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    Clinical Trial Results:
    Randomised phase II trial of oral vinorelbine and cisplatin followed by maintenance with single agent oral vinorelbine (NVBO) versus gemcitabine (GEM) and cisplatin (CDDP) followed by maintenance with single agent gemcitabine in first line Locally Advanced or Metastatic Non-Small-Cell Lung Cancer patients with squamous histological type

    Summary
    EudraCT number
    		 2012-003531-40
    Trial protocol
    		 ES   IT   AT   PL   FR  
    Global end of trial date
    06 Dec 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    PM259CA230J1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pierre Fabre Médicament
    Sponsor organisation address
    45 place Abel Gance, Boulogne, France, 92100
    Public contact
    Marcello RIGGI, Pierre Fabre Medicament, +33 149 10 81 77, marcello.riggi@pierre-fabre.com
    Scientific contact
    Marcello RIGGI, Pierre Fabre Medicament, +33 149 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
    19 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the Disease Control Rate (CR, PR, SD in both arms) on the whole study period (combination and maintenance periods).
    Protection of trial subjects
    This study was performed in accordance with the principles stated in the Declaration of Helsinki and subsequent amendments and in accordance with the Good Clinical Practice Guideline (CPMP/ICH/135/95). Patient information was based on the elements set out in the Declaration of Helsinki and the ICH GCP Guideline and measures taken to safeguard subject’s privacy and protection of personal data, according to European Directive 95/46 EC.
    Background therapy
    		 NVBO+CDDP arm: A systematic anti-emetic treatment was recommended before treatment administration (at day 1 with NVBO+CDDP and day 8 with NVBO alone). NVBO dose was 60 mg/m2 in cycle 1 and was to be increased to 80 mg/m2 in the subsequent cycles (on day 1 and day 8 of each cycle). Dose escalation at cycle 2 was determined based on haematological tolerance. NVBO was recommended to be taken with food. Following NVBO intake and saline hyper-hydration, i.v. CDDP was administered at the dose of 80 mg/m² on day 1 of each cycle and according to the investigational centre routine. GEM+CDDP arm: A systematic anti-emetic treatment was recommended before treatment administration. GEM (1250 mg/m²; i.v.) was administered on day 1 and day 8 of each cycle. Following GEM intake and saline hyperhydration, i.v. CDDP was administered at the dose of 80 mg/m² on day 1, every 3 weeks and according to the investigational centre routine. Erythropoietin was be given to patients who experienced anaemia grade 3-4. Growth factors may be given to patients who experienced febrile neutropenia (FN), grade 4 asymptomatic neutropenia lasting more than 7 days or neutropenic infection, according to institutional routine. Patients receiving opiates were given preventive treatment for constipation and followed carefully.
    Evidence for comparator
    		 GEM plus CDDP has been the standard doublet for squamous cell NSCLC. The importance of histological types was highlighted in a trial [Scagliotti GV, 2008], in which GEM plus CDDP combination was demonstrated to be more effective on squamous cell carcinomas than PEM plus CDDP. Therefore, this doublet was chosen as the reference treatment.
    Actual start date of recruitment
    01 Dec 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Brazil: 15
    Worldwide total number of subjects
    113
    EEA total number of subjects
    98
    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)
    65
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Twenty five centres in 6 countries screened 114 patients between the 18 of March 2013 and 19 August 2015. Of the 114 patients randomised, one patient was not treated due to forbidden radiotherapy resulting in 113 patients.

    Pre-assignment
    Screening details
    		 A 28-day screening period was planned before randomisation and screened for NSCLC stage IIIB or stage IV or relapsing after a local treatment chemo naive adult patients. All screened patients were randomised 1:1 in the 2 arms

    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
    		 NVBO+CDDP arm:
    Arm description
    		 o Combination period: NVBO 60 mg/m² on day 1 and day 8 (increased to 80 mg/m² at 2nd cycle according to haematological tolerance) with i.v. CDDP 80 mg/m² on day 1 every 3 weeks. o Maintenance period (after 4 cycles for patients with OR or SD): NVBO at the last dose of cycle 4, day 1 – day 8 every 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oral Vinorelbine
    Investigational medicinal product code
    NVBO
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    During the combination period patients received 60 mg/m2 of NVBO at cycle 1 and 80 mg/m2 during subsequent cycles at days 1 and 8 of each cycle. During the maintenance period, patient with OR or SD received the same dose as cycle 4 at days 1 and 8 of each cycle. NVBO was provided in sealed polystyrene box containing 16 blister packs of one soft capsule 20 mg or 30 mg vinorelbine each which should be used capsule per capsule for all patients according to dosage.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    CDDP
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the combination period patients received 80 mg/m2 of CDDP at day 1 of each cycle. CDDP was provided free of charge to each centre, in a commercial box containing one 50 mL or 100 mL vial of CDDP 1mg/mL (single use vials). CDDP was to be used vial per vial for all patients according to dosage.

    Arm title
    		 GEM + CDDP arm
    Arm description
    		 o Combination period: GEM 1250 mg/m² on day 1 and day 8 with i.v. CDDP 75 mg/m² on day 1 every 3 weeks. o Maintenance period (after 4 cycles for patients with OR or SD): GEM at the last dose as cycle 4, day 1 – day 8 every 3 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    CDDP
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the combination period patients received 80 mg/m2 of CDDP at day 1 of each cycle. CDDP was provided free of charge to each centre, in a commercial box containing one 50 mL or 100 mL vial of CDDP 1mg/mL (single use vials). CDDP was to be used vial per vial for all patients according to dosage.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    GEM
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the combination period patients received 1250 mg/m2 of GEM at day 1 and day 8 of each cycle. During the maintenance period, patients received the same dose of GEM as cycle 4 at day 1 and day 8 of each cycle. GEM was provided in a commercial box containing one vial of 200 mg or 1 g.

    Number of subjects in period 1
    		NVBO+CDDP arm: GEM + CDDP arm
    Started
    57
    56
    Completed
    0
    0
    Not completed
    57
    56
         Progressive or recurrent disease
    35
    38
         Death
    4
    1
         Study drug related adverse event
    6
    7
         Other reasons
    9
    2
         non study drug related adverse event
    2
    8
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NVBO+CDDP arm:
    Reporting group description
    		 o Combination period: NVBO 60 mg/m² on day 1 and day 8 (increased to 80 mg/m² at 2nd cycle according to haematological tolerance) with i.v. CDDP 80 mg/m² on day 1 every 3 weeks. o Maintenance period (after 4 cycles for patients with OR or SD): NVBO at the last dose of cycle 4, day 1 – day 8 every 3 weeks.

    Reporting group title
    GEM + CDDP arm
    Reporting group description
    		 o Combination period: GEM 1250 mg/m² on day 1 and day 8 with i.v. CDDP 75 mg/m² on day 1 every 3 weeks. o Maintenance period (after 4 cycles for patients with OR or SD): GEM at the last dose as cycle 4, day 1 – day 8 every 3 weeks.

    Reporting group values
    		 NVBO+CDDP arm: GEM + CDDP arm Total
    Number of subjects
    		 57 56 113
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 37 28 65
        From 65-84 years
    		 20 28 48
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 60.5 ( 7.6 ) 63.6 ( 6.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 11 28
        Male
    		 40 45 85
    Performance status reported in baseline clinical examination
    Units: Subjects
        70
    		 2 3 5
        80
    		 22 22 44
        90
    		 23 21 44
        100
    		 10 10 20
    Smoker history
    Units: Subjects
        Never smoked
    		 1 0 1
        Stopped smoking >=10 years ago
    		 8 11 19
        Stopped smoking <10 years ago
    		 22 22 44
        Smoker
    		 26 23 49
    Histopathological diagnosis method
    Histopathological type: squamous cell or epidermoid carcinoma (n=113)
    Units: Subjects
        Cytological
    		 16 12 28
        Histological
    		 41 43 84
        Histological/Cytological
    		 0 1 1
    TMN classification of Primary Tumor
    TMN classification at the time of first diagnosis
    Units: Subjects
        T1
    		 1 1 2
        T1B
    		 1 2 3
        T2
    		 7 5 12
        T2A
    		 2 2 4
        T2B
    		 1 3 4
        T3
    		 17 19 36
        T4
    		 27 23 50
        TX
    		 1 1 2
    TMN classification of Lymph node
    Units: Subjects
        N0
    		 6 8 14
        N1
    		 2 3 5
        N2
    		 25 21 46
        N3
    		 23 23 46
        NX
    		 1 1 2
    TMN classification of Distant metastasis
    Units: Subjects
        M0
    		 4 7 11
        M1
    		 22 22 44
        M1A
    		 9 13 22
        M1B
    		 22 14 36
    Stage at diagnosis
    Units: Subjects
        IA
    		 0 1 1
        IB
    		 2 0 2
        IIIA
    		 0 1 1
        IIIB
    		 3 5 8
        IV
    		 52 49 101
    Number of metastasis localizations
    Units: Subjects
        Zero
    		 2 4 6
        One
    		 8 11 19
        Two
    		 25 18 43
        >= Three
    		 22 23 45
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 70.82 ( 14.87 ) 74.86 ( 17 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 169.25 ( 9.82 ) 168.54 ( 8.08 ) -
    Body surface area
    Units: m²
        arithmetic mean (standard deviation)
    		 1.81 ( 0.22 ) 1.84 ( 0.22 ) -
    Delay between first histopathological diagnosis and study entry
    Units: months
        arithmetic mean (standard deviation)
    		 2.14 ( 4.92 ) 1.90 ( 3.20 ) -

    End points

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    End points reporting groups
    Reporting group title
    NVBO+CDDP arm:
    Reporting group description
    		 o Combination period: NVBO 60 mg/m² on day 1 and day 8 (increased to 80 mg/m² at 2nd cycle according to haematological tolerance) with i.v. CDDP 80 mg/m² on day 1 every 3 weeks. o Maintenance period (after 4 cycles for patients with OR or SD): NVBO at the last dose of cycle 4, day 1 – day 8 every 3 weeks.

    Reporting group title
    GEM + CDDP arm
    Reporting group description
    		 o Combination period: GEM 1250 mg/m² on day 1 and day 8 with i.v. CDDP 75 mg/m² on day 1 every 3 weeks. o Maintenance period (after 4 cycles for patients with OR or SD): GEM at the last dose as cycle 4, day 1 – day 8 every 3 weeks.

    Primary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR)
    End point description
    DCR, defined as the sum of confirmed CR, PR and SD rates, was observed in 42/57 patients (73.7%): [95% CI: 62.4%; 100%] in NVBO+CDDP arm and 42/56 patients (75.0%): [95% CI: 63.7%; 100%] in GEM+CDDP arm. Mean (SD) treatment duration was 15.21 (13.62) weeks for patients in NVBO+CDDP arm (n=57) and 16.77 (14.60) weeks for patients in GEM+CDDP arm (n=56).
    End point type
    Primary
    End point timeframe
    DCR according to investigator was calculated among the BOCR responders (CR and PR) and stable patients in the ITT population on the whole study period (from the date of randomisation until the documentation of progression or death due to any cause).
    End point values
    		 NVBO+CDDP arm: GEM + CDDP arm
    Number of subjects analysed
    57
    56
    Units: pourcentage
        number (confidence interval 95%)
    73.7 (62.4 to 83.0)
    75.0 (63.7 to 84.2)
    Statistical analysis title
    		 Primary efficacy analysis
    Statistical analysis description
    Mean (SD) treatment duration was 15.21 (13.62) weeks for patients in NVBO+CDDP arm (n=57) and 16.77 (14.60) weeks for patients in GEM+CDDP arm (n=56). The 95% CIs are calculated using the Brookmeyer and Crowley method and computed following the exact method.
    Comparison groups
    NVBO+CDDP arm: v GEM + CDDP arm
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 62.4
         upper limit
    		 100

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    Objective response rate was defined as the sum of CR and PR rate and evaluated on the whole study treatment period (combination + maintenance periods), from the date of randomisation until the end of study treatment period in the ITT population (n=113). The mean (SD) duration of follow-up was 11.52 (7.88) months for NVBO+CDDP arm and 11.09 (9.79) for the GEM+CDDP arm. ORR was observed in 31 patients (27.4%). Among them, 14 (24.6%) were from NVBO+CDDP arm and 17 (30.4%) from GEM+CDDP arm).
    End point type
    Secondary
    End point timeframe
    Objective response rate was evaluated on the whole study treatment period (from the date of randomisation until the end of study treatment period) in the ITT population (n=113).
    End point values
    		 NVBO+CDDP arm: GEM + CDDP arm
    Number of subjects analysed
    57
    56
    Units: pourcentage
        number (confidence interval 95%)
    24.6 (14.1 to 37.8)
    30.4 (18.8 to 44.1)
    No statistical analyses for this end point

    Secondary: Best Overall Confirmed Response (BOCR)

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    End point title
    		 Best Overall Confirmed Response (BOCR)
    End point description
    The BOCR was determined once all the data for the patient were known and was categorised in 5 classes: confirmed CR, confirmed PR, SD, PD or not evaluated (NE) for the whole study treatment period in the ITT population. No patients presented with CR, 31 patients (27.4%) presented with PR while SD of ≥6 weeks was observed in 53 patients (46.9%) and PD in 20 patients (17.7%).
    End point type
    Secondary
    End point timeframe
    Best Overall Confirmed Response was recorded from the date of randomisation until end of study treatment period. Tumour assessment was performed according to the RECIST guideline and was carried out at baseline and every 6 weeks until progressive disease.
    End point values
    		 NVBO+CDDP arm: GEM + CDDP arm
    Number of subjects analysed
    57
    56
    Units: patients
        PR
    14
    17
        SD ⩾ 6 weeks
    28
    25
        PD
    11
    9
        Not evaluable
    0
    2
        Missing
    4
    3
    No statistical analyses for this end point

    Secondary: Duration of disease control

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    End point title
    		 Duration of disease control
    End point description
    The duration of disease control (CR, PR and stable diasease of at least 24 weeks) was analysed in the subset of patients with disease control in ITT population for response on the whole study treatment period. In ITT population, the subset of patients with disease control rate included 42 patients in each arm. The estimated duration of disease control for these patients ranged from 1.45-22.11 months for NVBO+CDDP arm and 1.68-18.20 months for GEM+CDDP arm, respectively. The estimated median duration of disease control was 4.8 months [95% CI: 4.1; 5.7] in NVBO+CDDP arm and 5.2 months [95% CI: 4.3; 6.6] in GEM+CDDP arm. Duration of disease control was estimated using Kaplan-Meier analyses. CIs on the median were calculated using the Brookmeyer and Crowley method.
    End point type
    Secondary
    End point timeframe
    Duration of disease control according to investigator was calculated among the BOCR stable patients from the date of randomisation until the documentation of progression or death due to any cause.
    End point values
    		 NVBO+CDDP arm: GEM + CDDP arm
    Number of subjects analysed
    57
    56
    Units: months
        median (confidence interval 95%)
    4.8 (4.1 to 5.7)
    5.2 (4.3 to 6.6)
    Attachments
    		 KM curve of the duration of disease control
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    PFS was analysed in the ITT population and estimated using Kaplan-Meier approachs. CIs on the median were calculated using the Brookmeyer and Crowley method. Patients who were lost to follow-up, or reached the time point of analysis without a known record of progression or death had the PFS censored at the date of last tumour assessment or last contact showing no progression or death, whichever occurred last. In the ITT population, the disease progressed in 36 (64.3%) from NVBO+CDDP arm and 40 patients (74.1%) during the treatment.
    End point type
    Secondary
    End point timeframe
    PFS was calculated from the date of randomisation until the date of progression (first date where PD is assessed) or the date of death due to any cause if no progression was recorded before. The mean duration of follow-up was 11.52 vs 11.09 months.
    End point values
    		 NVBO+CDDP arm: GEM + CDDP arm
    Number of subjects analysed
    57
    56
    Units: months
        median (confidence interval 95%)
    4.2 (2.8 to 4.9)
    4.3 (3.1 to 5.5)
    Attachments
    		 Progression Free Survival- Survival curves - Kapla
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was analysed in the ITT population on the whole study period and estimated using Kaplan-Meier analyses. CIs on the median were calculated using the Brookmeyer and Crowley method. Patients who were lost to follow-up, or reached the time point of analysis without a known record of progression or death had the PFS censored at the date of last tumour assessment or last contact showing no progression or death, whichever occurred last. At the cutoff date (19-May-2017) or last contact, death was reported for 98 patients (86%) while 13 patients (11.4%) were still alive. Two patients (1.8%) were lost to follow-up and one patient remained untreated (0.9%).
    End point type
    Secondary
    End point timeframe
    OS was the duration between the date of randomisation and the date of death (any cause). Patients lost to fup or without a known record of death were censored at the date of last contact. For alive patients, survival time was censored at date of last news
    End point values
    		 NVBO+CDDP arm: GEM + CDDP arm
    Number of subjects analysed
    57
    56
    Units: months
        median (confidence interval 95%)
    10.2 (6.9 to 12.9)
    8.4 (5.3 to 11.9)
    Attachments
    		 Overall Survival time - Kaplan-M
    No statistical analyses for this end point

    Secondary: Time to first response

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    End point title
    		 Time to first response
    End point description
    Time to first response was calculated using Kaplan-Meier cumulative incidence. In the ITT population, the estimated time to first response ranged in NVBO+CDDP arm (n=14) from 1.1-2.8 months and 1.2-4.1 months in GEM+CDDP arm (n=17). The estimated median time to first response was 1.6 months [95% CI: 1.2; 2.7] in NVBO+CDDP arm and 1.5 months [95% CI: 1.3; 2.7] in GEM+CDDP arm.
    End point type
    Secondary
    End point timeframe
    Time to first response was calculated among responders (confirmed CR and PR) in the ITT population from the date of randomisation up to the first report of documented response. The date of first response was the first date where CR or PR was assessed.
    End point values
    		 NVBO+CDDP arm: GEM + CDDP arm
    Number of subjects analysed
    57
    56
    Units: months
        median (confidence interval 95%)
    1.6 (1.2 to 2.7)
    1.5 (1.3 to 2.7)
    Attachments
    		 Time to first response
    No statistical analyses for this end point

    Other pre-specified: Anti-cancer treatment during follow-up

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    End point title
    		 Anti-cancer treatment during follow-up
    End point description
    The number of patients with further CT and other therapy during follow-up period was presented in the ITT population. About 20% of the patients had further CT and other therapy during the follow-up period. Around 49% patients in NVBO+CDDP arm and around 27% patients in GEM+CDDP arm had at least one further CT.
    End point type
    Other pre-specified
    End point timeframe
    The number of patients with anti-cancer treatment was measured during the follow-up period (time from 30 days after the last study treatment administration until death or decision for study closure or last contact).
    End point values
    		 NVBO+CDDP arm: GEM + CDDP arm
    Number of subjects analysed
    57
    56
    Units: patients
        Patients with at least one further chemotherapy
    28
    15
        Patients with at least one further other therapy
    23
    20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any adverse or intercurrent event occurring during the study period was recorded in the CRF. All SAEs occurring after signing of the ICF and up to 30 days after the last study administration.
    Adverse event reporting additional description
    At the cutoff date (19-May-17) or last contact, death was reported for 98 patients while 13 patients were still alive. 2 patients were lost to follow-up and 1 patient remained untreated. The RDI during the whole study treatment period was 86.05% for NVBO treatment in NVBO+CDDP arm and 82.16% for GEM treatment in GEM+CDDP arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    NVBO + CDDP arm
    Reporting group description
    		 -

    Reporting group title
    GEM + CDDP arm
    Reporting group description
    		 -

    Serious adverse events
    		 NVBO + CDDP arm GEM + CDDP arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 57 (50.88%)
    31 / 56 (55.36%)
         number of deaths (all causes)
    51
    47
         number of deaths resulting from adverse events
    3
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial insufficiency
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 57 (1.75%)
    6 / 56 (10.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 56 (5.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 57 (7.02%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 57 (7.02%)
    4 / 56 (7.14%)
         occurrences causally related to treatment / all
    5 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 57 (12.28%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    6 / 57 (10.53%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 56 (5.36%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure acute
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 57 (1.75%)
    5 / 56 (8.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 56 (5.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NVBO + CDDP arm GEM + CDDP arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 57 (100.00%)
    56 / 56 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    5 / 57 (8.77%)
    5 / 56 (8.93%)
         occurrences all number
    20
    12
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 57 (10.53%)
    4 / 56 (7.14%)
         occurrences all number
    12
    4
    Hypotension
         subjects affected / exposed
    5 / 57 (8.77%)
    5 / 56 (8.93%)
         occurrences all number
    6
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    46 / 57 (80.70%)
    43 / 56 (76.79%)
         occurrences all number
    132
    112
    Chest pain
         subjects affected / exposed
    14 / 57 (24.56%)
    12 / 56 (21.43%)
         occurrences all number
    34
    47
    Pyrexia
         subjects affected / exposed
    7 / 57 (12.28%)
    8 / 56 (14.29%)
         occurrences all number
    8
    11
    Asthenia
         subjects affected / exposed
    4 / 57 (7.02%)
    7 / 56 (12.50%)
         occurrences all number
    6
    19
    Oedema peripheral
         subjects affected / exposed
    2 / 57 (3.51%)
    7 / 56 (12.50%)
         occurrences all number
    3
    16
    Pain
         subjects affected / exposed
    4 / 57 (7.02%)
    5 / 56 (8.93%)
         occurrences all number
    9
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 57 (40.35%)
    31 / 56 (55.36%)
         occurrences all number
    75
    105
    Dyspnoea
         subjects affected / exposed
    20 / 57 (35.09%)
    30 / 56 (53.57%)
         occurrences all number
    48
    66
    Haemoptysis
         subjects affected / exposed
    3 / 57 (5.26%)
    9 / 56 (16.07%)
         occurrences all number
    10
    10
    Dysphonia
         subjects affected / exposed
    5 / 57 (8.77%)
    1 / 56 (1.79%)
         occurrences all number
    14
    2
    Productive cough
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 56 (5.36%)
         occurrences all number
    4
    11
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 57 (14.04%)
    7 / 56 (12.50%)
         occurrences all number
    21
    20
    Insomnia
         subjects affected / exposed
    8 / 57 (14.04%)
    6 / 56 (10.71%)
         occurrences all number
    14
    10
    Investigations
    Weight decreased
         subjects affected / exposed
    19 / 57 (33.33%)
    21 / 56 (37.50%)
         occurrences all number
    48
    57
    Weight increased
         subjects affected / exposed
    9 / 57 (15.79%)
    13 / 56 (23.21%)
         occurrences all number
    18
    63
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 56 (5.36%)
         occurrences all number
    3
    4
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    4 / 57 (7.02%)
    2 / 56 (3.57%)
         occurrences all number
    7
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 57 (10.53%)
    4 / 56 (7.14%)
         occurrences all number
    8
    31
    Dysgeusia
         subjects affected / exposed
    6 / 57 (10.53%)
    3 / 56 (5.36%)
         occurrences all number
    9
    6
    Paraesthesia
         subjects affected / exposed
    4 / 57 (7.02%)
    4 / 56 (7.14%)
         occurrences all number
    8
    16
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    6 / 57 (10.53%)
    8 / 56 (14.29%)
         occurrences all number
    11
    19
    Deafness
         subjects affected / exposed
    4 / 57 (7.02%)
    5 / 56 (8.93%)
         occurrences all number
    12
    14
    Eye disorders
    Eye disorder
         subjects affected / exposed
    5 / 57 (8.77%)
    5 / 56 (8.93%)
         occurrences all number
    15
    13
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    30 / 57 (52.63%)
    28 / 56 (50.00%)
         occurrences all number
    67
    86
    Vomiting
         subjects affected / exposed
    23 / 57 (40.35%)
    12 / 56 (21.43%)
         occurrences all number
    33
    24
    Constipation
         subjects affected / exposed
    17 / 57 (29.82%)
    17 / 56 (30.36%)
         occurrences all number
    33
    30
    Diarrhoea
         subjects affected / exposed
    18 / 57 (31.58%)
    9 / 56 (16.07%)
         occurrences all number
    29
    12
    Abdominal pain
         subjects affected / exposed
    11 / 57 (19.30%)
    7 / 56 (12.50%)
         occurrences all number
    13
    13
    Stomatitis
         subjects affected / exposed
    3 / 57 (5.26%)
    13 / 56 (23.21%)
         occurrences all number
    5
    32
    Abdominal pain upper
         subjects affected / exposed
    3 / 57 (5.26%)
    7 / 56 (12.50%)
         occurrences all number
    7
    19
    Dyspepsia
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 56 (7.14%)
         occurrences all number
    3
    6
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 57 (8.77%)
    12 / 56 (21.43%)
         occurrences all number
    19
    56
    Dry skin
         subjects affected / exposed
    4 / 57 (7.02%)
    3 / 56 (5.36%)
         occurrences all number
    7
    4
    Pruritus
         subjects affected / exposed
    4 / 57 (7.02%)
    3 / 56 (5.36%)
         occurrences all number
    7
    5
    Renal and urinary disorders
    renal and urinary disorders
         subjects affected / exposed
    3 / 57 (5.26%)
    7 / 56 (12.50%)
         occurrences all number
    5
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 57 (10.53%)
    6 / 56 (10.71%)
         occurrences all number
    12
    6
    Back pain
         subjects affected / exposed
    5 / 57 (8.77%)
    7 / 56 (12.50%)
         occurrences all number
    11
    34
    Pain in extremity
         subjects affected / exposed
    7 / 57 (12.28%)
    3 / 56 (5.36%)
         occurrences all number
    8
    3
    Musculoskeletal pain
         subjects affected / exposed
    3 / 57 (5.26%)
    6 / 56 (10.71%)
         occurrences all number
    3
    17
    Bone pain
         subjects affected / exposed
    4 / 57 (7.02%)
    4 / 56 (7.14%)
         occurrences all number
    11
    15
    Musculoskeletal chest pain
         subjects affected / exposed
    7 / 57 (12.28%)
    0 / 56 (0.00%)
         occurrences all number
    16
    0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 56 (7.14%)
         occurrences all number
    3
    4
    Bronchitis
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 56 (5.36%)
         occurrences all number
    4
    3
    Rhinitis
         subjects affected / exposed
    4 / 57 (7.02%)
    2 / 56 (3.57%)
         occurrences all number
    7
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 57 (28.07%)
    20 / 56 (35.71%)
         occurrences all number
    34
    58

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2012
    The rationale of this amendment is to extend the duration of contraception after chemotherapy with cisplatin to 6 months for patients of both sexes and with gemcitabine to 6 months for men only. In addition, typing errors regarding cisplatin and gemcitabine storage have been corrected in this amendment. These are based on the current summary of product characteristics of cisplatin and gemcitabine.
    28 Mar 2014
    The objectives of this amendment are: - to extend the recruitment period until 31 December 2014, considering that the expected accrual is not reached, - to clarify the assessments of Biochemistry tests. - to update the Sponsor’s Personnel, - to update the Investigator’s Brochure, - to update the World Medical Association Declaration of Helsinki (October 2013).
    21 Oct 2014
    The objective of this amendment is to extend the recruitment period until 30 June 2015, considering that the expected accrual is not reached.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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