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    Clinical Trial Results:
    Niraparib versus niraparib-bevacizumab combination in Women with platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer. Part 1: AVANOVA1 - A phase I study to evaluate the safety and tolerability of bevacizumab-niraparib combination therapy and determine the Recommended Phase 2 Dose (RP2D) in women with platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer. Part 2: AVANOVA2 - A two-arm, open-label, phase II randomized study to evaluate the efficacy of niraparib versus niraparib-bevacizumab combination in women with platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer.

    Summary
    EudraCT number
    		 2014-004269-26
    Trial protocol
    		 DK   SE   NO   FI  
    Global end of trial date
    01 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Dec 2023
    First version publication date
    30 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENGOT-ov24-NSGO/AVANOVA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02354131
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Nordic Society of Gynaecological Oncology - Clinical Trial Unit (NSGO-CTU)
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Medical Director, Mansoor Raza Mirza, Nordic Society of Gynaecological Oncology - Clinical Trial Unit (NSGO-CTU), +45 35453311, mansoor.raza.mirza@regionh.dk
    Scientific contact
    Medical Director, Mansoor Raza Mirza, Nordic Society of Gynaecological Oncology - Clinical Trial Unit (NSGO-CTU), +45 35453311, mansoor.raza.mirza@regionh.dk
    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 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1 (Phase 1): To evaluate the safety and tolerability of bevacizumab-niraparib combination therapy. Furthermore to determine the Recommended Phase 2 Dose (RP2D) of bevacizumab-niraparib combination for platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer. Part 2 (Phase 2): The primary objective is to obtain preliminary evidence of efficacy of bevacizumab-niraparib combination or niraparib single agent treatment for patients with platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer. Progression-Free Survival (PFS) between bevacizumab-niraparib combination or niraparib single agent for the patient cohorts will be determined, incl. the secondary endpoints Overall Respose Rate (ORR) and Disease Control Rate (DCR).
    Protection of trial subjects
    The IDSMC was established to provide independent review and assessment of the efficacy and safety data in a systematic manner and to safeguard the interest and safety of the participating patients in the study. For phase 1 a go/no go decision was made by IDMC after all subjects in the corresponding cohort had passed cycle one without a DLT. The composition of the IDMC consisted of 3 independent individuals, who made recommendation to Sponsor, based on their review of safety information to continue or stop the trial. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the ICH-GCP guidelines. Local principal investigators were responsible for ensuring study conductance according to the protocol, the ethical principles of the Declaration of Helsinki, current ICH guidelines on Good Clinical practice (GCP) and applicable local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jan 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Sweden: 22
    Country: Number of subjects enrolled
    Denmark: 60
    Country: Number of subjects enrolled
    Finland: 21
    Worldwide total number of subjects
    109
    EEA total number of subjects
    105
    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)
    49
    From 65 to 84 years
    59
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential candidates for the trial may be identified by a member of the treatment team or by referrals from other departments/hospitals/GP. Enrollment will occur only after the patient has given written informed consent, all screening assessments have been completed and the patient meets all eligibility criteria.

    Pre-assignment
    Screening details
    		 Written ICF, In-Exclusion Criteria, Demographics, BRCA testing, Medical history, Physical examination, ECOG PS , Gyn examination,, height + weight, Blood Pressure, Pulse + Temperature, O2 Saturation, ECG, Serum pregnancy test, Urinanalysis, TSH, Coagulation parameters, CA 125, CT scan, concomitant medication and baseline symptoms

    Period 1
    Period 1 title
    Phase 2 (Part 2)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 2 (Arm 1)
    Arm description
    		 Patients receive niraparib 300mg daily until progression
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Niraparib
    Investigational medicinal product code
    MK-4827
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients receive niraparib 300mg daily until progression

    Arm title
    		 Phase 2 (Arm 2)
    Arm description
    		 Patients receive bevacizumab 15 mg/kg iv q 3 weeks + niraparib 300mg daily until progression
    Arm type
    		 Experimental

    Investigational medicinal product name
    Niraparib
    Investigational medicinal product code
    MK-4827
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients receive niraparib 300mg daily until progression

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients receive bevacizumab 15 mg/kg iv q 3 weeks

    Number of subjects in period 1 [1]
    		Phase 2 (Arm 1) Phase 2 (Arm 2)
    Started
    49
    48
    Completed
    5
    15
    Not completed
    44
    33
         Consent withdrawn by subject
    -
    1
         Disease progression
    36
    21
         Performance status deteriorated
    -
    1
         Serious compliance issues
    1
    -
         Unknown
    -
    1
         Adverse event
    5
    9
         Investigator decision
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: This trial consists of a Phase 1 (Part 1) and a Phase 2 (Part 2). In Part 1, 12 subjects were included; in Part 2, 97 subjects were included. Part 2 is reported as the baseline period, and therefore the number of subjects in the baseline period (97 subjects) is not the same as the worldwide number of enrolled subjects (109).
    Period 2
    Period 2 title
    Phase 1 (Part 1)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Phase 1 (Arm 1)
    Arm description
    		 Arm to determine safety and Recommended Phase 2 Dose (RP2D) for the phase 2 trial
    Arm type
    		 Dose-escalation

    Investigational medicinal product name
    Niraparib
    Investigational medicinal product code
    MK-4827
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients receive bevacizumab 15 mg/kg iv q 3 weeks (fixed dose) + niraparib 100mg to 300mg daily (depending on dose-escalation step) until progression

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients receive bevacizumab 15 mg/kg iv q 3 weeks (fixed dose) + niraparib 100mg to 300mg daily (depending on dose-escalation step) until progression

    Number of subjects in period 2 [2]
    		Phase 1 (Arm 1)
    Started
    12
    Completed
    1
    Not completed
    11
         Disease progression
    9
         Adverse event, non-fatal
    1
         Pancreatitis (unrelated to study)
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: This trial consists of a Phase 1 (Part 1) and a Phase 2 (Part 2). In Part 1, 12 subjects were included; in Part 2, 97 subjects were included. Part 1 is reported as Period 2, and therefore the number of subjects in Period 2 (12 subjects) is not the same as the numer of subjects completing the preceding period (Period 1).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 2 (Arm 1)
    Reporting group description
    		 Patients receive niraparib 300mg daily until progression

    Reporting group title
    Phase 2 (Arm 2)
    Reporting group description
    		 Patients receive bevacizumab 15 mg/kg iv q 3 weeks + niraparib 300mg daily until progression

    Reporting group values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2) Total
    Number of subjects
    		 49 48 97
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 23 42
        From 65-84 years
    		 30 24 54
        85 years and over
    		 0 1 1
    Gender categorical
    Units: Subjects
        Female
    		 49 48 97
    Primary tumour site
    Units: Subjects
        Ovary
    		 33 38 71
        Fallopian tube
    		 9 5 14
        Peritoneum
    		 7 5 12
    FIGO stage at diagnosis
    Units: Subjects
        I or II
    		 5 3 8
        IIIA or IIIB
    		 2 2 4
        IIIC
    		 26 29 55
        IV
    		 15 14 29
        Unknown
    		 1 0 1
    Chemotherapy-free interval
    Units: Subjects
        6-12 months
    		 17 20 37
        >12 months
    		 32 28 60
    HRD status
    *Two patients in Part 2 Arm 1 (niraparib) and one in Part 2 Arm 2 (niraparib plus bevacizumab) had BRCA-mutated tumours but were considered as HRD negative or unknown for stratification in error.
    Units: Subjects
        Positive*
    		 30 28 58
        Negative or unknown
    		 19 20 39
    BRCA mutation status
    ** Subjects with BRCA mutations could have either somatic BRCA mutation, germline BRCA mutation or both somatic and germline BRCA mutations.
    Units: Subjects
        BRCA mutated **
    		 18 15 33
        Non-BRCA mutated
    		 31 33 64
    Number of previous lines of therapy
    Units: Subjects
        One
    		 27 21 48
        Two
    		 19 24 43
        ≥ Three
    		 3 3 6
    Previous bevacizumab
    Units: Subjects
        Yes
    		 13 10 23
        No
    		 36 38 74
    Previous non-ovarian cancer
    Units: Subjects
        Yes
    		 6 5 11
        No
    		 43 43 86
    Pre-existing diabetes
    Units: Subjects
        Yes
    		 2 0 2
        No
    		 47 48 95
    Pre-existing hypertension
    Units: Subjects
        Yes
    		 17 20 37
        No
    		 32 28 60
    Histology
    Units: Subjects
        High grade
    		 49 48 97
        Low grade
    		 0 0 0
        Unknown
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Phase 1 (Arm 1)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Phase 1 Arm 1 of the trial to determine safety and Recommended Phase 2 Dose (RP2D) for Phase 2 of the trial.

    Subject analysis sets values
    		 Phase 1 (Arm 1)
    Number of subjects
    12
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    7
        From 65-84 years
    5
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    12
    Primary tumour site
    Units: Subjects
        Ovary
    12
        Fallopian tube
    0
        Peritoneum
    0
    FIGO stage at diagnosis
    Units: Subjects
        I or II
    2
        IIIA or IIIB
    1
        IIIC
    5
        IV
    4
        Unknown
    0
    Chemotherapy-free interval
    Units: Subjects
        6-12 months
    3
        >12 months
    9
    HRD status
    *Two patients in Part 2 Arm 1 (niraparib) and one in Part 2 Arm 2 (niraparib plus bevacizumab) had BRCA-mutated tumours but were considered as HRD negative or unknown for stratification in error.
    Units: Subjects
        Positive*
    4
        Negative or unknown
    8
    BRCA mutation status
    ** Subjects with BRCA mutations could have either somatic BRCA mutation, germline BRCA mutation or both somatic and germline BRCA mutations.
    Units: Subjects
        BRCA mutated **
    3
        Non-BRCA mutated
    9
    Number of previous lines of therapy
    Units: Subjects
        One
    7
        Two
    3
        ≥ Three
    2
    Previous bevacizumab
    Units: Subjects
        Yes
    1
        No
    11
    Previous non-ovarian cancer
    Units: Subjects
        Yes
    2
        No
    10
    Pre-existing diabetes
    Units: Subjects
        Yes
    0
        No
    12
    Pre-existing hypertension
    Units: Subjects
        Yes
    7
        No
    5
    Histology
    Units: Subjects
        High grade
    8
        Low grade
    1
        Unknown
    3

    End points

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    End points reporting groups
    Reporting group title
    Phase 2 (Arm 1)
    Reporting group description
    		 Patients receive niraparib 300mg daily until progression

    Reporting group title
    Phase 2 (Arm 2)
    Reporting group description
    		 Patients receive bevacizumab 15 mg/kg iv q 3 weeks + niraparib 300mg daily until progression
    Reporting group title
    Phase 1 (Arm 1)
    Reporting group description
    		 Arm to determine safety and Recommended Phase 2 Dose (RP2D) for the phase 2 trial

    Subject analysis set title
    Phase 1 (Arm 1)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Phase 1 Arm 1 of the trial to determine safety and Recommended Phase 2 Dose (RP2D) for Phase 2 of the trial.

    Primary: Part 2: Progression-Free Survival (PFS) (ITT)

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    End point title
    		 Part 2: Progression-Free Survival (PFS) (ITT)
    End point description
    Progression-Free Survival (PFS) of patients treated with Niraparib-bevacizumab combination against niraparib alone. The progression events are defined by well-documented and verifiable imaging data. PFS will be censored if the patient is lost to follow-up or refuses to continue in the study (i.e. withdraws consent). For patients alive and without progression at the time of analysis, PFS will be censored. In any case of censoring, the date of censoring will be the last time point documenting survival status.
    End point type
    Primary
    End point timeframe
    PFS is defined as the duration of time from date of randomization/enrolment to date of progression or death, whichever occurs first.
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    49
    48
    Units: months
        median (confidence interval 95%)
    5.5 (3.8 to 6.3)
    11.9 (8.5 to 16.7)
    Statistical analysis title
    		 Comparison of PFS between arms
    Statistical analysis description
    The two treatment arms are compared using the log-rank test
    Comparison groups
    Phase 2 (Arm 1) v Phase 2 (Arm 2)
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094

    Secondary: Part 1: Best overall response by RECIST 1.1

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    End point title
    		 Part 1: Best overall response by RECIST 1.1
    End point description
    Anti-tumor activity will be described in terms of best overall response by disease that is measurable according to RECIST. All patients who have been on study treatment for at least 1 (one) dose will be evaluable for response.
    End point type
    Secondary
    End point timeframe
    from start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2) Phase 1 (Arm 1)
    Number of subjects analysed
    49
    48
    12
    Units: patients
        CR
    5
    7
    1
        PR
    8
    22
    5
        SD
    21
    16
    5
        PD
    15
    3
    1
    No statistical analyses for this end point

    Secondary: Part 1: Progression free survival (PFS)

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    End point title
    		 Part 1: Progression free survival (PFS)
    End point description
    Anti-tumor activity will be described in terms of progression free survival (PFS). All patients who have been on study treatment for at least 1 (one) doses will be evaluable for response.
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of follow-up
    End point values
    		 Phase 1 (Arm 1)
    Number of subjects analysed
    12
    Units: months
        median (confidence interval 95%)
    11.6 (8.4 to 20.1)
    No statistical analyses for this end point

    Secondary: Part 2: Objective Response Rate (ORR)

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    End point title
    		 Part 2: Objective Response Rate (ORR)
    End point description
    Objective Response Rate (ORR) is determined as the rate of patients with an observed tumor response. ORR will be evaluated for three types of responders: • Patients who have a response as defined per RECIST and as defined using the 50% response criteria for CA-125 (“responders”) • Patients who have a response as defined per RECIST but no response as defined using the 50% response criteria for CA-125 (“RECIST responders”) • Patients who do not have a response as defined per RECIST but who do have a response as defined using the 50% response criteria for CA-125 (“CA-125 responders”)
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    49
    48
    Units: patients
        CR
    5
    7
        PR
    8
    22
        SD
    21
    16
        PD
    15
    3
    No statistical analyses for this end point

    Secondary: Part 2: Disease control rate (DCR) (CR+PR+SD)

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    End point title
    		 Part 2: Disease control rate (DCR) (CR+PR+SD)
    End point description
    The analysis of disease control rate will be performed for each treatment arm by calculating the point estimate of the percentage of patients in the treatment arm who have complete response or partial response or stable disease for at least 12 weeks, assessed according to RECIST 1.1 criteria.
    End point type
    Secondary
    End point timeframe
    from start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    49
    48
    Units: patients
        Yes
    14
    30
        No
    35
    18
    No statistical analyses for this end point

    Secondary: Part 2: Patient reported outcomes (PROs)

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    End point title
    		 Part 2: Patient reported outcomes (PROs)
    End point description
    Quality of Life scores, assessed by EORTC’s general EORTC-QLQ-C30 questionnaire, will be calculated using EORTC’s Scoring Manual.
    End point type
    Secondary
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    49
    47
    Units: score
    arithmetic mean (standard deviation)
        Time=1
    67.7 ( 23.7 )
    65.6 ( 25.4 )
        Time=2
    67.0 ( 23.4 )
    59.1 ( 21.0 )
        Time=3
    67.1 ( 18.3 )
    62.4 ( 20.6 )
        Time=4
    66.7 ( 19.3 )
    64.0 ( 28.4 )
        Time=5
    64.4 ( 23.9 )
    68.6 ( 19.1 )
        Time=6
    74.5 ( 24.4 )
    66.7 ( 22.1 )
        Time=7
    75.8 ( 25.1 )
    58.3 ( 28.5 )
        Time=8
    66.7 ( 27.6 )
    65.4 ( 20.9 )
        Time=9
    50 ( 23.6 )
    64.3 ( 15.0 )
        Time=10
    50 ( 23.6 )
    75.0 ( 35.4 )
    No statistical analyses for this end point

    Secondary: Part 2: Progression-free survival 2 (PFS2)

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    End point title
    		 Part 2: Progression-free survival 2 (PFS2)
    End point description
    Progression Free Survival 2 (PFS2) is defined as the time from enrolment/randomization until second investigator assessed disease progression or death. PFS2 will be censored if the patient is lost to follow-up or refuses to continue in the study (i.e. withdraws consent). For patients alive and without progression at the time of analysis, PFS2 will be censored. In any case of censoring, the date of censoring will be the last time point documenting survival status.
    End point type
    Secondary
    End point timeframe
    Time from randomization to second objective disease evaluation.
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    49
    48
    Units: months
        median (confidence interval 95%)
    15.7 (13.7 to 17.3)
    20.5 (18.1 to 22.9)
    No statistical analyses for this end point

    Secondary: Part 2: Time to first subsequent therapy (TFST)

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    End point title
    		 Part 2: Time to first subsequent therapy (TFST)
    End point description
    Time to first subsequent therapy (TFST) is defined as the time from enrolment/randomization until initiation of second-line anti-cancer treatment or death. TFST will be censored if the patient is lost to follow-up or refuses to continue in the study (i.e. withdraws consent). For patients alive and without initiation of second-line treatment at the time of analysis, TFST will be censored. In any case of censoring, the date of censoring will be the last time point documenting survival status.
    End point type
    Secondary
    End point timeframe
    Time from randomization to first subsequent therapy or death.
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    49
    48
    Units: months
        median (confidence interval 95%)
    7.2 (5.2 to 8.8)
    14.3 (10.3 to 17.5)
    No statistical analyses for this end point

    Secondary: Part 2: Time to second subsequent therapy (TSST)

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    End point title
    		 Part 2: Time to second subsequent therapy (TSST)
    End point description
    Time to second subsequent therapy (TSST) is defined as the time from enrolment/randomization until initiation of third-line anti-cancer treatment or death. TSST will be censored if the patient is lost to follow-up or refuses to continue in the study (i.e. withdraws consent). For patients alive and without initiation of third-line treatment at the time of analysis, TSST will be censored. In any case of censoring, the date of censoring will be the last time point documenting survival status.
    End point type
    Secondary
    End point timeframe
    Time from randomization to second subsequent therapy or death.
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    49
    48
    Units: months
        median (confidence interval 95%)
    17.3 (14.2 to 20.2)
    21.8 (18.7 to 27.7)
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; PFS (HRDpos)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (HRDpos)
    End point description
    Progression-free survival in the subgroup of HRD positive patients
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    30
    28
    Units: months
        median (confidence interval 95%)
    6.1 (3.9 to 9.0)
    11.9 (8.5 to 22.9)
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; PFS (HRDneg)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (HRDneg)
    End point description
    Progression-free survival in the subgroup of HRD negative patients
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    19
    20
    Units: months
        median (confidence interval 95%)
    4.2 (2.1 to 5.9)
    11.3 (5.3 to 16.7)
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; PFS (BRCA-mutated)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (BRCA-mutated)
    End point description
    Progression-free survival in patients with BRCA mutation
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    18
    15
    Units: months
        median (confidence interval 95%)
    8.9 (3.9 to 13.0)
    14.4 (6.2 to 20.7)
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; PFS (non-BRCA-mutated)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (non-BRCA-mutated)
    End point description
    Progression-free survival in patients with BRCA wild type
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    31
    33
    Units: months
        median (confidence interval 95%)
    4.1 (2.2 to 5.9)
    12.5 (6.0 to 16.7)
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; PFS (chemo-free interval 6-12 months)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (chemo-free interval 6-12 months)
    End point description
    Progression-free survival in patients with a chemo free interval between 6 and 12 months
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    17
    20
    Units: months
        median (confidence interval 95%)
    2.2 (1.8 to 6.0)
    11.3 (4.2 to 16.7)
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; PFS (chemo-free interval over 12 months)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (chemo-free interval over 12 months)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    32 [1]
    28 [2]
    Units: months
        number (not applicable)
    6.1
    13.1
    Notes
    [1] - The median in months is indicated as 'number' (95% CI 4.1-9.3).
    [2] - The median in months is indicated as 'number' (95% CI 8.5-NE).
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; OS (HRDpos)

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    End point title
    		 Part 2: Expl. Sub-group analyses; OS (HRDpos)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    30 [3]
    28 [4]
    Units: month
        number (not applicable)
    28.1
    34.9
    Notes
    [3] - The median in months is indicated as 'number' (95% CI 19.9-NE).
    [4] - The median in months is indicated as 'number' (95% CI 25.8-NE).
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; OS (HRDneg)

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    End point title
    		 Part 2: Expl. Sub-group analyses; OS (HRDneg)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    19 [5]
    20 [6]
    Units: months
        number (not applicable)
    25.7
    24.8
    Notes
    [5] - The median in months is indicated as 'number' (95% CI 17.6-34.9).
    [6] - The median in months is indicated as 'number' (95% CI 17.6-NE).
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; OS (chemo-free interval 6-12 months)

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    End point title
    		 Part 2: Expl. Sub-group analyses; OS (chemo-free interval 6-12 months)
    End point description
    Overall survival survival in patients with a chemo-free interval of 6-12 months
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    17 [7]
    20 [8]
    Units: months
        number (not applicable)
    26.5
    27.7
    Notes
    [7] - The median in months is indicated as 'number' (95% CI 7.2-NE).
    [8] - The median in months is indicated as 'number' (95% CI 16.1-NE).
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses OS (chemo-free interval over 12 months)

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    End point title
    		 Part 2: Expl. Sub-group analyses OS (chemo-free interval over 12 months)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    32 [9]
    28 [10]
    Units: months
        number (not applicable)
    27.8
    31.8
    Notes
    [9] - The median in months is indicated as 'number' (95% CI 19.5-NE).
    [10] - The median in months is indicated as 'number' (95% CI 24.6-NE).
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; OS (non-BRCA-mutated)

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    End point title
    		 Part 2: Expl. Sub-group analyses; OS (non-BRCA-mutated)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    31 [11]
    33 [12]
    Units: months
        number (not applicable)
    22.6
    29.0
    Notes
    [11] - The median in months is indicated as 'number' (95% CI 18.2-28.1).
    [12] - The median in months is indicated as 'number' (95% CI 23.5-NE).
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; PFS (Bevacizumab naive)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (Bevacizumab naive)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    36
    38
    Units: months
        median (confidence interval 95%)
    6.0 (4.1 to 8.9)
    14.4 (10.4 to 19.6)
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; PFS (Prior Bevacizumab)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (Prior Bevacizumab)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    13
    10
    Units: months
        median (confidence interval 95%)
    3.1 (1.8 to 5.1)
    5.9 (3.5 to 11.3)
    No statistical analyses for this end point

    Other pre-specified: Part 2: Expl. Sub-group analyses; Confirmed complete response

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    End point title
    		 Part 2: Expl. Sub-group analyses; Confirmed complete response
    End point description
    End point type
    Other pre-specified
    End point timeframe
    start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    49
    48
    Units: responders
        CR
    5
    7
        PR or less
    44
    41
    No statistical analyses for this end point

    Post-hoc: Part 2: Expl. Sub-group analyses; PFS (non-BRCA-mutated & HRD)

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    End point title
    		 Part 2: Expl. Sub-group analyses; PFS (non-BRCA-mutated & HRD)
    End point description
    Progression-free survival in the subgroup of HRD positive patients with BRCA wild type
    End point type
    Post-hoc
    End point timeframe
    From start of treatment until end of follow-up
    End point values
    		 Phase 2 (Arm 1) Phase 2 (Arm 2)
    Number of subjects analysed
    12 [13]
    13 [14]
    Units: month
        number (not applicable)
    15.7
    21.6
    Notes
    [13] - The median in months is indicated as 'number' (95% CI 7.2-20.2).
    [14] - The median in months is indicated as 'number' (95% CI 13.3-NE).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs will be collected and recorded for each patient from the day of first dose until treatment discontinuation visit. Serious adverse events will be collected as of 14 days prior to randomization until 30 days after last dose/study discontinuation.
    Adverse event reporting additional description
    For SAE's reported as 'Occurrences causally related to treatment number', the following were included: SAE unlikely related, SAE likely related, SAE related
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2014AB
    Reporting groups
    Reporting group title
    Phase 2 (Arm 1)
    Reporting group description
    		 -

    Reporting group title
    Phase 2 (Arm 2)
    Reporting group description
    		 -

    Reporting group title
    Phase 1 (Arm 1)
    Reporting group description
    		 -

    Serious adverse events
    		 Phase 2 (Arm 1) Phase 2 (Arm 2) Phase 1 (Arm 1)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 49 (34.69%)
    23 / 48 (47.92%)
    6 / 12 (50.00%)
         number of deaths (all causes)
    29
    25
    8
         number of deaths resulting from adverse events
    1
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Laryngeal haemorrhage
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Intracranial haemorrhage
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
    Additional description: metabolic encephalopathy secondary to narcotics
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    2 / 49 (4.08%)
    1 / 48 (2.08%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 49 (2.04%)
    5 / 48 (10.42%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
    Additional description: Increased GGT
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Fatigue
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 48 (4.17%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 48 (8.33%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Constipation
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 48 (2.08%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Ileus
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 48 (2.08%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 48 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 49 (4.08%)
    2 / 48 (4.17%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 48 (2.08%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lung embolia
    Additional description: Blood clot in lung
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Gallbladder obstruction
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disease
    Additional description: Shock liver
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Renal failure
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Pain in extremity
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Fracture in distal radius
    Additional description: Fracture in distal radius, left side
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 48 (2.08%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 48 (2.08%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
    0 / 12 (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
    Infection
    Additional description: Infections, Infection - focus unknown, infection of unknown origin
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 48 (6.25%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
    Additional description: Oedema limbs
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 2 (Arm 1) Phase 2 (Arm 2) Phase 1 (Arm 1)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 49 (100.00%)
    48 / 48 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 49 (22.45%)
    28 / 48 (58.33%)
    12 / 12 (100.00%)
         occurrences all number
    12
    58
    42
    Haemorrhage
         subjects affected / exposed
    2 / 49 (4.08%)
    2 / 48 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    2
    3
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 49 (42.86%)
    24 / 48 (50.00%)
    10 / 12 (83.33%)
         occurrences all number
    33
    65
    21
    Mucosal inflammation
         subjects affected / exposed
    5 / 49 (10.20%)
    7 / 48 (14.58%)
    0 / 12 (0.00%)
         occurrences all number
    5
    11
    0
    Discomfort
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Pain
    Additional description: General pain
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    6 / 12 (50.00%)
         occurrences all number
    0
    0
    13
    Hot flush
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Night sweats
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Fever
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 49 (8.16%)
    10 / 48 (20.83%)
    2 / 12 (16.67%)
         occurrences all number
    5
    12
    2
    Dysphonia
         subjects affected / exposed
    2 / 49 (4.08%)
    4 / 48 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    3
    4
    0
    Dyspnoea
         subjects affected / exposed
    10 / 49 (20.41%)
    8 / 48 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    11
    11
    1
    Epistaxis
         subjects affected / exposed
    3 / 49 (6.12%)
    5 / 48 (10.42%)
    1 / 12 (8.33%)
         occurrences all number
    3
    6
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 49 (12.24%)
    6 / 48 (12.50%)
    1 / 12 (8.33%)
         occurrences all number
    9
    16
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    4 / 49 (8.16%)
    7 / 48 (14.58%)
    4 / 12 (33.33%)
         occurrences all number
    12
    9
    18
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 48 (6.25%)
    1 / 12 (8.33%)
         occurrences all number
    0
    4
    1
    Lactate dehydrogenase increased
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    3 / 49 (6.12%)
    3 / 48 (6.25%)
    0 / 12 (0.00%)
         occurrences all number
    4
    4
    0
    Palpitations
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 49 (10.20%)
    10 / 48 (20.83%)
    5 / 12 (41.67%)
         occurrences all number
    5
    17
    8
    Peripheral sensory neuropathy
         subjects affected / exposed
    8 / 49 (16.33%)
    11 / 48 (22.92%)
    1 / 12 (8.33%)
         occurrences all number
    10
    13
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 49 (42.86%)
    22 / 48 (45.83%)
    3 / 12 (25.00%)
         occurrences all number
    46
    51
    11
    Leukopenia
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 48 (6.25%)
    1 / 12 (8.33%)
         occurrences all number
    2
    10
    1
    Neutropenia
         subjects affected / exposed
    5 / 49 (10.20%)
    6 / 48 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    6
    11
    0
    Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 49 (24.49%)
    9 / 48 (18.75%)
    2 / 12 (16.67%)
         occurrences all number
    26
    22
    5
    Eye disorders
    Corneal abrasion
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 49 (18.37%)
    11 / 48 (22.92%)
    3 / 12 (25.00%)
         occurrences all number
    15
    15
    9
    Ascites
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    0
    1
    Constipation
         subjects affected / exposed
    22 / 49 (44.90%)
    20 / 48 (41.67%)
    4 / 12 (33.33%)
         occurrences all number
    32
    39
    12
    Diarrhoea
         subjects affected / exposed
    9 / 49 (18.37%)
    10 / 48 (20.83%)
    3 / 12 (25.00%)
         occurrences all number
    11
    25
    3
    Dysgeusia
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 48 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    5
    0
    Gastrointestinal disorder
         subjects affected / exposed
    4 / 49 (8.16%)
    4 / 48 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    4
    5
    0
    Nausea
         subjects affected / exposed
    29 / 49 (59.18%)
    31 / 48 (64.58%)
    6 / 12 (50.00%)
         occurrences all number
    50
    61
    15
    Vomiting
         subjects affected / exposed
    8 / 49 (16.33%)
    18 / 48 (37.50%)
    1 / 12 (8.33%)
         occurrences all number
    12
    37
    5
    Stomatitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Mucosal dryness
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 49 (12.24%)
    6 / 48 (12.50%)
    1 / 12 (8.33%)
         occurrences all number
    11
    7
    2
    Dry skin
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 48 (6.25%)
    0 / 12 (0.00%)
         occurrences all number
    0
    4
    0
    Pain of skin
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 48 (6.25%)
    0 / 12 (0.00%)
         occurrences all number
    0
    6
    0
    Rash
         subjects affected / exposed
    4 / 49 (8.16%)
    8 / 48 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    5
    15
    0
    Nail disorder
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Skin discolouration
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 49 (2.04%)
    10 / 48 (20.83%)
    5 / 12 (41.67%)
         occurrences all number
    1
    32
    14
    Renal disorder
    Additional description: Renal function decreased
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    5 / 12 (41.67%)
         occurrences all number
    0
    0
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 49 (6.12%)
    6 / 48 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    4
    11
    0
    Muscular weakness
         subjects affected / exposed
    0 / 49 (0.00%)
    4 / 48 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    5
    0
    Myalgia
         subjects affected / exposed
    1 / 49 (2.04%)
    5 / 48 (10.42%)
    0 / 12 (0.00%)
         occurrences all number
    1
    10
    0
    Pain in extremity
         subjects affected / exposed
    4 / 49 (8.16%)
    2 / 48 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    4
    3
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    5 / 49 (10.20%)
    7 / 48 (14.58%)
    4 / 12 (33.33%)
         occurrences all number
    15
    18
    7
    Respiratory tract infection
         subjects affected / exposed
    3 / 49 (6.12%)
    9 / 48 (18.75%)
    0 / 12 (0.00%)
         occurrences all number
    3
    15
    0
    Infection
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    6 / 12 (50.00%)
         occurrences all number
    0
    0
    6
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    6 / 49 (12.24%)
    15 / 48 (31.25%)
    5 / 12 (41.67%)
         occurrences all number
    7
    39
    8
    Hypomagnesaemia
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 48 (6.25%)
    1 / 12 (8.33%)
         occurrences all number
    2
    4
    2
    Oedema peripheral
         subjects affected / exposed
    4 / 49 (8.16%)
    2 / 48 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    4
    3
    0
    Decreased appetite
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    0
    0
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Feb 2017
    The study design in Phase 2 (part 2) was changed from 3 arms to 2 arms, and the study was expanded to the whole platinum-sensitive population regardless of gBRCA and HRD status. The study title, secondary objectives, planned patient number, study rationale, risk-benefit-assessment, study design of part 2, stratification factors, study arms, dosing and duration of treatment, inclusion and exclusion criteriae and study statistics were adapted. Sponsor name was changed. The protocol version number was updated from 2.0 to 3.1. The protocol v.3.0 also included changes previously approved locally in Swedish local amendment 02 (18.4.2016) in order to harmonize the study protocol for all participating countries.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31375879
    http://www.ncbi.nlm.nih.gov/pubmed/31474354
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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