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    Clinical Trial Results:
    Best Approach in Recurrent-Ovarian-Cancer-with Cediranib-Olaparib: an Italian multicenter randomized phase II study of weekly paclitaxel vs. Cediranib-Olaparib with continuous schedule vs. Cediranib-Olaparib with intermittent schedule in patients with platinum resistant high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer_The BAROCCO study

    Summary
    EudraCT number
    		 2016-003964-38
    Trial protocol
    		 IT  
    Global end of trial date
    25 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2022
    First version publication date
    13 Jul 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IRFMN-OVA-7289
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS
    Sponsor organisation address
    Via Mario Negri 2, Milan, Italy,
    Public contact
    Laboratorio Metodologia della Ricerca Clinica, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 039 0239014684, eliana.rulli@marionegri.it
    Scientific contact
    Laboratorio Metodologia della Ricerca Clinica, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 039 0239014684, eliana.rulli@marionegri.it
    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
    01 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study primary objective is to compare the efficacy of Olaparib and Cediranib vs. weekly paclitaxel in terms of progression free survival (PFS) in platinum refractory or resistant recurrent ovarian cancerT The primary objective for safety is to compare the safety of Olaparib and Cediranib as intermittent vs. continuous regimen in terms of number of evacuations per day.
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 123
    Worldwide total number of subjects
    123
    EEA total number of subjects
    123
    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)
    77
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients will be randomized in a 1:1:1 ratio to the treatments as specified below: • Paclitaxel 80 mg/mq every week. • Cediranib 20 mg/day + Olaparib 600 mg/day (300 mg twice daily) given every day. • Cediranib 20 mg/day given 5 days per weeks + Olaparib 600 mg/day (300 mg twice daily) given 7 days per weeks. Treatment will be continued until

    Pre-assignment
    Screening details
    		 NA

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Paclitaxel (ARM A)
    Arm description
    		 Paclitaxel 80 mg/mq every week.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80 mg/mq every week.

    Arm title
    		 Cediranib+Olaparib (ARM B)
    Arm description
    		 Cediranib 20 mg/day + Olaparib 600 mg / day (i.e. 300 mg BD) given every day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cediranib 20 mg/day + Olaparib 600 mg / day (i.e. 300 mg BD) given every day.

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cediranib 20 mg/day + Olaparib 600 mg / day (i.e. 300 mg BD) given every day.

    Arm title
    		 Cediranib-Olaparib (ARM C)
    Arm description
    		 Cediranib 20 mg/day given 5 days per weeks + Olaparib 600 mg / day (i.e. 300 mg BD) given 7 days per weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cediranib 20 mg/day given 5 days per weeks + Olaparib 600 mg / day (i.e. 300 mg BD) given 7 days per weeks.

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cediranib 20 mg/day given 5 days per weeks + Olaparib 600 mg / day (i.e. 300 mg BD) given 7 days per weeks.

    Number of subjects in period 1
    		Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C)
    Started
    41
    41
    41
    Completed
    41
    41
    41

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paclitaxel (ARM A)
    Reporting group description
    		 Paclitaxel 80 mg/mq every week.

    Reporting group title
    Cediranib+Olaparib (ARM B)
    Reporting group description
    		 Cediranib 20 mg/day + Olaparib 600 mg / day (i.e. 300 mg BD) given every day.

    Reporting group title
    Cediranib-Olaparib (ARM C)
    Reporting group description
    		 Cediranib 20 mg/day given 5 days per weeks + Olaparib 600 mg / day (i.e. 300 mg BD) given 7 days per weeks.

    Reporting group values
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C) Total
    Number of subjects
    		 41 41 41 123
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 25 24 28 77
        From 65-84 years
    		 16 17 13 46
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 62.5 (56.6 to 69.7) 64.2 (54.0 to 68.4) 59.9 (54.6 to 68.4) -
    Gender categorical
    Units: Subjects
        Female
    		 41 41 41 123
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis set is defined as all randomized patients, without major violations of eligibility criteria. Patients will be analyzed according to randomization arm.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    the PP analysis set is defined as all patients of the ITT analysis set, who received at least 4 weeks of treatment, unless they interrupted before for disease progression or death. Patients randomized to the control arm, receiving the experimental treatment and patients randomized to the experimental arm, receiving the control treatment will be excluded.

    Subject analysis set title
    Safety 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety 1 Analysis Set is defined as all patients included of the ITT Analysis Set, who were randomized to the two experimental arms, excluding patients who interrupted before 4 weeks, unless the interruption is due to diarrhea. Patients randomized to the continue schedule (arm B), receiving in the first cycle the intermittent schedule (as arm C) and patients randomized to the intermittent schedule, receiving the continue schedule will be excluded.

    Subject analysis set title
    Safety 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety 2 Analysis Set is defined as all patients included of the ITT Analysis Set, who received at least one dose of study treatment, whether withdrawn prematurely or not. Patients will be considered in the treatment arm they actually received.

    Subject analysis sets values
    		 ITT PP Safety 1 Safety 2
    Number of subjects
    123
    106
    65
    110
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    77
    68
    46
    70
        From 65-84 years
    46
    38
    19
    40
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    62.5 (55.2 to 69.3)
    62.1 (55.2 to 68.7)
    59.9 (54.0 to 65.9)
    62.4 (55.2 to 68.7)
    Gender categorical
    Units: Subjects
        Female
    123
    106
    65
    110

    End points

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    End points reporting groups
    Reporting group title
    Paclitaxel (ARM A)
    Reporting group description
    		 Paclitaxel 80 mg/mq every week.

    Reporting group title
    Cediranib+Olaparib (ARM B)
    Reporting group description
    		 Cediranib 20 mg/day + Olaparib 600 mg / day (i.e. 300 mg BD) given every day.

    Reporting group title
    Cediranib-Olaparib (ARM C)
    Reporting group description
    		 Cediranib 20 mg/day given 5 days per weeks + Olaparib 600 mg / day (i.e. 300 mg BD) given 7 days per weeks.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis set is defined as all randomized patients, without major violations of eligibility criteria. Patients will be analyzed according to randomization arm.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    the PP analysis set is defined as all patients of the ITT analysis set, who received at least 4 weeks of treatment, unless they interrupted before for disease progression or death. Patients randomized to the control arm, receiving the experimental treatment and patients randomized to the experimental arm, receiving the control treatment will be excluded.

    Subject analysis set title
    Safety 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety 1 Analysis Set is defined as all patients included of the ITT Analysis Set, who were randomized to the two experimental arms, excluding patients who interrupted before 4 weeks, unless the interruption is due to diarrhea. Patients randomized to the continue schedule (arm B), receiving in the first cycle the intermittent schedule (as arm C) and patients randomized to the intermittent schedule, receiving the continue schedule will be excluded.

    Subject analysis set title
    Safety 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety 2 Analysis Set is defined as all patients included of the ITT Analysis Set, who received at least one dose of study treatment, whether withdrawn prematurely or not. Patients will be considered in the treatment arm they actually received.

    Primary: PFS (ITT)

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    End point title
    		 PFS (ITT)
    End point description
    The study primary endpoint is the PFS defined as the time from randomization to the date of first progression or death for any cause, whichever comes first
    End point type
    Primary
    End point timeframe
    Study treatment
    End point values
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C) ITT
    Number of subjects analysed
    41
    41
    41
    123
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    3.1 (1.9 to 6.3)
    5.6 (3.2 to 7.4)
    3.8 (2.0 to 5.8)
    4.0 (2.0 to 6.7)
    Statistical analysis title
    		 Progression Free Survival (Arm B vs Arm A)
    Statistical analysis description
    PFS will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in PFS between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib+Olaparib (ARM B) v ITT
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.14
    Statistical analysis title
    		 Progression Free Survival (Arm C vs Arm A)
    Statistical analysis description
    PFS will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in PFS between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib-Olaparib (ARM C) v ITT
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.55

    Primary: PFS (PP)

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    End point title
    		 PFS (PP)
    End point description
    PFS is defined as the time from randomization to the date of first progression or death for any cause, whichever comes first.
    End point type
    Primary
    End point timeframe
    Study treatment
    End point values
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C) PP
    Number of subjects analysed
    27
    40
    39
    106
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    3.8 (1.9 to 6.7)
    5.6 (3.2 to 7.4)
    3.8 (2.0 to 5.8)
    4.2 (2.1 to 6.7)
    Statistical analysis title
    		 Progression Free Survival (Arm B vs Arm A)
    Statistical analysis description
    PFS will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in PFS between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib+Olaparib (ARM B) v PP
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.29
    Statistical analysis title
    		 Progression Free Survival (Arm C vs Arm A)
    Statistical analysis description
    PFS will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in PFS between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib-Olaparib (ARM C) v PP
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.79

    Secondary: PFS2 (ITT)

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    End point title
    		 PFS2 (ITT)
    End point description
    PFS2 defined as time from randomization to second disease progression according to RECIST 1.1 or to clinical assessment, or death by any cause.
    End point type
    Secondary
    End point timeframe
    Study treatment
    End point values
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C) ITT
    Number of subjects analysed
    41
    41
    41
    123
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    8.8 (6.9 to 21.5)
    11.6 (8.4 to 18.4)
    9.6 (5.5 to 14.1)
    10.0 (6.4 to 17.4)
    Statistical analysis title
    		 Second Progression Free Survival (Arm B vs Arm A)
    Statistical analysis description
    PFS2 will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in PFS2 between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib+Olaparib (ARM B) v ITT
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.42
    Statistical analysis title
    		 Second Progression Free Survival (Arm C vs Arm A)
    Statistical analysis description
    PFS2 will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in PFS2 between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib-Olaparib (ARM C) v ITT
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.8

    Secondary: PFS2 (PP)

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    End point title
    		 PFS2 (PP)
    End point description
    PFS2 defined as time from randomization to second disease progression according to RECIST 1.1 or to clinical assessment, or death by any cause.
    End point type
    Secondary
    End point timeframe
    Study treatment
    End point values
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C) PP
    Number of subjects analysed
    27
    40
    39
    106
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    9.3 (7.4 to 21.5)
    11.6 (8.4 to 18.4)
    9.6 (5.5 to 14.1)
    10.2 (6.5 to 18.4)
    Statistical analysis title
    		 Second Progression Free Survival (Arm B vs Arm A)
    Statistical analysis description
    PFS2 will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in PFS2 between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib+Olaparib (ARM B) v PP
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.48
    Statistical analysis title
    		 Second Progression Free Survival (Arm C vs Arm A)
    Statistical analysis description
    PFS2 will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in PFS2 between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib-Olaparib (ARM C) v PP
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.86

    Secondary: OS (ITT)

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    End point title
    		 OS (ITT)
    End point description
    Overall Survival (OS), defined for each patient as the time from randomization to the date of death for any cause.
    End point type
    Secondary
    End point timeframe
    Study treatment
    End point values
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C) ITT
    Number of subjects analysed
    41
    41
    41
    123
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    9.3 (7.4 to 21.5)
    11.6 (8.4 to 23.0)
    9.6 (5.5 to 14.1)
    10.2 (6.5 to 17.4)
    Statistical analysis title
    		 Overall survival (Arm B vs Arm A)
    Statistical analysis description
    OS will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in OS between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib+Olaparib (ARM B) v ITT
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.46
    Statistical analysis title
    		 Overall survival (Arm C vs Arm A)
    Statistical analysis description
    OS will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in OS between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib-Olaparib (ARM C) v ITT
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.92

    Secondary: OS (PP)

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    End point title
    		 OS (PP)
    End point description
    Overall Survival (OS), defined for each patient as the time from randomization to the date of death for any cause.
    End point type
    Secondary
    End point timeframe
    Study treatment
    End point values
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C) PP
    Number of subjects analysed
    27
    40
    39
    106
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    9.3 (7.4 to 21.5)
    11.6 (8.4 to 23)
    9.6 (5.5 to 14.1)
    10.2 (7.1 to 18.8)
    Statistical analysis title
    		 Overall survival (Arm B vs Arm A)
    Statistical analysis description
    OS will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in OS between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Cediranib+Olaparib (ARM B) v Paclitaxel (ARM A) v PP
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.53
    Statistical analysis title
    		 Overall survival (Arm C vs Arm A)
    Statistical analysis description
    OS will be described with the Kaplan-Meier method. KM estimates for median and quartile event times, and event-free rates at selected times will be calculated. Differences in OS between arms will be also tested by univariate and multivariate Cox’s models including stratification variables and other clinical-biological features as covariates. Results will be presented as hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
    Comparison groups
    Paclitaxel (ARM A) v Cediranib-Olaparib (ARM C) v PP
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.99

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Paclitaxel (ARM A)
    Reporting group description
    		 Paclitaxel

    Reporting group title
    Cediranib+Olaparib (ARM B)
    Reporting group description
    		 Cediranib+Olaparib Continuous schedule

    Reporting group title
    Cediranib-Olaparib (ARM C)
    Reporting group description
    		 Cediranib+Olaparib Intermittent schedule

    Serious adverse events
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 41 (56.10%)
    23 / 41 (56.10%)
    23 / 41 (56.10%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 41 (7.32%)
    5 / 41 (12.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Asthenia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Paclitaxel (ARM A) Cediranib+Olaparib (ARM B) Cediranib-Olaparib (ARM C)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 41 (75.61%)
    31 / 41 (75.61%)
    31 / 41 (75.61%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 41 (7.32%)
    2 / 41 (4.88%)
         occurrences all number
    16
    3
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 41 (2.44%)
    13 / 41 (31.71%)
    9 / 41 (21.95%)
         occurrences all number
    1
    22
    18
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 41 (21.95%)
    6 / 41 (14.63%)
    10 / 41 (24.39%)
         occurrences all number
    13
    22
    16
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 41 (21.95%)
    21 / 41 (51.22%)
    18 / 41 (43.90%)
         occurrences all number
    15
    42
    30
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 41 (14.63%)
    24 / 41 (58.54%)
    22 / 41 (53.66%)
         occurrences all number
    7
    41
    32
    Diarrhoea
         subjects affected / exposed
    2 / 41 (4.88%)
    6 / 41 (14.63%)
    3 / 41 (7.32%)
         occurrences all number
    2
    21
    3
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
    18 / 41 (43.90%)
    17 / 41 (41.46%)
         occurrences all number
    1
    37
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2018
    PRINCIPAL CHANGES: 1. Update of IB Olaparib 2. Update of Informed Consent

    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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