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    Clinical Trial Results:
    Randomized phase III study comparing vinflunine-gemcitabine and gemcitabine-carboplatin combinations in patients ineligible to cisplatin with advanced or metastatic urothelial carcinoma.

    Summary
    EudraCT number
    		 2014-005396-82
    Trial protocol
    		 ES   FR   PL   CZ   AT   GB   BE   IT  
    Global end of trial date
    08 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Nov 2018
    First version publication date
    22 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    L00070IN312P1
    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, F 92100
    Public contact
    Responsable ensayos clínicos intern, Pierre Fabre Ibérica, S. A., 34 934833049, anabelen.paules@pierre-fabre.es
    Scientific contact
    Responsable ensayos clínicos intern, Pierre Fabre Ibérica, S. A., 34 934833049, anabelen.paules@pierre-fabre.es
    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
    23 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the median Progression Free Survival without related Severe Acute Toxicity* between arms (called SAT-PFS). *[enlarged definition of the Severe Acute Toxicity (SAT) from the EORTC study 30986 adding vinflunine specific risks: neutropenia G4 > 7 days, neutropenic fever G3/4, neutropenic systemic sepsis G3/G4 (neutropenia G3/4), G3/G4 thrombocytopenia with bleeding, G3/4 renal toxicity, G3/4 mucositis, constipation G4 requiring surgery, and death].
    Protection of trial subjects
    A Data Monitoring Committee (DMC) was to be convened to review all the safety and efficacy data and make recommendations regarding the decision to stop or continue the trial after the interim analysis
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Feb 2016
    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
    Taiwan: 2
    Worldwide total number of subjects
    2
    EEA total number of subjects
    0
    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)
    1
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Only 2 patients were included and treated in 2 centres in Taiwan. Due to delay in implementing the study across Europe and the difficulties to include patients in Taïwan, the Sponsor has decided on 26/Jun/2016 to stop the recruitment of patients in Taiwan and in July 2016 not to initiate the study in Europe.

    Pre-assignment
    Screening details
    		 A total of 4 patients with a confirmed diagnosis of locally advanced or metastatic predominantly transitional cell carcinoma of the urothelium (TCCU) [were screened in Taiwan, two were screen failures and 2 were eligible to participate to the study and were randomized into the study on 22/Feb/2016 and 28/Mar/2016, respectively in 2 sites in Taiwan

    Period 1
    Period 1 title
    treatment period (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 VG
    Arm description
    		 vinflunine plus gemcitabine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vinflunine
    Investigational medicinal product code
    L0070
    Other name
    Javlor
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    administered on Day (D) 1, every 21 days as a 20-minute IV infusion with two starting dose options based on randomization calculated creatinine clearance by Cockroft-Gault formula (CrCl), - CrCl ≥40 mL/min: 280 mg/m2; in case of significant* haematological or non-haematological toxicity, dose reduced to 250 mg/m2. - CrCl < 40 mL/min (but ≥ 30): 250 mg/m2; in case of significant* haematological or non-haematological toxicity, dose reduced to 225 mg/m2.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    GEM
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (GEM): administered on D1 and 8 of every 21-day cycle as a 30-minute IV infusion, Starting dose at 750 mg/m2 on D1 and 8 during the first cycle, escalated to 1000 mg/m2 if no toxicity of Grade > 2 occurs in Cycle 1, and pursued on the same dose in the absence of significant haematological or non-haematological toxicity and if CrCl ≥30 mL/min

    Arm title
    		 Arm GC
    Arm description
    		 ►Gemcitabine (GEM): administered on D1 and 8 of every 21-day cycle as a 30minute IV infusion,Starting dose at 1000 mg/m2 and pursued on the same dose in the absence significant haematological or non-haematological toxicity ►Carboplatin (CBDCA): administered on D1 of every 21- day cycle as a 60 minutes IV infusion: AUC 4.5 (Calvert dose calculation formula) and pursued on the same dose in the absence of significant haematological or non-haematological toxicity
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    GEM
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    administered on D1 and 8 of every 21-day cycle as a 30minute IV infusion, Starting dose at 1000 mg/m2 and pursued on the same dose in the absence significant haematological or non-haematological toxicity

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    CBDCA
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    administered on D1 of every 21- day cycle as a 60 minutes IV infusion: AUC 4.5 (Calvert dose calculation formula) and pursued on the same dose in the absence of significant haematological or non-haematological toxicity

    Number of subjects in period 1
    		Arm VG Arm GC
    Started
    1
    1
    Completed
    0
    0
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm VG
    Reporting group description
    		 vinflunine plus gemcitabine

    Reporting group title
    Arm GC
    Reporting group description
    		 ►Gemcitabine (GEM): administered on D1 and 8 of every 21-day cycle as a 30minute IV infusion,Starting dose at 1000 mg/m2 and pursued on the same dose in the absence significant haematological or non-haematological toxicity ►Carboplatin (CBDCA): administered on D1 of every 21- day cycle as a 60 minutes IV infusion: AUC 4.5 (Calvert dose calculation formula) and pursued on the same dose in the absence of significant haematological or non-haematological toxicity

    Reporting group values
    		 Arm VG Arm GC Total
    Number of subjects
    		 1 1 2
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 1 1
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 1 1 2
    Performance status
    ECOG status
    Units: Subjects
        ECOG 0
    		 0 1 1
        ECOG 1
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Arm VG
    Reporting group description
    		 vinflunine plus gemcitabine

    Reporting group title
    Arm GC
    Reporting group description
    		 ►Gemcitabine (GEM): administered on D1 and 8 of every 21-day cycle as a 30minute IV infusion,Starting dose at 1000 mg/m2 and pursued on the same dose in the absence significant haematological or non-haematological toxicity ►Carboplatin (CBDCA): administered on D1 of every 21- day cycle as a 60 minutes IV infusion: AUC 4.5 (Calvert dose calculation formula) and pursued on the same dose in the absence of significant haematological or non-haematological toxicity

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival [1]
    End point description
    due to premature global end of trial as per amendement 02, Due to the low number of patients and according to clinical study protocol amendment PA02, no statistical analyses were performed, only the individual data collected of the 2 enrolled patients are provided by listings for efficacy and safety analyses.
    End point type
    Primary
    End point timeframe
    Each patient had to receive at least 2 cycles of study treatment until documented disease progression, unacceptable toxicity or patient refusal. Tumour response was assessed every 6 weeks according to RECIST guidelines
    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 premature end of trial with only two patients enrolled and treated; no formal statistical analysis was performed
    End point values
    		 Arm VG Arm GC
    Number of subjects analysed
    1
    1
    Units: month
        median (full range (min-max))
    10 (10 to 10.2)
    4 (4 to 4.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any adverse or inter-current event occurring during the study period (starting after the first dose of study medication and up to and including 30 days after the last dose of study medication).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Arm VG
    Reporting group description
    		 vinflunine plus gemcitabine

    Reporting group title
    Arm GC
    Reporting group description
    		 ►Gemcitabine (GEM): administered on D1 and 8 of every 21-day cycle as a 30minute IV infusion,Starting dose at 1000 mg/m2 and pursued on the same dose in the absence significant haematological or non-haematological toxicity ►Carboplatin (CBDCA): administered on D1 of every 21- day cycle as a 60 minutes IV infusion: AUC 4.5 (Calvert dose calculation formula) and pursued on the same dose in the absence of significant haematological or non-haematological toxicity

    Serious adverse events
    		 Arm VG Arm GC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Hyponatraemia
    Additional description: grade 2 hyponatraemia occurred during cycle 1 , was treated by an intravenous solution of sodium chloride 3%. It did not result in any change in the study medications and resolved during cycle 2.
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         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 VG Arm GC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    Blood and lymphatic system disorders
    Neutropenia
    Additional description: the patient treated in arm VG, experienced mainly neutropenia with Grade 3 intensity (n=7), none of them was considered as serious by the investigator and all episodes resolved.
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    Thrombocytopenia
    Additional description: For pt treated in arm GC, related adverse events were in the haematological SOC consistingthrombocytopenia, with one episode of grade 4 at Cycle 3 resulting in treatment discontinuation.
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    2
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Pyrexia
    Additional description: grade 1 pyrexia that occured at cylce 1 and was not related
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    decrease appetite
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Hiccups
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Adrenal insufficiency
    Additional description: not related event that occured at cylce 1 and was still on going
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2015
    Protocol Amendment N°1: general (i.e. applicable for countries), – substantial, was issued on 12-Nov-2015. The following changes were include - Allow the supply of Gemcitabine concentrate for solution for infusion. - Corrections of typing errors with regards to the Creatinine Clearance assessment in the Study flow chart, the pharmaceutical form, storage and labelling of Carboplatin. - Update of Sponsor’s personnel
    21 Sep 2016
    Protocol Amendement 02 Local, applicable for TAIWAN only, substantial, The following changes were included: - Modification of the end of study definition - Update of the Sponsor’s personnel list. Due to the low number of patients and according to clinical study protocol amendment PA02, no statistical analyses were performed, only the individual data collected of the 2 enrolled patients are provided by listings for efficacy and safety analyses.

    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 the low number of patients and according to clinical study protocol amendment PA02, no statistical analyses were performed, only the individual data collected of the 2 enrolled patients are provided by listings for efficacy and safety analyses
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