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    Clinical Trial Results:
    Multicenter, Double-Blind, Randomized, Parallel-Group Study to Assess the Efficacy and Safety of MYL-1402O Compared With Avastin®, in the First-line Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2015-005141-32
    Trial protocol
    		 ES   HU   HR   BG   IT  
    Global end of trial date
    22 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2022
    First version publication date
    25 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MYL-1402O-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04633564
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mylan GmbH
    Sponsor organisation address
    1000 Mylan Boulevard, Canonsburg, PA , United States, 15317
    Public contact
    Keri Vaughan, Mylan GmbH, keri.vaughan@viatris.com
    Scientific contact
    Dr Tazeen Idris, Mylan GmbH, TazeenAamena.Idris@viatris.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
    10 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the overall response rate (ORR) of MYL-1402O with that of Avastin, in combination with CP chemotherapy during the first 18 weeks of first-line treatment in patients with Stage IV nsNSCLC.
    Protection of trial subjects
    All laboratory specimens, evaluation forms, reports, and other records were identified in a manner designed to maintain patient confidentiality. All records were kept in a secure storage area with limited access. Clinical information was not be released without the written permission of the patient (or the patient’s legal guardian), except as necessary for monitoring and auditing by the sponsor, its designee, regulatory authorities or the IRB/IEC. The PI (or designee) and all employees and coworkers involved with this study have not disclosed or used for any purpose other than performance of the study any data, record, or other unpublished, confidential information disclosed to those individuals for the purpose of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    India: 191
    Country: Number of subjects enrolled
    Belarus: 24
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 19
    Country: Number of subjects enrolled
    Georgia: 58
    Country: Number of subjects enrolled
    Russian Federation: 140
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 160
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Viet Nam: 17
    Worldwide total number of subjects
    671
    EEA total number of subjects
    55
    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)
    473
    From 65 to 84 years
    197
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 671 patients were randomized from 89 sites. Intent To Treat population was used to determine Primary outcome. Date first patient randomized: 21 Jan 2017, Date Last Patient’s Last Assessment in Period 1 (Date of data Cut-Off): 05 Jun 19 Date Last Patient’s Last Assessment in Period 2 (Date of data Cut-Off): 22 Nov 20

    Pre-assignment
    Screening details
    		 This was a multicenter, randomized, double-blind, 2-arm, parallel group, equivalence study. The study consisted of screening/baseline, Treatment Period 1 and Period 2, an extended treatment period and safety follow up. A total of 1016 patients were screened; 345 patients were screening failures. A total of 671 patients were randomized.

    Period 1
    Period 1 title
    Period 1 (up to week 18)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MYL-1402O
    Arm description
    		 Patients began Period 1 by receiving bevacizumab combination therapy (MYL-1402O- 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each cycle consisted of 3 weeks (21 days ± 3 days) and a cycle started with the administration of bevacizumab (as MYL-1402O ).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    MYL-1402O
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab as MYL-1402O 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV

    Arm title
    		 Avastin
    Arm description
    		 Patients began Period 1 receiving bevacizumab combination therapy ( Avastin15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each cycle consisted of 3 weeks (21 days ± 3 days) and a cycle started with the administration of bevacizumab (as Avastin).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Avastin
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab as Avastin 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV

    Number of subjects in period 1
    		MYL-1402O Avastin
    Started
    337
    334
    Completed
    227
    220
    Not completed
    110
    114
         Physician decision
    4
    12
         Consent withdrawn by subject
    10
    8
         Adverse event, non-fatal
    28
    19
         Death
    8
    7
         Study terminated sponsor
    8
    6
         Progressive Disease
    47
    51
         Protocol Violation
    -
    1
         Lost to follow-up
    3
    5
         Not treated
    2
    5
    Period 2
    Period 2 title
    Period 2 (up to week 42)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MYL-1402O
    Arm description
    		 In Period 2, eligible patients will continue to receive bevacizumab ( MYL- 1402O) every 3 weeks as monotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    MYL-1402O
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab as MYL-1402O 15 mg/kg IV

    Arm title
    		 Avastin
    Arm description
    		 In Period 2, eligible patients will continue to receive bevacizumab (Avastin) every 3 weeks as monotherapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Avastin
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab as Avastin 15 mg/kg IV

    Number of subjects in period 2 [1]
    		MYL-1402O Avastin
    Started
    200
    199
    Completed
    107
    102
    Not completed
    93
    97
         Physician decision
    2
    4
         Consent withdrawn by subject
    5
    1
         Adverse event, non-fatal
    3
    4
         Study terminated sponsor
    9
    3
         Death
    -
    2
         Progressive Disease
    74
    82
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: MYL-1402O arm: 27 patients could not enter in Period 2 from Period 1 due to AE (5), Progressive disease (18), Withdrawal by subject (1), Study terminated by Sponsor (3). Avastin arm: 21 patients could not enter in Period 2 from Period 1 due to AE (5), Progressive disease (15), Study terminated by Sponsor (1).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MYL-1402O
    Reporting group description
    		 Patients began Period 1 by receiving bevacizumab combination therapy (MYL-1402O- 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each cycle consisted of 3 weeks (21 days ± 3 days) and a cycle started with the administration of bevacizumab (as MYL-1402O ).

    Reporting group title
    Avastin
    Reporting group description
    		 Patients began Period 1 receiving bevacizumab combination therapy ( Avastin15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each cycle consisted of 3 weeks (21 days ± 3 days) and a cycle started with the administration of bevacizumab (as Avastin).

    Reporting group values
    		 MYL-1402O Avastin Total
    Number of subjects
    		 337 334 671
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 237 236 473
        From 65-84 years
    		 99 98 197
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        least squares mean (standard deviation)
    		 59.3 ± 9.60 59.2 ± 9.73 -
    Gender categorical
    Units: Subjects
        Female
    		 124 123 247
        Male
    		 213 211 424
    Subject analysis sets

    Subject analysis set title
    Intent to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set consisted of all randomized patients. The ITT set consisted of a total of 671 patients (337 in the MYL-1402O arm and 334 in the Avastin arm) who were randomized into the study under Protocol.

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP set will consist of all randomized patients who complete at least one dose of MYL-1402O or Avastin and do not have protocol deviations having significant impact on the (study) endpoints during the study.

    Subject analysis sets values
    		 Intent to treat Per Protocol
    Number of subjects
    671
    634
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    473
    443
        From 65-84 years
    197
    191
        85 years and over
    1
    0
    Age continuous
    Units: years
        least squares mean (standard deviation)
    59.3 ± 9.66
    59.3 ± 9.73
    Gender categorical
    Units: Subjects
        Female
    247
    240
        Male
    424
    394

    End points

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    End points reporting groups
    Reporting group title
    MYL-1402O
    Reporting group description
    		 Patients began Period 1 by receiving bevacizumab combination therapy (MYL-1402O- 15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each cycle consisted of 3 weeks (21 days ± 3 days) and a cycle started with the administration of bevacizumab (as MYL-1402O ).

    Reporting group title
    Avastin
    Reporting group description
    		 Patients began Period 1 receiving bevacizumab combination therapy ( Avastin15 mg/kg IV + Carboplatin AUC 6 IV+ Paclitaxel 200 or 175 mg/m2 IV) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each cycle consisted of 3 weeks (21 days ± 3 days) and a cycle started with the administration of bevacizumab (as Avastin).
    Reporting group title
    MYL-1402O
    Reporting group description
    		 In Period 2, eligible patients will continue to receive bevacizumab ( MYL- 1402O) every 3 weeks as monotherapy.

    Reporting group title
    Avastin
    Reporting group description
    		 In Period 2, eligible patients will continue to receive bevacizumab (Avastin) every 3 weeks as monotherapy.

    Subject analysis set title
    Intent to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set consisted of all randomized patients. The ITT set consisted of a total of 671 patients (337 in the MYL-1402O arm and 334 in the Avastin arm) who were randomized into the study under Protocol.

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP set will consist of all randomized patients who complete at least one dose of MYL-1402O or Avastin and do not have protocol deviations having significant impact on the (study) endpoints during the study.

    Primary: ORR at Week 18

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    End point title
    		 ORR at Week 18
    End point description
    The primary efficacy endpoint is the ORR as assessed by an independent review during the first 18 Weeks, assessed according to RECIST 1.1.
    End point type
    Primary
    End point timeframe
    18 Weeks
    End point values
    		 MYL-1402O Avastin
    Number of subjects analysed
    337
    334
    Units: Percentage of participants
        number (confidence interval 95%)
    41.5 (36.3 to 46.8)
    43.1 (37.8 to 48.4)
    Statistical analysis title
    		 Risk Difference Analysis
    Comparison groups
    MYL-1402O v Avastin
    Number of subjects included in analysis
    671
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9
         upper limit
    		 5.9

    Secondary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    PFS, defined as the time from randomization to the first documentation of PD or to death due to any cause, whichever comes first; PFS rate was calculated at 42 weeks, median PFS was determined at 42 weeks.
    End point type
    Secondary
    End point timeframe
    Week 42
    End point values
    		 MYL-1402O Avastin
    Number of subjects analysed
    337
    334
    Units: Months
        median (confidence interval 95%)
    7.6 (7.0 to 9.5)
    9.0 (7.2 to 9.7)
    Statistical analysis title
    		 Kaplan-Meier Analysis
    Comparison groups
    MYL-1402O v Avastin
    Number of subjects included in analysis
    671
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0906
    Method
    		 Logrank
    Confidence interval

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    DOR, is defined as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of tumor progression (i.e., PD) or to death due to any cause, whichever comes first.
    End point type
    Secondary
    End point timeframe
    42 Weeks
    End point values
    		 MYL-1402O Avastin
    Number of subjects analysed
    337
    334
    Units: Months
        median (confidence interval 95%)
    7.7 (6.2 to 8.3)
    6.9 (5.8 to 8.5)
    Statistical analysis title
    		 Kaplan-Meier Analysis
    Comparison groups
    MYL-1402O v Avastin
    Number of subjects included in analysis
    671
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5698
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A treatment-emergent AE is an AE that started or deteriorated after the first administration of blinded MYL-1402O or Avastin through 100 days following the last dose of blinded MYL-1402O or Avastin.
    Adverse event reporting additional description
    Overall, study drug was administered to 664 patients during the study (335 in the MYL-1402O arm and 329 in the Avastin arm), who completed at least one dose or partial dose of MYL-1402O or Avastin.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    MYL-1402O
    Reporting group description
    		 -

    Reporting group title
    Avastin
    Reporting group description
    		 -

    Serious adverse events
    		 MYL-1402O Avastin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    59 / 335 (17.61%)
    55 / 329 (16.72%)
         number of deaths (all causes)
    101
    82
         number of deaths resulting from adverse events
    25
    14
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous Thrombosis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 335 (0.30%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired Healing
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         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
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    4 / 335 (1.19%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    4 / 335 (1.19%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    2 / 4
    1 / 3
    Dyspnoea
         subjects affected / exposed
    5 / 335 (1.49%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 335 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 335 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Aspiration
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Thrombosis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Platelet Count Decreased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur Fracture
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Angina Unstable
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardicac Arrest
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    COR Pulmonale Acute
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary Artery disease
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Arrhythmia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    2 / 335 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Cerebral small vessel ischaemic disease
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    7 / 335 (2.09%)
    5 / 329 (1.52%)
         occurrences causally related to treatment / all
    0 / 7
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Thrombocytopenia
         subjects affected / exposed
    4 / 335 (1.19%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    1 / 4
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    5 / 335 (1.49%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 335 (1.19%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 335 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Angle Closure Glaucoma
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 335 (0.30%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Perforation
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic Ulcer Haemorrhage
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peptic Ulcer Perforation
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 335 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelocaliectasis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Cyst Ruptured
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological Fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    3 / 335 (0.90%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 2
    2 / 2
    Pneumonia
         subjects affected / exposed
    3 / 335 (0.90%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 335 (0.90%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    2 / 335 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 335 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear Infection
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye Infection Fungal
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Salmonella
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Abscess
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 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
    		 MYL-1402O Avastin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    311 / 335 (92.84%)
    304 / 329 (92.40%)
    Investigations
    Alanine Amino-tranferase Increased
         subjects affected / exposed
    25 / 335 (7.46%)
    29 / 329 (8.81%)
         occurrences all number
    37
    45
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 335 (6.57%)
    19 / 329 (5.78%)
         occurrences all number
    29
    28
    Weight decreased
         subjects affected / exposed
    22 / 335 (6.57%)
    7 / 329 (2.13%)
         occurrences all number
    23
    7
    Vascular disorders
    Hypertension
         subjects affected / exposed
    19 / 335 (5.67%)
    16 / 329 (4.86%)
         occurrences all number
    24
    23
    Nervous system disorders
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    74 / 335 (22.09%)
    66 / 329 (20.06%)
         occurrences all number
    99
    91
    Headache
         subjects affected / exposed
    26 / 335 (7.76%)
    17 / 329 (5.17%)
         occurrences all number
    35
    20
    Hypoaesthesia
         subjects affected / exposed
    15 / 335 (4.48%)
    20 / 329 (6.08%)
         occurrences all number
    22
    25
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    111 / 335 (33.13%)
    112 / 329 (34.04%)
         occurrences all number
    232
    221
    Thrombocytopenia
         subjects affected / exposed
    104 / 335 (31.04%)
    80 / 329 (24.32%)
         occurrences all number
    225
    197
    Neutropenia
         subjects affected / exposed
    68 / 335 (20.30%)
    76 / 329 (23.10%)
         occurrences all number
    128
    144
    Leukopenia
         subjects affected / exposed
    38 / 335 (11.34%)
    41 / 329 (12.46%)
         occurrences all number
    67
    97
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    53 / 335 (15.82%)
    33 / 329 (10.03%)
         occurrences all number
    68
    42
    Pyrexia
         subjects affected / exposed
    31 / 335 (9.25%)
    21 / 329 (6.38%)
         occurrences all number
    57
    34
    Fatigue
         subjects affected / exposed
    26 / 335 (7.76%)
    27 / 329 (8.21%)
         occurrences all number
    31
    32
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    56 / 335 (16.72%)
    49 / 329 (14.89%)
         occurrences all number
    111
    108
    Vomiting
         subjects affected / exposed
    54 / 335 (16.12%)
    38 / 329 (11.55%)
         occurrences all number
    100
    59
    Diarrhoea
         subjects affected / exposed
    46 / 335 (13.73%)
    30 / 329 (9.12%)
         occurrences all number
    104
    55
    Stomatitis
         subjects affected / exposed
    22 / 335 (6.57%)
    8 / 329 (2.43%)
         occurrences all number
    29
    14
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    21 / 335 (6.27%)
    16 / 329 (4.86%)
         occurrences all number
    30
    18
    Cough
         subjects affected / exposed
    15 / 335 (4.48%)
    23 / 329 (6.99%)
         occurrences all number
    16
    30
    Epistaxis
         subjects affected / exposed
    6 / 335 (1.79%)
    17 / 329 (5.17%)
         occurrences all number
    6
    19
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    148 / 335 (44.18%)
    168 / 329 (51.06%)
         occurrences all number
    186
    198
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    11 / 335 (3.28%)
    17 / 329 (5.17%)
         occurrences all number
    18
    21
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 335 (4.78%)
    18 / 329 (5.47%)
         occurrences all number
    28
    46
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    43 / 335 (12.84%)
    32 / 329 (9.73%)
         occurrences all number
    54
    39

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2018
    • Change in Study Design including Removal of the Survival Period from the study; every subject will be part of the study till 42 weeks (Period 2), beyond which they can receive treatment under the extension period. During Extension Period only the related AEs will be collected. • Change in sample Size; verbatim “It is estimated that approximately 864 screened patients will yield approximately 640 patients for 1:1 randomization for having at least 628 evaluable patients, taking into account the attrition rate of 2%.” • Change in the Statistical consideration in the primary endpoint as per the FDA and EMA feedback. Details of Meta-analysis included. • End of Study modified to study Closure; “Study closure will occur when either all patients have discontinued the study, or 42 weeks from the date the last patient was randomized to treatment OR at the administrative closure of the study. Patients on treatment at study closure will be advised by the PI and/or their associated primary health care provider on alternate therapies as per standard for the country. All treatment provided under the auspices of this protocol will cease at study closure.” • Preferred method for Urine Protein evaluation changed from UPCR to Urine dipstick; “Inclusion Criteria: Urine protein (via dipstick): 0 or 1+. Patients with ≥ 2+ can be included only if a 24-hour urine specimen yields <2g of protein.” • Dose Modification Table, as recommended in the Avastin PI 2017 is included. • Editorial changes throughout the document for harmonization of the text. • Administrative changes for study conduct
    19 Feb 2019
    • Update the definition of primary endpoint “The primary efficacy endpoint Overall Response Rate (ORR) will be based on best tumor responses as assessed by an independent review at any time point during the first 18 weeks, and assessed according to RECIST 1.1 • ORR based on confirmed tumor responses will be evaluated as sensitivity analysis

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34819997
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