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    Clinical Trial Results:
    A Randomized, Multicenter, Open-Label Phase Ib/II Study of RO5083945 in Combination With Cisplatin and Gemcitabine/Pemetrexed Versus Cisplatin and Gemcitabine/Pemetrexed in Patients With Advanced or Recurrent Non-Small Cell Lung Cancer Who Have not Received Prior Chemotherapy

    Summary
    EudraCT number
    2010-018945-72
    Trial protocol
    DE   GB   BE  
    Global end of trial date
    01 Aug 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Mar 2016
    First version publication date
    02 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BP22349
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01185847
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann­La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann­La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann­La Roche AG, +41 61 6878333, global.trial_information@roche.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
    01 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Aug 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of RO5083945 in combination with standard chemotherapy in participants with advanced or recurrent NSCLC who have not received prior chemotherapy. In Part 1, participants received RO5083945 intravenously and standard chemotherapy (cisplatin plus either gemcitabine or pemetrexed) for up to 6 cycles of 3 weeks and then RO5083945 until disease progression, unacceptable toxicity, or withdrawal of consent. In Part 1, maximum tolerated dose (MTD) and recommended dose were established for Phase II. In Part 2, participants were randomized to receive either RO5083945 in combination with standard chemotherapy or chemotherapy alone for up to 6 cycles in non­-squamous group only. In the absence of disease progression, participants receiving RO5083945 could continue treatment with RO5083945 as monotherapy.
    Protection of trial subjects
    The investigator ensured that this study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” International Conference on Harmonisation Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the participant. For European Union/European Economic Area (EU/EEA) countries, the investigator ensured compliance with the EU Clinical Trial Directive (2001/20/ethics committee). In other countries where “Guideline for Good Clinical Practice” existed Roche and the investigators strictly ensured adherence to the stated provisions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Nov 2010
    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
    Poland: 6
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 12
    Worldwide total number of subjects
    93
    EEA total number of subjects
    93
    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)
    65
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants were classified into 2 histology groups, with squamous or non-­squamous NSCLC and sequentially enrolled into 2 consecutive cohorts (Cohort 1: chemotherapy plus [+] 1000 milligram [mg] RO5083945 followed by RO5083945 monotherapy; Cohort 2: chemotherapy + 1400 mg RO5083945 followed by RO5083945 monotherapy).

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy
    Arm description
    Chemotherapy (75 milligrams per square meter [mg/m^2] cisplatin + 1250 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously, every three weeks (q3w) for a maximum of 6 cycles (18 weeks) followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    Experimental

    Investigational medicinal product name
    RO5083945
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1000 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1250 mg/m^2 gemcitabine intravenously q3w for a maximum of 6 cycles (18 weeks).

    Arm title
    Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy
    Arm description
    Chemotherapy (75 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine ) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    Experimental

    Investigational medicinal product name
    RO5083945
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1000 mg RO5083945 intravenously q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1000 mg/m^2 gemcitabine intravenously q3w for a maximum of 6 cycles (18 weeks).

    Arm title
    Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945
    Arm description
    Chemotherapy (60 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    Experimental

    Investigational medicinal product name
    RO5083945
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1000 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 60 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1000 mg/m^2 gemcitabine intravenously q3w for a maximum of 6 cycles (18 weeks).

    Arm title
    Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy
    Arm description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    Experimental

    Investigational medicinal product name
    RO5083945
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1000 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 500 mg/m^2 pemetrexed intravenously q3w for a maximum of 6 cycles (18 weeks).

    Arm title
    Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy
    Arm description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    Experimental

    Investigational medicinal product name
    RO5083945
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1400 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 500 mg/m^2 pemetrexed intravenously q3w for a maximum of 6 cycles (18 weeks).

    Arm title
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy
    Arm description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1400 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    Experimental

    Investigational medicinal product name
    RO5083945
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1400 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 500 mg/m^2 pemetrexed intravenously q3w for a maximum of 6 cycles (18 weeks).

    Arm title
    Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Arm description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) administered intravenously q3w for a maximum of 6 cycles (18 weeks).
    Arm type
    Active comparator

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 500 mg/m^2 pemetrexed intravenously q3w for a maximum of 6 cycles (18 weeks).

    Number of subjects in period 1
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945 Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Started
    8
    1
    8
    3
    11
    41
    21
    Completed
    0
    0
    0
    0
    0
    0
    13
    Not completed
    8
    1
    8
    3
    11
    41
    8
         Progressive disease
    4
    -
    4
    3
    10
    23
    5
         Intercurrent illness
    -
    -
    -
    -
    -
    9
    -
         Non-compliance of subject
    -
    -
    -
    -
    -
    2
    -
         Not received treatment
    -
    -
    1
    -
    -
    -
    -
         Adverse event, serious fatal
    -
    1
    -
    -
    -
    1
    2
         Adverse event, non-fatal
    4
    -
    2
    -
    1
    -
    -
         Unspecified
    -
    -
    -
    -
    -
    2
    -
         Consent withdrawn by subject
    -
    -
    1
    -
    -
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 milligrams per square meter [mg/m^2] cisplatin + 1250 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously, every three weeks (q3w) for a maximum of 6 cycles (18 weeks) followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine ) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945
    Reporting group description
    Chemotherapy (60 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1400 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) administered intravenously q3w for a maximum of 6 cycles (18 weeks).

    Reporting group values
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945 Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy Total
    Number of subjects
    8 1 8 3 11 41 21
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.5 ± 7.87 61 ± 0 63.5 ± 6.59 55 ± 6.08 56.9 ± 10.6 56.3 ± 10.25 58.7 ± 11.4 -
    Gender categorical
    Units: Subjects
        Female
    1 0 0 0 4 15 3 23
        Male
    7 1 8 3 7 26 18 70

    End points

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    End points reporting groups
    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 milligrams per square meter [mg/m^2] cisplatin + 1250 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously, every three weeks (q3w) for a maximum of 6 cycles (18 weeks) followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine ) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945
    Reporting group description
    Chemotherapy (60 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1400 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) administered intravenously q3w for a maximum of 6 cycles (18 weeks).

    Primary: Progression-Free Survival (PFS) Assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

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    End point title
    Progression-Free Survival (PFS) Assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [1]
    End point description
    PFS was defined as the time between randomization and date of first documented disease progression (unequivocal appearance of new malignant lesions denotes) or death, whichever occurred first. Intent-to­Treat (ITT) Population defined as all randomized participants. Participants were assigned to the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Baseline and every 6 weeks thereafter until disease progression up to 33 months
    Notes
    [1] - 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: The data was reported only for the non-squamous NSCLC Phase 2 Arm A (RO5083945 + chemotherapy) and Arm B (chemotherapy).
    End point values
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects analysed
    41
    21
    Units: months
        median (confidence interval 95%)
    5.4 (4.1 to 6.5)
    6 (3.7 to 8.4)
    Statistical analysis title
    PFS
    Comparison groups
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy v Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7981
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.92

    Primary:  Percentage of Participants with Disease Progression or Death Assessed as per RECIST Version 1.1

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    End point title
     Percentage of Participants with Disease Progression or Death Assessed as per RECIST Version 1.1 [2] [3]
    End point description
    PFS was defined as the time between randomization and date of first documented disease progression (unequivocal appearance of new malignant lesions denotes) or death, whichever occurred first. ITT population.
    End point type
    Primary
    End point timeframe
    Baseline and every 6 weeks thereafter until disease progression up to 33 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    [3] - 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: The study was conducted in two phases. The endpoint was assessed in Phase 2 only, therefore the data for the Phase 1 arm group are not presented.
    End point values
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects analysed
    41
    21
    Units: percentage of participants
        number (not applicable)
    92.7
    90.5
    No statistical analyses for this end point

    Primary: Number of Participants With Positive Human Anti-human Antibodies (HAHA) Values 

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    End point title
    Number of Participants With Positive Human Anti-human Antibodies (HAHA) Values  [4]
    End point description
    Levels of HAHA in serum were detected at baseline. Safety Population.
    End point type
    Primary
    End point timeframe
    Predose on Day 1 of each cycle and on follow-up
    Notes
    [4] - 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: No statistical analysis was planned for this endpoint.
    End point values
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945 Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects analysed
    8
    1
    7 [5]
    3
    11
    41
    21
    Units: participants
        number (not applicable)
    0
    0
    1
    0
    1
    6
    1
    Notes
    [5] - Participants who received treatment were included in the analysis.
    No statistical analyses for this end point

    Primary: Pharmacokinetic (PK) Parameters of RO5083945, Cisplatin, Gemcitabine, and Pemetrexed

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    End point title
    Pharmacokinetic (PK) Parameters of RO5083945, Cisplatin, Gemcitabine, and Pemetrexed [6]
    End point description
    PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
    End point type
    Primary
    End point timeframe
    Multiple sampling Cycles 1­6 (18 weeks)
    Notes
    [6] - 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: No statistical analysis was planned for this endpoint.
    End point values
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945 Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    0 [13]
    Units: micrograms per milliliter (mcg/L)
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Notes
    [7] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
    [8] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
    [9] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
    [10] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
    [11] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
    [12] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
    [13] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR)

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    End point title
    Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR) [14]
    End point description
    Best overall response was defined as CR or PR as assessed by investigator using RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) having reduction in short axis to < 10 millimeter (mm); PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Best Overall Response was not evaluated due to no further plans for clinical development of RO5083945.
    End point type
    Secondary
    End point timeframe
    Baseline and every 6 weeks thereafter up to 33 months
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study was conducted in two phases. The endpoint was assessed in Phase 2 only, therefore the data for the Phase 1 arm group are not presented.
    End point values
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: percentage of participants
        number (not applicable)
    Notes
    [15] - Best Overall Response was not evaluated due to no further plans for clinical development of RO508394
    [16] - Best Overall Response was not evaluated due to no further plans for clinical development of RO508394
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response [17]
    End point description
    Duration of response was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first). Duration of response was not evaluated due to no further plans for clinical development of RO5083945.
    End point type
    Secondary
    End point timeframe
    Baseline and every 6 weeks thereafter up to 33 months
    Notes
    [17] - 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: The study was conducted in two phases. The endpoint was assessed in Phase 2 only, therefore the data for the Phase 1 arm group are not presented.
    End point values
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [18] - Duration of response was not evaluated due to no further plans for clinical development of RO5083945
    [19] - Duration of response was not evaluated due to no further plans for clinical development of RO5083945
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Stable Disease for at Least 6 Weeks, CR or PR

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    End point title
    Percentage of Participants With Stable Disease for at Least 6 Weeks, CR or PR [20]
    End point description
    Stable Disease was defined as the condition which neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease was not evaluated due to no further plans for clinical development of RO5083945.
    End point type
    Secondary
    End point timeframe
    Baseline and every 6 weeks thereafter up to 33 months
    Notes
    [20] - 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:  No statistical analysis was planned for this endpoint.
    End point values
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects analysed
    0 [21]
    0 [22]
    Units: percentage of participants
        number (not applicable)
    Notes
    [21] - Stable Disease was not evaluated due to no further plans for clinical development of RO5083945.
    [22] - Stable Disease was not evaluated due to no further plans for clinical development of RO5083945.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS) [23]
    End point description
    OS was defined as the time between randomization and date of death. Participants without an event will be censored at the last date known to be alive. OS was not evaluated due to no further plans for clinical development of RO5083945.
    End point type
    Secondary
    End point timeframe
    Baseline and every 6 weeks thereafter up to 33 months
    Notes
    [23] - 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: The study was conducted in two phases. The endpoint was assessed in Phase 2 only, therefore the data for the Phase 1 arm group are not presented.
    End point values
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: percentage of participants
        number (not applicable)
    Notes
    [24] - OS was not evaluated due to no further plans for clinical development of RO5083945.
    [25] - OS was not evaluated due to no further plans for clinical development of RO5083945.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to 28 days after the last dose of study medication
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 1250 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously, every three weeks (q3w) for a maximum of 6 cycles (18 weeks) followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine ) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945
    Reporting group description
    Chemotherapy (60 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1400 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Reporting group description
    Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) administered intravenously q3w for a maximum of 6 cycles (18 weeks).

    Serious adverse events
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945 Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 8 (75.00%)
    1 / 1 (100.00%)
    1 / 8 (12.50%)
    2 / 3 (66.67%)
    1 / 11 (9.09%)
    16 / 41 (39.02%)
    3 / 21 (14.29%)
         number of deaths (all causes)
    5
    1
    5
    2
    9
    28
    16
         number of deaths resulting from adverse events
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 41 (4.88%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 41 (4.88%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 1 (100.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945 Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    1 / 1 (100.00%)
    5 / 8 (62.50%)
    3 / 3 (100.00%)
    11 / 11 (100.00%)
    41 / 41 (100.00%)
    19 / 21 (90.48%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 41 (4.88%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    2 / 3 (66.67%)
    4 / 11 (36.36%)
    13 / 41 (31.71%)
    12 / 21 (57.14%)
         occurrences all number
    4
    0
    1
    2
    12
    27
    26
    Fatigue
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    13 / 41 (31.71%)
    4 / 21 (19.05%)
         occurrences all number
    3
    0
    0
    1
    1
    18
    4
    Pyrexia
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    2 / 3 (66.67%)
    1 / 11 (9.09%)
    3 / 41 (7.32%)
    6 / 21 (28.57%)
         occurrences all number
    3
    0
    0
    2
    1
    4
    9
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    5 / 41 (12.20%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    6
    0
    Chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    3 / 3 (100.00%)
    0 / 11 (0.00%)
    2 / 41 (4.88%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    2
    0
    Gait disturbance
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Xerosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 41 (7.32%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 41 (7.32%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    2 / 41 (4.88%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    2
    0
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    2
    Confusional state
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 41 (4.88%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 1 (100.00%)
    1 / 8 (12.50%)
    2 / 3 (66.67%)
    7 / 11 (63.64%)
    19 / 41 (46.34%)
    0 / 21 (0.00%)
         occurrences all number
    3
    1
    3
    2
    8
    21
    0
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Urine output decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    5 / 41 (12.20%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    2
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    Atrial flutter
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    5 / 8 (62.50%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    1 / 3 (33.33%)
    4 / 11 (36.36%)
    18 / 41 (43.90%)
    10 / 21 (47.62%)
         occurrences all number
    6
    0
    3
    1
    8
    30
    22
    Anaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    3 / 3 (100.00%)
    5 / 11 (45.45%)
    12 / 41 (29.27%)
    10 / 21 (47.62%)
         occurrences all number
    4
    0
    2
    4
    5
    13
    10
    Thrombocytopenia
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 1 (100.00%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    6 / 41 (14.63%)
    3 / 21 (14.29%)
         occurrences all number
    7
    1
    5
    0
    0
    10
    4
    Leukopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 41 (4.88%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    4 / 11 (36.36%)
    5 / 41 (12.20%)
    3 / 21 (14.29%)
         occurrences all number
    1
    0
    0
    2
    4
    5
    4
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 41 (9.76%)
    3 / 21 (14.29%)
         occurrences all number
    1
    0
    0
    0
    1
    4
    5
    Productive cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    2 / 41 (4.88%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    1
    2
    5
    1
    Epistaxis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    4 / 41 (9.76%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    4
    1
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Nasal dryness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Dysphonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    1 / 41 (2.44%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    2
    Pulmonary embolism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    1 / 41 (2.44%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    1
    2
    1
    1
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    1
    0
    1
    1
    2
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 41 (4.88%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    1
    Sciatica
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 41 (9.76%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    7
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    3 / 11 (27.27%)
    4 / 41 (9.76%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    1
    6
    7
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Deafness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hearing impaired
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Ototoxicity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    2 / 41 (4.88%)
    4 / 21 (19.05%)
         occurrences all number
    0
    0
    0
    2
    2
    2
    4
    Tinnitus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 41 (7.32%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 41 (4.88%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    1
    Nausea
         subjects affected / exposed
    4 / 8 (50.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    2 / 3 (66.67%)
    4 / 11 (36.36%)
    22 / 41 (53.66%)
    11 / 21 (52.38%)
         occurrences all number
    5
    0
    2
    4
    8
    44
    29
    Diarrhoea
         subjects affected / exposed
    4 / 8 (50.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    1 / 3 (33.33%)
    4 / 11 (36.36%)
    16 / 41 (39.02%)
    6 / 21 (28.57%)
         occurrences all number
    6
    0
    1
    1
    6
    22
    9
    Vomiting
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    2 / 3 (66.67%)
    3 / 11 (27.27%)
    17 / 41 (41.46%)
    5 / 21 (23.81%)
         occurrences all number
    4
    0
    1
    4
    5
    29
    6
    Stomatitis
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    2 / 3 (66.67%)
    5 / 11 (45.45%)
    18 / 41 (43.90%)
    2 / 21 (9.52%)
         occurrences all number
    4
    0
    0
    3
    7
    28
    2
    Constipation
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    1 / 3 (33.33%)
    4 / 11 (36.36%)
    8 / 41 (19.51%)
    7 / 21 (33.33%)
         occurrences all number
    2
    0
    5
    1
    4
    10
    10
    Dyspepsia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 41 (7.32%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    2
    Cheilitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    2 / 3 (66.67%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    0
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Oral mucosal erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Proctitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 41 (7.32%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Odynophagia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 41 (7.32%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Oliguria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    6 / 8 (75.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    3 / 3 (100.00%)
    11 / 11 (100.00%)
    28 / 41 (68.29%)
    4 / 21 (19.05%)
         occurrences all number
    11
    0
    2
    6
    23
    40
    4
    Dry skin
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    9 / 41 (21.95%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    2
    1
    1
    9
    1
    Alopecia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    6 / 41 (14.63%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    0
    0
    0
    7
    2
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    5 / 41 (12.20%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    1
    0
    7
    2
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 41 (7.32%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    3
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    0
    Exfoliative rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Telangiectasia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Hypertrichosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Hair colour changes
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Skin fissures
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    2 / 3 (66.67%)
    5 / 11 (45.45%)
    7 / 41 (17.07%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    2
    12
    15
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    8 / 41 (19.51%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    8
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    6 / 41 (14.63%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    0
    2
    7
    2
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 41 (4.88%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    1
    Bone pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Tendon pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    3 / 41 (7.32%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    0
    Muscle spasms
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 41 (7.32%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    6
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    4 / 8 (50.00%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    2 / 3 (66.67%)
    8 / 11 (72.73%)
    25 / 41 (60.98%)
    4 / 21 (19.05%)
         occurrences all number
    4
    0
    4
    2
    8
    39
    4
    Decreased appetite
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    18 / 41 (43.90%)
    7 / 21 (33.33%)
         occurrences all number
    4
    0
    3
    1
    0
    25
    9
    Hypocalcaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    4 / 41 (9.76%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    2
    1
    0
    4
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 41 (7.32%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    3
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 41 (2.44%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    0
    1
    1
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    Dehydration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Fluid imbalance
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Paronychia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    6 / 11 (54.55%)
    8 / 41 (19.51%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    12
    15
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    1 / 41 (2.44%)
    3 / 21 (14.29%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    3
    Oral fungal infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    2
    Candida infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Device related infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Furuncle
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Urethritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 41 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2010
    This amendment was done for including the following information: ­- To allow the two formulations of RO5083945 (RO508-3945/F02 and RO5083945/F03) to be used in this study. Formulation RO508-3945/F02 was used in earlier clinical trials. Formulation RO5083945/F03 contained RO508-3945 derived from a modified drug substance processes, i.e. different manufacturing site, different fermentation scale using the same cell line and a slightly modified purification process. ­- To include the preparation guidelines for both formulations. ­- To clarify the wording for blood collection timepoints has been updated to clarify this for participants not receiving RO5083945 (i.e. Phase II, Arm B participants). ­- Clarified the extension of blood pharmacodynamic (PD) parameters to permit residual sample material to be investigated to provide a more in-depth analysis of peripheral blood immunophenotype.
    25 Oct 2010
    This amendment was done for including the following information: ­ - To update with new data from the BO21495 and BP22350 studies. - To clarify timepoints for participants in Arm B i.e. those not receiving RO5083945. -­ To correct the typographical errors. - To clarify the treatment of epidermal growth factor receptor (EGFR)-related skin toxicity. - To limit analysis up to ITT and Safety populations which were deemed sufficient to gather preliminary evidence of superior activity and safety of RO5083945.
    31 Jan 2011
    This amendment was done to include the following information: - To update the clinical section for the first 2 participants with squamous cell NSCLC treated in the Phase Ib part of study BP22349 both experienced Grade 3 infusion-related reaction (IRR) event and added premedication required to reduce the incidence of IRRs events. ­- To update additional measures required for Phase 2 start to ensure the safety of squamous NSCLC participants. ­- To collect additional blood sample to confirm the biology of the IRRs in terms of cytokine release (levels and types). ­- Clarified that the recommended dose may be differ between histology groups. ­- To collect the blood samples at a later cycle if if the drug administration schedule is altered due to toxicity or other reasons. ­- To advice additional safety measures with early high dose oral supplementation for participants who developed hypomagnesemia. ­- To include PK blood samples collection for Phase II participants at Cycle 4 Day 15 and Cycle 6 Day 1. - To update the guidelines for prophylactic measures for EGFR-inhibition-associated rash based on clinical experience with RO5083945.
    26 Aug 2011
    This amendment was done to include the following information: ­- To correct inconsistency for tumour response criteria. - To add 2 additional PK samples for Phase Ib and 1 additional sample for Phase II to enable a better characterization of the PK profile of RO5083945 on Cycle 4, and to enable a better comparison of exposure parameters between Cycle 4 and Cycle 1. ­- Clarified to avoid the collection of cytological samples for tumour biopsies. ­- To include the need of prophylaxis treatment for EGFR-related skin toxicity. ­- To include the information for interruption of infusion if participants developed IRRs. ­- To extend time window for allowing more flexibility to perform the Safety Follow-Up Visit. ­- To revise the hypomagnesaemia management guidelines. ­- To clarify PK/PD sampling in Phase II as some PK/PD samplings were not applicable for participants in Arm B. ­- To include the information regarding gemcitabine dose reduction. ­ To implement a safety run-in stage within Phase II to closely monitor the hematological profile and to mitigate the risk of potential unexpected toxicities. ­- To provide clarification on storage conditions of RO5083945. ­- To allow more flexibility for scheduling visits during treatment.
    28 Jun 2012
    This amendment was done to reduce the dose of cisplatin from 75 mg/m^2 to 60 mg/m^2 as the first participant from the squamous histology group enrolled in the first cohort of RO5083945 1000 mg on Day 1 and Day 8 and then every two weeks, cisplatin 75 mg/m^2 q3w and the reduced dose of gemcitabine 1000 mg/m^2 Day 1 and Day 8 q3w died of sepsis (related to cisplatin as per investigator) in the presence of pancytopenia on Day 15 of Cycle 1.
    22 Nov 2012
    This amendment was done to include the initial results received from Phase II Study BP22349 in non-squamous NSCLC group. Based on these results the overall benefit risk ratio for the BP22349 Phase II in non-squamous was negative.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    21 Dec 2010
    In response to Grade 3 IRR events observed in the first 2 participants with squamous NSCLC treated in the Phase Ib part of study BP22349, recruitment of participants with squamous cell histology into study BP22349 was put on hold on 21 December 2010 in order to review the data and plan subsequent actions. A 2-step approach with intensified premedication was taken for squamous cancer NSCLC participants in the Phase Ib part of study BP22349 for the first infusion of RO5083945. In addition the same 2-step safety approach was taken if Grade 3 IRRs are seen in non-squamous participants in Phase Ib.
    08 Mar 2011

    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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