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    Clinical Trial Results:
    An open, 3-cohort, phase II trial testing oral administration of lucitanib in patients with FGFR1-amplified or non-amplified estrogen receptor positive metastatic breast cancer.

    Summary
    EudraCT number
    2013-000288-10
    Trial protocol
    BE   GB   IT   DE   ES   HU   FR  
    Global end of trial date
    05 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Apr 2018
    First version publication date
    13 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-80881-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02053636
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    BIG: BIG 2-13
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.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
    05 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the objective response rate (ORR) of single agent lucitanib in metastatic breast cancer patients with FGFR1-amplified, FGFR1-non-amplified with 11q amplification, or FGFR1-non-amplified without 11q amplification.
    Protection of trial subjects
    The study was performed in accordance with the ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Dec 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
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Canada: 4
    Worldwide total number of subjects
    76
    EEA total number of subjects
    60
    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)
    60
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Patients with metastatic breast cancer ER+/HER2-, in disease progression, who received at least first line anticancer therapy in the metastatic setting and no more than 2 lines of chemotherapy with or without targeted therapy. There was no limit of lines of endocrine therapy and targeted therapy.

    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
    No blinding implementation details. Allocation details: Patients were allocated based on their FGFR1 and 11q amplification status into one of the three Cohorts.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    Patients with FGFR1 amplified, irrespective of 11q amplification status.
    Arm type
    Experimental

    Investigational medicinal product name
    S 80881
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lucitanib was administered orally, once daily, on a continuous administration schedule in fasting conditions (at least 2 hours prior to and 2 hours after a meal), until unacceptable toxicity according to the investigator, disease progression or withdrawal of consent. The starting dose of lucitanib had been reduced from 15 mg to 10 mg per protocol Amendment No. 5. Patients enrolled prior to the protocol Amendment No. 5 who had already started on the 15 mg daily dose were permitted to continue receiving lucitanib at their current dose if the investigator deemed appropriate. Otherwise, the dose of lucitanib was to be reduced to 10 mg daily when starting the following cycle. Patients enrolled from protocol amendment No. 5 were not allowed to receive doses >10 mg daily.

    Arm title
    Cohort 2
    Arm description
    Patients with FGFR1-non-amplified and 11q amplification.
    Arm type
    Experimental

    Investigational medicinal product name
    S 80881
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lucitanib was administered orally, once daily, on a continuous administration schedule in fasting conditions (at least 2 hours prior to and 2 hours after a meal), until unacceptable toxicity according to the investigator, disease progression or withdrawal of consent. The starting dose of lucitanib had been reduced from 15 mg to 10 mg per protocol Amendment No. 5. Patients enrolled prior to the protocol Amendment No. 5 who had already started on the 15 mg daily dose were permitted to continue receiving lucitanib at their current dose if the investigator deemed appropriate. Otherwise, the dose of lucitanib was to be reduced to 10 mg daily when starting the following cycle. Patients enrolled from protocol amendment No. 5 were not allowed to receive doses >10 mg daily.

    Arm title
    Cohort 3
    Arm description
    Patients with FGFR1 and 11q non-amplified.
    Arm type
    Experimental

    Investigational medicinal product name
    S 80881
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lucitanib was administered orally, once daily, on a continuous administration schedule in fasting conditions (at least 2 hours prior to and 2 hours after a meal), until unacceptable toxicity according to the investigator, disease progression or withdrawal of consent. The starting dose of lucitanib had been reduced from 15 mg to 10 mg per protocol Amendment No. 5. Patients enrolled prior to the protocol Amendment No. 5 who had already started on the 15 mg daily dose were permitted to continue receiving lucitanib at their current dose if the investigator deemed appropriate. Otherwise, the dose of lucitanib was to be reduced to 10 mg daily when starting the following cycle. Patients enrolled from protocol amendment No. 5 were not allowed to receive doses >10 mg daily.

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3
    Started
    32
    18
    26
    Completed
    32
    18
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Patients with FGFR1 amplified, irrespective of 11q amplification status.

    Reporting group title
    Cohort 2
    Reporting group description
    Patients with FGFR1-non-amplified and 11q amplification.

    Reporting group title
    Cohort 3
    Reporting group description
    Patients with FGFR1 and 11q non-amplified.

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Total
    Number of subjects
    32 18 26 76
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    28 14 18 60
        From 65-84 years
    4 4 8 16
        85 years and over
    0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    32 18 26 76
        Male
    0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Patients with FGFR1 amplified, irrespective of 11q amplification status.

    Reporting group title
    Cohort 2
    Reporting group description
    Patients with FGFR1-non-amplified and 11q amplification.

    Reporting group title
    Cohort 3
    Reporting group description
    Patients with FGFR1 and 11q non-amplified.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Defined as all included patients who had taken at least one dose of study treatment.

    Primary: Objective Response Rate

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    End point title
    Objective Response Rate [1]
    End point description
    Objective Response Rate was defined as the proportion of patients for whom a confirmed complete response, or confirmed partial response as best overall response was observed during treatment, according to RECIST version 1.1 criteria, evaluated by the investigator. A partial or complete response as best response warranted confirmation at least 4 weeks after first documentation.
    End point type
    Primary
    End point timeframe
    Objective Response Rate was evaluated every 8 weeks +/- 5 days after the start of the investigational product and until the end of treatment.
    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 formal comparisons were intended or carried out between cohorts (i.e. Cohort 1 vs Cohort 2 vs Cohort 3) or between dosing regimens (i.e. 15 mg vs 10 mg).
    End point values
    Cohort 1 Cohort 2 Cohort 3 Full Analysis Set
    Number of subjects analysed
    32
    18
    26
    76
    Units: Patients
    6
    0
    4
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Emergent adverse events on treatment (EAEs) were defined as adverse events occurring or worsening (in terms of severity) or becoming serious between the first study drug intake date (included) and the last study drug intake date + 28 days (included).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    All patients who had taken at least one dose of study treatment.

    Serious adverse events
    All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 76 (50.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences causally related to treatment / all
    18 / 18
         deaths causally related to treatment / all
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 76 (98.68%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    62 / 76 (81.58%)
         occurrences all number
    194
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    21 / 76 (27.63%)
         occurrences all number
    39
    Fatigue
         subjects affected / exposed
    26 / 76 (34.21%)
         occurrences all number
    41
    Mucosal inflammation
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Oedema peripheral
         subjects affected / exposed
    10 / 76 (13.16%)
         occurrences all number
    12
    Pyrexia
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 76 (14.47%)
         occurrences all number
    12
    Dysphonia
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    6
    Dyspnoea
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Oropharyngeal pain
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    7
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    6
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 76 (22.37%)
         occurrences all number
    35
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 76 (25.00%)
         occurrences all number
    36
    Blood alkaline phosphatase increased
         subjects affected / exposed
    9 / 76 (11.84%)
         occurrences all number
    13
    Blood bilirubin increased
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    17 / 76 (22.37%)
         occurrences all number
    42
    Lipase increased
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    8
    Platelet count decreased
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    12
    Transaminases increased
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    10
    Weight decreased
         subjects affected / exposed
    10 / 76 (13.16%)
         occurrences all number
    11
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 76 (14.47%)
         occurrences all number
    13
    Headache
         subjects affected / exposed
    26 / 76 (34.21%)
         occurrences all number
    47
    Lethargy
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    19
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    7
    Neutropenia
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    14
    Thrombocytopenia
         subjects affected / exposed
    13 / 76 (17.11%)
         occurrences all number
    20
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Abdominal pain
         subjects affected / exposed
    14 / 76 (18.42%)
         occurrences all number
    17
    Abdominal pain upper
         subjects affected / exposed
    13 / 76 (17.11%)
         occurrences all number
    24
    Ascites
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Constipation
         subjects affected / exposed
    13 / 76 (17.11%)
         occurrences all number
    17
    Diarrhoea
         subjects affected / exposed
    28 / 76 (36.84%)
         occurrences all number
    69
    Dry mouth
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    7
    Dyspepsia
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    6
    nausea
         subjects affected / exposed
    36 / 76 (47.37%)
         occurrences all number
    54
    Stomatitis
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Vomiting
         subjects affected / exposed
    25 / 76 (32.89%)
         occurrences all number
    41
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Erythema
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    6
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    11
    Pruritus
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Proteinuria
         subjects affected / exposed
    25 / 76 (32.89%)
         occurrences all number
    88
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    36 / 76 (47.37%)
         occurrences all number
    45
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 76 (15.79%)
         occurrences all number
    17
    Back pain
         subjects affected / exposed
    10 / 76 (13.16%)
         occurrences all number
    12
    Bone pain
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    8
    Muscle spasms
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    7
    Myalgia
         subjects affected / exposed
    8 / 76 (10.53%)
         occurrences all number
    14
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    20 / 76 (26.32%)
         occurrences all number
    25

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2013
    The amendment concerned mainly: -Modifications in inclusion/exclusion criteria: restriction for normal serum potassium level at entry and normal creatinine clearance (> 60 ml/min). -Addition of clinical management rules in case of QTcF prolongation > 500 msec and LVEF decrease. -Addition of ECG and LVEF evaluation time points at C1D1 (pre-dose and tmax) and Day 28 respectively.
    16 Dec 2013
    The amendment aimed to, principally: -Implement an Independent Data Monitoring Committee, to provide the Steering Committee with independent recommendations regarding the continuation, modification or interruption of the trial based on benefice/risk ratio analysis. -Modify inclusion criteria: only one archived tumour sample mandatory at screening and ability to give consent. -Modify exclusion criteria: history of thromboembolic events and hereditary risk factors added. -Remove the serum blood sample for soluble growth factor analysis at the end of treatment visit. -Add a 10mL plasma blood sample at C1D1. -Collect archived primary tumour tissue, if available, to perform comparative assays with metastatic tissue samples. -Add optional new biopsies collection at baseline for cohort 1 and 2. -Add optional new biopsy collection between C1D14-C1D28, and at EOT for cohort 3. -Add Hungary to the study countries. -Clarify sample nature (free circulating DNA, circulating growth factors). -Prohibit radiotherapy during the study. -Postpone the study initiation date to November 2013.
    11 Jun 2014
    The main purpose of this mendment was to increase the level of safety management, following the temporary interruption of the study due to the incidence of hypertensive events observed. Main changes were: -Addition of a C1D4 visit to monitor early toxicities especially early increase in blood pressure. -Modification and strengthening of the management of hypertension, QTc prolongation, LVEF decreases and liver toxicities. A paragraph was added for nausea and vomiting management. The toxicity managements included also the possibility to reduce the daily dose to 10 mg, 7.5 mg and 5 mg. -Patients were to measure blood pressure daily at home on the 1st cycle and at least twice a week afterwards and at screening. -Update of the background information section: platelet count decrease and anorexia have been added as expected adverse events. -Inclusion criteria update (any prior first-line of anticancer therapy in the metastatic setting, AST/ALT ≤ 3 ULN irrespective of the presence of liver metastases). -Exclusion criteria update (history of clinically significant or uncontrolled cardiac disease, hypertension criterion, history of thrombotic disorders criterion, history of renal diseases, involvement in another clinical trial except for observational trials, uncontrolled diabetes mellitus). -Prohibition of any oral anticoagulant as concomitant treatment and prohibition of aspirin if taken concomitantly with oral anti-platelet agents. -Mention that patients with evidence of liver disease or injury should avoid drugs known to be hepatotoxic, ie paracetamol/acetaminophen. -Possibility to use tumours imagery anterior to ICF for baseline assessment if performed within the 28 day screening period prior to the 1st drug intake. -Implementation of time windows for scheduled visits and LVEF examination. -Possibility to send 20 slides of the screening tumour samples to ICR instead of the whole tumour block.
    25 Feb 2015
    It concerned mainly the update of prohibited, contraindicated and not recommended medications in association with lucitanib: -Exclusion criteria update and clarification: patients receiving administration of strong inhibitors of CYP2C8 and/or CYP3A4 or strong inducers of CYP3A4 added, mutation of Factor V of Leiden as an example of thromboembolism hereditary risk factors removed, serum potassium below LLN at screening. -Clarifications about coagulation test, time window to perform laboratory tests, ER/PR and HER2 testing, troponin test to be evaluated, liver toxicity management, decrease LVEF management and hypothyroidism management. -Implementation of recommendations in case of missed or incomplete intake of drug dose. -Update on permitted medication: LHRH analogue provided that the treatment was initiated prior to the initiation of study drug with documented disease progression. -Update on prohibited drugs: strong inhibitors of CYP3A4 or CYP2C8, strong dual inhibitors of CYP3A4 and CYP2C8 and strong inducers of CYP3A4 to be prohibited. Moderate inhibitors of CYP3A4 or CYP2C8 and moderate dual inhibitor of CYP3A4 and CYP2C8 not recommended. Herbal supplement strongly not recommended. Verapamil and diltiazem deleted from prohibited drugs.
    27 Aug 2015
    The amendment concerned mainly the reduction of the starting dose of lucitanib from 15 mg to 10 mg daily. Patients who were already on the 15 mg daily dose were permitted to continue at their current dose based on the investigator's decision (if well controlled hypertension and others toxicities at 15mg and patients benefited from this dose). Otherwise, lucitanib dose was to be reduced to 10 mg at the start of following cycle. Other changes included: -Introduction of the new formulation of lucitanib (tablets). -Clarification and updates on management of hypertension, minor clarification of general and renal toxicities management. -Possibility to send 20 representative and serial slides for the optional biopsies instead of tumour block in case of strict internal policy of the site. -Addition of 10 ml of blood collected at each time point (C1D1, C1D14, EOT) for circulating tumour DNA analysis. -Removal of optional on-treatment biopsy. -Clarification of adverse events definition .
    02 Feb 2016
    Following the report of a case of Posterior Reversible Encephalopathy Syndrome (PRES), this amendment was designed to add precautionary measures in case a patient experienced symptoms suggestive of PRES. It included: -An update of the background information section: information about a case of PRES with lucitanib observed within the context of FINESSE. -The addition of a paragraph for the management of symptoms suggestive of PRES and confirmed PRES. -Clarification of the exclusion criteria relative to treatment withdrawal window in case a patient received another IMP before the first dose of lucitanib.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 May 2014
    In May 2014, upon IDMC recommendation, the study Steering Committee and the Sponsor decided to temporarily interrupt patients’ enrolment due to the incidence of hypertension events. A protocol amendment (Amendment No. 3), including strict measures to follow and manage hypertension, was issued in June 2014. After approval of Amendment No. 3, the recruitment had been resumed with a restricted number of sites and controlled recruitment before the full activation of all sites.
    11 Sep 2014
    31 May 2016
    Halt on recruitment on 31-May-2016 by IDMC until the next IDMC meeting (90 days later). This was to allow more time for a consideration of efficacy in patients currently on treatment at 10mg, recognising that the lucitanib exposure in the 10 mg group at this time was very low (mean 22 days at the time of data lock).
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    On 4-August-2016, it was decided to prematurely and definitively halt the recruitment of patients: a data analysis from the lucitanib breast cancer clinical development program showed that lucitanib was not likely to be superior than standard of care
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