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    Clinical Trial Results:
    A Randomised, Parallel, Double Blinded Study to Compare the Efficacy and Safety of FKB238 to Avastin® In 1st Line Treatment for Patients with Advanced/Recurrent Non Squamous Non-Small Cell Lung Cancer in Combination of Paclitaxel and Carboplatin

    Summary
    EudraCT number
    		 2015-004104-33
    Trial protocol
    		 DE   HU   ES   GR   BG   HR   IT  
    Global end of trial date
    26 Jan 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 Mar 2022
    First version publication date
    09 Feb 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of date for global end of trial.

    Trial information

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    Trial identification
    Sponsor protocol code
    FKB238-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02810457
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 122990
    Sponsors
    Sponsor organisation name
    Centus Biotherapeutics Limited
    Sponsor organisation address
    1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, United Kingdom, CB2 0AA
    Public contact
    Clinical Trial Information, Centus Biotherapeutics Limited, Clinical-Trial@centusbio.com
    Scientific contact
    Clinical Trial Information, Centus Biotherapeutics Limited, Clinical-Trial@centusbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    07 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the efficacy equivalence of FKB238 and EU-Avastin when used in combination with paclitaxel/carboplatin as measured by overall response rate (ORR).
    Protection of trial subjects
    The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council for Harmonisation (ICH)/Good Clinical Practice (GCP), and applicable regulatory and data protection requirements. The investigator explained the benefits and risks of participation in the study to each subject or the subject’s legally acceptable representative and obtained written informed consent. Written informed consent was required to be obtained prior to the subject entering the study and before initiation of any study-related procedure.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Thailand: 36
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    Ukraine: 120
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    Vietnam: 9
    Country: Number of subjects enrolled
    Belarus: 50
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 23
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Croatia: 8
    Country: Number of subjects enrolled
    Georgia: 27
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Hungary: 52
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Peru: 13
    Country: Number of subjects enrolled
    Philippines: 13
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Russian Federation: 184
    Country: Number of subjects enrolled
    Serbia: 59
    Worldwide total number of subjects
    731
    EEA total number of subjects
    150
    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)
    462
    From 65 to 84 years
    269
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were screened at 146 centres in 24 countries (136 centres in 24 countries randomised patients) in Belarus, Bosnia and Herzegovina, Bulgaria, Croatia, Georgia, Germany, Greece, Hungary, Italy, Japan, Republic of Korea, Peru, Philippines, Poland, Romania, Russia, Serbia, Spain, Taiwan, Thailand, Turkey, Ukraine, United States, and Vietnam.

    Pre-assignment
    Screening details
    		 Of a total of 1023 patients who signed informed consent and were screened, 292 patients were not randomised (i.e., screen failures), with a total of 731 patients randomised to treatment. Of these patients, 728 received study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FKB238
    Arm description
    		 FKB238 was administered on Day 1 of each 21-day cycle until objective progressive disease (PD) or other criteria for treatment discontinuation were met. Paclitaxel and carboplatin (combination drugs) were administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment. All three drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle in the order of paclitaxel followed by carboplatin, then FKB238.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FKB238
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg on Day 1 of each 21-day cycle until objective PD or other criteria for treatment discontinuation were met. The initial dose of FKB238 was to be delivered over 90 minutes as an IV infusion. If the first infusion was well tolerated, the second infusion could be administered over 60 minutes. If the 60-minute infusion was well tolerated, all subsequent infusions could be administered over 30 minutes.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2, administered by IV infusion over 3 hours on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AUC 6.0, administered by IV infusion over 15 to 60 minutes on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment.

    Arm title
    		 Avastin
    Arm description
    		 Avastin was administered on Day 1 of each 21-day cycle until objective progressive disease (PD) or other criteria for treatment discontinuation were met. Paclitaxel and carboplatin (combination drugs) were administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment. All three drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle in the order of paclitaxel followed by carboplatin, then Avastin.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg on Day 1 of each 21-day cycle until objective PD or other criteria for treatment discontinuation were met. The initial dose of Avastin was to be delivered over 90 minutes as an IV infusion. If the first infusion was well tolerated, the second infusion could be administered over 60 minutes. If the 60-minute infusion was well tolerated, all subsequent infusions could be administered over 30 minutes.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2, administered by IV infusion over 3 hours on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AUC 6.0, administered by IV infusion over 15 to 60 minutes on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment.

    Number of subjects in period 1
    		FKB238 Avastin
    Started
    364
    367
    Received study treatment
    362
    366
    Completed
    37
    38
    Not completed
    327
    329
         Patient decision
    31
    35
         Objective PD assessed by RECIST v1.1
    191
    199
         Other
    64
    49
         Adverse event
    37
    43
         Lost to follow-up
    2
    2
         Did not receive study treatment
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FKB238
    Reporting group description
    		 FKB238 was administered on Day 1 of each 21-day cycle until objective progressive disease (PD) or other criteria for treatment discontinuation were met. Paclitaxel and carboplatin (combination drugs) were administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment. All three drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle in the order of paclitaxel followed by carboplatin, then FKB238.

    Reporting group title
    Avastin
    Reporting group description
    		 Avastin was administered on Day 1 of each 21-day cycle until objective progressive disease (PD) or other criteria for treatment discontinuation were met. Paclitaxel and carboplatin (combination drugs) were administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment. All three drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle in the order of paclitaxel followed by carboplatin, then Avastin.

    Reporting group values
    		 FKB238 Avastin Total
    Number of subjects
    		 364 367 731
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 238 224 462
        From 65-84 years
    		 126 143 269
    Gender categorical
    Units: Subjects
        Female
    		 119 129 248
        Male
    		 245 238 483
    Race
    Units: Subjects
        White
    		 316 320 636
        Black and African American
    		 1 0 1
        Asian, other than Japanese
    		 37 37 74
        Japanese
    		 2 3 5
        American Indian or Alaska Native
    		 1 4 5
        Other
    		 7 3 10

    End points

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    End points reporting groups
    Reporting group title
    FKB238
    Reporting group description
    		 FKB238 was administered on Day 1 of each 21-day cycle until objective progressive disease (PD) or other criteria for treatment discontinuation were met. Paclitaxel and carboplatin (combination drugs) were administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment. All three drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle in the order of paclitaxel followed by carboplatin, then FKB238.

    Reporting group title
    Avastin
    Reporting group description
    		 Avastin was administered on Day 1 of each 21-day cycle until objective progressive disease (PD) or other criteria for treatment discontinuation were met. Paclitaxel and carboplatin (combination drugs) were administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment. All three drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle in the order of paclitaxel followed by carboplatin, then Avastin.

    Subject analysis set title
    ITT Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised to treatment. Patients were included in the treatment group according to the randomisation assigned, regardless of the treatment actually given. All efficacy analyses were performed on the ITT population.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients randomised to treatment who received at least 1 dose of IP with no important protocol deviations. Patients were included in the treatment group according to the treatment actually given. All efficacy analyses were performed on the PPS.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients randomised to treatment who received at least 1 dose of Investigational Product (IP). Patients were included in the treatment group according to the treatment actually given. All safety analyses were performed on the Safety Population. Treatment groups were analysed according to the first IP actually received.

    Subject analysis set title
    Pharmacokinetics Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All Per Protocol Set patients who have at least one serum drug concentration data, which is defined in the study protocol, after IP administration. Patients were included in the treatment group according to the treatment actually given.

    Subject analysis set title
    ADA Evaluable Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All Per Protocol Set patients who have at least one anti-drug antibody (ADA) assessment prior to and after baseline data. Patients were included in the treatment group according to the treatment actually given.

    Primary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    The primary variable in this study was ORR, defined as the proportion of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) (by RECIST v1.1). A BOR is defined as the best response (in the order of CR, PR, stable disease (SD), progressive disease (PD), and not evaluable (NE)) among all post-baseline disease assessments that occur until progression, or last evaluable assessment in the absence of progression prior to the initiation of subsequent anti-cancer therapy, irrespective of whether or not subjects discontinued the study treatment. This assessment was performed using the Per Protocol Set (PPS) and the independent central radiological assessments.
    End point type
    Primary
    End point timeframe
    Until data cut-off, which occured 12 months after randomisation of the last patient enrolled
    End point values
    		 FKB238 Avastin
    Number of subjects analysed
    352
    354
    Units: percentage of subjects
        number (confidence interval 95%)
    51.7 (46.35 to 57.03)
    53.4 (48.04 to 58.68)
    Statistical analysis title
    		 Difference in BICR ORR
    Comparison groups
    FKB238 v Avastin
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0905
         upper limit
    		 0.0568
    Notes
    [1] - In order to compare the ORRs in the two treatment arms, the difference in ORRs will be calculated and a 95% Wald asymptotic confidence interval (CI) given. If the 95% CI is within the interval [± 0.1221], an equivalence between FKB238 and EU- Avastin, with respect to the ORR, is confirmed. BICR = Blinded independent central review.

    Secondary: Overall Response Rate (ORR) at Week 19

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    End point title
    		 Overall Response Rate (ORR) at Week 19
    End point description
    ORR (by RECIST v1.1) at Week 19 will be defined as the proportion of subjects with a BOR of CR or PR assessed at Week 19. Only tumour assessment performed up until 19 weeks (i.e., week 18 assessment + 7 day assessment window) from randomisation are considered in this analysis. This assessment was performed using the Per Protocol Set (PPS) and the independent central radiological assessments.
    End point type
    Secondary
    End point timeframe
    Until Week 19
    End point values
    		 FKB238 Avastin
    Number of subjects analysed
    352
    354
    Units: percentage of subjects
        number (confidence interval 95%)
    47.7 (42.41 to 53.09)
    50.8 (45.51 to 56.17)
    Statistical analysis title
    		 Risk difference in BICR ORR at Week 19
    Comparison groups
    FKB238 v Avastin
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1049
         upper limit
    		 0.0425
    Notes
    [2] - Comparison between groups: Risk difference in ORR at week 19. BICR = Blinded independent central review.

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    The event of interest for progression-free survival (PFS) is defined as first documented disease progression or death from any cause, whichever occurs first. Disease progression will be based on tumour assessments according to RECIST v1.1 criteria. The items of the overall response CR, PR, SD and NE will be taken as progression-free whereas PD will denote disease progression. PFS is defined as the interval from the date of randomisation until the earlier date of the first documentation of disease progression or death due to any reason. This assessment was performed using the ITT Population and the independent central radiological assessments.
    End point type
    Secondary
    End point timeframe
    Until data cut-off, which occurred 12 months after randomisation of the last patient enrolled
    End point values
    		 FKB238 Avastin
    Number of subjects analysed
    364
    367
    Units: Months
        median (confidence interval 95%)
    7.72 (7.46 to 7.98)
    7.62 (6.90 to 7.82)
    Statistical analysis title
    		 Hazard ratio analysis
    Statistical analysis description
    Hazard ratio and its 95% confidence interval are calculated using the cox regression model adjusting for the listed baseline characteristics with ties handled by the Efron method. Treatment hazard ratio < 1 favours FKB238.
    Comparison groups
    FKB238 v Avastin
    Number of subjects included in analysis
    731
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.16
    Notes
    [3] - Hazard ratio of FKB238 versus Avastin

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The event of interest is defined as death from any cause. OS is defined as the interval from date of randomisation until the date of death due to any cause. This assessment was performed using the ITT Population.
    End point type
    Secondary
    End point timeframe
    Until data cut-off, which occurred 12 months after randomisation of the last patient enrolled
    End point values
    		 FKB238 Avastin
    Number of subjects analysed
    364
    367
    Units: Months
        median (confidence interval 95%)
    14.13 (12.52 to 16.56)
    16.95 (14.65 to 19.02)
    Statistical analysis title
    		 Hazard ratio analysis
    Statistical analysis description
    Hazard ratio and its 95% confidence interval are calculated using the cox regression model adjusting for the listed baseline characteristics with ties handled by the Efron method. Treatment hazard ratio < 1 favours FKB238.
    Comparison groups
    FKB238 v Avastin
    Number of subjects included in analysis
    731
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.45
    Notes
    [4] - Hazard ratio of FKB238 versus Avastin

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was evaluated in this study as a secondary efficacy endpoint. Only the patients defined as responders in the primary analysis of ORR were taken into account for the analysis of DOR. The event of interest is defined as first documented disease progression or death due to any reason, whichever occurs first. DOR is defined as the interval from the first documented response (as defined per RECIST v1.1) until the earlier date of the first documented disease progression or death due to any reason. The date of first documented response will be taken as the date of the first tumour assessment with an overall visit response of CR or PR. DOR will be calculated in units of months. This assessment was performed using the ITT Population and the independent central radiological assessments.
    End point type
    Secondary
    End point timeframe
    Until data cut-off, which occurred 12 months after randomisation of the last patient enrolled
    End point values
    		 FKB238 Avastin
    Number of subjects analysed
    188
    197
    Units: duration of response (months)
        median (confidence interval 95%)
    6.47 (5.39 to 7.69)
    6.31 (4.93 to 7.29)
    Statistical analysis title
    		 Hazard ratio analysis
    Statistical analysis description
    Hazard ratio and its 95% confidence interval are calculated using the cox regression model adjusting for the listed baseline characteristics with ties handled by the Efron method. Treatment hazard ratio < 1 favours FKB238.
    Comparison groups
    FKB238 v Avastin
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.23
    Notes
    [5] - Hazard ratio of FKB238 versus Avastin

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    The Disease Control Rate (DCR) is defined as the proportion of patients defined as responders. The number and percentage of responders and non-responders and the 95% Pearson-Clopper CI of DCR for each treatment arm is provided. The odds ratio for treatment (Arm2 versus Arm1) and the corresponding 95% Wald CI will be produced based on a logistic regression analysis of DCR. This assessment of DCR was based on the ITT population using the independent central radiological assessments.
    End point type
    Secondary
    End point timeframe
    Until data cut-off, which occurred 12 months after randomisation of the last patient enrolled
    End point values
    		 FKB238 Avastin
    Number of subjects analysed
    364
    367
    Units: percentage of subjects with response
        number (confidence interval 95%)
    87.6 (83.81 to 90.84)
    87.5 (83.64 to 90.68)
    Statistical analysis title
    		 Comparison between arms: Odds ratio
    Statistical analysis description
    The DCR is compared between treatment arms using logistic regression adjusting for the listed baseline characteristics. Odds ratio > 1 favours FKB238.
    Comparison groups
    FKB238 v Avastin
    Number of subjects included in analysis
    731
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.58
    Notes
    [6] - Comparison between arms: Odds ratio

    Other pre-specified: Serum trough concentrations

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    End point title
    		 Serum trough concentrations
    End point description
    Serum trough concentration (Ctrough) and serum maximum concentration (Cmax; at completion of infusion) were compared between treatment arms and descriptive statistics provided. Ctrough and Cmax concentrations were summarised using the pharmacokinetics (PK) population for each visit at which samples were taken. The zero values provided for both treatment arms at Cycle 1, Day 1 pre-infusion are equivalent to a Not Calculable result.
    End point type
    Other pre-specified
    End point timeframe
    From pre-infusion Cycle 1, Day 1 through to pre-infusion Cycle 6, Day1
    End point values
    		 FKB238 Avastin
    Number of subjects analysed
    345
    351
    Units: ug/ml
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1 pre-infusion
    0 ± 0
    0 ± 0
        Cycle 1, Day 1 post-infusion
    255.15 ± 184.3
    245.11 ± 206.8
        Cycle 2, Day 1 pre-infusion
    42.74 ± 91.9
    48.48 ± 77.3
        Cycle 4, Day 1 pre-infusion
    77.16 ± 69.4
    83.26 ± 85.5
        Cycle 4, Day 1 post-infusion
    339.91 ± 91.3
    373.92 ± 51.6
        Cycle 6, Day 1 pre-infusion
    87.25 ± 124.5
    108.22 ± 69.8
    No statistical analyses for this end point

    Other pre-specified: Anti-Drug Antibody (ADA)

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    End point title
    		 Anti-Drug Antibody (ADA)
    End point description
    The ADA levels were summarised at baseline and post-baseline time points using descriptive statistics. This assessment was performed using the ADA Evaluable Population.
    End point type
    Other pre-specified
    End point timeframe
    Until data cut-off, which occurred 12 months after randomisation of the last patient enrolled
    End point values
    		 FKB238 Avastin
    Number of subjects analysed
    305
    305
    Units: Number of subjects
    number (not applicable)
        ADA prevalence (ADA positive, baseline or post)
    9
    9
        Treatment-emergent ADA positive (ADA incidence)
    7
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of informed consent, throughout the treatment period and up to and including the 30-days after the last dose of study treatment. All ongoing and any new AEs/SAEs identified during the 30 days after last dose were followed to resolution.
    Adverse event reporting additional description
    All safety summaries and analyses were based on the Safety Population. Adverse Events (AEs) were coded using the latest MedDRA version. AEs are categorised as treatment-emergent AEs. Intensity of AEs were assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 grading system.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Avastin
    Reporting group description
    		 Avastin was administered on Day 1 of each 21-day cycle until objective progressive disease (PD) or other criteria for treatment discontinuation were met. Paclitaxel and carboplatin (combination drugs) were administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment. All three drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle in the order of paclitaxel followed by carboplatin, then Avastin.

    Reporting group title
    FKB238
    Reporting group description
    		 FKB238 was administered on Day 1 of each 21-day cycle until objective progressive disease (PD) or other criteria for treatment discontinuation were met. Paclitaxel and carboplatin (combination drugs) were administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The number of cycles was to be determined based on the patients’ need and the investigator’s assessment. All three drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle in the order of paclitaxel followed by carboplatin, then FKB238.

    Serious adverse events
    		 Avastin FKB238
    Total subjects affected by serious adverse events
         subjects affected / exposed
    95 / 366 (25.96%)
    91 / 362 (25.14%)
         number of deaths (all causes)
    177
    195
         number of deaths resulting from adverse events
    23
    30
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to bone
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 366 (0.82%)
    5 / 362 (1.38%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    1 / 3
    0 / 5
    Fatigue
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    3 / 366 (0.82%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Haemoptysis
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    4 / 366 (1.09%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 366 (1.37%)
    6 / 362 (1.66%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 6
         deaths causally related to treatment / all
    0 / 3
    1 / 2
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 366 (0.27%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Pulmonary mass
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    3 / 366 (0.82%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 366 (0.55%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 366 (0.27%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Acute myocardial infarction
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Cor pulmonale
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral arteriosclerosis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral atrophy
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 366 (0.82%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    1 / 3
    0 / 2
    Dizziness
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Facial paresis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uraemic encephalopathy
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 366 (2.46%)
    5 / 362 (1.38%)
         occurrences causally related to treatment / all
    6 / 10
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 366 (1.37%)
    7 / 362 (1.93%)
         occurrences causally related to treatment / all
    5 / 5
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    18 / 366 (4.92%)
    7 / 362 (1.93%)
         occurrences causally related to treatment / all
    19 / 19
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 366 (0.82%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 366 (0.55%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia
         subjects affected / exposed
    9 / 366 (2.46%)
    10 / 362 (2.76%)
         occurrences causally related to treatment / all
    4 / 10
    5 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Avastin FKB238
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    348 / 366 (95.08%)
    341 / 362 (94.20%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    35 / 366 (9.56%)
    38 / 362 (10.50%)
         occurrences all number
    45
    53
    Aspartate aminotransferase increased
         subjects affected / exposed
    35 / 366 (9.56%)
    32 / 362 (8.84%)
         occurrences all number
    45
    43
    Blood alkaline phosphatase increased
         subjects affected / exposed
    27 / 366 (7.38%)
    19 / 362 (5.25%)
         occurrences all number
    39
    24
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    31 / 366 (8.47%)
    38 / 362 (10.50%)
         occurrences all number
    46
    48
    Neutrophil count decreased
         subjects affected / exposed
    25 / 366 (6.83%)
    24 / 362 (6.63%)
         occurrences all number
    30
    32
    Platelet count decreased
         subjects affected / exposed
    25 / 366 (6.83%)
    30 / 362 (8.29%)
         occurrences all number
    38
    48
    Weight decreased
         subjects affected / exposed
    56 / 366 (15.30%)
    41 / 362 (11.33%)
         occurrences all number
    62
    48
    White blood cell count decreased
         subjects affected / exposed
    26 / 366 (7.10%)
    24 / 362 (6.63%)
         occurrences all number
    36
    36
    Vascular disorders
    Hypertension
         subjects affected / exposed
    44 / 366 (12.02%)
    42 / 362 (11.60%)
         occurrences all number
    54
    47
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 366 (6.28%)
    18 / 362 (4.97%)
         occurrences all number
    24
    21
    Neuropathy peripheral
         subjects affected / exposed
    52 / 366 (14.21%)
    58 / 362 (16.02%)
         occurrences all number
    60
    63
    Paraesthesia
         subjects affected / exposed
    22 / 366 (6.01%)
    24 / 362 (6.63%)
         occurrences all number
    22
    26
    Peripheral sensory neuropathy
         subjects affected / exposed
    25 / 366 (6.83%)
    28 / 362 (7.73%)
         occurrences all number
    25
    28
    Polyneuropathy
         subjects affected / exposed
    23 / 366 (6.28%)
    16 / 362 (4.42%)
         occurrences all number
    31
    18
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    119 / 366 (32.51%)
    105 / 362 (29.01%)
         occurrences all number
    146
    135
    Leukopenia
         subjects affected / exposed
    50 / 366 (13.66%)
    43 / 362 (11.88%)
         occurrences all number
    89
    58
    Neutropenia
         subjects affected / exposed
    145 / 366 (39.62%)
    109 / 362 (30.11%)
         occurrences all number
    212
    163
    Thrombocytopenia
         subjects affected / exposed
    66 / 366 (18.03%)
    44 / 362 (12.15%)
         occurrences all number
    102
    78
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    59 / 366 (16.12%)
    37 / 362 (10.22%)
         occurrences all number
    71
    45
    Fatigue
         subjects affected / exposed
    45 / 366 (12.30%)
    41 / 362 (11.33%)
         occurrences all number
    48
    55
    Non-cardiac chest pain
         subjects affected / exposed
    11 / 366 (3.01%)
    18 / 362 (4.97%)
         occurrences all number
    15
    18
    Pyrexia
         subjects affected / exposed
    21 / 366 (5.74%)
    15 / 362 (4.14%)
         occurrences all number
    24
    17
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    21 / 366 (5.74%)
    19 / 362 (5.25%)
         occurrences all number
    23
    23
    Diarrhoea
         subjects affected / exposed
    35 / 366 (9.56%)
    35 / 362 (9.67%)
         occurrences all number
    41
    44
    Nausea
         subjects affected / exposed
    45 / 366 (12.30%)
    52 / 362 (14.36%)
         occurrences all number
    57
    72
    Vomiting
         subjects affected / exposed
    18 / 366 (4.92%)
    24 / 362 (6.63%)
         occurrences all number
    24
    29
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 366 (6.83%)
    17 / 362 (4.70%)
         occurrences all number
    26
    20
    Dyspnoea
         subjects affected / exposed
    29 / 366 (7.92%)
    17 / 362 (4.70%)
         occurrences all number
    29
    17
    Epistaxis
         subjects affected / exposed
    23 / 366 (6.28%)
    16 / 362 (4.42%)
         occurrences all number
    36
    20
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    159 / 366 (43.44%)
    154 / 362 (42.54%)
         occurrences all number
    162
    157
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    41 / 366 (11.20%)
    24 / 362 (6.63%)
         occurrences all number
    52
    31
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 366 (9.84%)
    32 / 362 (8.84%)
         occurrences all number
    48
    49
    Back pain
         subjects affected / exposed
    14 / 366 (3.83%)
    22 / 362 (6.08%)
         occurrences all number
    14
    25
    Myalgia
         subjects affected / exposed
    32 / 366 (8.74%)
    29 / 362 (8.01%)
         occurrences all number
    73
    61
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    20 / 366 (5.46%)
    18 / 362 (4.97%)
         occurrences all number
    24
    20
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    42 / 366 (11.48%)
    43 / 362 (11.88%)
         occurrences all number
    48
    56
    Hyperglycaemia
         subjects affected / exposed
    22 / 366 (6.01%)
    14 / 362 (3.87%)
         occurrences all number
    29
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2016
    Amendment 1: The purpose of this amendment was to give more detailed clarification on the study procedure for EGFR mutation and ALK gene arrangement status, brain CT/MRI at screening, blood pressure measurement, dose modifications for non-haematologic toxicity, other concomitant medications, primary efficacy assessment, and the type of palliative radiotherapy allowed. In addition, urine pregnancy test was added as an alternative to serum pregnancy test and there was a clarification of visit allowance for radiological tumour assessments and assessments for survival.
    20 Apr 2016
    Amendment 2: The purpose of this amendment was to give more detailed clarification on the study procedure for brain CT/MRI at screening and the definition for prior weight loss.
    12 Apr 2017
    Amendment 3: The purpose of this amendment was to add details to the study procedure for urinalysis and urine dipstick, secondary objectives and secondary endpoints, treatments administered, re-start of study treatment, stop and re-initiation of IP prior to/after surgery, haematologic toxicities of the IP, study populations, screening procedures and screening failures, recording of AEs, and safety laboratory determinations. Additionally, the exclusion criterion of hypersensitivity was updated to include active ingredients of the IP or combination drugs; a clarification was added that patients who discontinue breastfeeding may be included in the study; the exclusion criterion of treatment with any other investigational agent for any reason within 28 days before the first dose of IP was updated to clarify that this treatment may be for any reason, and the Coordinating Investigator and his role as a signatory to the clinical study report was introduced.
    22 May 2018
    Amendment 4: The main purpose of this amendment was to clarify procedures to be completed during the Extended Treatment Period and to update the Sponsor’s signature page.

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

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