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    Clinical Trial Results:
    Phase III study of IV vinflunine in combination with methotrexate versus methotrexate alone in patients with recurrent or metastatic squamous cell carcinoma of the head and neck previously treated with platinum-based chemotherapy (study L00070 IN 309 F0)

    Summary
    EudraCT number
    		 2011-005081-38
    Trial protocol
    		 DE   ES   IT   BE   EE   AT   PL   SK  
    Global end of trial date
    23 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2019
    First version publication date
    06 Mar 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    L00070 IN 309 F0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02347332
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pierre Fabre Médicament, Institut de Recherche Pierre Fabre
    Sponsor organisation address
    BP 13562, Toulouse, France, 31305
    Public contact
    Zahida Issiakhem, MD Clinical Development Physician (Department Medical Unit) , Pierre Fabre Médicament, Institut de Recherche Pierre Fabre , +33 (0) 5 34 50 61 71, zahida.issiakhem@pierre-fabre.com
    Scientific contact
    Zahida Issiakhem, MD Clinical Development Physician (Department Medical Unit) , Pierre Fabre Médicament, Institut de Recherche Pierre Fabre , +33 (0) 5 34 50 61 71, zahida.issiakhem@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
    20 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the overall survival (OS) of intravenous (IV) vinflunine (VFL) in combination with methotrexate (MTX) versus MTX alone in incurable recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) patients who have failed platinum based chemotherapy. Futility analysis showed that the probability of demonstrating a significant benefit in OS at the time of the final analysis was very low. Consequently, the sponsor decided to end trial and limit efficacy analysis to ITT patients. At the cut-off date October 20th 2017, 3 patients were ongoing and at the time of this report 1 patient is under compassional treatment. An addendum and update of the data on safety will be made once all patients are deceased and the global end of trial is reached.
    Protection of trial subjects
    The study was conducted according to Good Clinical Practices (GCPs) (CPMP/ICH/135/95), International Conference on Harmonisation (ICH) E11, the ethical principles that have their origins in the Declaration of Helsinki (1964) and its subsequent amendments. Each patient signed an Informed consent.
    Background therapy
    		 Vinflunine (VFL) is a microtubule inhibitor of the vinca-alkaloid class. Microtubules are an important chemotherapeutic target because of the crucial role they play during mitosis, particularly for rapidly dividing cancer cells. VFL inhibits tubulin assembly by perturbing microtubule dynamics and mitotic spindles without affecting assembled microtubules. An international program of phase II studies with VFL as a single agent has been carried out in chemonaïve patients, and also as salvage therapy in order to determine the tumour response in a large spectrum of solid tumours. In a phase III study, VFL given as second-line after failure of prior platinum-based chemotherapy demonstrated a survival advantage over best supportive care in advanced transitional cell carcinoma of the urothelial tract (TCCU). In a further phase III study, VFL showed similar efficacy to docetaxel in advanced non small cell lung cancer.Vinca-alkaloids have demonstrated activity in SCCHN; single agent vinorelbine showed activity after first-line cisplatin-based chemotherapy. VFL demonstrated superior antitumour activity to vinorelbine in preclinical animal models, and has well-established efficacy in the second-line treatment of TCCU and non small cell lung cancer after platinum failure. Vinca-alkaloids have been successfully combined with MTX in a variety of solid tumours including advanced TCCU, metastatic breast cancer and malignant mesothelioma. In patients with SCCHN who had relapsed after cisplatin plus 5 FU, a regimen combining vinorelbine, bleomycin and MTX showed activity with a response rate of 27% and acceptable toxicity. Recent preliminary phase I results of the vinflunine plus methotrexate combination in SCCHN, based on a clinical review, show encouraging antitumour activity and an acceptable safety profileTherefore the combination of VFL and MTX appears a promising salvage regimen after platinum failure.
    Evidence for comparator
    		 For patients with incurable recurrent/metastatic SCCHN who failed platinum-based therapy, single agent MTX at a dose of 40 mg/m2/week is considered as the best available evidence-based option. Also, other trials using this comparator have demonstrated that it is generally accepted as a reasonable choice, and is often used in general practice
    Actual start date of recruitment
    02 Apr 2012
    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
    Austria: 7
    Country: Number of subjects enrolled
    Belarus: 21
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Brazil: 36
    Country: Number of subjects enrolled
    Estonia: 5
    Country: Number of subjects enrolled
    France: 68
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Italy: 38
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Russian Federation: 120
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Taiwan: 28
    Country: Number of subjects enrolled
    Ukraine: 53
    Worldwide total number of subjects
    459
    EEA total number of subjects
    196
    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)
    357
    From 65 to 84 years
    102
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were stratified at inclusion by the following factors: performance status (0 versus 1), refractory or resistant to platinum versus other, prior radiotherapy, treatment with anti-epidermal growth factor receptor, centre, patients were randomly assigned in a 1:1 ratio to 1 of the 2 arms.

    Pre-assignment
    Screening details
    		 Adult patients with histological or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx with a WHO performance status < 1 with adequate haematological, hepatic and renal function. Disease must have been documented as progressive during or after platinum based chemotherapy

    Period 1
    Period 1 title
    Screening
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Patients randomised to Arm A received: VFL at a dose of 280 mg/m² on Day 1, over a 20 minute IV infusion, and MTX administered at a dose of 30 mg/m² by direct bolus IV injection on Days 1 and 8 of every three week cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vinflunine
    Investigational medicinal product code
    L0070
    Other name
    JAVLOR, (4’R) - 20’, 20’-difluoro 3'4’-dihydrovinorelbine L -(+) - tartrate (1 : 2)
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients randomised to arm A will receive vinflunine on day 1 as a 20 minute IV infusion at 280 mg/m² and methotrexate on days 1 and 8 as a bolus intravenous injection at 30 mg/m² of every three-week cycle. The total dose to be given will be calculated according to body surface area (BSA). In calculating BSA, actual heights and weights should be used. BSA should be recalculated prior to the next cycle dosing.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    On day 1, methotrexate will be administered by direct bolus injection through the side arm of the remaining NS or 5% glucose solution bag after completion of vinflunine infusion. On day 8, methotrexate will be administered though the side arm of a freely running NS or 5% glucose solution IV infusion.

    Arm title
    		 Arm B
    Arm description
    		 Patients randomised to arm B received methotrexate on a weekly basis as a bolus intravenous injection at the dose of 40 mg/m²/week. The drug was administered by direct injection through the side arm of a freely running NS or 5% glucose solution IV infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Patients randomised to arm B received methotrexate on a weekly basis as a bolus intravenous injection at the dose of 40 mg/m²/week. The drug was administered by direct injection through the side arm of a freely running NS or 5% glucose solution IV infusion.

    Number of subjects in period 1
    		Arm A Arm B
    Started
    230
    229
    Completed
    230
    229
    Period 2
    Period 2 title
    Overall Study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Patients randomised to Arm A received: VFL at a dose of 280 mg/m² on Day 1, over a 20 minute IV infusion, and MTX administered at a dose of 30 mg/m² by direct bolus IV injection on Days 1 and 8 of every three week cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vinflunine
    Investigational medicinal product code
    L0070
    Other name
    JAVLOR, (4’R) - 20’, 20’-difluoro 3'4’-dihydrovinorelbine L -(+) - tartrate (1 : 2)
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients randomised to arm A will receive vinflunine on day 1 as a 20 minute IV infusion at 280 mg/m² and methotrexate on days 1 and 8 as a bolus intravenous injection at 30 mg/m² of every three-week cycle. The total dose to be given will be calculated according to body surface area (BSA). In calculating BSA, actual heights and weights should be used. BSA should be recalculated prior to the next cycle dosing.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    On day 1, methotrexate will be administered by direct bolus injection through the side arm of the remaining NS or 5% glucose solution bag after completion of vinflunine infusion. On day 8, methotrexate will be administered though the side arm of a freely running NS or 5% glucose solution IV infusion.

    Arm title
    		 Arm B
    Arm description
    		 Patients randomised to arm B received methotrexate on a weekly basis as a bolus intravenous injection at the dose of 40 mg/m²/week. The drug was administered by direct injection through the side arm of a freely running NS or 5% glucose solution IV infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Patients randomised to arm B received methotrexate on a weekly basis as a bolus intravenous injection at the dose of 40 mg/m²/week. The drug was administered by direct injection through the side arm of a freely running NS or 5% glucose solution IV infusion.

    Number of subjects in period 2
    		Arm A Arm B
    Started
    230
    229
    Completed
    0
    0
    Not completed
    230
    229
         Adverse event, serious fatal
    6
    6
         Consent withdrawn by subject
    20
    14
         Physician decision
    4
    3
         Adverse event, non-fatal
    50
    41
         Progressive disease
    141
    159
         Lost to follow-up
    2
    1
         Protocol requirement
    1
    1
         Switch Post study program
    -
    1
         Protocol deviation
    1
    1
         Patients not treated
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients randomised to Arm A received: VFL at a dose of 280 mg/m² on Day 1, over a 20 minute IV infusion, and MTX administered at a dose of 30 mg/m² by direct bolus IV injection on Days 1 and 8 of every three week cycle.

    Reporting group title
    Arm B
    Reporting group description
    		 Patients randomised to arm B received methotrexate on a weekly basis as a bolus intravenous injection at the dose of 40 mg/m²/week. The drug was administered by direct injection through the side arm of a freely running NS or 5% glucose solution IV infusion.

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 230 229 459
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 182 175 357
        From 65-84 years
    		 48 54 102
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 58 (27 to 79) 59 (34 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 37 35 72
        Male
    		 193 194 387
    Subject analysis sets

    Subject analysis set title
    ARM A
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients randomised to Arm A received: • VFL at a dose of 280 mg/m² on Day 1, over a 20 minute IV infusion, and • MTX administered at a dose of 30 mg/m² by direct bolus IV injection on Days 1 and 8 of every three week cycle.

    Subject analysis set title
    ARM B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients randomised to Arm B, MTX was given at a dose of 40 mg/m²/week administered by direct bolus IV injection on Days 1, 8 and 15 of every three week cycle. One cycle of MTX is defined as a three week period.

    Subject analysis sets values
    		 ARM A ARM B
    Number of subjects
    230
    229
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    182
    175
        From 65-84 years
    48
    54
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    58 (27 to 79)
    59 (34 to 79)
    Gender categorical
    Units: Subjects
        Female
    37
    35
        Male
    193
    194

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients randomised to Arm A received: VFL at a dose of 280 mg/m² on Day 1, over a 20 minute IV infusion, and MTX administered at a dose of 30 mg/m² by direct bolus IV injection on Days 1 and 8 of every three week cycle.

    Reporting group title
    Arm B
    Reporting group description
    		 Patients randomised to arm B received methotrexate on a weekly basis as a bolus intravenous injection at the dose of 40 mg/m²/week. The drug was administered by direct injection through the side arm of a freely running NS or 5% glucose solution IV infusion.
    Reporting group title
    Arm A
    Reporting group description
    		 Patients randomised to Arm A received: VFL at a dose of 280 mg/m² on Day 1, over a 20 minute IV infusion, and MTX administered at a dose of 30 mg/m² by direct bolus IV injection on Days 1 and 8 of every three week cycle.

    Reporting group title
    Arm B
    Reporting group description
    		 Patients randomised to arm B received methotrexate on a weekly basis as a bolus intravenous injection at the dose of 40 mg/m²/week. The drug was administered by direct injection through the side arm of a freely running NS or 5% glucose solution IV infusion.

    Subject analysis set title
    ARM A
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients randomised to Arm A received: • VFL at a dose of 280 mg/m² on Day 1, over a 20 minute IV infusion, and • MTX administered at a dose of 30 mg/m² by direct bolus IV injection on Days 1 and 8 of every three week cycle.

    Subject analysis set title
    ARM B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients randomised to Arm B, MTX was given at a dose of 40 mg/m²/week administered by direct bolus IV injection on Days 1, 8 and 15 of every three week cycle. One cycle of MTX is defined as a three week period.

    Primary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    End point type
    Primary
    End point timeframe
    30 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    230
    229
    Units: Months
        median (confidence interval 95%)
    7.1 (5.7 to 8.4)
    6.8 (6.1 to 8.0)
    Attachments
    		 Overall Survival (ITT) in months
    Overall Survival (ITT) in months Fig
    Statistical analysis title
    		 Overall Survival (months) ITT
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval

    Secondary: Progression free Survival (ITT)

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    End point title
    		 Progression free Survival (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    230
    229
    Units: Months
        median (confidence interval 95%)
    2.8 (2.6 to 3.3)
    2.8 (2.1 to 3.1)
    Attachments
    		 Progression Free Survival (ITT) in months)
    Progression Free Survival (ITT) in months - Fig
    Statistical analysis title
    		 Progression Free Survival (months) (ITT)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Objective Response Rate (ITT)

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    End point title
    		 Objective Response Rate (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    230
    229
    Units: Number of patients (%)
        median (confidence interval 95%)
    17.8 (13.1 to 23.4)
    14.8 (10.5 to 20.1)
    Attachments
    		 Objective Response Rate (ORR) [ITT]
    Statistical analysis title
    		 Objective Response Rate
    Statistical analysis description
    The best response designation recorded from the date of randomisation until disease progression.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Disease Control Rate (DCR) (ITT)

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    End point title
    		 Disease Control Rate (DCR) (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    230
    229
    Units: Number of patients (%)
        median (confidence interval 95%)
    50.9 (44.2 to 57.5)
    46.3 (39.7 to 53.0)
    Attachments
    		 Disease Control Rate (DCR) [ITT]
    No statistical analyses for this end point

    Secondary: Duration Of Response (ITT)

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    End point title
    		 Duration Of Response (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    230
    229
    Units: Months
        median (confidence interval 95%)
    4.2 (2.5 to 5.6)
    4.2 (2.7 to 5.1)
    Attachments
    		 Duration of Response (Months) [ITT]
    Duration of Response (months) [ITT]
    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
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    230
    229
    Units: Months
        median (confidence interval 95%)
    4.4 (4.1 to 5.5)
    4.2 (4.1 to 4.5)
    Attachments
    		 Duration of Disease Control (months) [ITT]
    Duration of Disease Control (months) [ITT] Fig
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure

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    End point title
    		 Time to Treatment Failure
    End point description
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    230
    229
    Units: Months
        median (confidence interval 95%)
    2.4 (1.7 to 2.8)
    2.6 (1.6 to 2.8)
    Attachments
    		 Time to Treatment Failure (months) [ITT]
    Time to Treatment Failure (months) [ITT]
    No statistical analyses for this end point

    Secondary: Time to First response [ITT]

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    End point title
    		 Time to First response [ITT]
    End point description
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    230
    229
    Units: Months
        median (confidence interval 95%)
    2.0 (1.4 to 2.8)
    1.5 (1.4 to 2.8)
    Attachments
    		 Time to Time to First Response (months) [ITT]
    Time to First Response (months) [ITT]
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 years 6 months 29 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    VFL + MTX
    Reporting group description
    		 -

    Reporting group title
    MTX.
    Reporting group description
    		 -

    Serious adverse events
    		 VFL + MTX MTX.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    105 / 225 (46.67%)
    82 / 227 (36.12%)
         number of deaths (all causes)
    185
    194
         number of deaths resulting from adverse events
    5
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    12 / 225 (5.33%)
    16 / 227 (7.05%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    8 / 225 (3.56%)
    10 / 227 (4.41%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    5 / 225 (2.22%)
    5 / 227 (2.20%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    22 / 225 (9.78%)
    5 / 227 (2.20%)
         occurrences causally related to treatment / all
    28 / 28
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    7 / 225 (3.11%)
    8 / 227 (3.52%)
         occurrences causally related to treatment / all
    9 / 10
    10 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    10 / 225 (4.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    11 / 11
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    8 / 225 (3.56%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    12 / 97
    3 / 90
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    5 / 225 (2.22%)
    6 / 227 (2.64%)
         occurrences causally related to treatment / all
    6 / 6
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    5 / 225 (2.22%)
    6 / 227 (2.64%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 6
         deaths causally related to treatment / all
    2 / 5
    1 / 6
    General physical health deterioration
         subjects affected / exposed
    6 / 225 (2.67%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 225 (2.22%)
    5 / 227 (2.20%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    5 / 225 (2.22%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    5 / 225 (2.22%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 225 (2.22%)
    5 / 227 (2.20%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 225 (3.56%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    4 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VFL + MTX MTX.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    211 / 225 (93.78%)
    213 / 227 (93.83%)
    Investigations
    Weight decreased
         subjects affected / exposed
    69 / 225 (30.67%)
    63 / 227 (27.75%)
         occurrences all number
    248
    150
    Creatinine renal clearance decreased
         subjects affected / exposed
    17 / 225 (7.56%)
    10 / 227 (4.41%)
         occurrences all number
    49
    28
    Weight increased
         subjects affected / exposed
    12 / 225 (5.33%)
    15 / 227 (6.61%)
         occurrences all number
    47
    100
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 225 (4.89%)
    28 / 227 (12.33%)
         occurrences all number
    26
    74
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    20 / 225 (8.89%)
    12 / 227 (5.29%)
         occurrences all number
    58
    29
    Malignant neoplasm progression
         subjects affected / exposed
    12 / 225 (5.33%)
    16 / 227 (7.05%)
         occurrences all number
    12
    16
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 225 (10.67%)
    10 / 227 (4.41%)
         occurrences all number
    42
    27
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    89 / 225 (39.56%)
    71 / 227 (31.28%)
         occurrences all number
    219
    190
    Anaemia
         subjects affected / exposed
    82 / 225 (36.44%)
    56 / 227 (24.67%)
         occurrences all number
    245
    147
    Leukopenia
         subjects affected / exposed
    32 / 225 (14.22%)
    38 / 227 (16.74%)
         occurrences all number
    93
    102
    Febrile neutropenia
         subjects affected / exposed
    19 / 225 (8.44%)
    1 / 227 (0.44%)
         occurrences all number
    20
    1
    Thrombocytopenia
         subjects affected / exposed
    19 / 225 (8.44%)
    24 / 227 (10.57%)
         occurrences all number
    31
    65
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    62 / 225 (27.56%)
    54 / 227 (23.79%)
         occurrences all number
    181
    137
    Pyrexia
         subjects affected / exposed
    26 / 225 (11.56%)
    24 / 227 (10.57%)
         occurrences all number
    35
    27
    Fatigue
         subjects affected / exposed
    24 / 225 (10.67%)
    27 / 227 (11.89%)
         occurrences all number
    52
    53
    Pain
         subjects affected / exposed
    19 / 225 (8.44%)
    17 / 227 (7.49%)
         occurrences all number
    48
    55
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    56 / 225 (24.89%)
    25 / 227 (11.01%)
         occurrences all number
    163
    42
    Stomatitis
         subjects affected / exposed
    53 / 225 (23.56%)
    64 / 227 (28.19%)
         occurrences all number
    117
    158
    Nausea
         subjects affected / exposed
    36 / 225 (16.00%)
    23 / 227 (10.13%)
         occurrences all number
    66
    40
    Vomiting
         subjects affected / exposed
    26 / 225 (11.56%)
    13 / 227 (5.73%)
         occurrences all number
    37
    20
    Diarrhoea
         subjects affected / exposed
    23 / 225 (10.22%)
    13 / 227 (5.73%)
         occurrences all number
    34
    23
    Dysphagia
         subjects affected / exposed
    18 / 225 (8.00%)
    13 / 227 (5.73%)
         occurrences all number
    33
    45
    Abdominal pain
         subjects affected / exposed
    16 / 225 (7.11%)
    2 / 227 (0.88%)
         occurrences all number
    18
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    18 / 225 (8.00%)
    18 / 227 (7.93%)
         occurrences all number
    26
    34
    Cough
         subjects affected / exposed
    14 / 225 (6.22%)
    22 / 227 (9.69%)
         occurrences all number
    32
    52
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    14 / 225 (6.22%)
    12 / 227 (5.29%)
         occurrences all number
    40
    30
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    15 / 225 (6.67%)
    12 / 227 (5.29%)
         occurrences all number
    19
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    27 / 225 (12.00%)
    23 / 227 (10.13%)
         occurrences all number
    59
    45

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2014
    PA01 Three new exclusion criteria were added: • albumin level < 35 g/L, • weight loss ≥ 5% within the last 3 months, • recurrent pulmonary or upper airways infections (3 times or more in the last 3 months) requiring antibiotics and/or any infection requiring antibiotics within the last month before study entry. • Permitted the eligibility of patients who present with synchronous squamous cell carcinomas of head and neck region. • Included data from a dose-finding and pharmacokinetic phase I study (L00070 IN 117 F0) evaluating the combination of VFL with MTX. • Implemented changes in the treatment modifications guidelines. • Implemented changes on SAE reporting. • Shortened the inclusion period from 24 months to 19 months. • Increased the number of participating sites.
    19 Mar 2014
    PA04: Based on requests from the French Ethics Committee issued on 14 March 2014 that led to protocol version #4, the following modifications were implemented: • The exclusion criterion ‘known hypersensitivity to vinca-alkaloids or MTX’ was deleted as patients with prior treatment with vinca-alkaloids and MTX were excluded. • Mentioned that creatinine clearance is calculated by the Cockroft-Gault formula. • Specified that VFL metabolism depends on the isoform CYP3A4. • Stated that clinical data of VFL-related neurotoxicity are moderate, frequent but reversible. • Added mouthwashes as prophylaxis of oral mucositis. • Updated the references.
    21 Mar 2014
    PA05: Based on further requests from ANSM issued on 21 March 2014 leading to protocol version #5 the following modifications were implemented: • Deleted text stating that ECGs were performed in the first 40 patients who were to be analysed in the early safety analysis treated patients. • Specified the measures that were to be taken in case of QT/QTc interval > 500 msec (Grade 3).
    10 Apr 2014
    PA03: Based on the comments and requests from the French Competent Authorities (ANSM) issued on 07 March 2014 that led to protocol version #3, the following modifications were implemented: • Two new exclusion criteria were added: • serum potassium < lower limit of normal, • ECG demonstrating a QT/QTc interval > 480 msec. • ECGs would be performed throughout the study treatment to further monitor patient’s safety. • Men must use adequate methods of contraception throughout the study and for up to 3 months after the study treatment if their partners were women of childbearing potential. • The exclusion criterion ‘known hypersensitivity to vinca-alkaloids or MTX’ was deleted as patients with prior treatment with vinca-alkaloids and MTX were excluded. • Detailed the clinical symptoms/signs and radiological features of Posterior Reversible Encephalopathy Syndrome. • Medications that prolong QT/QTc interval were to be avoided. A list of such medications was provided. • Mentioned that creatinine clearance is calculated by the Cockroft-Gault formula. • Specified that VFL metabolism depends on the isoform CYP3A4. • Stated that clinical data of VFL-related neurotoxicity are moderate, frequent but reversible. • Added mouthwashes as prophylaxis of oral mucositis.
    23 Nov 2015
    PA10: (submitted only in Belgium, France, Spain, Poland, Estonia, Russia, Belarus and Ukraine) • The results of the second interim analysis (August 2015) of efficacy of Study L00070 IN 309 F0 led the IDMC to recommend the implementation of a futility analysis of overall survival which is the primary endpoint of Study L00070 IN 309 F0. • The results of the futility analysis showed that the probability of demonstrating a significant benefit in overall survival at the time of the final analysis was very low. • As a consequence, the sponsor stopped the recruitment of study patients on 16 October 2015. • This amendment: • updated the protocol to reflect the sponsor’s decision to stop study recruitment, • deleted ‘adequate renal function serum creatinine ≤ ULN’ in the inclusion criterion #11 in order to fulfil the SmPC of VFL.
    05 Feb 2016
    PA11 • Clarified amendment PA10 with regards to the participation of the patient after the end of treatment phase. • Modified the statistical analysis according to the PA10 amendment.

    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.
    Abbreviated CSR. Futility analysis showed that the probability of demonstrating a significant benefit in OS at the time of the final analysis was very low. Consequently, the sponsor decided to end trial and limit efficacy analysis to ITT patients.
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    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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