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    Clinical Trial Results:
    A GINECO phase II trial assessing the safety and efficacy of the Bevacizumab (FKB238), Olaparib (MEDI 4736) and Durvalumab combination in patients with advanced epithelial ovarian cancer in relapse: BOLD

    Summary
    EudraCT number
    		 2018-002281-39
    Trial protocol
    		 FR  
    Global end of trial date
    31 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2025
    First version publication date
    10 Apr 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GINECO-OV238
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ARCAGY-GINECO
    Sponsor organisation address
    8 rue Lamennais , Paris, France,
    Public contact
    Michèle TORRES-MACQUE, ARCAGY-GINECO, 33 142348323, reglementaire@arcagy.org
    Scientific contact
    Michèle TORRES-MACQUE, ARCAGY-GINECO, 33 142348323, reglementaire@arcagy.org
    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
    12 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is the rate of clinical and radiological non-progressive disease, as assessed by immune-related response criteria (irRC) (Wolchok et al. 2009) : • At 3 months in the PRR cohort • At 6 months in the PSR cohort
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The trial was conducted in agreement with the International Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP).
    Background therapy
    		 Bevacizumab and olaparib have already been tested on 12 patients in a phase I trial at their usual doses (10 mg/kg q2w and 400 mg bid – 50 mg capsules -, respectively), and no DLTs were observed (Dean et al., 2012). The addition of an anti-VEGF small molecule, cediranib, to olaparib doubled the median PFS in a randomized phase II trial in patients with platinum sensitive relapse, with a manageable safety profile (Liu et al., 2014). A recently reported phase I trial established the RDP2D of Durvalumab and Olaparib – 150 mg tablets –, when given in combination, at 1500 mg every 4 weeks, and 300 mg bid, respectively (Lee et al. 2017). In addition, the ENGOT/GINECO PAOLA phase III trial is currently evaluating the combination of Olaparib and Bevacizumab as first-line maintenance after platinum-paclitaxel combination, in patients with advanced high-grade serous ovarian carcinoma. Under the hypothesis of a survival benefit in favor of this combination, it would also be of interest to assess the value of adding Durvalumab in order to improve the efficacy of the overall combination. There are no trials to date assessing anti-VEGF in combination with anti-PARP and anti-PDL1 therapy. Beside additive efficacy, a synergistic effect could be expected : • Between bevacizumab and durvalumab, through normalization of blood vessel and potentiation of immunologic infiltration. • Between olaparib and durvalumab, through cytotoxicity-mediated release of antigens and impairment of mutation repair mechanisms, thereby increasing neoantigen loads. • Between olaparib and bevacizumab, through tumor environment modulation and signaling of DNA damage inhibition, which has already been tested with the anti-VEGF cediranib.
    Evidence for comparator
    		 The lifetime risk of ovarian cancer is around 1 to 2% in developed countries (Jayson et al., 2014). While there are effective treatment options that significantly prolong survival, advanced ovarian cancer (AOC) is still mostly a fatal disease, which requires additional therapeutic options. After first-line cytoreductive surgery and chemotherapy, 70 % of patients achieving complete remission will relapse. In patients with platinum sensitive relapse, long remissions may be obtained by platinum containing chemotherapy regimens and, in some cases, by surgery. Bevacizumab is indicated in first-relapse, in patients who did not previously receive this drug. Olaparib is SoC for mBRCA ½ PSR maintenance patients. However, relapsing AOC is no longer a curable disease and iterative relapses usually occur. In patients with platinum resistant disease, non-platinum cytotoxic agents such as paclitaxel, liposomal doxorubicin, or topotecan are indicated, in combination with bevacizumab, but the overall prognosis remains poor.There is clearly an unmet therapeutic need in patients with either platinum-resistant relapse or platinum-sensitive relapse.
    Actual start date of recruitment
    01 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 74
    Worldwide total number of subjects
    74
    EEA total number of subjects
    74
    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)
    33
    From 65 to 84 years
    40
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited between 01/03/2019 and 23/01/2020

    Pre-assignment
    Screening details
    		 93 patients were eligible in which 19 were excluded, 74 were enrolled and treated (41 in Platinum-resistant relapse cohort and 33 in Platinum-sensitive relapse cohort)

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Platinum-resistant relapse (PRR) cohort
    Arm description
    		 Platinum-resistant relapse was defined as disease progression <6 months after the last platinum dose and ≥1 line of previous platinum and taxane-containing chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Olaparib 300 mg was administered orally twice daily

    Investigational medicinal product name
    FKB238
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FKB238 (bevacizumab biosimilar; Centus Biotherapeutics, Cambridge, UK) 15 mg/kg was administered once every 3 weeks (Q3W) intravenously (initially 90 min, subsequently 60, then 30 min if well tolerated).

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 1.12 g was administered Q3W, 1-h intravenous infusion, more than 1 h after olaparib, starting from Cycle 1. Subsequent infusion durations could be reduced.

    Arm title
    		 Platinum-sensitive relapse (PSR) cohort
    Arm description
    		 Platinum-sensitive relapse was defined as disease progression ≥6 months after the last platinum dose in any prior line.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Olaparib 300 mg was administered orally twice daily

    Investigational medicinal product name
    FKB238
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FKB238 (bevacizumab biosimilar; Centus Biotherapeutics, Cambridge, UK) 15 mg/kg was administered once every 3 weeks (Q3W) intravenously (initially 90 min, subsequently 60, then 30 min if well tolerated).

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 1.12 g was administered Q3W, 1-h intravenous infusion, more than 1 h after olaparib, starting from Cycle 1. Subsequent infusion durations could be reduced.

    Number of subjects in period 1
    		Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Started
    41
    33
    Completed
    41
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Platinum-resistant relapse (PRR) cohort
    Reporting group description
    		 Platinum-resistant relapse was defined as disease progression <6 months after the last platinum dose and ≥1 line of previous platinum and taxane-containing chemotherapy.

    Reporting group title
    Platinum-sensitive relapse (PSR) cohort
    Reporting group description
    		 Platinum-sensitive relapse was defined as disease progression ≥6 months after the last platinum dose in any prior line.

    Reporting group values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort Total
    Number of subjects
    		 41 33 74
    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 15 34
        From 65-84 years
    		 21 18 39
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 66 (38 to 89) 65 (43 to 81) -
    Gender categorical
    Units: Subjects
        Female
    		 41 33 74
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 20 24 44
        ECOG 1
    		 21 9 30
    FIGO stage
    Units: Subjects
        II
    		 2 2 4
        III
    		 21 22 43
        IV
    		 14 6 20
        Unknown / Missing
    		 4 3 7
    Tumor origin
    Units: Subjects
        Ovarian
    		 37 29 66
        Primary peritoneal
    		 4 4 8
    Adenocarcinoma type at diagnosis
    Units: Subjects
        High-grade serous
    		 38 33 71
        Endometrioid Grade 2/3
    		 1 0 1
        Undifferentiated
    		 1 0 1
        Other
    		 1 0 1
    BRCA1/2 deleterious mutation
    Units: Subjects
        Yes
    		 4 11 15
        No
    		 37 22 59
    Germline BRCA mutation
    Units: Subjects
        BRCA1
    		 2 6 8
        BRCA2
    		 2 3 5
        NA
    		 37 24 61
    Somatic BRCA mutation (isolated)
    Units: Subjects
        BRCA1
    		 0 3 3
        BRCA2
    		 0 0 0
        NA
    		 41 30 71
    Prior systematic therapy : PARP inhibitor
    Units: Subjects
        PARP inhibitor: Olaparib
    		 4 9 13
        PARP inhibitor: Niraparib
    		 7 8 15
        PARP inhibitor: Rucaparib
    		 2 0 2
        No PARP inhibitor
    		 28 16 44
    Prior systematic therapy : Bevacizumab
    Units: Subjects
        Bevacizumab
    		 35 21 56
        No Bevacizumab
    		 6 12 18
    Prior systematic therapy : Antiangiogenic agent
    Units: Subjects
        Antiangiogenic agent
    		 36 28 64
        No antiangiogenic agent
    		 5 5 10
    Prior systematic therapy : Other antiangiogenic agent
    Units: Subjects
        Other antiangiogenic agent
    		 11 8 19
        NA
    		 30 25 55
    Prior systematic therapy : N lines chemotherapy
    Units: Number
        median (full range (min-max))
    		 3 (1 to 8) 2 (1 to 8) -
    Exposition to Treatment : Durvalumab
    Units: Number
        median (full range (min-max))
    		 8 (1 to 32) 10.5 (2 to 30) -
    Exposition to Treatment : Fkb238
    Units: Number
        median (full range (min-max))
    		 8 (1 to 32) 10 (1 to 30) -
    Exposition to Treatment : Olaparib
    Units: Number
        median (full range (min-max))
    		 7 (1 to 30) 9 (1 to 28) -
    Time between inclusion and last follow-up (in months)
    Units: month
        median (full range (min-max))
    		 14.28 (0.96 to 21.45) 15.57 (2.58 to 20.69) -
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-treat (ITT) population is defined as all patients included in the cohort considered, regardless of whether they actually received treatment.

    Subject analysis sets values
    		 ITT population
    Number of subjects
    74
    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)
    33
        From 65-84 years
    40
        85 years and over
    1
    Age continuous
    Units: years
        median (full range (min-max))
    65.5 (38 to 89)
    Gender categorical
    Units: Subjects
        Female
    74
    ECOG performance status
    Units: Subjects
        ECOG 0
    44
        ECOG 1
    30
    FIGO stage
    Units: Subjects
        II
    4
        III
    43
        IV
    20
        Unknown / Missing
    7
    Tumor origin
    Units: Subjects
        Ovarian
    66
        Primary peritoneal
    8
    Adenocarcinoma type at diagnosis
    Units: Subjects
        High-grade serous
    71
        Endometrioid Grade 2/3
    1
        Undifferentiated
    1
        Other
    1
    BRCA1/2 deleterious mutation
    Units: Subjects
        Yes
    15
        No
    59
    Germline BRCA mutation
    Units: Subjects
        BRCA1
    8
        BRCA2
    5
        NA
    61
    Somatic BRCA mutation (isolated)
    Units: Subjects
        BRCA1
    3
        BRCA2
    0
        NA
    71
    Prior systematic therapy : PARP inhibitor
    Units: Subjects
        PARP inhibitor: Olaparib
    13
        PARP inhibitor: Niraparib
    15
        PARP inhibitor: Rucaparib
    2
        No PARP inhibitor
    44
    Prior systematic therapy : Bevacizumab
    Units: Subjects
        Bevacizumab
    56
        No Bevacizumab
    18
    Prior systematic therapy : Antiangiogenic agent
    Units: Subjects
        Antiangiogenic agent
    64
        No antiangiogenic agent
    10
    Prior systematic therapy : Other antiangiogenic agent
    Units: Subjects
        Other antiangiogenic agent
    19
        NA
    55
    Prior systematic therapy : N lines chemotherapy
    Units: Number
        median (full range (min-max))
    2 (1 to 8)
    Exposition to Treatment : Durvalumab
    Units: Number
        median (full range (min-max))
    9 (1 to 32)
    Exposition to Treatment : Fkb238
    Units: Number
        median (full range (min-max))
    9 (1 to 32)
    Exposition to Treatment : Olaparib
    Units: Number
        median (full range (min-max))
    8.5 (1 to 30)
    Time between inclusion and last follow-up (in months)
    Units: month
        median (full range (min-max))
    15.44 (0.96 to 21.45)

    End points

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    End points reporting groups
    Reporting group title
    Platinum-resistant relapse (PRR) cohort
    Reporting group description
    		 Platinum-resistant relapse was defined as disease progression <6 months after the last platinum dose and ≥1 line of previous platinum and taxane-containing chemotherapy.

    Reporting group title
    Platinum-sensitive relapse (PSR) cohort
    Reporting group description
    		 Platinum-sensitive relapse was defined as disease progression ≥6 months after the last platinum dose in any prior line.

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-treat (ITT) population is defined as all patients included in the cohort considered, regardless of whether they actually received treatment.

    Primary: Rate of clinical and radiological non-progression disease

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    End point title
    		 Rate of clinical and radiological non-progression disease
    End point description
    End point type
    Primary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: Rate
    number (confidence interval 90%)
        Rate of non-progressive disease [90% CI] RECIST
    0.698 (0.559 to 0.8)
    0.438 (0.292 to 0.574)
        Rate of non-progressive disease [90% CI] irRECIST
    0.775 (0.643 to 0.863)
    0.561 (0.405 to 0.691)
    Statistical analysis title
    		 Kaplan-Meier estimates
    Comparison groups
    Platinum-resistant relapse (PRR) cohort v Platinum-sensitive relapse (PSR) cohort
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.05
    Method
    		 Kaplan-Meier estimates
    Confidence interval

    Primary: Rate of clinical and radiological non-progression disease : Maximum follow-up

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    End point title
    		 Rate of clinical and radiological non-progression disease : Maximum follow-up
    End point description
    End point type
    Primary
    End point timeframe
    Overall time
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: month
        Maximum Follow-up (months)
    3
    6
    Statistical analysis title
    		 Kaplan-Meier estimates
    Comparison groups
    Platinum-resistant relapse (PRR) cohort v Platinum-sensitive relapse (PSR) cohort
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.05
    Method
    		 Kaplan-Meier estimates
    Confidence interval

    Primary: Rate of clinical and radiological non-progression disease : Time to measure the rate according RECIST/clinical criteria

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    End point title
    		 Rate of clinical and radiological non-progression disease : Time to measure the rate according RECIST/clinical criteria
    End point description
    End point type
    Primary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: month
    number (not applicable)
        Time to measure the rate according RECIST/clinical
    2.744
    5.653
    Statistical analysis title
    		 Kaplan-Meier estimates
    Comparison groups
    Platinum-resistant relapse (PRR) cohort v Platinum-sensitive relapse (PSR) cohort
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.05
    Method
    		 Kaplan-Meier estimates
    Confidence interval

    Secondary: CA-125 decline

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    End point title
    		 CA-125 decline
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort ITT population
    Number of subjects analysed
    41
    33
    74
    Units: kU/L
    median (full range (min-max))
        CA-125 - Value (kU/L)
    281.10 (10.10 to 25000.00)
    42.75 (3.00 to 12000.00)
    148.00 (3.00 to 25000.00)
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: Rate
    number (not applicable)
        PFS (RECIST)
    0.5
    0.5
        PFS (irRECIST)
    0.5
    0.5
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) : Time in months

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    End point title
    		 Progression free survival (PFS) : Time in months
    End point description
    Median PFS (per RECIST and/or clinical progression) was 4.1 months (95% CI 3.5–5.9) in platinum-resistant patients and 4.9 months (95% CI 2.9–7.0) in platinum-sensitive patients. Efficacy outcomes were similar using irRECIST, with higher non-progression rates and longer median PFS in both groups: 5.4 months (95% CI 4.0–7.2) vs 7 months (95% CI 3.3– +Inf, which was published as the value 9999 in this EudraCT database), respectively.
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: month
    number (confidence interval 95%)
        Time in months RECIST
    4.1322 (3.4711 to 5.9174)
    4.8595 (2.8760 to 6.9752)
        Time in months irRECIST
    5.3884 (4.0331 to 7.1736)
    6.9752 (3.2727 to 9999)
    Attachments
    		 Progression Free Survival (PFS) RECIST
    Progression-free survival irRECIST
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: Rate
    number (confidence interval 95%)
        Time in months
    18.5455 (9.6198 to 21.6860)
    20.8595 (16.6612 to 36.4628)
    Attachments
    		 Overall survival (OS)
    No statistical analyses for this end point

    Secondary: Tumor response by RECIST

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    End point title
    		 Tumor response by RECIST
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort ITT population
    Number of subjects analysed
    41
    33
    74
    Units: Patients
        CR
    0
    1
    1
        PR
    11
    11
    22
        SD
    18
    16
    34
        PD
    10
    4
    14
    No statistical analyses for this end point

    Secondary: Tumor response by irRECIST

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    End point title
    		 Tumor response by irRECIST
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort ITT population
    Number of subjects analysed
    41
    33
    74
    Units: Patients
        CR
    1
    2
    3
        PR
    9
    12
    21
        SD
    24
    14
    38
        PD
    6
    4
    10
    No statistical analyses for this end point

    Secondary: Toxicity

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    End point title
    		 Toxicity
    End point description
    When n = 7 for PRR cohort and n = 13 for PSR cohort, treatment toxicity was analyzed. Toxicity was assessed by CTCAE V.5.0 scale.
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort ITT population
    Number of subjects analysed
    41
    33
    74
    Units: Adverse events
        Not graded
    1
    1
    2
        Grade 1
    515
    418
    933
        Grade 2
    238
    192
    430
        Grade 3
    70
    35
    105
        Grade 4
    3
    2
    5
        Grade 5
    3
    0
    3
        Unknown
    23
    46
    69
    No statistical analyses for this end point

    Other pre-specified: Subgroups analysis according to BRCA: Rate of clinical and radiological non-progression disease

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    End point title
    		 Subgroups analysis according to BRCA: Rate of clinical and radiological non-progression disease
    End point description
    Translational research
    End point type
    Other pre-specified
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: Rate
    number (confidence interval 90%)
        Rate of non-progressive disease RECIST no BRC1/2
    0.722 (0.578 to 0.824)
    0.455 (0.277 to 0.616)
        Rate of non-progressive disease RECIST with BRC1/2
    0.500 (0.103 to 0.809)
    0.400 (0.159 to 0.633)
        Rate of non-progressive disease irRECIST no BRC1/2
    0.806 (0.668 to 0.890)
    0.587 (0.395 to 0.737)
        Rate of non-progressive disease irRECIST BRC1/2
    0.500 (0.103 to 0.809)
    0.500 (0.230 to 0.721)
    No statistical analyses for this end point

    Other pre-specified: Subgroups analysis according to BRCA: Rate of clinical and radiological non-progression disease: Additional information

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    End point title
    		 Subgroups analysis according to BRCA: Rate of clinical and radiological non-progression disease: Additional information
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: month
    number (not applicable)
        Maximum Follow-up (months) no BCRA1/2 mutation
    3
    6
        Maximum Follow-up (months) BCRA1/2 mutation
    3
    6
        Time to measure the rate RECIST no BRCA1/2
    2.744
    5.653
        Time to measure the rate RECIST BRCA1/2
    1.322
    4.198
        Time to measure the rate irRECIST no BRCA1/2
    2.744
    5.653
        Time to measure the rate irRECIST BRCA1/2
    1.355
    4.231
        Stratum Number no BRCA1/2 mutation
    1
    1
        Stratum Number BRCA1/2 mutation
    2
    2
    No statistical analyses for this end point

    Other pre-specified: Subgroups analysis according to BRCA: Tumor objective response rate (ORR) according to RECIST

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    End point title
    		 Subgroups analysis according to BRCA: Tumor objective response rate (ORR) according to RECIST
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: Patients
        (no BRCA1/2 mutation)
    1
    1
        (BRCA1/2 mutation)
    1
    0
        CR (no BRCA1/2 mutation)
    0
    0
        CR (BRCA1/2 mutation)
    0
    1
        PR (no BRCA1/2 mutation)
    1
    3
        PR (BRCA1/2 mutation)
    10
    8
        SD (no BRCA1/2 mutation)
    0
    6
        SD (BRCA1/2 mutation)
    18
    10
        PD (no BRCA1/2 mutation)
    2
    1
        PD (BRCA1/2 mutation)
    8
    3
    No statistical analyses for this end point

    Other pre-specified: Subgroups analysis according to BRCA: Tumor objective response rate (ORR) according to irRECIST

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    End point title
    		 Subgroups analysis according to BRCA: Tumor objective response rate (ORR) according to irRECIST
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Overall study
    End point values
    		 Platinum-resistant relapse (PRR) cohort Platinum-sensitive relapse (PSR) cohort
    Number of subjects analysed
    41
    33
    Units: Patients
        (BRCA1/2 mutation)
    1
    0
        (no BRCA1/2 mutation)
    0
    1
        CR (BRCA1/2 mutation)
    1
    1
        CR (no BRCA1/2 mutation)
    0
    1
        PR (BRCA1/2 mutation)
    8
    9
        PR (no BRCA1/2 mutation)
    1
    3
        SD (BRCA1/2 mutation)
    23
    9
        SD (no BRCA1/2 mutation)
    1
    5
        PD (BRCA1/2 mutation)
    4
    3
        PD (no BRCA1/2 mutation)
    2
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Platinum resistant relapse (PRR)
    Reporting group description
    		 -

    Reporting group title
    Platinum sensitive relapse (PSR)
    Reporting group description
    		 -

    Serious adverse events
    		 Platinum resistant relapse (PRR) Platinum sensitive relapse (PSR)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 41 (39.02%)
    7 / 33 (21.21%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 41 (4.88%)
    5 / 33 (15.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalization
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurodesis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Performance status decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restrictive pulmonary disease
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Transaminase value increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Change in ECG
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drain site complication
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral fracture
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriospasm coronary
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anemia
         subjects affected / exposed
    8 / 41 (19.51%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subocclusive syndrome
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 33 (9.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteropathy NOS
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Jaundice cholestatic
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin rash
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroiditis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    7 / 41 (17.07%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 33 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella oxytoca infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial colitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Platinum resistant relapse (PRR) Platinum sensitive relapse (PSR)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 41 (100.00%)
    32 / 33 (96.97%)
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    8 / 41 (19.51%)
    14 / 33 (42.42%)
         occurrences all number
    8
    14
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    General disorders and administration site Conditions
         subjects affected / exposed
    36 / 41 (87.80%)
    32 / 33 (96.97%)
         occurrences all number
    36
    32
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal Disorders
         subjects affected / exposed
    25 / 41 (60.98%)
    20 / 33 (60.61%)
         occurrences all number
    25
    20
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    9 / 41 (21.95%)
    0 / 33 (0.00%)
         occurrences all number
    9
    0
    Investigations
    Investigations
         subjects affected / exposed
    12 / 41 (29.27%)
    7 / 33 (21.21%)
         occurrences all number
    12
    7
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural Complications
         subjects affected / exposed
    6 / 41 (14.63%)
    2 / 33 (6.06%)
         occurrences all number
    6
    2
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    4 / 41 (9.76%)
    4 / 33 (12.12%)
         occurrences all number
    4
    4
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    17 / 41 (41.46%)
    18 / 33 (54.55%)
         occurrences all number
    17
    18
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    28 / 41 (68.29%)
    16 / 33 (48.48%)
         occurrences all number
    28
    16
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Eye disorders
    Eye disorders
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 33 (9.09%)
         occurrences all number
    4
    3
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    38 / 41 (92.68%)
    31 / 33 (93.94%)
         occurrences all number
    38
    31
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    3 / 41 (7.32%)
    5 / 33 (15.15%)
         occurrences all number
    3
    5
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    11 / 41 (26.83%)
    8 / 33 (24.24%)
         occurrences all number
    11
    8
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    10 / 41 (24.39%)
    6 / 33 (18.18%)
         occurrences all number
    10
    6
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    13 / 41 (31.71%)
    6 / 33 (18.18%)
         occurrences all number
    13
    6
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue Disorders
         subjects affected / exposed
    23 / 41 (56.10%)
    19 / 33 (57.58%)
         occurrences all number
    23
    19
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    22 / 41 (53.66%)
    18 / 33 (54.55%)
         occurrences all number
    22
    18
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    26 / 41 (63.41%)
    18 / 33 (54.55%)
         occurrences all number
    26
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2019
    Protocol containing amendment n°1
    16 Sep 2019
    Protocol containing amendment n°2
    24 Aug 2020
    Protocol containing amendment n°4
    13 Jan 2021
    Protocol containing amendment n°5
    25 Jun 2021
    Protocol containing amendment n°6
    07 Dec 2021
    Protocol containing amendment n°7

    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.
    Single-arm nature, small sample size, use of archival tissue for translational research , and a minority of patients with BRCA mutation status in both populations. The study was not powered to show statistical differences in these subgroups.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38443333
    For support, Contact us.
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