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    Clinical Trial Results:
    Randomised Phase II Study comparing, as first-line chemotherapy, single-agent Oral Vinorelbine administered with two different schedules (metronomic and weekly schedules) in patients with Advanced Breast Cancer.

    Summary
    EudraCT number
    		 2014-003860-19
    Trial protocol
    		 PT   ES   AT   HU   RO   CZ   DE  
    Global end of trial date
    28 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Oct 2021
    First version publication date
    03 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PM0259CA233B0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pierre Fabre Médicament
    Sponsor organisation address
    45 place Abel Gance, Boulogne , France, 92100
    Public contact
    Christine TA THANH MINH, PIERRE FABRE MEDICAMENT, +33 (0)149108121, christine.ta.thanh.minh@pierre-fabre.com
    Scientific contact
    Christine TA THANH MINH, PIERRE FABRE MEDICAMENT, +33 (0)149108121, christine.ta.thanh.minh@pierre-fabre.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the Disease Control Rate (CR + PR + SD) in both arms (metronomic and weekly schedules) assessed during study treatments.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the current Declaration of Helsinki and was consistent with International Conference on Harmonisation Good Clinical practice (ICH GCP) and applicable regulatory requirements. The study was conducted in compliance with the protocol. The protocol, amendments, the subject information leaflet and the subject informed consent were approved by the appropriate independent Ethics Committee(s) in the involved countries prior to implementation.
    Background therapy
    		 Preventive medication with an oral 5-HT3 antagonist was recommended before each oral vinorelbine administration. The primary prophylactic use of Colony Stimulating Factor (CSF) was allowed during the treatment period. Granulocyte stimulating growth factors were permitted for patients experiencing febrile neutropenia, Grade 4 asymptomatic neutropenia or neutropenic infection, according to institutional rules. Pre-menopausal patients were allowed to receive LHRH analogues in order to block ovarian functions. Patients received full supportive care throughout the study, including treatment when required with antibiotics, anti-diarrhoeals, analgesics, antiemetics, and transfusion of blood products, according to local guidelines and the investigator’s opinion. Treatment with a bisphosphonate was allowed during the study period.
    Evidence for comparator
    		 This study evaluated two schedules of administration of oral vinorelbine: the metronomic and the weekly schedules.The currently registered and approved regimen of Oral Vinorelbine delivered in a weekly schedule was used as reference arm.
    Actual start date of recruitment
    03 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 9
    Worldwide total number of subjects
    163
    EEA total number of subjects
    163
    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)
    76
    From 65 to 84 years
    83
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 43 centres in 10 countries screened 218 hormone-receptor-positive (HRc) and HER2 negative patients with advanced breast cancer between the 22 of December 2015 and the 13 of December 2017. Of these 218 patients, 164 patients were randomised and 163 patients received at least one dose of study drug.

    Pre-assignment
    Screening details
    		 A 28-day screening period was planned before randomisation and screened HRc-positive and HER2 negative patients with advanced breast cancer. Once the screening period was successfully completed, patients who fulfilled the eligibility criteria were randomised in a 1:1 ratio in the 2 arms.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: metronomic schedule
    Arm description
    		 Patients received Oral Vinorelbine at metronomic schedules, i.e. three times weekly.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oral vinorelbine
    Investigational medicinal product code
    Other name
    Navelbine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received a fixed dose of 50 mg of Oral Vinorelbine (one capsule of 20mg plus one of 30mg) three times weekly (on Mondays, Wednesdays and Fridays or Tuesdays, Thursdays and Saturdays) continuously until disease progression, unacceptable toxicity, patient’s refusal or investigator’s decision. Each 3 weeks of treatment was considered as a separate cycle, therefore in Treatment Arm A, a cycle consisted of 9 fixed doses of 50 mg at days 1, 3, 5, 8, 10, 12, 15, 17 and 19.

    Arm title
    		 Arm B: weekly schedule
    Arm description
    		 Patients received Oral Vinorelbine at weekly schedules, i.e. once a week.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oral vinorelbine
    Investigational medicinal product code
    Other name
    Navelbine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received Oral Vinorelbine at the dose of 60 mg/m² on day 1, day 8 and day 15 of the first cycle. At the second and following cycles, the day 1, day 8 and day 15 were increased to 80 mg/m², according to haematological tolerance. The dosage was calculated according to BSA, using the Dubois and Dubois formula. Treatment was administered until disease progression, unacceptable toxicity, patient’s refusal or investigator’s decision. Each 3 weeks of treatment was considered a cycle, therefore in Treatment Arm B a cycle consisted of 3 doses at days 1, 8 and 15.

    Number of subjects in period 1
    		Arm A: metronomic schedule Arm B: weekly schedule
    Started
    82
    81
    Completed
    0
    2
    Not completed
    82
    79
         Physician decision
    2
    4
         Adverse event, non-fatal
    7
    10
         Other
    5
    3
         Progressive disease
    68
    57
         Withdrawal by subject
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: metronomic schedule
    Reporting group description
    		 Patients received Oral Vinorelbine at metronomic schedules, i.e. three times weekly.

    Reporting group title
    Arm B: weekly schedule
    Reporting group description
    		 Patients received Oral Vinorelbine at weekly schedules, i.e. once a week.

    Reporting group values
    		 Arm A: metronomic schedule Arm B: weekly schedule Total
    Number of subjects
    		 82 81 163
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 42 34 76
        From 65-84 years
    		 37 46 83
        85 years and over
    		 3 1 4
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (42 to 89) 66 (38 to 87) -
    Gender categorical
    Units: Subjects
        Female
    		 82 81 163
        Male
    		 0 0 0
    Karnofsky performance status (KPS)
    Units: Subjects
        70%
    		 5 4 9
        80%
    		 22 18 40
        90%
    		 22 27 49
        100%
    		 33 32 65
    Histological type at first diagnosis
    Units: Subjects
        Carcinoma
    		 24 27 51
        Ductal
    		 45 41 86
        Lobular
    		 10 12 22
        Inflammatory
    		 0 0 0
        Other
    		 3 0 3
        Unknown
    		 0 1 1
    Number of organs involved
    Units: Subjects
        01
    		 11 12 23
        02
    		 33 31 64
        >=3
    		 38 38 76
    Cancer stage at first diagnosis
    Units: Subjects
        IA
    		 7 9 16
        IB
    		 0 1 1
        IIA
    		 15 16 31
        IIB
    		 16 19 35
        IIIA
    		 15 10 25
        IIIB
    		 3 5 8
        IIIC
    		 6 7 13
        IV
    		 17 12 29
        Missing
    		 3 2 5
    Primary tumor site
    Units: Subjects
        Right breast
    		 44 41 85
        Left breast
    		 35 37 72
        Bilateral breast
    		 3 3 6
    Histological grade at first diagnosis
    Units: Subjects
        SBR I
    		 7 6 13
        SBR II
    		 31 33 64
        SBR III
    		 18 12 30
        Unknown
    		 26 30 56
    Body mass index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 27.3 ( 5.25 ) 27.3 ( 5.17 ) -
    Time between diagnosis and randomisation
    Units: months
        median (full range (min-max))
    		 67.65 (2.4 to 321.1) 78.00 (2.0 to 327.5) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: metronomic schedule
    Reporting group description
    		 Patients received Oral Vinorelbine at metronomic schedules, i.e. three times weekly.

    Reporting group title
    Arm B: weekly schedule
    Reporting group description
    		 Patients received Oral Vinorelbine at weekly schedules, i.e. once a week.

    Primary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR) [1]
    End point description
    DCR, defined as the sum of CR, PR and SD rates was observed in 52/82 patients (63.4% [95% CI: 52.0, 73.8]) in Arm A and 59/81 patients (72.8% [95% CI: 61.8, 82.1]) in Arm B.
    End point type
    Primary
    End point timeframe
    DCR according to investigator was calculated among the BOCR responders in the ITT analysis set on the treatment period (from the date of randomisation until the documentation of progression or death due to any cause.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study was designed to evaluate the disease control rate in each arm of oral vinorelbine but not to compare the two schedules (metronomic / weekly). No statistical analysis was performed on the primary efficacy endpoint
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: percentage
        number (confidence interval 95%)
    63.4 (52.0 to 73.8)
    72.8 (61.8 to 82.1)
    No statistical analyses for this end point

    Secondary: Duration of disease control

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    End point title
    		 Duration of disease control
    End point description
    Overall, for patients who achieved PR or SD (no CR was observed in any arm), 43 (82.7%) patients in Arm A and 44 (74.6%) patients in Arm B experienced disease progression or death. The median time to disease progression or death was 6.9 months (95% CI: 4.2, 8.6) in Arm A and 7.9 months (95% CI: 5.7, 10.0) in Arm B. The distribution of DCR was described by treatment arm using Kaplan-Meier methods, reporting estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points.
    End point type
    Secondary
    End point timeframe
    Duration of disease control was defined as the period from the date of randomisation until date of PD or death from any cause, whichever occurred first. Only responders (patients with BOCR of CR or PR) and stable patients were included in the analysis.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    52
    59
    Units: months
        median (confidence interval 95%)
    6.9 (4.2 to 8.6)
    7.9 (5.7 to 10.0)
    Attachments
    		 Duration of disease control (months)
    No statistical analyses for this end point

    Secondary: DCR without grade 3-4 toxicity

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    End point title
    		 DCR without grade 3-4 toxicity
    End point description
    DCR without grade 3-4 toxicity, defined as the sum of CR, PR and SD without grade 3-4 toxicity rates, was observed in 24/82 patients (29.3% [95% CI: 19.7, 40.4]) in Arm A and 18/81 patients (22.2% [95% CI: 13.7, 32.8]) in Arm B.
    End point type
    Secondary
    End point timeframe
    DCR without grade 3-4 toxicity was calculated among the BOCR responders and stable patients without grade 3-4 toxicity in the ITT population from the date of randomisation until the documentation of progression or death or first grade 3 or 4 AE.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: percent
        number (confidence interval 95%)
    29.3 (19.7 to 40.4)
    22.2 (13.7 to 32.8)
    No statistical analyses for this end point

    Secondary: DCR without grade 3-4 neutropenia

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    End point title
    		 DCR without grade 3-4 neutropenia
    End point description
    DCR without grade 3-4 neutropenia, defined as the sum of CR, PR and SD without grade 3-4 neutropenia rates, was observed in 35/82 patients (42.7% [95% CI: 31.8, 54.1]) in Arm A and 25/81 patients (30.9% [95% CI: 21.1, 42.1]) in Arm B.
    End point type
    Secondary
    End point timeframe
    DCR without grade 3-4 neutropenia was calculated among the BOCR responders and stable patients without grade 3-4 neutropenia in the ITT population from the date of randomisation until the documentation of progression, first grade 3-4 neutropenia or death.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: percent
        number (confidence interval 95%)
    42.7 (31.8 to 54.1)
    30.9 (21.1 to 42.1)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR, defined as the sum of CR and PR rates, was observed in 14/82 patients (17.1% [95% CI: 9.7, 27.0]) in Arm A and 17/81 patients (21.0% [95% CI: 12.7, 31.5]) in Arm B.
    End point type
    Secondary
    End point timeframe
    ORR according to investigator was calculated among the BOCR responders (CR and PR) in the ITT population from the date of randomisation until the documentation of progression or death.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: percent
        number (confidence interval 95%)
    17.1 (9.7 to 27.0)
    21.0 (12.7 to 31.5)
    No statistical analyses for this end point

    Secondary: ORR without grade 3-4 toxicity

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    End point title
    		 ORR without grade 3-4 toxicity
    End point description
    ORR without grade 3-4 toxicity, defined as the sum of CR and PR without grade 3-4 toxicity rates, was observed in 8/82 patients (9.8% [95% CI: 4.3, 18.3]) in Arm A and 6/81 patients (7.4% [95% CI: 2.8, 15.4]) in Arm B.
    End point type
    Secondary
    End point timeframe
    ORR without grade 3-4 toxicity was calculated among the BOCR responders (CR and PR) who had not experienced grade 3-4 toxicity in the ITT population from the date of randomisation until the documentation of progression, first grade 3 or 4 AE or death.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: percent
        number (confidence interval 95%)
    9.8 (4.3 to 18.3)
    7.4 (2.8 to 15.4)
    No statistical analyses for this end point

    Secondary: ORR without grade 3-4 neutropenia

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    End point title
    		 ORR without grade 3-4 neutropenia
    End point description
    ORR without grade 3-4 neutropenia, defined as the sum of CR and PR without grade 3-4 neutropenia rates, was observed in 10/82 patients (12.2% [95% CI: 6.0, 21.3]) in Arm A and 6/81 patients (7.4% [95% CI: 2.8, 15.4]) in Arm B.
    End point type
    Secondary
    End point timeframe
    ORR without grade 3-4 neutropenia was calculated among the BOCR responders (CR and PR) who hadn't experienced grade 3-4 neutropenia in the ITT population from the date of randomisation until the documentation of PD, first grade 3-4 neutropenia or death
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: percent
        number (confidence interval 95%)
    12.2 (6.0 to 21.3)
    7.4 (2.8 to 15.4)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR)

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    End point title
    		 Duration of response (DOR)
    End point description
    Overall, for patients who achieved PR (no CR was observed in any arm), 12 (85.7%) patients in Arm A and 10 (58.8%) patients in Arm B experienced disease progression or death. The median DOR was 8.5 months (95% CI: 4.2, 11.4) in Arm A and 9.3 months (95% CI: 6.8, 19.2) in Arm B. The distribution of duration of response was described by treatment arm using Kaplan-Meier methods, reporting estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points.
    End point type
    Secondary
    End point timeframe
    Duration of response was calculated among the BOCR responders (CR and PR) in the ITT population from the date of randomisation until the documentation of progression or death from any cause, whichever occurred first.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    14
    17
    Units: months
        median (confidence interval 95%)
    8.5 (4.2 to 11.4)
    9.3 (6.8 to 19.2)
    Attachments
    		 Duration of response (months) (ITT analysis set)
    No statistical analyses for this end point

    Secondary: Time to first response

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    End point title
    		 Time to first response
    End point description
    Overall, 14 patients in Arm A and 17 patients in Arm B achieved a PR (no CR). The median Time to first response was 2.8 months (95% CI: 1.3, 3.9) in Arm A and 2.8 months (95% CI: 1.4, 4.2) in Arm B. The distribution of Time to first response was described by treatment arm using Kaplan-Meier methods, reporting estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points.
    End point type
    Secondary
    End point timeframe
    Time to first response, defined as the time from the date of randomisation to the date of first CR or PR after randomisation, whichever occurred first was measured until the documentation of progression or death from any cause, whichever occurred first.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    14
    17
    Units: month
        median (confidence interval 95%)
    2.8 (1.3 to 3.9)
    2.8 (1.4 to 4.2)
    Attachments
    		 Time to first response (months) (ITT analysis set)
    No statistical analyses for this end point

    Secondary: Duration of stable disease

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    End point title
    		 Duration of stable disease
    End point description
    A total of 38 patients in Arm A and 42 patients in Arm B achieved SD. Of these, 31 (81.6%) patients in Arm A and 34 (81.0%) patients in Arm B experienced disease progression or death. The median duration of SD was 4.2 months (95% CI: 4.0, 6.7) in Arm A and 5.7 months (95% CI: 5.0, 7.8) in Arm B. The distribution of duration of stable disease was described by treatment arm using Kaplan-Meier methods, reporting estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points.
    End point type
    Secondary
    End point timeframe
    Duration of Stable Disease was measured from the date of randomisation until the date of PD or death from any cause, whichever occurred first.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    38
    42
    Units: month
        median (confidence interval 95%)
    4.2 (4.0 to 6.7)
    5.7 (5.0 to 7.8)
    Attachments
    		 Duration of stable disease (months) (ITT analysis
    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
    Overall, disease progression or death was reported in 80/82 (97.6%) patients in Arm A and 73/81 (90.1%) patients in Arm B. The median PFS was 4.0 months (95% CI: 2.8, 5.4) in Arm A and 5.6 months (95% CI: 4.4, 7.8) in Arm B. The distribution of progression-free survival was described by treatment arm using Kaplan-Meier methods, reporting estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points.
    End point type
    Secondary
    End point timeframe
    The progression-free survival (PFS) was measured from randomisation until the first radiographically documented progression of disease or death from any cause, whichever occurred first.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: month
        median (confidence interval 95%)
    4.0 (2.8 to 5.4)
    5.6 (4.4 to 7.8)
    Attachments
    		 PFS (months) (ITT analysis set)
    No statistical analyses for this end point

    Secondary: Progression-free survival without grade 3-4 toxicity

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    End point title
    		 Progression-free survival without grade 3-4 toxicity
    End point description
    Overall, grade 3-4 toxicity, disease progression or death was reported in 77 (93.9%) patients in Arm A and 74 (91.4%) patients in Arm B. The median PFS without grade 3-4 toxicity was 1.7 months (95% CI: 1.4, 2.8) in Arm A and 1.4 months (95% CI: 1.3, 2.1) in Arm B. The distribution of Progression-free survival without grade 3-4 toxicity was described by treatment arm using Kaplan-Meier methods, reporting estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points.
    End point type
    Secondary
    End point timeframe
    PFS without grade 3-4 toxicity was measured from randomisation until the first radiographically documented progression of disease, first AE with grade 3 or 4 toxicity or death from any cause, whichever occurred first.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: month
        median (confidence interval 95%)
    1.7 (1.4 to 2.8)
    1.4 (1.3 to 2.1)
    Attachments
    		 PFS without grade 3-4 toxicity (months)
    No statistical analyses for this end point

    Secondary: Progression-free survival without grade 3-4 neutropenia

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    End point title
    		 Progression-free survival without grade 3-4 neutropenia
    End point description
    Overall, grade 3-4 neutropenia, disease progression or death was reported in 76 (92.7%) patients in Arm A and 70 (86.4%) patients in Arm B. The median PFS without grade 3-4 neutropenia was 2.7 months (95% CI: 1.4, 3.9) in Arm A and 2.1 months (95% CI: 1.4, 2.6) in Arm B. The distribution of Progression-free survival without grade 3-4 neutropenia was described by treatment arm using Kaplan-Meier methods, reporting estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points.
    End point type
    Secondary
    End point timeframe
    PFS without grade 3-4 neutropenia was measured from randomisation until the first radiographically documented progression of disease, first grade 3 or 4 neutropenia or death from any cause, whichever occurred first.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: month
        median (confidence interval 95%)
    2.7 (1.4 to 3.9)
    2.1 (1.4 to 2.6)
    Attachments
    		 Progression-free survival without grade 3-4 neutro
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Death was reported in 50 (61.0%) patients in Arm A and 42 (51.9%) patients in Arm B. Median OS were 22.3 months (95% CI: 19.0, 27.3) in Arm A and 26.7 months (95% CI: 22.2, 37.8) in Arm B. The distribution of Overall Survival was described by treatment arm using Kaplan-Meier methods, reporting estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points.
    End point type
    Secondary
    End point timeframe
    Overall survival was measured from the date of randomisation until the date of death, regardless of the cause of death.
    End point values
    		 Arm A: metronomic schedule Arm B: weekly schedule
    Number of subjects analysed
    82
    81
    Units: month
        median (confidence interval 95%)
    22.3 (19.0 to 27.3)
    26.7 (22.2 to 37.8)
    Attachments
    		 Overall survival (months) (ITT analysis set)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any AE that first occurred during the treatment period (i.e. from first study treatment administration date up to last administration date + 30 days) was recorded in the CRF and included in the analysis of AEs (on-study AE).
    Adverse event reporting additional description
    At the cut-off date (07-NOV-2019), 2 patients were still on treatment. Death was reported for 88 patients, while 60 patients were still being followed for survival. Four patients were lost to follow-up. All patients in the safety analysis set received at least one cycle with a median number of cycle of 4.0 (1-41) in Arm A and 7.0 (1-45) in Arm B.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Arm A: metronomic schedule (Safety analysis set)
    Reporting group description
    		 All patients who received at least one dose of study drug and with at least one post-baseline safety data were included in the safety analysis set. A total of 82 patients were included in the safety analysis set.

    Reporting group title
    Arm B: weekly schedule (Safety analysis set)
    Reporting group description
    		 All patients who received at least one dose of study drug and with at least one post-baseline safety data were included in the safety analysis set. A total of 80 patients were included in the safety analysis set.

    Serious adverse events
    		 Arm A: metronomic schedule (Safety analysis set) Arm B: weekly schedule (Safety analysis set)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 82 (26.83%)
    13 / 80 (16.25%)
         number of deaths (all causes)
    50
    42
         number of deaths resulting from adverse events
    2
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (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
    Asthenia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthmatic crisis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Neuroglycopenia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Mastitis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 82 (3.66%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: metronomic schedule (Safety analysis set) Arm B: weekly schedule (Safety analysis set)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 82 (96.34%)
    78 / 80 (97.50%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    1
    5
    Weight decreased
         subjects affected / exposed
    28 / 82 (34.15%)
    35 / 80 (43.75%)
         occurrences all number
    37
    57
    Weight increased
         subjects affected / exposed
    3 / 82 (3.66%)
    5 / 80 (6.25%)
         occurrences all number
    3
    5
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 82 (6.10%)
    4 / 80 (5.00%)
         occurrences all number
    6
    4
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 82 (1.22%)
    5 / 80 (6.25%)
         occurrences all number
    1
    6
    Headache
         subjects affected / exposed
    3 / 82 (3.66%)
    9 / 80 (11.25%)
         occurrences all number
    3
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 82 (6.10%)
    4 / 80 (5.00%)
         occurrences all number
    5
    14
    Neutropenia
         subjects affected / exposed
    28 / 82 (34.15%)
    57 / 80 (71.25%)
         occurrences all number
    64
    175
    Thrombocytopenia
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    2
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 82 (19.51%)
    26 / 80 (32.50%)
         occurrences all number
    38
    57
    Fatigue
         subjects affected / exposed
    13 / 82 (15.85%)
    11 / 80 (13.75%)
         occurrences all number
    17
    15
    Mucosal inflammation
         subjects affected / exposed
    2 / 82 (2.44%)
    6 / 80 (7.50%)
         occurrences all number
    2
    8
    Pyrexia
         subjects affected / exposed
    6 / 82 (7.32%)
    9 / 80 (11.25%)
         occurrences all number
    7
    11
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 82 (9.76%)
    8 / 80 (10.00%)
         occurrences all number
    10
    14
    Abdominal pain upper
         subjects affected / exposed
    7 / 82 (8.54%)
    9 / 80 (11.25%)
         occurrences all number
    9
    11
    Constipation
         subjects affected / exposed
    14 / 82 (17.07%)
    14 / 80 (17.50%)
         occurrences all number
    16
    17
    Diarrhoea
         subjects affected / exposed
    23 / 82 (28.05%)
    30 / 80 (37.50%)
         occurrences all number
    30
    91
    Dyspepsia
         subjects affected / exposed
    5 / 82 (6.10%)
    3 / 80 (3.75%)
         occurrences all number
    7
    3
    Nausea
         subjects affected / exposed
    27 / 82 (32.93%)
    44 / 80 (55.00%)
         occurrences all number
    55
    99
    Vomiting
         subjects affected / exposed
    8 / 82 (9.76%)
    31 / 80 (38.75%)
         occurrences all number
    14
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    3
    5
    Dyspnoea
         subjects affected / exposed
    8 / 82 (9.76%)
    4 / 80 (5.00%)
         occurrences all number
    17
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 82 (3.66%)
    9 / 80 (11.25%)
         occurrences all number
    4
    14
    Rash
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 82 (6.10%)
    6 / 80 (7.50%)
         occurrences all number
    5
    6
    Back pain
         subjects affected / exposed
    8 / 82 (9.76%)
    5 / 80 (6.25%)
         occurrences all number
    11
    6
    Bone pain
         subjects affected / exposed
    7 / 82 (8.54%)
    7 / 80 (8.75%)
         occurrences all number
    10
    8
    Pain in extremity
         subjects affected / exposed
    2 / 82 (2.44%)
    5 / 80 (6.25%)
         occurrences all number
    2
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 82 (3.66%)
    5 / 80 (6.25%)
         occurrences all number
    3
    6
    Respiratory tract infection
         subjects affected / exposed
    6 / 82 (7.32%)
    1 / 80 (1.25%)
         occurrences all number
    7
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 82 (1.22%)
    6 / 80 (7.50%)
         occurrences all number
    1
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 82 (10.98%)
    16 / 80 (20.00%)
         occurrences all number
    12
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2019
    Considering all data collected during the time period of the study, the sponsor decided to anticipate the end of study and to proceed with the final statistical analysis earlier. This decision was based on the following considerations observed on September 10th, 2019: • After 45 months of study duration, among the 165 randomised patients (164 treated), 152 events (progression or death) were observed. For 12 randomised patients, neither disease progression nor death were recorded (1 patient never received the study drug, 3 patients did not yet progress, 4 drop out patients and 4 patients with only non-radiological progression), and 1 patient was removed from clinical database (no local data privacy form available). • The maturity of PFS data could thus be considered as being reached. • 85 deaths were observed, and it was estimated that maturity of OS data (i.e. at least 80% of events) would not be reached by the end-of-study (with the current definition in the protocol). The study was not designed to get mature OS data, however the median OS was reached.

    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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