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    Clinical Trial Results:
    Randomized double blind placebo-controlled phase II trial of Vargatef® in addition to first line chemotherapy with interval debulking surgery in patients with adenocarcinoma of the ovary, the fallopian tube or serous adenocarcinoma of the peritoneum

    Summary
    EudraCT number
    		 2011-006288-23
    Trial protocol
    		 FR  
    Global end of trial date
    16 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Apr 2023
    First version publication date
    23 Apr 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GINECO-OV-119
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01583322
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ARCAGY-GINECO
    Sponsor organisation address
    8 rue Lamennais, Paris, France, 75008
    Public contact
    Sébastien ARMANET, ARCAGY, 33 184852020, sarmanet@arcagy.org
    Scientific contact
    Sébastien ARMANET, ARCAGY, 33 184852020, sarmanet@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
    27 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the median Progression-free Survival (PFS) in each study arm (neoadjuvant/adjuvant treatment with or without Nintedanib(Vargatef®).
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and with the French laws and regulations: - Huriet law (n°88-1138) of December 20th 1988, concerning protection of participants undergoing biomedical research, modified by the Public health law (n°2004-806) of August 9th 2004. - Data Protection Act n°78-17, modified by the law n°2004-801 of August 6th 2004 ensuring the confidentiality of personal information. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” (November 2006) ICH Tripartite Guideline (January 1997). The investigator ensured compliance with the EU Clinical Trial Directive (2001/20/EC). The study protocol and all the amendments were reviewed by an Independent Ethics Committee (EC): Comité de Protection des Personnes (CPP) Ile de France n° 1 Docteur Catherine Grillot-Courvalin, Présidente du CPP Ile de France n° 1 Hôpital Hôtel-Dieu 1, place du Parvis Notre-Dame – Place Jean-Paul II 75004 PARIS The EC provided an initial approval on the 29th of March 2012
    Background therapy
    		 Maximal primary cyto-reductive surgery followed by carboplatin-paclitaxel 3-weeks cycles of chemotherapy remains the standard of care as first treatment in advanced ovarian cancer. Neoadjuvant chemotherapy represents an alternative strategy for patients with stage IIIC or IV who are not considered to be completely resectable. Chemotherapy followed by interval debulking result in fewer and simpler operations and lesser morbidity for the patients involving less inconvenience and toxicity for the patient with equivalent survival outcomes. The background therapy treatments for this trial are : Carboplatine: AUC 5 or 6, IV, q 3 weeks Paclitaxel: 175 mg/m², IV, q 3 weeks Patients will receive a total number of 6 courses. Two additional cycles are allowed if required (maximum 8 cycles).
    Evidence for comparator
    		 Vargatef® (Nintedanib) is an orally available potent small molecule triple kinase inhibitor inhibiting VEGFR 1-3, FGFR 1-3 as well as PDGF receptor a and ß in the low nanomolar range. Considering its antiangiogenic mechanism of action demonstrated in vivo, it is anticipated that treatment with Vargatef® (Nintedanib) will slow tumor growth in human cancers. Moreover, tumor regression may also be achieved by induction of apoptosis of immature tumor vessels. In addition, a therapeutic effect may also result from inhibition of tumor autocrine and paracrine growth factor loops involving VEGF, PDGF and bFGF. It is likely that long-term treatment may be needed to ensure maximal clinical benefit. Based on results of previous phase I and II clinical trials, it was decided to set up a large randomized phase III study (GCIG/ENGOT/AGO-OVAR 12 trial). The objective of this study was to investigate the efficacy and safety of Vargatef® (Nintedanib) plus chemotherapy as compared with placebo plus chemotherapy in patients with advanced ovarian cancer. Vargatef® (Nintedanib)/placebo monotherapy was continued for a maximum of 120 weeks after randomization or until AEs or disease progression, whichever occurs first. The results showed that adding nintedanib to carboplatin–paclitaxel after upfront surgery improved PFS (but not OS), although adverse events (AEs) were increased.
    Actual start date of recruitment
    11 Jan 2013
    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: 188
    Worldwide total number of subjects
    188
    EEA total number of subjects
    188
    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)
    97
    From 65 to 84 years
    91
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited in 31 centres in France during January 11th, 2013 to May 13th, 2015.

    Pre-assignment
    Screening details
    		 Of 191 screeed patients 3 were excluded for not meeting the eligibility criteria. Subsequently, 124 were allocated to the study treatment nintedanib, 64 were allocated to the placebo.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    The trial was performed according to a parallel group, double-blind, placebo-controlled design. Patients, investigators and the sponsor’s trial team involved in analyzing of this double-blind trial remained blinded with regard to the randomized treatment assignments up to database lock, with the exception of particular instances which required immediate unblinding (DSMB).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: standard arm (placebo arm)
    Arm description
    		 1. Neoadjuvant therapy (3 cycles) Vargatef® placebo 200mg bid will be administered twice daily during the first 2 cycles except on day 1 of each cycle (day of chemotherapy). Placebo will not be administered during cycle before surgery (third cycle). Patients with insufficient tumor response to allow interval debulking surgery after 3 cycles of neoadjuvant therapy will receive 4 cycles of neo-adjuvant therapy. In those patients, placebo will be skipped during cycle preceding surgery (Cycle 4). Interval Debulking Surgery: will be performed 3 to 4 weeks after the last chemotherapy administration. 3. Adjuvant therapy: will start 4 weeks after surgery and after complete surgical wound healing 4. Maintenance therapy: Placebo 200mg bid will be administered during 2 years or until disease progression which ever occur first.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Vargatef® (Nintedanib) 200mg bid
    Investigational medicinal product code
    BIBF1120
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Neo-adjuvant therapy (3 to 4 cycles): 400 mg per day (200mg twice daily) during the first 2 to 3 cycles except on day 1 of each cycle (day of chemotherapy). Vargatef® (Nintedanib) will not be administered during cycle before surgery (i.e. cycle 3 or 4). Maintenance therapy: Vargatef® (Nintedanib): 200 mg bid will be administered during 2 years or until disease progression which ever occur first.

    Arm title
    		 Arm B: experimental arm (Vargatef® arm)
    Arm description
    		 1. Neo-adjuvant therapy (3 cycles): Vargatef® (Nintedanib) 200mg bid will be administered twice daily during the first 2 cycles except on day 1 of each cycle (day of chemotherapy). Vargatef® (Nintedanib) will not be administered during cycle before surgery (cycle 3). Patients with insufficient tumor response to allow interval debulking surgery after 3 cycles of neoadjuvant therapy will receive 4 cycles of neo-adjuvant therapy. In those patients, Vargatef® (Nintedanib) will be skipped during cycle preceding surgery (Cycle 4). 2. Interval Debulking Surgery: will be performed 3 to 4 weeks after the last chemotherapy administration. 3. Adjuvant therapy: will start 4 weeks after surgery and after complete surgical wound healing 4. Maintenance therapy: Vargatef® (Nintedanib) 200 mg bid will be administered during 2 years or until disease progression which ever occur first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vargatef® (Nintedanib) 200mg bid
    Investigational medicinal product code
    BIBF1120
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Neo-adjuvant therapy (3 to 4 cycles): 400 mg per day (200mg twice daily) during the first 2 to 3 cycles except on day 1 of each cycle (day of chemotherapy). Vargatef® (Nintedanib) will not be administered during cycle before surgery (i.e. cycle 3 or 4). Maintenance therapy: Vargatef® (Nintedanib): 200 mg bid will be administered during 2 years or until disease progression which ever occur first.

    Number of subjects in period 1
    		Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Started
    64
    124
    Completed
    64
    120
    Not completed
    0
    4
         poor treatment compliance
    -
    2
         Protocol deviation
    -
    2

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm A: standard arm (placebo arm)
    Reporting group description
    		 1. Neoadjuvant therapy (3 cycles) Vargatef® placebo 200mg bid will be administered twice daily during the first 2 cycles except on day 1 of each cycle (day of chemotherapy). Placebo will not be administered during cycle before surgery (third cycle). Patients with insufficient tumor response to allow interval debulking surgery after 3 cycles of neoadjuvant therapy will receive 4 cycles of neo-adjuvant therapy. In those patients, placebo will be skipped during cycle preceding surgery (Cycle 4). Interval Debulking Surgery: will be performed 3 to 4 weeks after the last chemotherapy administration. 3. Adjuvant therapy: will start 4 weeks after surgery and after complete surgical wound healing 4. Maintenance therapy: Placebo 200mg bid will be administered during 2 years or until disease progression which ever occur first.

    Reporting group title
    Arm B: experimental arm (Vargatef® arm)
    Reporting group description
    		 1. Neo-adjuvant therapy (3 cycles): Vargatef® (Nintedanib) 200mg bid will be administered twice daily during the first 2 cycles except on day 1 of each cycle (day of chemotherapy). Vargatef® (Nintedanib) will not be administered during cycle before surgery (cycle 3). Patients with insufficient tumor response to allow interval debulking surgery after 3 cycles of neoadjuvant therapy will receive 4 cycles of neo-adjuvant therapy. In those patients, Vargatef® (Nintedanib) will be skipped during cycle preceding surgery (Cycle 4). 2. Interval Debulking Surgery: will be performed 3 to 4 weeks after the last chemotherapy administration. 3. Adjuvant therapy: will start 4 weeks after surgery and after complete surgical wound healing 4. Maintenance therapy: Vargatef® (Nintedanib) 200 mg bid will be administered during 2 years or until disease progression which ever occur first.

    Reporting group values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm) Total
    Number of subjects
    		 64 124 188
    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)
    		 34 63 97
        From 65-84 years
    		 30 61 91
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.1 ± 8 63.7 ± 10 -
    Gender categorical
    Units: Subjects
        Female
    		 64 124 188
        Male
    		 0 0 0
    ECOG performance
    Units: Subjects
        zero
    		 21 49 70
        one
    		 32 63 95
        two
    		 10 10 20
        missing
    		 1 2 3
    Tumor histological type
    Units: Subjects
        Serous/papillary
    		 56 108 164
        Endometrioid
    		 0 3 3
        Mucinous
    		 0 1 1
        Clear cells
    		 0 3 3
        Undifferenciated
    		 1 4 5
        Other
    		 6 5 11
        Not available
    		 1 0 1
    Tumor histological grade
    Units: Subjects
        01
    		 3 2 5
        02
    		 3 10 13
        03
    		 50 85 135
        Unknown
    		 7 27 34
        Not available
    		 1 0 1
    FIGO stage
    Units: Subjects
        IIIC
    		 47 98 145
        IV
    		 16 26 42
        Not available
    		 1 0 1
    Uterus
    Units: Subjects
        No
    		 16 24 40
        Yes
    		 0 1 1
        Not available
    		 0 1 1
        Not recorded
    		 48 98 146
    Vagina
    Units: Subjects
        No
    		 16 25 41
        Not available
    		 0 1 1
        Not recorded
    		 48 98 146
    Bladder
    Units: Subjects
        No
    		 16 25 41
        Not available
    		 0 1 1
        Not recorded
    		 48 98 146
    Rectum
    Units: Subjects
        No
    		 15 24 39
        Yes
    		 1 1 2
        Not available
    		 0 1 1
        Not recorded
    		 48 98 146
    Abdominal peritoneum
    Units: Subjects
        No
    		 9 15 24
        Yes
    		 7 11 18
        Not available
    		 0 0 0
        Not recorded
    		 48 98 146
    Pelvic lymph nodes
    Units: Subjects
        No
    		 12 22 34
        Yes
    		 4 3 7
        Not available
    		 0 1 1
        Not recorded
    		 48 98 146
    Para-aortic lymph nodes
    Units: Subjects
        No
    		 13 22 35
        Yes
    		 3 3 6
        Not available
    		 0 1 1
        Not recorded
    		 48 98 146
    Liver
    Units: Subjects
        No
    		 13 19 32
        Yes
    		 3 7 10
        Not available
    		 0 0 0
        Not recorded
    		 48 98 146
    Lung
    Units: Subjects
        No
    		 13 21 34
        Yes
    		 3 4 7
        Not available
    		 0 1 1
        Not recorded
    		 48 98 146
    Mediastinal lymph nodes
    Units: Subjects
        No
    		 13 18 31
        Yes
    		 10 7 17
        Not available
    		 1 1 2
        Not recorded
    		 40 98 138
    Other tumor site
    Units: Subjects
        No
    		 1 13 14
        Yes
    		 15 12 27
        Not available
    		 0 1 1
        Not recorded
    		 48 98 146
    Diagnostic surgery : Coelioscopy
    Units: Subjects
        No
    		 1 9 10
        Yes
    		 62 115 177
        Not available
    		 1 0 1
    Diagnostic surgery : Subumbilical median
    Units: Subjects
        No
    		 55 104 159
        Yes
    		 8 20 28
        Not available
    		 1 0 1
    Diagnostic surgery : Supra and subumbilical median
    Units: Subjects
        No
    		 57 114 171
        Yes
    		 6 10 16
        Not available
    		 1 0 1
    Diagnostic surgery : Other
    Units: Subjects
        No
    		 47 76 123
        Yes
    		 16 48 64
        Not available
    		 1 0 1
    Resection
    Units: Subjects
        Resection
    		 6 17 23
        No resection
    		 57 107 164
        Not available
    		 1 0 1
    Medical history : Arterial hypertension
    Units: Subjects
        No
    		 41 66 107
        Former
    		 0 1 1
        Ongoing
    		 19 41 60
        Not available
    		 0 2 2
        Not recorded
    		 4 14 18
    Medical history : Other heart disease
    Units: Subjects
        No
    		 55 103 158
        Former
    		 2 1 3
        Ongoing
    		 3 4 7
        Not available
    		 0 2 2
        Not recorded
    		 4 14 18
    Medical history : Hypercholesterolemia
    Units: Subjects
        No
    		 45 82 127
        Former
    		 1 5 6
        Ongoing
    		 14 21 35
        Not available
    		 0 2 2
        Not recorded
    		 4 14 18
    Medical history : Mood disorders
    Units: Subjects
        No
    		 53 96 149
        Former
    		 2 1 3
        Ongoing
    		 5 11 16
        Not available
    		 0 2 2
        Not recorded
    		 4 14 18
    Medical history : Pain
    Units: Subjects
        No
    		 44 92 136
        Ongoing
    		 16 16 32
        Not available
    		 2 0 2
        Not recorded
    		 2 16 18
    Medical history : Other disease or surgery
    Units: Subjects
        No
    		 7 15 22
        Former
    		 23 44 67
        Ongoing
    		 30 50 80
        Not available
    		 0 1 1
        Not recorded
    		 4 14 18
    Relevant treatments : Antihypertensive
    Units: Subjects
        No
    		 31 52 83
        Ongoing
    		 18 38 56
        Not available
    		 0 0 0
        Not recorded
    		 15 34 49
    Relevant treatments : Other heart disease
    Units: Subjects
        No
    		 46 84 130
        Ongoing
    		 3 6 9
        Not available
    		 0 0 0
        Not recorded
    		 15 34 49
    Relevant treatments : Cholesterol lowering treatment
    Units: Subjects
        No
    		 37 69 106
        Former
    		 0 1 1
        Ongoing
    		 12 20 32
        Not available
    		 0 0 0
        Not recorded
    		 15 34 49
    Relevant treatments : Antidepressant
    Units: Subjects
        No
    		 44 76 120
        Ongoing
    		 5 13 18
        Not available
    		 0 1 1
        Not recorded
    		 15 34 49
    Relevant treatments : Anxiolytic
    Units: Subjects
        No
    		 42 75 117
        Ongoing
    		 7 15 22
        Not available
    		 0 0 0
        Not recorded
    		 15 34 49
    Relevant treatments : Analgesic
    Units: Subjects
        No
    		 30 67 97
        Former
    		 1 0 1
        Ongoing
    		 18 23 41
        Not available
    		 0 0 0
        Not recorded
    		 15 34 49
    Relevant treatments : Other
    Units: Subjects
        No
    		 11 17 28
        Former
    		 6 10 16
        Ongoing
    		 32 62 94
        Not available
    		 0 1 1
        Not recorded
    		 15 34 49
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 65.5 ± 14.3 64.2 ± 12.7 -
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 161.6 ± 7 161.2 ± 6 -
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 24.6 ± 4.8 25.2 ± 5.5 -
    Sugar-Baker Index
    Units: score
        arithmetic mean (standard deviation)
    		 20.1 ± 8 22.1 ± 8 -
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients included in the study and randomized whatever the actual product intake.

    Subject analysis sets values
    		 ITT
    Number of subjects
    188
    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)
    97
        From 65-84 years
    91
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.5 ± 9
    Gender categorical
    Units: Subjects
        Female
    188
        Male
    0
    ECOG performance
    Units: Subjects
        zero
    70
        one
    95
        two
    20
        missing
    3
    Tumor histological type
    Units: Subjects
        Serous/papillary
    164
        Endometrioid
    3
        Mucinous
    1
        Clear cells
    3
        Undifferenciated
    5
        Other
    11
        Not available
    1
    Tumor histological grade
    Units: Subjects
        01
    5
        02
    13
        03
    135
        Unknown
    34
        Not available
    1
    FIGO stage
    Units: Subjects
        IIIC
    145
        IV
    42
        Not available
    1
    Uterus
    Units: Subjects
        No
    40
        Yes
    1
        Not available
    1
        Not recorded
    146
    Vagina
    Units: Subjects
        No
    41
        Not available
    1
        Not recorded
    146
    Bladder
    Units: Subjects
        No
    41
        Not available
    1
        Not recorded
    146
    Rectum
    Units: Subjects
        No
    39
        Yes
    2
        Not available
    1
        Not recorded
    48
    Abdominal peritoneum
    Units: Subjects
        No
    24
        Yes
    18
        Not available
    0
        Not recorded
    146
    Pelvic lymph nodes
    Units: Subjects
        No
    34
        Yes
    7
        Not available
    1
        Not recorded
    146
    Para-aortic lymph nodes
    Units: Subjects
        No
    35
        Yes
    6
        Not available
    1
        Not recorded
    146
    Liver
    Units: Subjects
        No
    32
        Yes
    10
        Not available
    0
        Not recorded
    146
    Lung
    Units: Subjects
        No
    34
        Yes
    7
        Not available
    1
        Not recorded
    146
    Mediastinal lymph nodes
    Units: Subjects
        No
    31
        Yes
    10
        Not available
    1
        Not recorded
    138
    Other tumor site
    Units: Subjects
        No
    14
        Yes
    27
        Not available
    1
        Not recorded
    146
    Diagnostic surgery : Coelioscopy
    Units: Subjects
        No
    10
        Yes
    177
        Not available
    1
    Diagnostic surgery : Subumbilical median
    Units: Subjects
        No
    159
        Yes
    28
        Not available
    1
    Diagnostic surgery : Supra and subumbilical median
    Units: Subjects
        No
    171
        Yes
    16
        Not available
    1
    Diagnostic surgery : Other
    Units: Subjects
        No
    123
        Yes
    64
        Not available
    1
    Resection
    Units: Subjects
        Resection
    23
        No resection
    164
        Not available
    1
    Medical history : Arterial hypertension
    Units: Subjects
        No
    107
        Former
    1
        Ongoing
    60
        Not available
    2
        Not recorded
    18
    Medical history : Other heart disease
    Units: Subjects
        No
    158
        Former
    3
        Ongoing
    7
        Not available
    2
        Not recorded
    18
    Medical history : Hypercholesterolemia
    Units: Subjects
        No
    127
        Former
    6
        Ongoing
    35
        Not available
    2
        Not recorded
    18
    Medical history : Mood disorders
    Units: Subjects
        No
    149
        Former
    3
        Ongoing
    16
        Not available
    2
        Not recorded
    18
    Medical history : Pain
    Units: Subjects
        No
    136
        Ongoing
    32
        Not available
    2
        Not recorded
    18
    Medical history : Other disease or surgery
    Units: Subjects
        No
    22
        Former
    67
        Ongoing
    80
        Not available
    1
        Not recorded
    18
    Relevant treatments : Antihypertensive
    Units: Subjects
        No
    83
        Ongoing
    56
        Not available
    0
        Not recorded
    49
    Relevant treatments : Other heart disease
    Units: Subjects
        No
    130
        Ongoing
    9
        Not available
    0
        Not recorded
    49
    Relevant treatments : Cholesterol lowering treatment
    Units: Subjects
        No
    106
        Former
    1
        Ongoing
    32
        Not available
    0
        Not recorded
    49
    Relevant treatments : Antidepressant
    Units: Subjects
        No
    120
        Ongoing
    18
        Not available
    1
        Not recorded
    49
    Relevant treatments : Anxiolytic
    Units: Subjects
        No
    117
        Ongoing
    22
        Not available
    0
        Not recorded
    49
    Relevant treatments : Analgesic
    Units: Subjects
        No
    97
        Former
    1
        Ongoing
    41
        Not available
    0
        Not recorded
    49
    Relevant treatments : Other
    Units: Subjects
        No
    28
        Former
    16
        Ongoing
    94
        Not available
    1
        Not recorded
    49
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    65.05 ± 13.8
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    161.3 ± 6
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    25 ± 5.3
    Sugar-Baker Index
    Units: score
        arithmetic mean (standard deviation)
    21.4 ± 8

    End points

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    End points reporting groups
    Reporting group title
    Arm A: standard arm (placebo arm)
    Reporting group description
    		 1. Neoadjuvant therapy (3 cycles) Vargatef® placebo 200mg bid will be administered twice daily during the first 2 cycles except on day 1 of each cycle (day of chemotherapy). Placebo will not be administered during cycle before surgery (third cycle). Patients with insufficient tumor response to allow interval debulking surgery after 3 cycles of neoadjuvant therapy will receive 4 cycles of neo-adjuvant therapy. In those patients, placebo will be skipped during cycle preceding surgery (Cycle 4). Interval Debulking Surgery: will be performed 3 to 4 weeks after the last chemotherapy administration. 3. Adjuvant therapy: will start 4 weeks after surgery and after complete surgical wound healing 4. Maintenance therapy: Placebo 200mg bid will be administered during 2 years or until disease progression which ever occur first.

    Reporting group title
    Arm B: experimental arm (Vargatef® arm)
    Reporting group description
    		 1. Neo-adjuvant therapy (3 cycles): Vargatef® (Nintedanib) 200mg bid will be administered twice daily during the first 2 cycles except on day 1 of each cycle (day of chemotherapy). Vargatef® (Nintedanib) will not be administered during cycle before surgery (cycle 3). Patients with insufficient tumor response to allow interval debulking surgery after 3 cycles of neoadjuvant therapy will receive 4 cycles of neo-adjuvant therapy. In those patients, Vargatef® (Nintedanib) will be skipped during cycle preceding surgery (Cycle 4). 2. Interval Debulking Surgery: will be performed 3 to 4 weeks after the last chemotherapy administration. 3. Adjuvant therapy: will start 4 weeks after surgery and after complete surgical wound healing 4. Maintenance therapy: Vargatef® (Nintedanib) 200 mg bid will be administered during 2 years or until disease progression which ever occur first.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients included in the study and randomized whatever the actual product intake.

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    PFS was assessed by tumour measurements according to the RECIST version 1.1 and defined for all patients that entered the trial and measured from the date of randomization until the date of disease progression or death, from any cause, whichever occurs first.
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Number of subjects analysed
    58
    120
    Units: month
        median (full range (min-max))
    16.8 (13.0 to 21.4)
    14.2 (12.2 to 15.4)
    Statistical analysis title
    		 log-rank test
    Comparison groups
    Arm A: standard arm (placebo arm) v Arm B: experimental arm (Vargatef® arm)
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Upper CI95% not reached for Arm 1
    End point type
    Secondary
    End point timeframe
    Cut off 30 SEP 2017
    End point values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Number of subjects analysed
    64 [1]
    124
    Units: month
        median (confidence interval 95%)
    44.1 (32.7 to 44.1)
    37.7 (29.8 to 40.1)
    Notes
    [1] - Some information are not available for analysis
    Statistical analysis title
    		 log-rank test
    Comparison groups
    Arm A: standard arm (placebo arm) v Arm B: experimental arm (Vargatef® arm)
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval

    Secondary: Response Rate

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    End point title
    		 Response Rate
    End point description
    End point type
    Secondary
    End point timeframe
    After 2 cycles of NACT 24 months ?
    End point values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Number of subjects analysed
    58
    120
    Units: percent
        number (not applicable)
    57.1
    34.9
    No statistical analyses for this end point

    Secondary: Best Response

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    End point title
    		 Best Response
    End point description
    End point type
    Secondary
    End point timeframe
    48 months
    End point values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Number of subjects analysed
    58
    120
    Units: Subjects
        complete response
    28
    53
        partial response
    19
    29
        stable
    10
    28
        progression
    0
    4
        not evaluable
    0
    1
        not available
    1
    5
    No statistical analyses for this end point

    Secondary: Rate of complete debulking

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    End point title
    		 Rate of complete debulking
    End point description
    Complete debulking at IDS (%)
    End point type
    Secondary
    End point timeframe
    3 to 4 weeks after the last chemotherapy administration.
    End point values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Number of subjects analysed
    58
    120
    Units: percent
    number (not applicable)
        Complete resection (CCI=0)
    78.7
    74.3
        No complete resection (CCI=1, 2 or 3)
    21.3
    25.7
    No statistical analyses for this end point

    Secondary: Biological progression-free interval (PFIbio)

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    End point title
    		 Biological progression-free interval (PFIbio)
    End point description
    Patients' status at the last contact (%)
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Number of subjects analysed
    64
    124
    Units: percent
    number (not applicable)
        Alive without progression
    55.2
    60.0
        CA-125 Progression
    44.8
    40.0
    No statistical analyses for this end point

    Secondary: Quality of Life (FOSI score )

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    End point title
    		 Quality of Life (FOSI score )
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm) ITT
    Number of subjects analysed
    64
    124
    188
    Units: subjects
        Baseline
    62
    121
    183
        End of neo-adjuvant visit
    48
    81
    129
        End of adjuvant visit
    47
    74
    121
        3 month
    39
    65
    104
        6 month
    27
    41
    68
        9 month
    18
    32
    50
        12 month
    17
    21
    38
        15 month
    11
    16
    27
        18 month
    9
    12
    21
        21 month
    8
    10
    18
        24 month
    6
    10
    16
        End of maintenance visit
    28
    54
    82
    No statistical analyses for this end point

    Secondary: Quality of Life (mean FOSI score)

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    End point title
    		 Quality of Life (mean FOSI score)
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm) ITT
    Number of subjects analysed
    64
    124
    188
    Units: FOSI score
    arithmetic mean (standard deviation)
        Baseline
    23.5 ± 4.6
    23 ± 4.7
    23.2 ± 4.6
        End of neo-adjuvant visit
    25 ± 3.6
    24.2 ± 4.4
    24.5 ± 4.1
        End of adjuvant visit
    25 ± 3.5
    23.3 ± 4.8
    24 ± 4.4
        3 month
    25.9 ± 3.5
    23.5 ± 4.9
    24.4 ± 4.5
        6 month
    23.8 ± 5.5
    25.4 ± 3.3
    24.8 ± 4.4
        9 month
    24.7 ± 4.4
    24.1 ± 4.0
    24.3 ± 4.1
        12 month
    24.5 ± 4.0
    23.5 ± 4.1
    23.9 ± 4.0
        15 month
    25.2 ± 2.7
    23.8 ± 4.0
    24.3 ± 3.6
        18 month
    24.7 ± 2.7
    24.1 ± 4.2
    24.3 ± 3.6
        21 month
    24.1 ± 3.6
    23 ± 3.8
    23.5 ± 3.6
        24 month
    24.1 ± 5.2
    23.2 ± 5.2
    23.5 ± 5.0
        End of maintenance visit
    22.8 ± 4.5
    22.6 ± 5.1
    22.6 ± 4.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Arm A: standard arm (placebo arm)
    Reporting group description
    		 1. Neoadjuvant therapy (3 cycles) Vargatef® placebo 200mg bid will be administered twice daily during the first 2 cycles except on day 1 of each cycle (day of chemotherapy). Placebo will not be administered during cycle before surgery (third cycle). Patients with insufficient tumor response to allow interval debulking surgery after 3 cycles of neoadjuvant therapy will receive 4 cycles of neo-adjuvant therapy. In those patients, placebo will be skipped during cycle preceding surgery (Cycle 4). Interval Debulking Surgery: will be performed 3 to 4 weeks after the last chemotherapy administration. 3. Adjuvant therapy: will start 4 weeks after surgery and after complete surgical wound healing 4. Maintenance therapy: Placebo 200mg bid will be administered during 2 years or until disease progression which ever occur first.

    Reporting group title
    Arm B: experimental arm (Vargatef® arm)
    Reporting group description
    		 1. Neo-adjuvant therapy (3 cycles): Vargatef® (Nintedanib) 200mg bid will be administered twice daily during the first 2 cycles except on day 1 of each cycle (day of chemotherapy). Vargatef® (Nintedanib) will not be administered during cycle before surgery (cycle 3). Patients with insufficient tumor response to allow interval debulking surgery after 3 cycles of neoadjuvant therapy will receive 4 cycles of neo-adjuvant therapy. In those patients, Vargatef® (Nintedanib) will be skipped during cycle preceding surgery (Cycle 4). 2. Interval Debulking Surgery: will be performed 3 to 4 weeks after the last chemotherapy administration. 3. Adjuvant therapy: will start 4 weeks after surgery and after complete surgical wound healing 4. Maintenance therapy: Vargatef® (Nintedanib) 200 mg bid will be administered during 2 years or until disease progression which ever occur first.

    Serious adverse events
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 64 (51.56%)
    70 / 124 (56.45%)
         number of deaths (all causes)
    1
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Left breast cancer
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Second malignacy
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep veinous thrombosis
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflamatory compressif lymphocele
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative compressive lymphocele
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right jugular vein thrombosis extending to right lateral sinus
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 9
    Right sural thrombo phlebitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper venous thrombosis
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Ureteral stent removal
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenectomy
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary compression
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma closure
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileostomy closure
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small bowel anastomosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Alteration of general health
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 124 (2.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deterioration of the general status
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease evolution
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 124 (2.42%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAC infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Erythroderma
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergic reaction to taxol
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 64 (4.69%)
    10 / 124 (8.06%)
         occurrences causally related to treatment / all
    6 / 9
    12 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    Pneumonitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax post pleural punture
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right pleural effusion
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Manic episode
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma GT increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic toxicity
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increase transaminitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver enzyme elevation
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    PAC infection
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 124 (2.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Intraperitoneal effusion
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipomatous hyperthrophy of the interatrial septum
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Bilateral peripheral motor and sensitive deficit of upper limb
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional syndroma
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain metastasis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right vulnar nerve surgery
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suspicion of limbic encephalitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Abdominal lymphocel
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anemia
         subjects affected / exposed
    1 / 64 (1.56%)
    4 / 124 (3.23%)
         occurrences causally related to treatment / all
    1 / 3
    9 / 14
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aplasia : Neutropenia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile aplasia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 64 (0.00%)
    4 / 124 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematologic toxicity
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    2 / 64 (3.13%)
    3 / 124 (2.42%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele chyleux
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 124 (2.42%)
         occurrences causally related to treatment / all
    0 / 0
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet decreased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 64 (3.13%)
    4 / 124 (3.23%)
         occurrences causally related to treatment / all
    3 / 6
    13 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 64 (3.13%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pancreatitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascitis
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel obstruction
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bridled ileus
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal fistula after surgery
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Digestive bleeding
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Digestive occlusion (clamp) after interavl debulking surgery
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disembowelment
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecal stasis in the transverse colon
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colocutaneous fistula
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematemesis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incomplete bowel obstruction
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal occlusion
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra peritoneal effusion
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left strangulated diapragmatic hernia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occlusive syndrome/ Occlusion
         subjects affected / exposed
    3 / 64 (4.69%)
    10 / 124 (8.06%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colonic perforation
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reccurent digestive occlusion (clamp) after interavl debulking surgery
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Recto vaginal fistula
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe disgestive toxicityal status
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sub-occlusion on eventration
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain syndrome
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumoral abdominal pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 124 (2.42%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting due to chemotherapy
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cyolysis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute intrinsic renal failure
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral dilation
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute renal failure
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ureteral fistula
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Disc herniation
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture of the right neck femur
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abcess on ileostomy cicatrix
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    Pyelonepritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right lung infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis of unknown origin
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock assoiated with pneumonitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe sepsis related to Staphylococcus aurea in febrile neutropenia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcus infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Denutrition
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deshydratation
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deshydratation due to ileostomy
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A: standard arm (placebo arm) Arm B: experimental arm (Vargatef® arm)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 64 (96.88%)
    124 / 124 (100.00%)
    Injury, poisoning and procedural complications
    Alopecia
         subjects affected / exposed
    44 / 64 (68.75%)
    72 / 124 (58.06%)
         occurrences all number
    44
    72
    Ungual toxicity
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 124 (1.61%)
         occurrences all number
    1
    2
    Vascular disorders
    Thrombo-embolism
         subjects affected / exposed
    3 / 64 (4.69%)
    10 / 124 (8.06%)
         occurrences all number
    3
    10
    Cardiac disorders
    Arterial hypertention
         subjects affected / exposed
    18 / 64 (28.13%)
    40 / 124 (32.26%)
         occurrences all number
    18
    40
    Nervous system disorders
    Motor neuropathy
         subjects affected / exposed
    7 / 64 (10.94%)
    14 / 124 (11.29%)
         occurrences all number
    7
    14
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    28 / 64 (43.75%)
    50 / 124 (40.32%)
         occurrences all number
    28
    50
    Neutropenia
         subjects affected / exposed
    29 / 64 (45.31%)
    68 / 124 (54.84%)
         occurrences all number
    29
    68
    Lymphopenia
         subjects affected / exposed
    20 / 64 (31.25%)
    28 / 124 (22.58%)
         occurrences all number
    20
    28
    Anaemia
         subjects affected / exposed
    40 / 64 (62.50%)
    94 / 124 (75.81%)
         occurrences all number
    40
    94
    Thrombopenia
         subjects affected / exposed
    16 / 64 (25.00%)
    65 / 124 (52.42%)
         occurrences all number
    16
    65
    Febrile neutropenia
         subjects affected / exposed
    1 / 64 (1.56%)
    6 / 124 (4.84%)
         occurrences all number
    1
    6
    Haemorrhage
         subjects affected / exposed
    3 / 64 (4.69%)
    13 / 124 (10.48%)
         occurrences all number
    3
    13
    Oedema
         subjects affected / exposed
    5 / 64 (7.81%)
    13 / 124 (10.48%)
         occurrences all number
    5
    13
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    45 / 64 (70.31%)
    91 / 124 (73.39%)
         occurrences all number
    45
    91
    Nausea
         subjects affected / exposed
    30 / 64 (46.88%)
    75 / 124 (60.48%)
         occurrences all number
    30
    75
    Fever
         subjects affected / exposed
    6 / 64 (9.38%)
    12 / 124 (9.68%)
         occurrences all number
    6
    12
    Paraesthesia - Dysesthesia
         subjects affected / exposed
    27 / 64 (42.19%)
    26 / 124 (20.97%)
         occurrences all number
    27
    26
    Fistula
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 124 (0.81%)
         occurrences all number
    1
    1
    Pain
         subjects affected / exposed
    38 / 64 (59.38%)
    70 / 124 (56.45%)
         occurrences all number
    38
    70
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    13 / 64 (20.31%)
    36 / 124 (29.03%)
         occurrences all number
    13
    36
    Constipation
         subjects affected / exposed
    24 / 64 (37.50%)
    21 / 124 (16.94%)
         occurrences all number
    24
    21
    Diarrhoea
         subjects affected / exposed
    15 / 64 (23.44%)
    78 / 124 (62.90%)
         occurrences all number
    15
    78
    Digestive perforation
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences all number
    0
    2
    Digestive Fistula
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 124 (0.81%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Hand-foot syndrome
         subjects affected / exposed
    3 / 64 (4.69%)
    3 / 124 (2.42%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 64 (17.19%)
    21 / 124 (16.94%)
         occurrences all number
    11
    21
    Myalgia
         subjects affected / exposed
    9 / 64 (14.06%)
    6 / 124 (4.84%)
         occurrences all number
    9
    6
    Infections and infestations
    Oral Mucositis
         subjects affected / exposed
    7 / 64 (10.94%)
    11 / 124 (8.87%)
         occurrences all number
    7
    11
    Mucositis
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 124 (1.61%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2012
    substantial modifications
    04 Sep 2012
    substantial modifications
    11 Dec 2012
    substantial modifications
    16 Apr 2013
    substantial modifications
    11 Jun 2013
    substantial modifications
    03 Oct 2013
    substantial modifications
    18 Jul 2014
    substantial modifications
    05 Nov 2014
    substantial modifications
    08 Dec 2014
    substantial modifications
    16 Jul 2015
    substantial modifications
    30 Sep 2015
    substantial modifications
    10 Nov 2015
    substantial modifications
    19 Jan 2016
    substantial modifications
    11 Jan 2017
    substantial modifications

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

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