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    Clinical Trial Results:
    Phase II study assessing the maintenance treatment with vinflunine after first-line therapy with gemcitabine and cisplatin in patients with advanced or metastatic transitional cell carcinoma of the urothelial (TCCU) tract.

    Summary
    EudraCT number
    2011-000272-34
    Trial protocol
    DE   AT   IT  
    Global end of trial date
    14 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Dec 2018
    First version publication date
    16 Dec 2018
    Other versions
    Summary report(s)
    Jasima final synopsis of CSR

    Trial information

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    Trial identification
    Sponsor protocol code
    L00070-IN-214-P1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pierre Fabre medicament
    Sponsor organisation address
    45 place Abel Gance, Boulogne, France, 92100
    Public contact
    RIGGI, Pierre Fabre Medicament, +33 (0) 1.49.10.81.77, marcello.riggi@pierre-fabre.com
    Scientific contact
    RIGGI, Pierre Fabre Medicament, +33 (0) 1.49.10.81.77, marcello.riggi@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
    13 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the progression-free survival-rate (PFSrate) at 3 months of IV Vinflunine (VFL) as Maintenance Therapy (MT) for patients with advanced or metastatic Transitional cell carcinoma of the urothelium (TCCU) who achieved disease control (i.e. CR, PR or SD) after four cycles of first line standard doublet chemotherapy regimen with Gemcitabine-Cisplatin (GC).
    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. Freely given written informed consent was to be obtained from every subject or his or her legally acceptable representative prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the trial.
    Background therapy
    Standard anti-emetic prophylaxis was recommended from the first cycle, prior to each treatment administration of vinflunine IV infusion and consisted of a single oral dose of dexamethasone 8 mg or equivalent dose of methylprednisolone. Laxatives and dietary measures were recommended, starting from day 1 of each vinflunine administration to day 5. For patients considered at increased risk of serious constipation, defined as history of chronic or refractory constipation, concomitant treatment with opioids, peritoneal carcinomatosis or abdominal tumour masses, persistent symptoms under vinflunine despite the days 1 to 5 dietary measures and laxatives administration, the use of a stool softener and a stimulant was recommended to maximise efficacy.
    Evidence for comparator
    The study was a non comparative, single arm, phase II trial as it aimed at evaluating the efficacy of single agent VFL as Maintenance Therapy following standard chemotherapy regimen by Gemcitabine-cisplatin (GC) combination regimen. Vinflunine is already approved as monotherapy in second line for patients with advanced/metastatic TCCU.
    Actual start date of recruitment
    30 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    28 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    9
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Between February 17th 2012 and July 24th 2013, a total of 20 patients with advanced or metastatic TCCU were registered at 11 investigational centres in Germany, Austria and Italy. 1 patient was withdrawn from study before first drug administration, he was considered as screen failure.

    Pre-assignment
    Screening details
    Treatment with GC chemotherapy was not part of this study. Inclusion into the trial had to take place only after completion of the 4 cycles of GC treatment. Only patients who achieved a complete response (CR), a Partial response (PR) or a stable disease (SD) after the 4 cycles of GC therapy were eligible to enter into the study to receive IV VFL.

    Period 1
    Period 1 title
    Maintenance treatment (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Vinflunine arm
    Arm description
    The study population was patients aged ≥ 18 years with advanced or metastatic TCCU, who achieved disease control (CR, PR or SD) after four cycles of first line chemotherapy regimen with GC treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Vinflunine
    Investigational medicinal product code
    Other name
    Vinflunine ditartrate, Javlor
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study drug administration had to start within 7 days after registration. Vinflunine was administered on Day 1, every 21 days as a 20 minute intravenous (IV) infusion. For cycle 1, the starting dose of vinflunine was defined according to calculated creatinine clearance at registration (Cockroft-Gault formula), age, ECOG PS and prior pelvic irradiation. The treatment with vinflunine as MT was to be administered until documented disease progression, unacceptable toxicity, intercurrent illness or other reaction which could require discontinuation of study drug or patient refusal. As per the VFL Summary of Product Characteristics (SmPC), the recommended dose of VFL as single agent is 320 mg/m² as a 20 minute intravenous infusion every 3 weeks in patient without renal impairment (CrCl > 60 mL/mn) and 280 mg/m2 in patients with an ECOG PS of 1 or 0 with prior pelvic irradiation. In case of documented progression occurring before the first evaluation, the treatment was discontinued.

    Number of subjects in period 1
    Vinflunine arm
    Started
    19
    Completed
    0
    Not completed
    19
         Physician decision
    1
         Drug related toxicity
    2
         Non-drug related toxicity
    1
         Patient's refusal/convenience
    8
         Progression Disease
    6
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vinflunine arm
    Reporting group description
    The study population was patients aged ≥ 18 years with advanced or metastatic TCCU, who achieved disease control (CR, PR or SD) after four cycles of first line chemotherapy regimen with GC treatment.

    Reporting group values
    Vinflunine arm Total
    Number of subjects
    19 19
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    9 9
        From 65-84 years
    10 10
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    67.2 (48.9 to 77.4) -
    Gender categorical
    Units: Subjects
        Female
    6 6
        Male
    13 13
    ECOG PS
    Units: Subjects
        Zero
    11 11
        One
    8 8
    Primary tumour site
    Units: Subjects
        Upper urinary tract
    2 2
        Bladder
    17 17
    Body surface area (BSA)
    Units: square meter
        arithmetic mean (standard deviation)
    1.9 ( 0.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Vinflunine arm
    Reporting group description
    The study population was patients aged ≥ 18 years with advanced or metastatic TCCU, who achieved disease control (CR, PR or SD) after four cycles of first line chemotherapy regimen with GC treatment.

    Primary: PFS Rate at 3 months

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    End point title
    PFS Rate at 3 months [1]
    End point description
    As exploratory analysis, the primary efficacy endpoint was analysed on the first 20 patients included before termination of the study, that is to say, on the 19 patients, representing the ITT population and on the 15 evaluable patients for response.
    End point type
    Primary
    End point timeframe
    The primary efficacy parameter was the PFS rate at the fixed time point of 3 months after registration into the study. The PFS Rate has been estimated using Kaplan Meier Method.
    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: Due to early study termination, the analysis of the primary efficacy endpoint on the first 20 evaluable patients and on the total and required number of 70 evaluable patients for the second step Fleming design could not be performed.
    End point values
    Vinflunine arm
    Number of subjects analysed
    19
    Units: percentage
    82
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any AE occurring during the study period (starting after the first dose of medication and up to and including 30 days after the last dose of medication),spontaneously reported by the patient or observed by others was recorded.
    Adverse event reporting additional description
    Each patient was assessed for occurrence of adverse events throughout the study period. Adverse events were graded according to NCI- CTC AE criteria The adverse events as well as baseline signs and symptoms were coded using the Medical Dictionary for Regulatory Activities (MedDRA).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Treated patients
    Reporting group description
    -

    Serious adverse events
    Treated patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 19 (42.11%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
    Additional description: Grade 4
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    Fatigue
    Additional description: Grade 3
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
    Additional description: Grade 3
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Visual acuity reduced
    Additional description: Grade 3
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
    Additional description: Grade 3
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
    Additional description: Grade 5
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Ureteric fistula
    Additional description: Grade 1
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Grade 3
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary tract infection
    Additional description: Grade 3
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.7%
    Non-serious adverse events
    Treated patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 19 (94.74%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    7 / 19 (36.84%)
         occurrences all number
    25
    Infusion site pain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Injection site reaction
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    4
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    4
    Investigations
    Glomerular filtration rate
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Hypertonia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Paraesthesia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    14 / 19 (73.68%)
         occurrences all number
    76
    Anaemia
         subjects affected / exposed
    18 / 19 (94.74%)
         occurrences all number
    99
    Thrombocytopenia
         subjects affected / exposed
    6 / 19 (31.58%)
         occurrences all number
    18
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    4
    Tinnitus
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    4
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    3
    Visual acuity reduced
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    4
    Constipation
         subjects affected / exposed
    4 / 19 (21.05%)
         occurrences all number
    5
    Diarrhoea
         subjects affected / exposed
    4 / 19 (21.05%)
         occurrences all number
    15
    Dyspepsia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    7 / 19 (36.84%)
         occurrences all number
    16
    Stomatitis
         subjects affected / exposed
    5 / 19 (26.32%)
         occurrences all number
    18
    Vomiting
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 19 (36.84%)
         occurrences all number
    23
    Renal and urinary disorders
    Bladder pain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    4
    Hypokalaemia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2011
    Study becoming an European study (Austria, Germany, Italy...) with updating number of centres involved. Including an update of the prohibited and non-recommended concomitant treatments regarding the use of dexamethasone as anti-emesis prophylaxis in the study. Including an update of Vinflunine IV Summary of product characteristics and Investigator's brochure. Including an update of registration form.
    14 May 2012
    Local requirement of performing monthly pregnancy test for women of childbearing potential during the treatment phase of patients included.
    25 Jun 2012
    Change of study selection criteria and the registration form (to involve patients > 75 years with dose adaptation, to other one additional week to complete the patients baseline clinical assessments, to adapt one exclusion criterion related to other malignancies + a cut-off value for haemoglobin.

    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.
    Due to difficulties in recruiting patients, the decision to stop the study before the first interim analysis was taken by the sponsor in agreement with the investigators. The study population consisted of 20 patients included, of whom 19 were treated
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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