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    Clinical Trial Results:
    A Randomized, Open-Label, Phase II Study Assessing the Efficacy and the Safety of Bevacizumab in Neoadjuvant Therapy in Patients With Figo Stage IIIC/IV Ovarian, Tubal or Peritoneal Adenocarcinoma, Initially Unresectable

    Summary
    EudraCT number
    		 2012-001144-22
    Trial protocol
    		 FR  
    Global end of trial date
    17 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Aug 2017
    First version publication date
    31 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML28337
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01739218
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of neoadjuvant bevacizumab and chemotherapy measured by the complete resection rate after interval debulking surgery (IDS)
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki, 1964, as revised by subsequent amendments, following International Conference of Harmonization (ICH) recommendations, the French law, “Loi Huriet" (Law dated December 20, 1988) and the Law No 78-17 namely "Loi informatique et liberté" (Information and Freedom law). This was documented by the investigator’s signature on the protocol agreeing to carry out all of its terms in accordance with the applicable regulations and law, and to follow ICH good clinical practice guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jan 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 29 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 95
    Worldwide total number of subjects
    95
    EEA total number of subjects
    95
    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)
    59
    From 65 to 84 years
    35
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 99 participants were randomized in the study, and 95 participants received at least one dose of any study treatment.

    Pre-assignment
    Screening details
    		 Four participants were randomized to "Carboplatin + Paclitaxel + Bevacizumab" arm, but did not receive any study treatment (3 participants due to protocol violation and 1 participant due to consent withdrawal).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Carboplatin + Paclitaxel
    Arm description
    		 Participants received 4 cycles of neoadjuvant therapy prior to IDS (performed 28 days after the last neoadjuvant course if resectable tumor; participants with unresectable tumor went through follow-up period) and 22 cycles of adjuvant therapy before entering long-term follow-up (28 days after last treatment administration and every 6 months until disease progression or study end [maximum up to 38 months]). Each cycle was 3 weeks in length. Carboplatin and paclitaxel were administered during Cycles 1 to 8. Bevacizumab was administered only during the adjuvant treatment period in Cycles 6 to 26.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered at a dose calculated according to the Calvert formula ([participant's glomerular filtration rate + 25] multiplied by the target area under the concentration-time curve [AUC] of 5 milligrams per milliliter per minute [mg/mL/min]), as intravenous [IV] infusion over 30-60 minutes [min] every 3 weeks).

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered at a dose of 15 milligrams per kilogram [mg/kg] as IV infusion over 30-90 min every 3 weeks.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered at a dose of 175 milligrams per meter-squared [mg/m^2] as IV infusion over 3 hours using a rate controlling device every 3 weeks, or at a dose of 80 mg/m^2 as IV infusion over 1 hour using a rate controlling device every week (only during Cycles 5 to 8).

    Arm title
    		 Carboplatin + Paclitaxel + Bevacizumab
    Arm description
    		 Participants received 4 cycles of neoadjuvant therapy prior to IDS (performed 28 days after the last neoadjuvant course if resectable tumor; participants with unresectable tumor went through follow-up period) and 22 cycles of adjuvant therapy before entering long-term follow-up (28 days after last treatment administration and every 6 months until disease progression or study end [maximum up to 38 months]). Each cycle was 3 weeks in length. Carboplatin and paclitaxel were administered during Cycles 1 to 8. Bevacizumab was administered during both the neoadjuvant and adjuvant treatment periods in Cycles 1 to 26 (no treatment in Cycles 4 and 5).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered at a dose calculated according to the Calvert formula ([participant's glomerular filtration rate + 25] multiplied by the target AUC of 5 mg/mL/min), as IV infusion over 30-60 min every 3 weeks.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered at a dose of 15 milligrams per kilogram [mg/kg] as IV infusion over 30-90 min every 3 weeks.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered at a dose of 175 mg/m^2 as IV infusion over 3 hours using a rate controlling device every 3 weeks, or at a dose of 80 mg/m^2 as IV infusion over 1 hour using a rate controlling device every week (only during Cycles 5 to 8).

    Number of subjects in period 1
    		Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Started
    37
    58
    Completed
    4
    11
    Not completed
    33
    47
         Consent withdrawn by subject
    2
    4
         Physician decision
    3
    8
         Disease progression
    23
    30
         Death
    2
    -
         Adverse event
    1
    -
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received 4 cycles of neoadjuvant therapy prior to IDS (performed 28 days after the last neoadjuvant course if resectable tumor; participants with unresectable tumor went through follow-up period) and 22 cycles of adjuvant therapy before entering long-term follow-up (28 days after last treatment administration and every 6 months until disease progression or study end [maximum up to 38 months]). Each cycle was 3 weeks in length. Carboplatin and paclitaxel were administered during Cycles 1 to 8. Bevacizumab was administered only during the adjuvant treatment period in Cycles 6 to 26.

    Reporting group title
    Carboplatin + Paclitaxel + Bevacizumab
    Reporting group description
    		 Participants received 4 cycles of neoadjuvant therapy prior to IDS (performed 28 days after the last neoadjuvant course if resectable tumor; participants with unresectable tumor went through follow-up period) and 22 cycles of adjuvant therapy before entering long-term follow-up (28 days after last treatment administration and every 6 months until disease progression or study end [maximum up to 38 months]). Each cycle was 3 weeks in length. Carboplatin and paclitaxel were administered during Cycles 1 to 8. Bevacizumab was administered during both the neoadjuvant and adjuvant treatment periods in Cycles 1 to 26 (no treatment in Cycles 4 and 5).

    Reporting group values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab Total
    Number of subjects
    		 37 58 95
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.3 ± 9.6 62.3 ± 9.6 -
    Gender Categorical
    Units: Subjects
        Female
    		 37 58 95
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received 4 cycles of neoadjuvant therapy prior to IDS (performed 28 days after the last neoadjuvant course if resectable tumor; participants with unresectable tumor went through follow-up period) and 22 cycles of adjuvant therapy before entering long-term follow-up (28 days after last treatment administration and every 6 months until disease progression or study end [maximum up to 38 months]). Each cycle was 3 weeks in length. Carboplatin and paclitaxel were administered during Cycles 1 to 8. Bevacizumab was administered only during the adjuvant treatment period in Cycles 6 to 26.

    Reporting group title
    Carboplatin + Paclitaxel + Bevacizumab
    Reporting group description
    		 Participants received 4 cycles of neoadjuvant therapy prior to IDS (performed 28 days after the last neoadjuvant course if resectable tumor; participants with unresectable tumor went through follow-up period) and 22 cycles of adjuvant therapy before entering long-term follow-up (28 days after last treatment administration and every 6 months until disease progression or study end [maximum up to 38 months]). Each cycle was 3 weeks in length. Carboplatin and paclitaxel were administered during Cycles 1 to 8. Bevacizumab was administered during both the neoadjuvant and adjuvant treatment periods in Cycles 1 to 26 (no treatment in Cycles 4 and 5).

    Subject analysis set title
    mITT Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified intent-to-treat (mITT) population included all randomized participants who received at least one dose of any component of study treatment (bevacizumab, paclitaxel or carboplatin). Participants were grouped according to their initially assigned treatment.

    Primary: Percentage of Participants With Complete Resection After IDS

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    End point title
    		 Percentage of Participants With Complete Resection After IDS [1]
    End point description
    Complete resection is defined as removal of all macroscopic residual tumor at IDS, that is completeness of cytoreduction (CC) score = 0. The CC score indicates quantity of malignancy that remains following surgery. A CC score of 0 = no tumor visualization after the complete resection; 1 = residual tumor nodules less than 0.5 centimeters (cm) in diameter; 2 = residual tumor nodules between 0.5 cm and 5 cm in diameter; and 3 = residual tumor nodules greater than 5 cm in diameter, or a layer of disease that is not completely peritonectomized. Participants with missing CC score, or without IDS were considered as failure. The percentage of participants with complete resection and associated 95% one-sided confidence interval (CI) was assessed using Pearson-Clopper’s exact method. Analysis was performed on mITT population. The value “99999” in results indicates that as planned higher side of CI was not calculated.
    End point type
    Primary
    End point timeframe
    After IDS (approximately 4 months from randomization)
    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: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    37
    58
    Units: percentage of participants
        number (confidence interval 95%)
    51.4 (36.8 to 99999)
    58.6 (47 to 99999)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Different CC Scores After IDS

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    End point title
    		 Percentage of Participants With Different CC Scores After IDS [2]
    End point description
    The CC score indicates quantity of malignancy that remains following surgery. A CC score of 0 = no tumor visualization after the complete resection; 1 = residual tumor nodules less than (<) 0.5 cm in diameter; 2 = residual tumor nodules between 0.5 cm and 5 cm in diameter; and 3 = residual tumor nodules greater than (>) 5 cm in diameter, or a layer of disease that is not completely peritonectomized. Analysis was performed on mITT population. Here, 'Number of Subjects Analysed' signifies the number of participants who underwent IDS.
    End point type
    Primary
    End point timeframe
    After IDS (approximately 4 months from randomization)
    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: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    22
    40
    Units: percentage of participants
    number (not applicable)
        CC Score = 0
    86.4
    85
        CC Score = 1
    9.1
    7.5
        CC Score = 2
    4.5
    2.5
        CC Score = 3
    0
    5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    		 Percentage of Participants with Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
    End point description
    Objective response was defined as percentage of participants with a confirmed complete response (CR) or partial response (PR) assessed according to RECIST v1.1. Target lesions (TLs) were selected based on their size (those with the longest diameter) and their suitability for accurate repeated measurements. Measurable pathological nodes with short axis (SA) of greater than or equal to (>/=) 15 millimeter (mm) were also identified as TLs. All other lesions (or sites of disease) were identified as non-TLs. CR was defined as disappearance of all TLs/non-TLs and SA reduction to <10 mm for nodal TLs/ non-TLs. PR was defined as >/=30 percent (%) decrease in sum of diameters (SD) of TLs, taking as reference the baseline SD, and persistence of >/=1 non-TLs. Confirmation of response at a consecutive tumor assessment >/=4 weeks apart was required. Analysis was performed on mITT population. Participants without tumor assessment after start of study treatment were considered as non-responders.
    End point type
    Secondary
    End point timeframe
    At IDS (approximately 3 months); at Cycle 26 (approximately 22 months); and at last tumor assessment (up to approximately 38 months)
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    37
    58
    Units: percentage of participants
    number (not applicable)
        At IDS
    62.2
    67.2
        At Cycle 26
    18.9
    19
        At Last Tumor Assessment
    21.6
    36.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Response According to Cancer Antigen (CA)-125 Levels

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    End point title
    		 Percentage of Participants with Response According to Cancer Antigen (CA)-125 Levels
    End point description
    The CA-125 response was defined as >/=50% reduction in CA-125 level from baseline and confirmation and maintenance of this reduction at the next visit. Analysis was performed on mITT population. Only participants with a baseline value >/=70 units per milliliter (U/mL) were included in this analysis. Last observation carried forward method (LOCF) was used in case of missing values at last CA-125 assessment. Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    At IDS (approximately 3 months); at Cycle 26 (approximately 22 months); and at last CA-125 assessment (up to approximately 38 months)
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    36
    58
    Units: percentage of participants
    number (not applicable)
        At IDS (n=36,58)
    80.6
    87.9
        At Cycle 26 (n=7,14)
    100
    92.9
        At Last CA-125 Assessment (n=36,58)
    69.4
    63.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants with RECIST v1.1 Objective Response and CA-125 Response

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    End point title
    		 Percentage of Participants with RECIST v1.1 Objective Response and CA-125 Response
    End point description
    Objective response was defined as percentage of participants with a CR or PR according to RECIST v1.1. CR was defined as the disappearance of all TLs/non-TLs and SA reduction to <10 mm for nodal TLs/ non-TLs. PR was defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD, and persistence of 1 or more non-TLs. Confirmation of response at a consecutive tumor assessment >/=4 weeks apart was required. The CA-125 response was defined as >/=50% reduction in CA-125 level from baseline and confirmation and maintenance of this reduction at the next visit. The response according to RECIST v1.1 and CA-125 level was derived, at a given visit, only if the delay between tumor assessment and CA-125 sample was less than or equal to (</=) 28 days. Analysis was performed on mITT population. LOCF method was used in case of missing values at last response assessment. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    At Cycle 26 (approximately 22 months) and at last response assessment (up to approximately 38 months)
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    37
    58
    Units: percentage of participants
    number (not applicable)
        At Cycle 26 (n=7,12)
    100
    75
        At Last Response Assessment (n=37,58)
    16.2
    27.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with RECIST v1.1 Objective Response Without CA-125 Response

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    End point title
    		 Percentage of Participants with RECIST v1.1 Objective Response Without CA-125 Response
    End point description
    Objective response was defined as percentage of participants with a CR or PR according to RECIST v1.1. CR was defined as the disappearance of all TLs/non-TLs and SA reduction to <10 mm for nodal TLs/ non-TLs. PR was defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD, and persistence of 1 or more non-TLs. Confirmation of response at a consecutive tumor assessment >/=4 weeks apart was required. The CA-125 response was defined as >/=50% reduction in CA-125 level from baseline and confirmation and maintenance of this reduction at the next visit. The response according to RECIST v1.1 and CA-125 level was derived, at a given visit, only if the delay between tumor assessment and CA-125 sample was </=28 days. Analysis was performed on mITT population. LOCF method was used in case of missing values at last response assessment. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    At Cycle 26 (approximately 22 months) and at last response assessment (up to approximately 38 months)
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    37
    58
    Units: percentage of participants
    number (not applicable)
        At Cycle 26 (n=7,12)
    0
    8.3
        At Last Response Assessment (n=37,58)
    5.4
    8.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with CA-125 Response Without RECIST v1.1 Objective Response

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    End point title
    		 Percentage of Participants with CA-125 Response Without RECIST v1.1 Objective Response
    End point description
    Objective response was defined as percentage of participants with a CR or PR according to RECIST v1.1. CR was defined as the disappearance of all TLs/non-TLs and SA reduction to <10 mm for nodal TLs/ non-TLs. PR was defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD, and persistence of 1 or more non-TLs. Confirmation of response at a consecutive tumor assessment >/=4 weeks apart was required. The CA-125 response was defined as >/=50% reduction in CA-125 level from baseline and confirmation and maintenance of this reduction at the next visit. The response according to RECIST v1.1 and CA-125 level was derived, at a given visit, only if the delay between tumor assessment and CA-125 sample was </=28 days. Analysis was performed on mITT population. LOCF method was used in case of missing values at last response assessment. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    At Cycle 26 (approximately 22 months) and at last response assessment (up to approximately 38 months)
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    37
    58
    Units: percentage of participants
    number (not applicable)
        At Cycle 26 (n=7,12)
    0
    16.7
        At Last Response Assessment (n=37,58)
    54.1
    36.2
    No statistical analyses for this end point

    Secondary: Number of Participants With Disease Progression or Death From any Cause

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    End point title
    		 Number of Participants With Disease Progression or Death From any Cause
    End point description
    Progressive disease (PD) was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to disease progression or death due to any cause (up to approximately 38 months)
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    37
    58
    Units: participants
        number (not applicable)
    24
    26
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) According to RECIST v1.1

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    End point title
    		 Progression-Free Survival (PFS) According to RECIST v1.1
    End point description
    PFS was defined as the time from first intake of any study medication until the first radiographically documented PD assessed using RECIST v1.1 criteria or death from any cause, whichever occurred first. Participants with no PFS events were censored at the time of the last evaluable tumor assessment. Participants with no tumor assessment at and after the baseline visit were censored on the date of first study treatment. PD was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. The median PFS (with the associated 95% CI) was estimated using the Kaplan-Meier method. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to disease progression or death due to any cause (up to approximately 38 months)
    End point values
    		 Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab
    Number of subjects analysed
    37
    58
    Units: months
        median (confidence interval 95%)
    21.2 (14.5 to 26.7)
    23.5 (18.5 to 30.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events (SAEs): from randomization up to last assessment (up to approximately 38 months); non-SAEs: from Day 1 up to 28 days after last dose (up to approximately 23 months)
    Adverse event reporting additional description
    Analysis was performed on safety (SAF) population, which included all participants who received at least one dose of any component of study treatment (bevacizumab, paclitaxel or carboplatin). Participants were grouped according to the treatment actually received. Events related to treatment indicate bevacizumab-related events.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Carboplatin + Paclitaxel + Bevacizumab
    Reporting group description
    		 Participants received 4 cycles of neoadjuvant therapy prior to IDS (performed 28 days after the last neoadjuvant course if resectable tumor; participants with unresectable tumor went through follow-up period) and 22 cycles of adjuvant therapy before entering long-term follow-up (28 days after last treatment administration and every 6 months until disease progression or study end [maximum up to 38 months]). Each cycle was 3 weeks in length. Carboplatin and paclitaxel were administered during Cycles 1 to 8. Bevacizumab was administered during both the neoadjuvant and adjuvant treatment periods in Cycles 1 to 26 (no treatment in Cycles 4 and 5).

    Reporting group title
    Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received 4 cycles of neoadjuvant therapy prior to IDS (performed 28 days after the last neoadjuvant course if resectable tumor; participants with unresectable tumor went through follow-up period) and 22 cycles of adjuvant therapy before entering long-term follow-up (28 days after last treatment administration and every 6 months until disease progression or study end [maximum up to 38 months]). Each cycle was 3 weeks in length. Carboplatin and paclitaxel were administered during Cycles 1 to 8. Bevacizumab was administered only during the adjuvant treatment period in Cycles 6 to 26.

    Serious adverse events
    		 Carboplatin + Paclitaxel + Bevacizumab Carboplatin + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 55 (38.18%)
    18 / 40 (45.00%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septum perforation
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (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
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial injury
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (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
    Anaemia
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sigmoiditis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal ischaemia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infected lymphocele
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site abscess
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Carboplatin + Paclitaxel + Bevacizumab Carboplatin + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 55 (100.00%)
    39 / 40 (97.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 55 (38.18%)
    9 / 40 (22.50%)
         occurrences all number
    23
    11
    Hot flush
         subjects affected / exposed
    5 / 55 (9.09%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    Lymphocele
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    38 / 55 (69.09%)
    22 / 40 (55.00%)
         occurrences all number
    55
    46
    Oedema peripheral
         subjects affected / exposed
    8 / 55 (14.55%)
    6 / 40 (15.00%)
         occurrences all number
    9
    7
    Impaired healing
         subjects affected / exposed
    8 / 55 (14.55%)
    5 / 40 (12.50%)
         occurrences all number
    10
    6
    Fatigue
         subjects affected / exposed
    6 / 55 (10.91%)
    4 / 40 (10.00%)
         occurrences all number
    8
    5
    Mucosal inflammation
         subjects affected / exposed
    8 / 55 (14.55%)
    2 / 40 (5.00%)
         occurrences all number
    11
    4
    Pain
         subjects affected / exposed
    6 / 55 (10.91%)
    3 / 40 (7.50%)
         occurrences all number
    6
    3
    Pyrexia
         subjects affected / exposed
    5 / 55 (9.09%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    6 / 55 (10.91%)
    1 / 40 (2.50%)
         occurrences all number
    6
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    29 / 55 (52.73%)
    8 / 40 (20.00%)
         occurrences all number
    44
    10
    Dyspnoea
         subjects affected / exposed
    8 / 55 (14.55%)
    4 / 40 (10.00%)
         occurrences all number
    9
    6
    Cough
         subjects affected / exposed
    8 / 55 (14.55%)
    2 / 40 (5.00%)
         occurrences all number
    10
    3
    Dysphonia
         subjects affected / exposed
    7 / 55 (12.73%)
    2 / 40 (5.00%)
         occurrences all number
    7
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 55 (9.09%)
    2 / 40 (5.00%)
         occurrences all number
    6
    3
    Anxiety
         subjects affected / exposed
    4 / 55 (7.27%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Investigations
    Weight decreased
         subjects affected / exposed
    8 / 55 (14.55%)
    3 / 40 (7.50%)
         occurrences all number
    8
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 55 (7.27%)
    2 / 40 (5.00%)
         occurrences all number
    6
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 40 (10.00%)
         occurrences all number
    2
    5
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    25 / 55 (45.45%)
    18 / 40 (45.00%)
         occurrences all number
    27
    23
    Paraesthesia
         subjects affected / exposed
    9 / 55 (16.36%)
    4 / 40 (10.00%)
         occurrences all number
    13
    4
    Headache
         subjects affected / exposed
    11 / 55 (20.00%)
    6 / 40 (15.00%)
         occurrences all number
    18
    6
    Dysgeusia
         subjects affected / exposed
    4 / 55 (7.27%)
    5 / 40 (12.50%)
         occurrences all number
    4
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    6 / 55 (10.91%)
    2 / 40 (5.00%)
         occurrences all number
    10
    4
    Dysaesthesia
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Neurotoxicity
         subjects affected / exposed
    5 / 55 (9.09%)
    1 / 40 (2.50%)
         occurrences all number
    5
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    25 / 55 (45.45%)
    24 / 40 (60.00%)
         occurrences all number
    30
    27
    Neutropenia
         subjects affected / exposed
    21 / 55 (38.18%)
    16 / 40 (40.00%)
         occurrences all number
    37
    24
    Thrombocytopenia
         subjects affected / exposed
    11 / 55 (20.00%)
    12 / 40 (30.00%)
         occurrences all number
    20
    23
    Lymphopenia
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 40 (5.00%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    29 / 55 (52.73%)
    18 / 40 (45.00%)
         occurrences all number
    39
    27
    Nausea
         subjects affected / exposed
    35 / 55 (63.64%)
    22 / 40 (55.00%)
         occurrences all number
    62
    50
    Constipation
         subjects affected / exposed
    25 / 55 (45.45%)
    17 / 40 (42.50%)
         occurrences all number
    44
    25
    Diarrhoea
         subjects affected / exposed
    20 / 55 (36.36%)
    13 / 40 (32.50%)
         occurrences all number
    34
    20
    Vomiting
         subjects affected / exposed
    17 / 55 (30.91%)
    14 / 40 (35.00%)
         occurrences all number
    20
    21
    Abdominal pain upper
         subjects affected / exposed
    5 / 55 (9.09%)
    10 / 40 (25.00%)
         occurrences all number
    5
    14
    Gastrointestinal motility disorder
         subjects affected / exposed
    6 / 55 (10.91%)
    4 / 40 (10.00%)
         occurrences all number
    6
    4
    Gingival bleeding
         subjects affected / exposed
    6 / 55 (10.91%)
    4 / 40 (10.00%)
         occurrences all number
    6
    6
    Abdominal distension
         subjects affected / exposed
    4 / 55 (7.27%)
    5 / 40 (12.50%)
         occurrences all number
    4
    5
    Haemorrhoids
         subjects affected / exposed
    6 / 55 (10.91%)
    2 / 40 (5.00%)
         occurrences all number
    10
    6
    Abdominal pain lower
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 40 (5.00%)
         occurrences all number
    3
    3
    Aphthous stomatitis
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    Stomatitis
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    32 / 55 (58.18%)
    20 / 40 (50.00%)
         occurrences all number
    32
    21
    Pruritus
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Rash
         subjects affected / exposed
    4 / 55 (7.27%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    Dry skin
         subjects affected / exposed
    2 / 55 (3.64%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 40 (2.50%)
         occurrences all number
    5
    1
    Urticaria
         subjects affected / exposed
    1 / 55 (1.82%)
    4 / 40 (10.00%)
         occurrences all number
    1
    4
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 40 (10.00%)
         occurrences all number
    5
    5
    Proteinuria
         subjects affected / exposed
    8 / 55 (14.55%)
    2 / 40 (5.00%)
         occurrences all number
    9
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 55 (38.18%)
    6 / 40 (15.00%)
         occurrences all number
    32
    8
    Myalgia
         subjects affected / exposed
    15 / 55 (27.27%)
    9 / 40 (22.50%)
         occurrences all number
    25
    12
    Back pain
         subjects affected / exposed
    7 / 55 (12.73%)
    3 / 40 (7.50%)
         occurrences all number
    7
    3
    Muscle spasms
         subjects affected / exposed
    6 / 55 (10.91%)
    2 / 40 (5.00%)
         occurrences all number
    6
    5
    Pain in extremity
         subjects affected / exposed
    5 / 55 (9.09%)
    3 / 40 (7.50%)
         occurrences all number
    6
    4
    Musculoskeletal pain
         subjects affected / exposed
    5 / 55 (9.09%)
    2 / 40 (5.00%)
         occurrences all number
    5
    2
    Neck pain
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    10 / 55 (18.18%)
    5 / 40 (12.50%)
         occurrences all number
    13
    9
    Nasopharyngitis
         subjects affected / exposed
    7 / 55 (12.73%)
    3 / 40 (7.50%)
         occurrences all number
    8
    3
    Bronchitis
         subjects affected / exposed
    6 / 55 (10.91%)
    2 / 40 (5.00%)
         occurrences all number
    8
    2
    Rhinitis
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 40 (10.00%)
         occurrences all number
    5
    5
    Tooth abscess
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 40 (2.50%)
         occurrences all number
    5
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 55 (18.18%)
    9 / 40 (22.50%)
         occurrences all number
    14
    14
    Hypokalaemia
         subjects affected / exposed
    5 / 55 (9.09%)
    4 / 40 (10.00%)
         occurrences all number
    5
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jan 2013
    Added an exploratory objective in order to evaluate T cell repertory diversity and use immune repertoire diversity as a universal biomarker of immune status; Added an exclusion criterion (carcinosarcoma); Corrected the time points for tumor assessments, CA- 125 dosage, exploratory samples, and safety
    18 Apr 2013
    Added precisions about the schedule of assessments; Added collection of platelet count and liver function test at each visit.
    07 Aug 2013
    Updated the schedule of assessments and precision for assessment of creatinine clearance
    14 Mar 2014
    Removed blood RNA collection (exploratory objective); Added an independent review of photos aiming to evaluate extend of carcinomatosis after neoadjuvant therapy (exploratory objective)
    01 Oct 2015
    Updated the management of participants with any circulating tumor cells Grade 4 non-hematologic adverse event and the related method of analysis
    08 Feb 2016
    Updated the management of participants with any circulating tumor cells Grade 4 non-hematologic adverse event; Added a last follow-up visit

    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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