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    Clinical Trial Results:
    STELLA – A Randomized, Multicenter, Multinational, Double-Blind Study to Assess the Efficacy and Safety of MB02 (Bevacizumab Biosimilar Drug) Versus Avastin® in Combination With Carboplatin and Paclitaxel for the Treatment of Subjects With Stage IIIB/IV Non-squamous Non-Small Cell Lung Cancer (NSCLC)

    Summary
    EudraCT number
    		 2017-001769-26
    Trial protocol
    		 HU   BG   GR   ES  
    Global end of trial date
    27 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Mar 2021
    First version publication date
    10 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MB02-C-02-17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03296163
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    mAbxience Research SL
    Sponsor organisation address
    MANUEL POMBO ANGULO 28, MADRID, Spain, 28050
    Public contact
    Amalia Florez, mAbxience Research SL, +34 91771 15 00, amalia.florez@mabxience.com
    Scientific contact
    Ana Del Campo, mAbxience Research SL, +34 91771 15 00, ana.delcampo@mabxience.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
    31 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare the ORR of MB02 and EU approved Avastin® when they are administered in combination with carboplatin and paclitaxel in subjects with Stage IIIB/IV non-squamous NSCLC as assessed according to RECIST
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles in the accepted version of the Declaration of Helsinki and all applicable regulatory authorities’ regulations in compliance with International Council for Harmonisation (ICH) good clinical practice (GCP) guidelines (ICH E6), and according to the appropriate regulatory requirements in the countries where the study was conducted. Ethical approval was sought and granted at each centre. All patients provided written informed consent before any study-specific procedures were done.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2018
    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
    Bulgaria: 6
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    India: 60
    Country: Number of subjects enrolled
    Malaysia: 27
    Country: Number of subjects enrolled
    Philippines: 13
    Country: Number of subjects enrolled
    Thailand: 27
    Country: Number of subjects enrolled
    Georgia: 69
    Country: Number of subjects enrolled
    Russian Federation: 107
    Country: Number of subjects enrolled
    Serbia: 55
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Ukraine: 189
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Chile: 27
    Country: Number of subjects enrolled
    Mexico: 6
    Worldwide total number of subjects
    627
    EEA total number of subjects
    33
    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)
    408
    From 65 to 84 years
    219
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Screening period for this study was from 23-January-2018, date of the first ICF, through 18-February-2019, the date of last ICF (804 subjects). The recruitment period was from 06-February-2018 through 05-March-2019 (627 subjects).

    Pre-assignment
    Screening details
    		 A total of 804 subjects were screened, of which 177 subjects were screening failures. Most screening failures (144 of 177) were the result of subjects failing to meet eligibility criteria (i.e., protocol-specified inclusion [54 subjects] or exclusion [90 subjects] criteria).

    Period 1
    Period 1 title
    Combination Therapy period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MB02 (Bevacizumab biosimilar) arm
    Arm description
    		 MB02 (test; bevacizumab biosimilar drug sourced from mAbxience Spain), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle in combination with chemotherapy (carboplatin and paclitaxel).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MB02 (Bevacizumab Biosimilar Drug) + Carboplatin/Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MB02 (Bevacizumab Biosimilar Drug): 15 mg/kg IV every 3 weeks on Day 1 Carboplatin: Carboplatin AUC 6 IV every 3 weeks on Day 1 for 6 cycles Paclitaxel: Paclitaxel 200 mg/m2 IV every 3 weeks on Day 1 for 6 cycles

    Arm title
    		 Avastin® ( EU-Bevacizumab, Ref.product) arm
    Arm description
    		 Avastin® (reference; sourced from the EU), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle in combination with chemotherapy (carboplatin and paclitaxel).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    EU-approved Avastin® + Carboplatin/Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    EU-approved Avastin®: 15 mg/kg IV every 3 weeks on Day 1 Carboplatin: Carboplatin AUC 6 IV every 3 weeks on Day 1 for 6 cycles Paclitaxel: Paclitaxel 200 mg/m2 IV every 3 weeks on Day 1 for 6 cycles

    Number of subjects in period 1
    		MB02 (Bevacizumab biosimilar) arm Avastin® ( EU-Bevacizumab, Ref.product) arm
    Started
    315
    312
    Completed
    207
    220
    Not completed
    108
    92
         Consent withdrawn by subject
    17
    12
         Physician decision
    7
    5
         Disease progression
    27
    38
         Adverse event, non-fatal
    29
    20
         Subject decision
    2
    1
         Death
    14
    12
         Lost to follow-up
    6
    2
         Did not receive treatment
    4
    2
         Protocol deviation
    2
    -
    Period 2
    Period 2 title
    Monotherapy
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    After 6 cycles (i.e., at the start of Cycle 7), subjects could have continued to receive MB02/Avastin® monotherapy treatment every 3 weeks until evidence of disease progression or until unacceptable toxic effects developed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avastin® ( EU-Bevacizumab, Ref.product)
    Arm description
    		 Avastin® (reference; sourced from the EU), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle
    Arm type
    		 Active comparator

    Investigational medicinal product name
    EU-approved Avastin®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    EU-approved Avastin®: 15 mg/kg IV every 3 weeks on Day 1

    Arm title
    		 MB02 (Bevacizumab biosimilar) arm
    Arm description
    		 MB02 (test; bevacizumab biosimilar drug sourced from mAbxience Spain), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    MB02 (Bevacizumab Biosimilar Drug)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MB02 (Bevacizumab Biosimilar Drug): 15 mg/kg IV every 3 weeks on Day 1

    Number of subjects in period 2
    		Avastin® ( EU-Bevacizumab, Ref.product) MB02 (Bevacizumab biosimilar) arm
    Started
    220
    207
    Completed
    74
    68
    Not completed
    146
    139
         Consent withdrawn by subject
    6
    5
         Physician decision
    8
    6
         Disease progression
    106
    109
         Adverse event, non-fatal
    11
    10
         Subject decision
    3
    3
         Death
    8
    5
         Lost to follow-up
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MB02 (Bevacizumab biosimilar) arm
    Reporting group description
    		 MB02 (test; bevacizumab biosimilar drug sourced from mAbxience Spain), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle in combination with chemotherapy (carboplatin and paclitaxel).

    Reporting group title
    Avastin® ( EU-Bevacizumab, Ref.product) arm
    Reporting group description
    		 Avastin® (reference; sourced from the EU), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle in combination with chemotherapy (carboplatin and paclitaxel).

    Reporting group values
    		 MB02 (Bevacizumab biosimilar) arm Avastin® ( EU-Bevacizumab, Ref.product) arm Total
    Number of subjects
    		 315 312 627
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 206 202 408
        From 65-84 years
    		 109 110 219
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 61.0 (54.0 to 67.0) 61.0 (56.0 to 67.5) -
    Gender categorical
    Units: Subjects
        Female
    		 122 122 244
        Male
    		 193 190 383
    Body surface area (BSA)
    Units: m2
        median (inter-quartile range (Q1-Q3))
    		 1.780 (1.600 to 1.940) 1.790 (1.595 to 1.940) -

    End points

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    End points reporting groups
    Reporting group title
    MB02 (Bevacizumab biosimilar) arm
    Reporting group description
    		 MB02 (test; bevacizumab biosimilar drug sourced from mAbxience Spain), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle in combination with chemotherapy (carboplatin and paclitaxel).

    Reporting group title
    Avastin® ( EU-Bevacizumab, Ref.product) arm
    Reporting group description
    		 Avastin® (reference; sourced from the EU), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle in combination with chemotherapy (carboplatin and paclitaxel).
    Reporting group title
    Avastin® ( EU-Bevacizumab, Ref.product)
    Reporting group description
    		 Avastin® (reference; sourced from the EU), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle

    Reporting group title
    MB02 (Bevacizumab biosimilar) arm
    Reporting group description
    		 MB02 (test; bevacizumab biosimilar drug sourced from mAbxience Spain), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects.

    Primary: Objective response rate (ORR) at Week 18

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    End point title
    		 Objective response rate (ORR) at Week 18
    End point description
    Objective response rate was assigned for a subject if the subject displayed either complete response (CR) or partial response (PR) per RECIST version 1.1 at Week 18, as assessed by independent radiological review committee (IRC). Overall Response (OR) = CR + PR.
    End point type
    Primary
    End point timeframe
    18 weeks from randomization
    End point values
    		 MB02 (Bevacizumab biosimilar) arm Avastin® ( EU-Bevacizumab, Ref.product) arm
    Number of subjects analysed
    315
    312
    Units: percentage of subjects
        number (confidence interval 95%)
    40.3 (34.9 to 46.0)
    44.6 (39.0 to 50.3)
    Statistical analysis title
    		 Equivalence based on risk ratio (RR) with 90% CI
    Statistical analysis description
    Equivalence analysis was based on the risk ratio (RR) (MB02/EU-approved Avastin) with an equivalence margin predefined [0.73, 1.36]. The ORR estimate was stratified using the Cochran-Mantel-Haenszel estimate of the RR and corresponding 2-sided 90% and 95% confidence interval (CI).
    Comparison groups
    MB02 (Bevacizumab biosimilar) arm v Avastin® ( EU-Bevacizumab, Ref.product) arm
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.91
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.06
    Statistical analysis title
    		 Equivalence based on Risk Difference with 90%CI
    Statistical analysis description
    The ORR estimate was stratified using the Cochran-Mantel-Haenszel estimate of the risk difference (RD) (MB02-EU-approved Avastin) with an equivalence margin predefined [-12%, 12%] and corresponding 2-sided 90% and 95% confidence interval (CI).
    Comparison groups
    MB02 (Bevacizumab biosimilar) arm v Avastin® ( EU-Bevacizumab, Ref.product) arm
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -10.51
         upper limit
    		 2.47
    Statistical analysis title
    		 Equivalence based on Risk Difference with 95%CI
    Statistical analysis description
    The ORR estimate was stratified using the Cochran-Mantel-Haenszel estimate of the risk difference (RD) (MB02-EU-approved Avastin) with an equivalence margin predefined [-12%, 12%] and corresponding 2-sided 90% and 95% confidence interval (CI).
    Comparison groups
    MB02 (Bevacizumab biosimilar) arm v Avastin® ( EU-Bevacizumab, Ref.product) arm
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.76
         upper limit
    		 3.71
    Statistical analysis title
    		 Equivalence based on risk ratio (RR) with 95%CI
    Statistical analysis description
    Equivalence analysis was based on the risk ratio (RR) (MB02/EU-approved Avastin) with an equivalence margin predefined [0.73, 1.36]. The ORR estimate was stratified using the Cochran-Mantel-Haenszel estimate of the RR and corresponding 2-sided 90% and 95% confidence interval (CI).
    Comparison groups
    Avastin® ( EU-Bevacizumab, Ref.product) arm v MB02 (Bevacizumab biosimilar) arm
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.758
         upper limit
    		 1.092

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study completion. An average of two years (from the beginning of the study at 06-February-2018 till last patient last visit in 27-February-2020).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    MB02 (Bevacizumab biosimilar) arm
    Reporting group description
    		 MB02 (test; bevacizumab biosimilar drug sourced from mAbxience Spain), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle in combination with chemotherapy (carboplatin and paclitaxel).

    Reporting group title
    Avastin® ( EU-Bevacizumab, Ref.product) arm
    Reporting group description
    		 Avastin® (reference; sourced from the EU), administered as an IV infusion at an intended dose of 15 mg/kg on Day 1 of every 3-week treatment cycle in combination with chemotherapy (carboplatin and paclitaxel).

    Serious adverse events
    		 MB02 (Bevacizumab biosimilar) arm Avastin® ( EU-Bevacizumab, Ref.product) arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 311 (18.65%)
    54 / 310 (17.42%)
         number of deaths (all causes)
    91
    90
         number of deaths resulting from adverse events
    23
    24
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 311 (0.32%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 311 (0.32%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 311 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    2 / 311 (0.64%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 311 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 311 (0.96%)
    6 / 310 (1.94%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 8
    0 / 11
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 311 (0.64%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 311 (0.64%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         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
    Dyspnea
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemoptysis
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 311 (0.32%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonay embolism
         subjects affected / exposed
    6 / 311 (1.93%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    4 / 6
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary hemorrhage
         subjects affected / exposed
    1 / 311 (0.32%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 311 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (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
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         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
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial fibrilation
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiorespiratory arrest
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischemia
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 311 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysmetria
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischemic stroke
         subjects affected / exposed
    1 / 311 (0.32%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage intracranial
         subjects affected / exposed
    2 / 311 (0.64%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 311 (0.32%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 311 (1.29%)
    7 / 310 (2.26%)
         occurrences causally related to treatment / all
    5 / 5
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 311 (0.96%)
    6 / 310 (1.94%)
         occurrences causally related to treatment / all
    4 / 4
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 311 (0.64%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastric ulcer
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhoids
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperchlorhydria
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (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
    1 / 311 (0.32%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 311 (0.64%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nephrotic syndrome
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Infections and infestations
    Brain abscess
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    3 / 311 (0.96%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 311 (0.32%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 311 (2.57%)
    8 / 310 (2.58%)
         occurrences causally related to treatment / all
    4 / 8
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 311 (0.64%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypernatremia
         subjects affected / exposed
    1 / 311 (0.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcemia
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalemia
         subjects affected / exposed
    1 / 311 (0.32%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 311 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    1 / 311 (0.32%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MB02 (Bevacizumab biosimilar) arm Avastin® ( EU-Bevacizumab, Ref.product) arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    230 / 311 (73.95%)
    234 / 310 (75.48%)
    Investigations
    Weight decreased
         subjects affected / exposed
    23 / 311 (7.40%)
    27 / 310 (8.71%)
         occurrences all number
    27
    36
    Platelet count decreased
         subjects affected / exposed
    26 / 311 (8.36%)
    19 / 310 (6.13%)
         occurrences all number
    52
    34
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 311 (4.82%)
    21 / 310 (6.77%)
         occurrences all number
    33
    28
    Aspartate aminotransferase increased
         subjects affected / exposed
    14 / 311 (4.50%)
    22 / 310 (7.10%)
         occurrences all number
    35
    26
    Neutrophil count decreased
         subjects affected / exposed
    18 / 311 (5.79%)
    18 / 310 (5.81%)
         occurrences all number
    32
    25
    Vascular disorders
    Hypertension
         subjects affected / exposed
    24 / 311 (7.72%)
    26 / 310 (8.39%)
         occurrences all number
    32
    35
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    38 / 311 (12.22%)
    41 / 310 (13.23%)
         occurrences all number
    70
    60
    Peripheral sensory neuropathy
         subjects affected / exposed
    22 / 311 (7.07%)
    23 / 310 (7.42%)
         occurrences all number
    30
    36
    Paresthesia
         subjects affected / exposed
    21 / 311 (6.75%)
    13 / 310 (4.19%)
         occurrences all number
    34
    18
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    101 / 311 (32.48%)
    94 / 310 (30.32%)
         occurrences all number
    193
    191
    Leukopenia
         subjects affected / exposed
    24 / 311 (7.72%)
    18 / 310 (5.81%)
         occurrences all number
    42
    34
    Neutropenia
         subjects affected / exposed
    34 / 311 (10.93%)
    45 / 310 (14.52%)
         occurrences all number
    75
    81
    Thrombocytopenia
         subjects affected / exposed
    41 / 311 (13.18%)
    42 / 310 (13.55%)
         occurrences all number
    95
    75
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    39 / 311 (12.54%)
    36 / 310 (11.61%)
         occurrences all number
    85
    82
    Asthenia
         subjects affected / exposed
    39 / 311 (12.54%)
    29 / 310 (9.35%)
         occurrences all number
    67
    53
    General physical health deterioration
         subjects affected / exposed
    23 / 311 (7.40%)
    29 / 310 (9.35%)
         occurrences all number
    23
    29
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    47 / 311 (15.11%)
    44 / 310 (14.19%)
         occurrences all number
    84
    81
    Diarrhea
         subjects affected / exposed
    29 / 311 (9.32%)
    27 / 310 (8.71%)
         occurrences all number
    38
    39
    Vomiting
         subjects affected / exposed
    22 / 311 (7.07%)
    11 / 310 (3.55%)
         occurrences all number
    31
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 311 (6.43%)
    22 / 310 (7.10%)
         occurrences all number
    31
    26
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    155 / 311 (49.84%)
    163 / 310 (52.58%)
         occurrences all number
    193
    206
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    18 / 311 (5.79%)
    25 / 310 (8.06%)
         occurrences all number
    33
    53
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    23 / 311 (7.40%)
    30 / 310 (9.68%)
         occurrences all number
    44
    53
    Arthralgia
         subjects affected / exposed
    19 / 311 (6.11%)
    20 / 310 (6.45%)
         occurrences all number
    31
    26
    Infections and infestations
    Respiratory tract infection viral
         subjects affected / exposed
    16 / 311 (5.14%)
    16 / 310 (5.16%)
         occurrences all number
    22
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 311 (4.50%)
    20 / 310 (6.45%)
         occurrences all number
    16
    30

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2018
    The main reason for the amendment was to implement the FDA recommendations received after the FDA Scientific Advice was provided on 04-October-2018. Other minor updates were also made as a result of recommendations received from the DSMB recommendations and to clarify aspects of the protocol which were unclear in version 1.0.
    24 May 2019
    The main reason to issue the present amendment was to clarify the procedures applicable to subjects that were responding to treatment at Week 52 and were offered the opportunity to be treated with biosimilar MB02 monotherapy until disease progression, unacceptable toxicity, or death.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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