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    Clinical Trial Results:
    Phase II study evaluating oral vinorelbine as a single agent in patients with hormone receptor breast cancer with bone metastases previously treated by a hormone therapy

    Summary
    EudraCT number
    2009-014497-18
    Trial protocol
    FR   AT   IT   ES  
    Global end of trial date
    17 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Jan 2019
    First version publication date
    31 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PM0259 CA 228 BO
    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
    Gustavo VILLANOVA M.D Oncology Medical Affairs Department, Pierre Fabre Médicament, +33 (0)149108265, gustavo.villanova@pierre-fabre.com
    Scientific contact
    Gustavo VILLANOVA M.D Oncology Medical Affairs Department, Pierre Fabre Médicament, +33 (0)149108265, gustavo.villanova@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
    16 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 May 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the Progression-Free Survival (PFS) of oral vinorelbine as a single agent in patients with hormone receptor positive breast cancer with bone metastases previously treated by a hormone therapy.
    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 Harmonization Good Clinical Practice (ICH GCP) and applicable regulatory requirements. The study was conducted in compliance with the protocol. The protocol, amendments, and the subject informed consent received Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval/favourable opinion prior to initiation of the study and/or their implementation.
    Background therapy
    Prophylactic oral anti-emetic medication with a 5-HT3 antagonist was recommended before each oral vinorelbine administration. Oral antiemetic treatments were provided to the patients at home. The use of corticosteroids as anti-emetic treatment was allowed. Patients had to receive full supportive care including antibiotics, antidiarrhoeals, analgesics, transfusion of blood products, when appropriate. The use of drugs with laxative properties had to be avoided. Prophylactic use of Colony Stimulating Factor (CSF) was allowed during the study treatment. Granulocyte stimulating growth factors could be given to patients who experienced febrile neutropenia, grade 4 asymptomatic neutropenia or neutropenic infection according to institutional rules. Patients had to be under treatment by a bisphosphonate since at least one month before entering the study.
    Evidence for comparator
    No control arm was planned as the study aimed at evaluating the clinical benefit of oral vinorelbine in patients suffering from bone metastases from breast cancer after failure to hormone therapy.
    Actual start date of recruitment
    14 Apr 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety, Scientific research
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Russian Federation: 7
    Worldwide total number of subjects
    70
    EEA total number of subjects
    50
    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)
    46
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 70 patients with hormone receptor positive breast cancer with bone metastases previously treated by a hormone therapy were enrolled and received at least one dose of study treatment.

    Pre-assignment
    Screening details
    No further information

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    The study was an open label non-randomized trial.

    Arms
    Arm title
    Vinorelbine arm
    Arm description
    Patients were included after written informed consent was obtained and all screening assessments have been performed.
    Arm type
    Experimental

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Navelbine
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received Oral vinorelbine single agent at the dose of 60 mg/m² weekly at the first cycle (1 cycle = 4 weeks of treatment) then at the increased dose of 80 mg/m² at cycle 2 and subsequent cycles in the absence of a grade 3 or grade 4 neutropenia. Oral vinorelbine was given on days 1, 8, 15 and 22 of a cycle. Patients had to receive at least 3 cycles of treatment unless documented disease progression, unacceptable toxicity or patient refusal. Vinorelbine was supplied as soft capsules that had to be rapidly swallowed with a glass of water without chewing or sucking them. It was recommended to take the capsules with some food. The treatment was administered on an outpatient setting. However, the patient had to return to the hospital at Day 1 of each cycle to receive study drugs at the hospital under the supervision of the investigator. The study medication had to be stored refrigerated (2°C to 8°C) and protected from light in the original closed container.

    Number of subjects in period 1
    Vinorelbine arm
    Started
    70
    Completed
    0
    Not completed
    70
         Investigator decision
    4
         Non-drug related toxicity
    2
         Patient's decision to stop
    9
         Drug related toxicity
    5
         Maximum benefit
    3
         Documented Progressive disease (radiological)
    45
         clinical progression
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    -

    Reporting group values
    Treatment period Total
    Number of subjects
    70 70
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    46 46
        From 65-84 years
    24 24
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    60.6 (37.6 to 77.7) -
    Gender categorical
    Units: Subjects
        Female
    70 70
        Male
    0 0
    Primary tymor site
    Units: Subjects
        Right breast
    35 35
        Left breast
    34 34
        Bilateral
    1 1
    Hormone receptors status at study entry
    Units: Subjects
        Oetrogen positive/ Progesterone positive
    53 53
        Oestrogen positive/Progesterone negative
    12 12
        Oestrogen negative/Progesterone positive
    4 4
        unknown
    1 1
    Karnosky performance status at baseline
    Units: Subjects
        70%
    4 4
        80%
    14 14
        90%
    28 28
        100%
    24 24
    Metastatic sites at initial diagnosis
    Units: Subjects
        Bone
    58 58
        Bone + Lymph node
    10 10
        Bone + Soft tissue
    2 2
    Prior (neo)adjuvant chemotherapy
    Prior chemotherapy was given to 44 patients (62.9%), mainly in the adjuvant setting for 42 patients (60%) and consisted mainly of anthracycline containing regimen in 58.6% of the patients.
    Units: Subjects
        Yes
    44 44
        No
    26 26
    Prior endocrine therapy
    Units: Subjects
        Adjuvant
    32 32
        Adjuvant + advanced disease
    23 23
        Advanced disease
    14 14
        Neoadjuvant + adjuvant
    1 1
    ECOG PS
    Units: percent
        median (full range (min-max))
    90 (70 to 100) -
    Weight
    Units: kg
        median (full range (min-max))
    73 (45 to 108) -
    Body surface area
    Units: m²
        median (full range (min-max))
    1.8 (1.4 to 2.2) -

    End points

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    End points reporting groups
    Reporting group title
    Vinorelbine arm
    Reporting group description
    Patients were included after written informed consent was obtained and all screening assessments have been performed.

    Primary: Progression-free survival

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    End point title
    Progression-free survival [1]
    End point description
    PFS was estimated on the ITT population (all treated patients) using Kaplan Meier curves and Confidence intervals on the median PFS were calculated using the reflected method. Patients lost to follow-up, or without a known record of progression or death at the time of analysis had the progression-free survival censored at the date of last tumour assessment or last contact of a follow-up showing no progression, whichever occurred last.
    End point type
    Primary
    End point timeframe
    PFS was calculated from the registration date until the date of progression or death due to any cause if no progression was recorded first. Median duration of follow-up at final analysis was 43.3 months.
    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: No statistical analysis can be added because the study is a single-arm study.
    End point values
    Vinorelbine arm
    Number of subjects analysed
    70
    Units: months
        median (confidence interval 95%)
    8.2 (5.5 to 9.8)
    Attachments
    Kaplan Meier estimates of PFS
    No statistical analyses for this end point

    Secondary: Clinical benefit rate

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    End point title
    Clinical benefit rate
    End point description
    The clinical benefit rate is defined as the percentage of confirmed CR, confirmed PR and stabilization for at least 24 weeks observed in the ITT population.
    End point type
    Secondary
    End point timeframe
    The clinical benefit rate was evaluated unitl the date of progression or death due to any cause if no progression was recorded first.
    End point values
    Vinorelbine arm
    Number of subjects analysed
    70
    Units: pourcentage
        number (confidence interval 95%)
    55.7 (43.3 to 67.6)
    No statistical analyses for this end point

    Secondary: Overall response rate

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    End point title
    Overall response rate
    End point description
    Overall Response Rate (ORR) was defined as the sum of CR and PR rate (using the best confirmed response recorded from the date of randomisation to the end of treatment) in the ITT population, according to investigator assessment.
    End point type
    Secondary
    End point timeframe
    Overall Response Rate (ORR) was evaluated from the randomisation to the end of treatment
    End point values
    Vinorelbine arm
    Number of subjects analysed
    70
    Units: patients
        Non evaluable
    3
        PR confirmed
    2
        CR not confirmed (SD)
    1
        SD > or = 24 weeks
    36
        SD < 24 weeks
    15
        PD
    13
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    Analyses of Overall Survival were performed with the Kaplan-Meier method. Overall survival of patients lost to follow-up or without a known record of death was censored at the date of last news. At DCO, 38 patients (54%) have died (35 from progression, 3 from other reason and 3 have been lost to follow-up). The remaining 29 patients were still alive.
    End point type
    Secondary
    End point timeframe
    Overall Survival was evaluated from the date of registration to the date of death due to any cause in the ITT population. Median duration of follow-up at final analysis was 43.3 months.
    End point values
    Vinorelbine arm
    Number of subjects analysed
    70
    Units: months
        median (confidence interval 95%)
    35.2 (26.8 to 47.1)
    Attachments
    Kaplan-Meier Survival Time
    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
    The disease control rate (sum of confirmed CR, confirmed PR and stabilisation rate) were evaluated for the ITT population.
    End point type
    Secondary
    End point timeframe
    The duration of disease control (CR, PR and stabilization of at least 24 weeks) was measured from the date of registration until the criteria for disease progression is met or the date of death or start of new anticancer therapy.
    End point values
    Vinorelbine arm
    Number of subjects analysed
    70
    Units: months
        median (confidence interval 95%)
    8.9 (7.3 to 11.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Each patient was assessed for occurrence of AEs throughout the study period (starting after the 1st dose of study medication and up to and including 30 days after the last dose). At DCO, all patients have discontinued (med duration: 5.8 (0.9-18.4)months).
    Adverse event reporting additional description
    Any AE occurring during the study period, spontaneously reported by the patient or observed by others, was recorded in the CRF. The relative dose intensity was 83.0% [22.9-108.2]. More than 1/3 of the patients received more than 90% of the planned dose. The median number of cycles was 6 (1-18).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    -

    Serious adverse events
    Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 70 (17.14%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Pneumonia
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Monoparesis
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Upper limb fracture
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    pulmonary infection
         subjects affected / exposed
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 70 (97.14%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 70 (7.14%)
         occurrences all number
    11
    Investigations
    Weight decreased
         subjects affected / exposed
    17 / 70 (24.29%)
         occurrences all number
    70
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 70 (8.57%)
         occurrences all number
    9
    Dyspnoea
         subjects affected / exposed
    4 / 70 (5.71%)
         occurrences all number
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    58 / 70 (82.86%)
         occurrences all number
    304
    Neutropenia
         subjects affected / exposed
    57 / 70 (81.43%)
         occurrences all number
    243
    Thrombocytopenia
         subjects affected / exposed
    12 / 70 (17.14%)
         occurrences all number
    24
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 70 (7.14%)
         occurrences all number
    6
    Headache
         subjects affected / exposed
    14 / 70 (20.00%)
         occurrences all number
    28
    Paraesthesia
         subjects affected / exposed
    6 / 70 (8.57%)
         occurrences all number
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    8 / 70 (11.43%)
         occurrences all number
    10
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    4 / 70 (5.71%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    40 / 70 (57.14%)
         occurrences all number
    116
    Pyrexia
         subjects affected / exposed
    15 / 70 (21.43%)
         occurrences all number
    17
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    16 / 70 (22.86%)
         occurrences all number
    26
    Abdominal pain upper
         subjects affected / exposed
    10 / 70 (14.29%)
         occurrences all number
    13
    Constipation
         subjects affected / exposed
    28 / 70 (40.00%)
         occurrences all number
    51
    Diarrhoea
         subjects affected / exposed
    38 / 70 (54.29%)
         occurrences all number
    99
    Nausea
         subjects affected / exposed
    49 / 70 (70.00%)
         occurrences all number
    163
    Vomiting
         subjects affected / exposed
    32 / 70 (45.71%)
         occurrences all number
    66
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    12 / 70 (17.14%)
         occurrences all number
    43
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    52 / 70 (74.29%)
         occurrences all number
    221
    Myalgia
         subjects affected / exposed
    5 / 70 (7.14%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 70 (15.71%)
         occurrences all number
    17
    Infections and infestations
    Cystitis
         subjects affected / exposed
    5 / 70 (7.14%)
         occurrences all number
    6
    Urinary tract infection
         subjects affected / exposed
    6 / 70 (8.57%)
         occurrences all number
    12
    Bronchitis
         subjects affected / exposed
    5 / 70 (7.14%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2010
    - Allow intake of oral vinorelbine at home at Day 8, Day 15, and Day 22 of every cycle. - Update to the name of the Clinical Pharmacy Responsible Person for the study. - Prolongation of the patient enrolment period until Q2 2011.
    01 Apr 2010
    - Allow intake of oral vinorelbine at home at Day 8, Day 15, and Day 22 of every cycle. Information added to the master ICF - Modalities of dispensation of the study treatment at Day 1 of each cycle - Modalities of storage of study treatment at the patient’s home. - Procedure for administration of Navelbine Oral (blood tests, agreement of the investigator before each intake at home) - Completion of a patient diary - Modalities of return of remaining capsules or empty blisters. - Improve the information given regarding the examinations to be followed by the patient and the person in charge of the study treatment at each study site.
    10 May 2010
    Update of the Investigator’s list
    22 Feb 2011
    - Allow inclusion of patients with unknown HER2 status. - Prolongation of the patient enrolment period until 31-Mar-2012. - Update the name of the Clinical Trial Coordinator and the address of the Clinical Pharmacy.
    17 Oct 2011
    Update of the Investigator’s list
    25 Sep 2013
    Update of the Investigator’s list

    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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