    Amendment 3 (date 16 December 2013) - The main objective of this amendment was to introduce new safety monitoring for visual toxicities. This amendment implemented routine ophthalmic examinations (baseline, C4D1(day 85), every 3 cycles on day 1 (every 12 weeks) thereafter, end of treatment and as clinically indicated) in order to monitor for the potential risk of retinal/ocular changes and included recommendations for LGX818 dose modifications for visual toxicity. In addition, definitions of ophthalmologic DLTs were provided. In addition, prohibited medications were updated.
    17 Jun 2014
    Amendment 4 (date 17 June 2014) - The main purpose of this amendment was to provide guidelines for the management of pneumonitis that was experienced due to BYL719 and Cetuximab combination treatment. In addition, procedures relating to monitoring of patients at risk for tumor lysis syndrome (TLS) were adjusted. This amendment also clarified that patients participating in this trial could also be participated in another optional companion sample collection protocol with a dedicated informed consent. The companion sample collection protocol was intended to collect the samples needed to investigate the mechanisms that underlied the development of acquired resistance to treatment. The biomarker section was updated to indicate that tumor biopsies was banked for the purpose of assay development. Lastly, changes clarified on treatment imaging window for response assessment, addition of the definition of best overall response to the statistical section.
    20 Jul 2015
    Amendment 5 (date 20 July 2015) - The purpose of this amendment was to document a change in study sponsorship from Novartis to Array BioPharma. Study design and procedures were not affected. This amendment also removed reference to an optional companion sample collection protocol, as that companion protocol had enrolled no patients from the current study.

    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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