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    Clinical Trial Results:
    A Multicenter Open-Label Single-Arm Phase II Study Evaluating the Safety and Efficacy of Bevacizumab in Combination With Carboplatin and Paclitaxel in Patients With Metastatic, Recurrent or Persistent Cervical Cancer

    Summary
    EudraCT number
    2014-005491-28
    Trial protocol
    ES   PT   PL   GR   FR   BG   IT  
    Global end of trial date
    31 Dec 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Dec 2019
    First version publication date
    27 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO29594
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02467907
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to determine the safety of bevacizumab in combination with carboplatin and paclitaxel therapy for metastatic, recurrent or persistent cervical cancer, as defined by the frequency and severity of gastrointestinal (GI) perforation/fistula, GI-vaginal fistula and genitourinary (GU) fistula events.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Jul 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    Costa Rica: 4
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Mexico: 11
    Country: Number of subjects enrolled
    Panama: 7
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    South Africa: 8
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Turkey: 7
    Worldwide total number of subjects
    150
    EEA total number of subjects
    79
    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)
    131
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    222 patients were screened for this study and 150 received study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Arm description
    Administration of bevacizumab, carboplatin and paclitaxel once every 3 weeks, for at least 6 cycles, until disease progression (as assessed by the investigator), unacceptable toxicity, physician or participant decision or withdrawal of consent. If either chemotherapy or bevacizumab is discontinued, the participant may continue to receive the other ongoing therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin, RO4876646
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (i.v.) administration of 15 mg/kg bevacizumab once every 3 weeks

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of carboplatin at 5 milligrams per milliliter*minute (mg/mL*min) on Day 1 every 3 weeks for at least 6 cycles

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of paclitaxel at a dose of 175 milligrams per square meter (mg/m^2) on Day 1 every 3 weeks for at least 6 cycles

    Number of subjects in period 1
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Started
    150
    Completed
    41
    Not completed
    109
         Death
    71
         Physician decision
    4
         Consent withdrawn by subject
    23
         Lost to follow-up
    10
         Sponsor decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Reporting group description
    Administration of bevacizumab, carboplatin and paclitaxel once every 3 weeks, for at least 6 cycles, until disease progression (as assessed by the investigator), unacceptable toxicity, physician or participant decision or withdrawal of consent. If either chemotherapy or bevacizumab is discontinued, the participant may continue to receive the other ongoing therapy.

    Reporting group values
    Bevacizumab in Combination with Carboplatin and Paclitaxel Total
    Number of subjects
    150 150
    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)
    131 131
        From 65-84 years
    19 19
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.4 ± 11.60 -
    Gender categorical
    Units: Subjects
        Female
    150 150
        Male
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Reporting group description
    Administration of bevacizumab, carboplatin and paclitaxel once every 3 weeks, for at least 6 cycles, until disease progression (as assessed by the investigator), unacceptable toxicity, physician or participant decision or withdrawal of consent. If either chemotherapy or bevacizumab is discontinued, the participant may continue to receive the other ongoing therapy.

    Primary: Percentage of Participants with GI Perforation/Fistula, GI-Vaginal Fistula and GU Fistula Events

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    End point title
    Percentage of Participants with GI Perforation/Fistula, GI-Vaginal Fistula and GU Fistula Events [1]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline up to 24 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no formal statistical test / hypothesis testing specified.
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of participants
    number (confidence interval 95%)
        All perforation/fistula
    11.3 (6.7 to 17.5)
        GI perforation/fistula
    4.7 (1.9 to 9.4)
        GI-vaginal fistula
    4.0 (1.5 to 8.5)
        GU fistula
    4.7 (1.9 to 9.4)
    No statistical analyses for this end point

    Primary: Percentage of Participants with GI Perforation/Fistula, GI-Vaginal Fistula and GU Fistula Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0

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    End point title
    Percentage of Participants with GI Perforation/Fistula, GI-Vaginal Fistula and GU Fistula Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 [2]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline up to 24 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no formal statistical test / hypothesis testing specified.
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of participants
    number (not applicable)
        GI perforation/fistula (All Grades)
    4.7
        GI perforation/fistula (Grade 3)
    1.3
        GI perforation/fistula (Grade 4)
    1.3
        GI perforation/fistula (Grade 5)
    0.7
        GI-vaginal fistula (All Grades)
    4.0
        GI-vaginal fistula (Grade 3)
    2.0
        GI-vaginal fistula (Grade 4)
    0
        GI-vaginal fistula (Grade 5)
    0
        GU fistula (All Grades)
    4.7
        GU fistula (Grade 3)
    2.0
        GU fistula (Grade 4)
    0
        GU fistula (Grade 5)
    0
    No statistical analyses for this end point

    Primary: Time to First GI Perforation/Fistula, GI-Vaginal Fistula or GU Fistula Events

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    End point title
    Time to First GI Perforation/Fistula, GI-Vaginal Fistula or GU Fistula Events [3]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline up to 24 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no formal statistical test / hypothesis testing specified.
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: months
    arithmetic mean (standard deviation)
        First perforation/fistula (N=17)
    4.24 ± 3.118
        First GI perforation/fistula (N=7)
    4.23 ± 2.694
        First GI-vaginal fistula (N=6)
    3.75 ± 2.049
        First GU fistula (N=7)
    5.05 ± 4.083
    No statistical analyses for this end point

    Secondary: Dose Intensity (Ratio of Actual Dose Administered Versus Intended Dose) for Bevacizumab During the Treatment Period

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    End point title
    Dose Intensity (Ratio of Actual Dose Administered Versus Intended Dose) for Bevacizumab During the Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of intended dose
        arithmetic mean (standard deviation)
    100.014 ± 0.1568
    No statistical analyses for this end point

    Secondary: Dose Intensity (Ratio of Actual Dose Administered Versus Intended Dose) for Carboplatin During the Treatment Period

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    End point title
    Dose Intensity (Ratio of Actual Dose Administered Versus Intended Dose) for Carboplatin During the Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of intended dose
        arithmetic mean (standard deviation)
    98.290 ± 4.3623
    No statistical analyses for this end point

    Secondary: Dose Intensity (Ratio of Actual Dose Administered Versus Intended Dose) for Paclitaxel During the Treatment Period

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    End point title
    Dose Intensity (Ratio of Actual Dose Administered Versus Intended Dose) for Paclitaxel During the Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of intended dose
        arithmetic mean (standard deviation)
    98.274 ± 5.3525
    No statistical analyses for this end point

    Secondary: Duration of Treatment for Bevacizumab

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    End point title
    Duration of Treatment for Bevacizumab
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: months
        arithmetic mean (standard deviation)
    9.58 ± 8.874
    No statistical analyses for this end point

    Secondary: Duration of Treatment for Carboplatin

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    End point title
    Duration of Treatment for Carboplatin
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: months
        arithmetic mean (standard deviation)
    4.26 ± 2.286
    No statistical analyses for this end point

    Secondary: Duration of Treatment for Paclitaxel

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    End point title
    Duration of Treatment for Paclitaxel
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: months
        arithmetic mean (standard deviation)
    4.27 ± 2.386
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events (AEs)

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    End point title
    Percentage of Participants with Adverse Events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of participants
        number (confidence interval 95%)
    98.0 (94.3 to 99.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Serious Adverse Events (SAEs)

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    End point title
    Percentage of Participants with Serious Adverse Events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of participants
        number (confidence interval 95%)
    31.3 (24.0 to 39.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events of Special Interest (AESIs)

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    End point title
    Percentage of Participants with Adverse Events of Special Interest (AESIs)
    End point description
    AESIs included arterial thromboembolic events (ATE), bleeding, heart failure (CHF)/left ventricular systolic dysfunction, febrile neutropenia, hypertension, proteinuria, posterior reversible encephalopathy syndrome (PRES), venous thromboembolic event; and wound-healing complication.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of participants
        number (confidence interval 95%)
    82.7 (75.6 to 88.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with AEs Leading to Treatment Interruption or Permanent discontinuation

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    End point title
    Percentage of Participants with AEs Leading to Treatment Interruption or Permanent discontinuation
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: percentage of participants
    number (not applicable)
        Discontinuation of Bevacizumab
    32.0
        Discontinuation of Paclitaxel/Platin
    28.0
        Interruption of Bevacizumab
    42.7
        Interruption of Paclitaxel/Platin
    46.0
    No statistical analyses for this end point

    Secondary: Count of Participants that Died during Study

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    End point title
    Count of Participants that Died during Study
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    74
    Units: participants
    number (not applicable)
        Disease Progression
    61
        Adverse Event
    8
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) According to Response Evaluation Criteria for Solid Tumors (RECIST) Version 1.1

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    End point title
    Progression-Free Survival (PFS) According to Response Evaluation Criteria for Solid Tumors (RECIST) Version 1.1
    End point description
    PFS is defined as time from the first dose of study treatment [bevacizumab or chemotherapy] to the first occurrence of investigator-assessed disease progression (PD) according to RECIST v1.1 or death from any cause.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: months
        median (confidence interval 95%)
    10.9 (10.1 to 13.7)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival is defined as the time from first study drug (bevacizumab or chemotherapy) to death due to any cause
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    150
    Units: months
        median (confidence interval 95%)
    25.0 (20.9 to 30.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.1

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    End point title
    Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.1
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 months
    End point values
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Number of subjects analysed
    138
    Units: percentage of participants
    number (confidence interval 95%)
        Complete Response
    13.8 (8.5 to 20.7)
        Partial Response
    47.1 (38.6 to 55.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 24 months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Reporting group description
    Administration of bevacizumab, carboplatin and paclitaxel once every 3 weeks, for at least 6 cycles, until disease progression (as assessed by the investigator), unacceptable toxicity, physician or participant decision or withdrawal of consent. If either chemotherapy or bevacizumab is discontinued, the participant may continue to receive the other ongoing therapy.

    Serious adverse events
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 150 (31.33%)
         number of deaths (all causes)
    74
         number of deaths resulting from adverse events
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    HYPOVOLAEMIC SHOCK
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    RADIATION PROCTITIS
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PNEUMOTHORAX
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    6 / 150 (4.00%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    LEUKOPENIA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    SUPRAPUBIC PAIN
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    ANAL FISTULA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    AORTOENTERIC FISTULA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    COLITIS
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    GASTROINTESTINAL PERFORATION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    NAUSEA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    4 / 150 (2.67%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    FEMALE GENITAL TRACT FISTULA
         subjects affected / exposed
    4 / 150 (2.67%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    METRORRHAGIA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PELVIC PAIN
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    UTERINE HAEMORRHAGE
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    VULVOVAGINAL PAIN
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    ANURIA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    HYDRONEPHROSIS
         subjects affected / exposed
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    URINARY TRACT OBSTRUCTION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    UROGENITAL FISTULA
         subjects affected / exposed
    5 / 150 (3.33%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    ABSCESS SOFT TISSUE
         subjects affected / exposed
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    PERITONITIS
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SOFT TISSUE INFECTION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    4 / 150 (2.67%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bevacizumab in Combination with Carboplatin and Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    145 / 150 (96.67%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    52 / 150 (34.67%)
         occurrences all number
    91
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    8 / 150 (5.33%)
         occurrences all number
    13
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    38 / 150 (25.33%)
         occurrences all number
    64
    FATIGUE
         subjects affected / exposed
    26 / 150 (17.33%)
         occurrences all number
    31
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    10 / 150 (6.67%)
         occurrences all number
    14
    OEDEMA PERIPHERAL
         subjects affected / exposed
    11 / 150 (7.33%)
         occurrences all number
    13
    PYREXIA
         subjects affected / exposed
    10 / 150 (6.67%)
         occurrences all number
    12
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    8 / 150 (5.33%)
         occurrences all number
    8
    INSOMNIA
         subjects affected / exposed
    8 / 150 (5.33%)
         occurrences all number
    12
    Reproductive system and breast disorders
    PELVIC PAIN
         subjects affected / exposed
    12 / 150 (8.00%)
         occurrences all number
    18
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    8 / 150 (5.33%)
         occurrences all number
    11
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    12 / 150 (8.00%)
         occurrences all number
    19
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    19 / 150 (12.67%)
         occurrences all number
    32
    PLATELET COUNT DECREASED
         subjects affected / exposed
    17 / 150 (11.33%)
         occurrences all number
    22
    WEIGHT DECREASED
         subjects affected / exposed
    12 / 150 (8.00%)
         occurrences all number
    12
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    10 / 150 (6.67%)
         occurrences all number
    19
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    70 / 150 (46.67%)
         occurrences all number
    104
    LEUKOPENIA
         subjects affected / exposed
    27 / 150 (18.00%)
         occurrences all number
    45
    NEUTROPENIA
         subjects affected / exposed
    53 / 150 (35.33%)
         occurrences all number
    103
    THROMBOCYTOPENIA
         subjects affected / exposed
    41 / 150 (27.33%)
         occurrences all number
    68
    Respiratory, thoracic and mediastinal disorders
    EPISTAXIS
         subjects affected / exposed
    31 / 150 (20.67%)
         occurrences all number
    38
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    29 / 150 (19.33%)
         occurrences all number
    45
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    37 / 150 (24.67%)
         occurrences all number
    43
    PARAESTHESIA
         subjects affected / exposed
    20 / 150 (13.33%)
         occurrences all number
    24
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    18 / 150 (12.00%)
         occurrences all number
    36
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    25 / 150 (16.67%)
         occurrences all number
    41
    CONSTIPATION
         subjects affected / exposed
    41 / 150 (27.33%)
         occurrences all number
    54
    DIARRHOEA
         subjects affected / exposed
    45 / 150 (30.00%)
         occurrences all number
    73
    GINGIVAL BLEEDING
         subjects affected / exposed
    12 / 150 (8.00%)
         occurrences all number
    15
    HAEMORRHOIDS
         subjects affected / exposed
    8 / 150 (5.33%)
         occurrences all number
    9
    NAUSEA
         subjects affected / exposed
    66 / 150 (44.00%)
         occurrences all number
    136
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    8 / 150 (5.33%)
         occurrences all number
    11
    VOMITING
         subjects affected / exposed
    51 / 150 (34.00%)
         occurrences all number
    85
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    12 / 150 (8.00%)
         occurrences all number
    15
    PROTEINURIA
         subjects affected / exposed
    29 / 150 (19.33%)
         occurrences all number
    51
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    70 / 150 (46.67%)
         occurrences all number
    73
    RASH
         subjects affected / exposed
    11 / 150 (7.33%)
         occurrences all number
    17
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    42 / 150 (28.00%)
         occurrences all number
    77
    BACK PAIN
         subjects affected / exposed
    16 / 150 (10.67%)
         occurrences all number
    23
    BONE PAIN
         subjects affected / exposed
    13 / 150 (8.67%)
         occurrences all number
    21
    MYALGIA
         subjects affected / exposed
    32 / 150 (21.33%)
         occurrences all number
    47
    PAIN IN EXTREMITY
         subjects affected / exposed
    11 / 150 (7.33%)
         occurrences all number
    13
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    21 / 150 (14.00%)
         occurrences all number
    37
    HYPERURICAEMIA
         subjects affected / exposed
    10 / 150 (6.67%)
         occurrences all number
    12
    HYPOMAGNESAEMIA
         subjects affected / exposed
    21 / 150 (14.00%)
         occurrences all number
    33
    Infections and infestations
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    11 / 150 (7.33%)
         occurrences all number
    12
    URINARY TRACT INFECTION
         subjects affected / exposed
    22 / 150 (14.67%)
         occurrences all number
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2016
    Protocol was amended with inclusion of an independent radiology review of MRI scans and other minor changes.
    12 Jul 2018
    Protocol was amended to clarify eligibility criteria, update information on continued access to bevacizumab and update the medical monitor for the study.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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