Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    INTERNATIONAL RANDOMIZED PHASE II TRIAL OF THE COMBINATION OF VINCRISTINE AND IRINOTECAN WITH OR WITHOUT TEMOZOLOMIDE (VI OR VIT) IN CHILDREN AND ADULTS WITH REFRACTORY OR RELAPSED RHABDOMYOSARCOMA

    Summary
    EudraCT number
    		 2010-023135-42
    Trial protocol
    		 FR   NL   ES   GB   IT  
    Global end of trial date
    25 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 May 2024
    First version publication date
    10 May 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VIT-0910
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 VHP: 201116, ClinicalTrials.gov: NCT01355445
    Sponsors
    Sponsor organisation name
    Centre Oscar Lambret
    Sponsor organisation address
    3 rue Frédéric Combemale – BP307, LILLE, France, 59020
    Public contact
    CELLULE PROMOTION, Centre Oscar Lambret, 33 320295918, promotion@o-lambret.fr
    Scientific contact
    Anne-Sophie Defachelles, Centre Oscar Lambret, 33 320295918, promotion@o-lambret.fr
    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
    12 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of the combination of temozolomide with vincristine and irinotecan in children and adult patients with refractory or relapsed rhabdomyosarcoma as assessed by confirmed objective tumor response after 2 courses
    Protection of trial subjects
    This study will be conducted in accordance with the ethical principles of the 1964 Helsinki declaration, revised in 2013 in Fortaleza, with the rules of Good Clinical Practice (GCP) defined by the International Conference on Harmonization (ICH-E6, 17/7/96). The clinical trial may not begin before approval of the Ethics Committees and authorization by competent authorities concerned is obtained.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jun 2011
    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
    Netherlands: 16
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    France: 57
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    120
    EEA total number of subjects
    86
    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)
    2
    Children (2-11 years)
    60
    Adolescents (12-17 years)
    32
    Adults (18-64 years)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The trial was opened in 37 centres, from five countries (France, United Kingdom, Netherland, Italy, Spain). 120 patients were enrolled from 14.03.2012 to 06.04.2018.

    Pre-assignment
    Screening details
    		 Firstly, 80 patients were included between 14.03.2012 and 19.06.2014. As preliminary results indicated that more precision was needed, 40 additional patients in the relapse status have been enrolled between 17.06.2016 and 06.04.2018, up to 120 patients (60 patients in the VI arm and 60 patients in the VIT arm).

    Period 1
    Period 1 title
    Overall trial (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 VI
    Arm description
    		 The treatment was given every 3 weeks. Vincristine was given by intravenous infusion on day 1 and day 8 of each course before irinotecan Irinotecan was given by intravenous infusion on day 1 and day 5 of each course.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    1.5 mg/m² or 0.05 mg/kg for patient ≤ 10 kg (maximum 2.0 mg) on day 1 and 8 of each course (every 3 weeks)

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    50 mg/m²/day given intravenously infusion over 1 hour on days 1-5 of each course (every 3 weeks)

    Arm title
    		 Arm VIT
    Arm description
    		 The treatment was given every 3 weeks. Vincristine was given by intravenous infusion on day 1 and day 8 of each course before irinotecan Irinotecan was given by intravenous infusion on day 1 and day 5 of each course, one hour following the administration of temozolide (TMZ). TMZ was given orally, prior to vincristine and irinotecan, on days 1-5 repeated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    1.5 mg/m² or 0.05 mg/kg for patient ≤ 10 kg (maximum 2.0 mg) on day 1 and 8 of each course (every 3 weeks)

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    50 mg/m²/day given intravenously infusion over 1 hour on days 1-5 of each course (every 3 weeks), one hour following the administration of temozolide (TMZ).

    Investigational medicinal product name
    Temozolide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose of TMZ was 125 mg/m²/day. The dose of TMZ was to be escalated to 150 mg/m²/day at cycle 2 for patients who did not experience > grade 3 toxicity of any kind. The dose of TMZ was rounded to the nearest 5 mg. TMZ was given orally, on an empty stomach, prior to vincristine and irinotecan, on days 1-5 repeated every 3-weeks. If the patient vomited within 20 minutes after TMZ, the dose had to be re-administered.

    Number of subjects in period 1
    		Arm VI Arm VIT
    Started
    60
    60
    Completed
    58
    60
    Not completed
    2
    0
         Patient decision
    1
    -
         patient ineligible after amendment
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm VI
    Reporting group description
    		 The treatment was given every 3 weeks. Vincristine was given by intravenous infusion on day 1 and day 8 of each course before irinotecan Irinotecan was given by intravenous infusion on day 1 and day 5 of each course.

    Reporting group title
    Arm VIT
    Reporting group description
    		 The treatment was given every 3 weeks. Vincristine was given by intravenous infusion on day 1 and day 8 of each course before irinotecan Irinotecan was given by intravenous infusion on day 1 and day 5 of each course, one hour following the administration of temozolide (TMZ). TMZ was given orally, prior to vincristine and irinotecan, on days 1-5 repeated.

    Reporting group values
    		 Arm VI Arm VIT Total
    Number of subjects
    		 60 60 120
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 0 2 2
        Children (2-11 years)
    		 33 27 60
        Adolescents (12-17 years)
    		 15 17 32
        Adults (18-64 years)
    		 12 14 26
    Age continuous
    Units: years
        median (full range (min-max))
    		 10.5 (3 to 45) 12 (1 to 45) -
    Gender categorical
    Units: Subjects
        Female
    		 18 28 46
        Male
    		 42 32 74

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Arm VI
    Reporting group description
    		 The treatment was given every 3 weeks. Vincristine was given by intravenous infusion on day 1 and day 8 of each course before irinotecan Irinotecan was given by intravenous infusion on day 1 and day 5 of each course.

    Reporting group title
    Arm VIT
    Reporting group description
    		 The treatment was given every 3 weeks. Vincristine was given by intravenous infusion on day 1 and day 8 of each course before irinotecan Irinotecan was given by intravenous infusion on day 1 and day 5 of each course, one hour following the administration of temozolide (TMZ). TMZ was given orally, prior to vincristine and irinotecan, on days 1-5 repeated.

    Primary: Objective response rate (ORR) after 2 courses of treatment in each arm (VI, VIT)

    		 Close Top of page
    End point title
    		 Objective response rate (ORR) after 2 courses of treatment in each arm (VI, VIT)
    End point description
    The primary efficacy endpoint is defined as the documented objective response, i.e. complete or partial response, after the first 2 cycles of treatment, based on central radiological review. Responses have been evaluated using the three-dimension WHO response criteria for the primary lesions and according to RECIST 1.1 criteria for metastatic sites. Patients who had a clinical progression reported before 2 cycles with no radiological confirmation of the progression were counted as progressions (all of them died shortly after the diagnosis of progression). A radiological review by the independent radiological experts’ committee has been done for 88 cases. For the others, evaluation from the center has been taking into account.
    End point type
    Primary
    End point timeframe
    From start of treatment to 2 courses of treatment
    End point values
    		 Arm VI Arm VIT
    Number of subjects analysed
    58
    55
    Units: Number of participants
    18
    24
    Statistical analysis title
    		 ORR between two arms
    Statistical analysis description
    A multivariate logistic regression gives the adjusted odds ratio of treatment failure (no objective response) for the VIT arm compared to the VI arm. Model is adjusted on possible confounding factors in the treatment arm effect estimate: histology (non-alveolar vs alveolar), disease staging at study entry (metastatic vs loco-regional) and disease status (refractory vs relapse).
    Comparison groups
    Arm VIT v Arm VI
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.09
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 1.12
    Notes
    [1] - bilateral test

    Secondary: Best overall response over the treatment duration in each arm (VI, VIT)

    		 Close Top of page
    End point title
    		 Best overall response over the treatment duration in each arm (VI, VIT)
    End point description
    Best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started) over the whole treatment duration, using the three-dimension WHO response criteria for the primary lesions and according to RECIST 1.1 criteria for metastatic sites, based on central radiological review when available, and excluding response related to local treatment. Objective response as best response includes complete response and partial response as best response.
    End point type
    Secondary
    End point timeframe
    Start of treatment to end of treatment (before local treatment if any)
    End point values
    		 Arm VI Arm VIT
    Number of subjects analysed
    58
    58
    Units: Number of participants
        Objective Response
    22
    33
        Complete Response
    4
    9
        Partial Response
    18
    24
        Minor Partial Response
    1
    3
        Stable Disease
    16
    13
        Progressive Disease
    19
    9
    Statistical analysis title
    		 Best overall response between two arms
    Statistical analysis description
    A multivariate logistic regression gives the adjusted odds ratio of non-objective response for the best overall response for the VIT arm compared to the VI arm. Model is adjusted on possible confounding factors in the treatment arm effect estimate: histology (non-alveolar vs alveolar), disease staging at study entry (metastatic vs loco-regional) and disease status (refractory vs relapse).
    Comparison groups
    Arm VI v Arm VIT
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.023
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.88
    Notes
    [2] - bilateral

    Secondary: Duration of treatment response in each arm (VI, VIT)

    		 Close Top of page
    End point title
    		 Duration of treatment response in each arm (VI, VIT)
    End point description
    Overall, 55 patients (22 VI and 33 VIT) had achieved an objective response under study treatment and before local treatment, and are thus evaluable for the duration of response. Duration of response defined as the time from first documentation of objective tumour response to the first objective or clinical documentation of progression, as defined by the radiological review committee when available, based on the information from the treating centre in the other cases. Patients without progression will be censored at the date of death or at the date of last news.
    End point type
    Secondary
    End point timeframe
    From first documentation of objective tumour response to date of last news.
    End point values
    		 Arm VI Arm VIT
    Number of subjects analysed
    22
    33
    Units: Months
        median (confidence interval 95%)
    8.8 (2.5 to 20.1)
    12.3 (2.9 to 20.9)
    Statistical analysis title
    		 Treatment response between two arms
    Statistical analysis description
    A multivariate Cox model gives the adjusted hazard ratio of progression after objective response under treatment for the VIT arm compared to the VI arm. Model is adjusted on possible confounding factors in the treatment arm effect estimate: histology (non-alveolar vs alveolar), disease staging at study entry (metastatic vs loco-regional) and disease status (refractory vs relapse).
    Comparison groups
    Arm VI v Arm VIT
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.282
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.35
    Notes
    [3] - bilateral test

    Secondary: Progression-free survival (PFS) in each arm (VI, VIT)

    		 Close Top of page
    End point title
    		 Progression-free survival (PFS) in each arm (VI, VIT)
    End point description
    Progression-free survival defined as the time interval from the date of first treatment administration (or date of randomization for untreated patients) to the date of first objective or clinical documentation of tumour progression or death due to any cause. Patients alive without progression will be censored at the date of last news. Progression was defined according to WHO criteria for the primary tumour and RECIST 1.1 criteria for metastatic sites, based on central review when available, on the evaluation from the treating centre in the other cases. Patients who had a clinical progression according to the treating physician with no radiological confirmation of the progression but who died shortly after the diagnosis of progression were counted as progressions at the corresponding date.
    End point type
    Secondary
    End point timeframe
    Start of treatment (or date of randomization for untreated patients) to date of last news.
    End point values
    		 Arm VI Arm VIT
    Number of subjects analysed
    58
    60
    Units: Months
        median (confidence interval 95%)
    3.2 (2.4 to 6.7)
    4.7 (4.1 to 8.5)
    Statistical analysis title
    		 PFS between two arms
    Statistical analysis description
    A multivariate Cox model gives the adjusted hazard ratio of progression for the VIT arm compared to the VI arm. Model is adjusted on possible confounding factors in the treatment arm effect estimate: histology (non-alveolar vs alveolar), disease staging at study entry (metastatic vs loco-regional) and disease status (refractory vs relapse).
    Comparison groups
    Arm VIT v Arm VI
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.036
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.97
    Notes
    [4] - bilateral test

    Secondary: Time to treatment failure in each arm (VI, VIT)

    		 Close Top of page
    End point title
    		 Time to treatment failure in each arm (VI, VIT)
    End point description
    Time to treatment failure defined as the time interval from the date of first treatment administration to the first documentation of treatment failure, defined as tumour progression, discontinuation of study treatment before one year, or death, whichever occurs first. Data of patients still on-treatment at last follow-up were censored at the date of last treatment administration.
    End point type
    Secondary
    End point timeframe
    Start of treatment (or date of randomization for untreated patients) to date of last news before one year.
    End point values
    		 Arm VI Arm VIT
    Number of subjects analysed
    58
    60
    Units: Months
        median (confidence interval 95%)
    2.8 (1.64 to 3.21)
    3.99 (2.99 to 4.40)
    Statistical analysis title
    		 Treatment failure between two arms
    Statistical analysis description
    A multivariate Cox model gives the adjusted hazard ratio of treatment failure for the VIT arm compared to the VI arm. Model is adjusted on possible confounding factors in the treatment arm effect estimate: histology (non-alveolar vs alveolar), disease staging at study entry (metastatic vs loco-regional) and disease status (refractory vs relapse).
    Comparison groups
    Arm VIT v Arm VI
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.0391
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.24
    Notes
    [5] - bilateral test

    Secondary: Overall survival (OS) failure in each arm (VI, VIT)

    		 Close Top of page
    End point title
    		 Overall survival (OS) failure in each arm (VI, VIT)
    End point description
    Overall survival defined as the time interval from the date of first treatment administration (or date of randomization for untreated patients) to date of death from any cause. Patients alive will be censored at the date of last news.
    End point type
    Secondary
    End point timeframe
    Start of treatment (or date of randomization for untreated patients) to date of last news.
    End point values
    		 Arm VI Arm VIT
    Number of subjects analysed
    58
    60
    Units: Months
        median (confidence interval 95%)
    10.0 (7.1 to 12.6)
    15.0 (10.0 to 21.2)
    Statistical analysis title
    		 OS between two arms
    Statistical analysis description
    A multivariate Cox model gives the adjusted hazard ratio of death for the VIT arm compared to the VI arm. Model is adjusted on possible confounding factors in the treatment arm effect estimate: histology (non-alveolar vs alveolar), disease staging at study entry (metastatic vs loco-regional) and disease status (refractory vs relapse).
    Comparison groups
    Arm VI v Arm VIT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.53
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.83
    Notes
    [6] - bilateral test

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    The AE reporting period begins upon signature of the informed consent form by the study subject and ends 30 days after last study treatment dose.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Arm VI
    Reporting group description
    		 -

    Reporting group title
    Arm VIT
    Reporting group description
    		 -

    Serious adverse events
    		 Arm VI Arm VIT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 54 (42.59%)
    28 / 58 (48.28%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    0
    Investigations
    NEUTROPENIA
    Additional description: NEUTROPENIA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR PAIN
    Additional description: TUMOUR PAIN
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    EMBOLISM
    Additional description: EMBOLISM
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    APHASIA
    Additional description: APHASIA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
    Additional description: DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HEADACHE
    Additional description: HEADACHE
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDROCEPHALUS
    Additional description: HYDROCEPHALUS
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MYOCLONIC
    Additional description: MYOCLONIC
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL NEUROPATHY
    Additional description: PERIPHERAL NEUROPATHY
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
    Additional description: SEIZURE
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
    Additional description: SYNCOPE
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ANOREXIA
    Additional description: ANOREXIA
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASTHENIA
    Additional description: ASTHENIA
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
    Additional description: GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HYPERTHERMIA
    Additional description: HYPERTHERMIA
         subjects affected / exposed
    2 / 54 (3.70%)
    4 / 58 (6.90%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN, OTHER
    Additional description: PAIN, OTHER
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT DECREASED
    Additional description: WEIGHT DECREASED
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
    Additional description: ABDOMINAL PAIN
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
    Additional description: ASCITES
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
    Additional description: COLITIS
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
    Additional description: CONSTIPATION
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
    Additional description: DIARRHOEA
         subjects affected / exposed
    4 / 54 (7.41%)
    10 / 58 (17.24%)
         occurrences causally related to treatment / all
    4 / 6
    14 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTUSSUSCEPTION
    Additional description: INTUSSUSCEPTION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
    Additional description: LARGE INTESTINE PERFORATION
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
    Additional description: NAUSEA
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
    Additional description: PANCREATITIS
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
    Additional description: SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
    Additional description: VOMITING
         subjects affected / exposed
    4 / 54 (7.41%)
    10 / 58 (17.24%)
         occurrences causally related to treatment / all
    3 / 4
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLESTASIS
    Additional description: CHOLESTASIS
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER DISORDER
    Additional description: LIVER DISORDER
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
    Additional description: DYSPNOEA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BACTERIAL INFECTION, NOS
    Additional description: BACTERIAL INFECTION, NOS
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS INFECTIVE
    Additional description: CHOLECYSTITIS INFECTIVE
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
    Additional description: CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
    Additional description: DEVICE RELATED INFECTION
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
    Additional description: FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 54 (5.56%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    1 / 4
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FUNGIC INFECTION
    Additional description: FUNGIC INFECTION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
    Additional description: SEPSIS
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
    Additional description: URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL INFECTION
    Additional description: VIRAL INFECTION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
    Additional description: WOUND INFECTION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
    Additional description: DEHYDRATION
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
    Additional description: HYPOKALAEMIA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
    Additional description: HYPONATRAEMIA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm VI Arm VIT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 54 (100.00%)
    58 / 58 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR PAIN
    Additional description: TUMOUR PAIN
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 58 (3.45%)
         occurrences all number
    5
    2
    Vascular disorders
    EPISTAXIS
    Additional description: EPISTAXIS
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    HAEMATOMA
    Additional description: HAEMATOMA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    HOT FLUSH
    Additional description: HOT FLUSH
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    HYPERTENSION
    Additional description: HYPERTENSION
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 58 (3.45%)
         occurrences all number
    2
    2
    HYPOTENSION
    Additional description: HYPOTENSION
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    MENO/METRORRHAGIA
    Additional description: MENO/METRORRHAGIA
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    2
    PURPURA
    Additional description: PURPURA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    ANOREXIA
    Additional description: ANOREXIA
         subjects affected / exposed
    8 / 54 (14.81%)
    15 / 58 (25.86%)
         occurrences all number
    9
    24
    ASTHENIA
    Additional description: ASTHENIA
         subjects affected / exposed
    16 / 54 (29.63%)
    29 / 58 (50.00%)
         occurrences all number
    27
    52
    FACE OEDEMA
    Additional description: FACE OEDEMA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    HYPERTHERMIA
    Additional description: HYPERTHERMIA
         subjects affected / exposed
    6 / 54 (11.11%)
    4 / 58 (6.90%)
         occurrences all number
    12
    5
    MALAISE
    Additional description: MALAISE
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    OEDEMA PERIPHERAL
    Additional description: OEDEMA PERIPHERAL
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 58 (1.72%)
         occurrences all number
    4
    1
    PAIN, OTHER
    Additional description: PAIN, OTHER
         subjects affected / exposed
    7 / 54 (12.96%)
    8 / 58 (13.79%)
         occurrences all number
    8
    9
    WEIGHT DECREASED
    Additional description: WEIGHT DECREASED
         subjects affected / exposed
    8 / 54 (14.81%)
    10 / 58 (17.24%)
         occurrences all number
    9
    14
    Immune system disorders
    CHOLINERGIC SYNDROME
    Additional description: CHOLINERGIC SYNDROME
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    DERMATITIS ALLERGIC
    Additional description: DERMATITIS ALLERGIC
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    HYPERSENSITIVITY
    Additional description: HYPERSENSITIVITY
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    SEASONAL ALLERGY
    Additional description: SEASONAL ALLERGY
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
    Additional description: COUGH
         subjects affected / exposed
    6 / 54 (11.11%)
    6 / 58 (10.34%)
         occurrences all number
    8
    9
    DYSPNOEA
    Additional description: DYSPNOEA
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 58 (1.72%)
         occurrences all number
    3
    1
    NASAL DISCOMFORT
    Additional description: NASAL DISCOMFORT
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    THROAT IRRITATION
    Additional description: THROAT IRRITATION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    Psychiatric disorders
    AFFECT LABILITY
    Additional description: AFFECT LABILITY
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    AGITATION
    Additional description: AGITATION
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    2
    ANXIETY
    Additional description: ANXIETY
         subjects affected / exposed
    2 / 54 (3.70%)
    4 / 58 (6.90%)
         occurrences all number
    2
    4
    DELIRIUM
    Additional description: DELIRIUM
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    DEPRESSION
    Additional description: DEPRESSION
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    INSOMNIA
    Additional description: INSOMNIA
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences all number
    1
    2
    SLEEP TERROR
    Additional description: SLEEP TERROR
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Investigations
    ANAEMIA
    Additional description: ANAEMIA
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    4
    HYPOALBUMINEMIA
    Additional description: HYPOALBUMINEMIA
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    4
    HYPOKALAEMIA
    Additional description: HYPOKALAEMIA
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences all number
    1
    2
    HYPONATRAEMIA
    Additional description: HYPONATRAEMIA
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    HYPOPHOSPHATAEMIA
    Additional description: HYPOPHOSPHATAEMIA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    LEUKOPENIA
    Additional description: LEUKOPENIA
         subjects affected / exposed
    4 / 54 (7.41%)
    6 / 58 (10.34%)
         occurrences all number
    17
    15
    LYMPHOCYTOSIS
    Additional description: LYMPHOCYTOSIS
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    2
    LYMPHOPENIA
    Additional description: LYMPHOPENIA
         subjects affected / exposed
    3 / 54 (5.56%)
    4 / 58 (6.90%)
         occurrences all number
    12
    5
    NEUTROPENIA
    Additional description: NEUTROPENIA
         subjects affected / exposed
    8 / 54 (14.81%)
    15 / 58 (25.86%)
         occurrences all number
    27
    31
    THROMBOCYTOPENIA
    Additional description: THROMBOCYTOPENIA
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 58 (3.45%)
         occurrences all number
    2
    2
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
    Additional description: INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    INJURY
    Additional description: INJURY
         subjects affected / exposed
    0 / 54 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    0
    4
    Cardiac disorders
    BRADYCARDIA
    Additional description: BRADYCARDIA
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    PALPITATIONS
    Additional description: PALPITATIONS
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    TACHYCARDIA
    Additional description: TACHYCARDIA
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 58 (5.17%)
         occurrences all number
    2
    3
    Nervous system disorders
    AGEUSIA
    Additional description: AGEUSIA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    CRANIAL NERVE DISORDER
    Additional description: CRANIAL NERVE DISORDER
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 58 (1.72%)
         occurrences all number
    2
    1
    DEPRESSED LEVEL OF CONSCIOUSNESS
    Additional description: DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences all number
    1
    2
    DIZZINESS
    Additional description: DIZZINESS
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    DYSGEUSIA
    Additional description: DYSGEUSIA
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    3
    HEADACHE
    Additional description: HEADACHE
         subjects affected / exposed
    6 / 54 (11.11%)
    10 / 58 (17.24%)
         occurrences all number
    7
    19
    HEMIPLEGIA
    Additional description: HEMIPLEGIA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    HYPOAESTHESIA
    Additional description: HYPOAESTHESIA
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 58 (1.72%)
         occurrences all number
    2
    2
    MEMORY IMPAIRMENT
    Additional description: MEMORY IMPAIRMENT
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    MONOPLEGIA
    Additional description: MONOPLEGIA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    NEURALGIA
    Additional description: NEURALGIA
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 58 (1.72%)
         occurrences all number
    2
    1
    NEUROTOXICITY, NOS
    Additional description: NEUROTOXICITY, NOS
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    PERIPHERAL NEUROPATHY
    Additional description: PERIPHERAL NEUROPATHY
         subjects affected / exposed
    8 / 54 (14.81%)
    16 / 58 (27.59%)
         occurrences all number
    9
    22
    PSYCHOMOTOR HYPERACTIVITY
    Additional description: PSYCHOMOTOR HYPERACTIVITY
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    SEIZURE
    Additional description: SEIZURE
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    SYNCOPE
    Additional description: SYNCOPE
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    TREMOR
    Additional description: TREMOR
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    ANAEMIA
    Additional description: ANAEMIA
         subjects affected / exposed
    54 / 54 (100.00%)
    58 / 58 (100.00%)
         occurrences all number
    1479
    1609
    LEUKOPENIA
    Additional description: LEUKOPENIA
         subjects affected / exposed
    9 / 54 (16.67%)
    14 / 58 (24.14%)
         occurrences all number
    18
    25
    LYMPHOPENIA
    Additional description: LYMPHOPENIA
         subjects affected / exposed
    7 / 54 (12.96%)
    9 / 58 (15.52%)
         occurrences all number
    17
    14
    NEUTROPENIA
    Additional description: NEUTROPENIA
         subjects affected / exposed
    54 / 54 (100.00%)
    58 / 58 (100.00%)
         occurrences all number
    360
    476
    THROMBOCYTOPENIA
    Additional description: THROMBOCYTOPENIA
         subjects affected / exposed
    5 / 54 (9.26%)
    5 / 58 (8.62%)
         occurrences all number
    8
    6
    Ear and labyrinth disorders
    DEAFNESS UNILATERAL
    Additional description: DEAFNESS UNILATERAL
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    Eye disorders
    DIPLOPIA
    Additional description: DIPLOPIA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    DRY EYE
    Additional description: DRY EYE
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    EYE DISORDER
    Additional description: EYE DISORDER
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    EYELID OEDEMA
    Additional description: EYELID OEDEMA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    PAPILLOEDEMA
    Additional description: PAPILLOEDEMA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    PHOTOPHOBIA
    Additional description: PHOTOPHOBIA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    VISUAL IMPAIRMENT
    Additional description: VISUAL IMPAIRMENT
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
    Additional description: ABDOMINAL DISTENSION
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    ABDOMINAL PAIN
    Additional description: ABDOMINAL PAIN
         subjects affected / exposed
    20 / 54 (37.04%)
    29 / 58 (50.00%)
         occurrences all number
    29
    58
    ANAL HAEMORRHAGE
    Additional description: ANAL HAEMORRHAGE
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    ANAL INCONTINENCE
    Additional description: ANAL INCONTINENCE
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    ANORECTAL DISORDER
    Additional description: ANORECTAL DISORDER
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    CONSTIPATION
    Additional description: CONSTIPATION
         subjects affected / exposed
    10 / 54 (18.52%)
    22 / 58 (37.93%)
         occurrences all number
    12
    30
    DIARRHOEA
    Additional description: DIARRHOEA
         subjects affected / exposed
    43 / 54 (79.63%)
    48 / 58 (82.76%)
         occurrences all number
    107
    162
    DYSPEPSIA
    Additional description: DYSPEPSIA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    2
    GASTROOESOPHAGEAL REFLUX DISEASE
    Additional description: GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    NAUSEA
    Additional description: NAUSEA
         subjects affected / exposed
    24 / 54 (44.44%)
    34 / 58 (58.62%)
         occurrences all number
    47
    77
    OESOPHAGITIS
    Additional description: OESOPHAGITIS
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    PANCREATITIS
    Additional description: PANCREATITIS
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    SALIVARY HYPERSECRETION
    Additional description: SALIVARY HYPERSECRETION
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    STOMATITIS
    Additional description: STOMATITIS
         subjects affected / exposed
    3 / 54 (5.56%)
    10 / 58 (17.24%)
         occurrences all number
    3
    17
    VOMITING
    Additional description: VOMITING
         subjects affected / exposed
    35 / 54 (64.81%)
    44 / 58 (75.86%)
         occurrences all number
    90
    132
    Hepatobiliary disorders
    BLOOD ALKALINE PHOSPHATASE INCREASED
    Additional description: BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 58 (3.45%)
         occurrences all number
    4
    4
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
    Additional description: GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 58 (3.45%)
         occurrences all number
    3
    2
    HEPATIC FAILURE
    Additional description: HEPATIC FAILURE
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    LIVER DISORDER
    Additional description: LIVER DISORDER
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    TRANSAMINASES INCREASED
    Additional description: TRANSAMINASES INCREASED
         subjects affected / exposed
    9 / 54 (16.67%)
    13 / 58 (22.41%)
         occurrences all number
    28
    25
    Skin and subcutaneous tissue disorders
    ALOPECIA
    Additional description: ALOPECIA
         subjects affected / exposed
    10 / 54 (18.52%)
    13 / 58 (22.41%)
         occurrences all number
    14
    17
    DECUBITUS ULCER
    Additional description: DECUBITUS ULCER
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    DRY SKIN
    Additional description: DRY SKIN
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences all number
    1
    2
    ECZEMA
    Additional description: ECZEMA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    PRURITUS
    Additional description: PRURITUS
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    RADIODERMATITIS
    Additional description: RADIODERMATITIS
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    RASH
    Additional description: RASH
         subjects affected / exposed
    6 / 54 (11.11%)
    7 / 58 (12.07%)
         occurrences all number
    8
    11
    SKIN EXFOLIATION
    Additional description: SKIN EXFOLIATION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    SKIN LESION, NOS
    Additional description: SKIN LESION, NOS
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    BLOOD CREATININE INCREASED
    Additional description: BLOOD CREATININE INCREASED
         subjects affected / exposed
    5 / 54 (9.26%)
    1 / 58 (1.72%)
         occurrences all number
    8
    1
    BLOOD UREA INCREASED
    Additional description: BLOOD UREA INCREASED
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    MICTURITION URGENCY
    Additional description: MICTURITION URGENCY
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    URINARY RETENTION
    Additional description: URINARY RETENTION
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    MUSCLE FATIGUE
    Additional description: MUSCLE FATIGUE
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    2
    MUSCLE HAEMORRHAGE
    Additional description: MUSCLE HAEMORRHAGE
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    MUSCLE SPASMS
    Additional description: MUSCLE SPASMS
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences all number
    3
    2
    MUSCLE SPASTICITY
    Additional description: MUSCLE SPASTICITY
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    MUSCLE TWITCHING
    Additional description: MUSCLE TWITCHING
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    MUSCULOSKELETAL PAIN
    Additional description: MUSCULOSKELETAL PAIN
         subjects affected / exposed
    12 / 54 (22.22%)
    15 / 58 (25.86%)
         occurrences all number
    15
    27
    TRISMUS
    Additional description: TRISMUS
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    CONJUNCTIVITIS
    Additional description: CONJUNCTIVITIS
         subjects affected / exposed
    1 / 54 (1.85%)
    4 / 58 (6.90%)
         occurrences all number
    1
    4
    DEVICE RELATED INFECTION
    Additional description: DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    EAR INFECTION
    Additional description: EAR INFECTION
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 58 (1.72%)
         occurrences all number
    2
    1
    FEBRILE NEUTROPENIA
    Additional description: FEBRILE NEUTROPENIA
         subjects affected / exposed
    6 / 54 (11.11%)
    10 / 58 (17.24%)
         occurrences all number
    8
    12
    FUNGIC INFECTION
    Additional description: FUNGIC INFECTION
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    GASTROENTERITIS
    Additional description: GASTROENTERITIS
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    INFECTION, NOS
    Additional description: INFECTION, NOS
         subjects affected / exposed
    0 / 54 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    0
    5
    INFLUENZA LIKE ILLNESS
    Additional description: INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    LOWER RESPIRATORY TRACT INFECTION
    Additional description: LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences all number
    1
    3
    PARONYCHIA
    Additional description: PARONYCHIA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    PNEUMONIA
    Additional description: PNEUMONIA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    SEPSIS
    Additional description: SEPSIS
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    UPPER RESPIRATORY TRACT INFECTION
    Additional description: UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    5 / 54 (9.26%)
    6 / 58 (10.34%)
         occurrences all number
    5
    12
    URINARY TRACT INFECTION
    Additional description: URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 54 (5.56%)
    3 / 58 (5.17%)
         occurrences all number
    4
    3
    VIRAL INFECTION
    Additional description: VIRAL INFECTION
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 58 (3.45%)
         occurrences all number
    3
    2
    Metabolism and nutrition disorders
    DEHYDRATION
    Additional description: DEHYDRATION
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences all number
    1
    2
    HYPERCALCAEMIA
    Additional description: HYPERCALCAEMIA
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    HYPERGLYCAEMIA
    Additional description: HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    HYPERKALAEMIA
    Additional description: HYPERKALAEMIA
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    HYPERMAGNESAEMIA
    Additional description: HYPERMAGNESAEMIA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    HYPOALBUMINEMIA
    Additional description: HYPOALBUMINEMIA
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 58 (0.00%)
         occurrences all number
    5
    0
    HYPOCALCAEMIA
    Additional description: HYPOCALCAEMIA
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 58 (3.45%)
         occurrences all number
    3
    2
    HYPOKALAEMIA
    Additional description: HYPOKALAEMIA
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 58 (3.45%)
         occurrences all number
    2
    3
    HYPOMAGNESAEMIA
    Additional description: HYPOMAGNESAEMIA
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    HYPONATRAEMIA
    Additional description: HYPONATRAEMIA
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 58 (3.45%)
         occurrences all number
    1
    3
    HYPOPHOSPHATAEMIA
    Additional description: HYPOPHOSPHATAEMIA
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    MALNUTRITION
    Additional description: MALNUTRITION
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2011
    International amendment n°1 of 15-July-2011 (VHP procedure: the date refers to the date of preparation of the text submitted to VHP): 1. As requested by the National Cancer Research Network (NCRN), several clarifications and modifications that could impact directly on patient safety have been added on the protocol. 2. Removal of the pharmacogenetic study, mainly due to lack of funding 3. Update of international trial site list
    28 Feb 2012
    International amendment n°2 of 4-May-2012 (VHP procedure): Changes in the protocol: - addition of a selection criteria and dose adjustments required in case of bone marrow disease - new instructions about the management of vincristine : definition of the dose level -1 (-50%), and dose reduction to be respected in case of grade 3 or 4 peripheral neurotoxicity - introduction of country-specific guidelines which describe the management of temozolomide and Cefixime in The Netherlands, and the administration of temozolomide to patients from UK who have difficulties swallowing capsules - changes in SAE reporting (all SAE should be reported to the sponsor, and pregnancies should be reported immediately as SAE to the sponsor during treatment and up to 6 months after the last administration, a period during which a method of contraception is required)
    30 Jan 2014
    International amendment n°3 of 30-Jan-2014 (VHP procedure): 1. Update of the safety reference document (SPC) of temozolomide 2. Changes in of the protocol: addition of recommendations in case of liver abnormalities according to the new version of the SPC of temozolomide
    27 Jan 2015
    International amendment n°4 of 27-Jan-2015 (VHP procedure): Changes in the protocol: - an interim analysis was performed on 80 patients being treated or on follow-up, and preliminary results about efficacy and safety have been presented to an Independent Data Monitoring Committee (IDMC) and to the Steering Committee (SC) who both recommended to continue the trial and to increase the number of subjects by 40 extra patients with recurrent RMS. This amendment was submitted to follow this recommendation, and to randomize additional patients according to prior radiotherapy (yes vs no), country and recurrence (metastatic vs locoregional) due to the importance of these factors on the PFS curve
    09 Jul 2018
    International amendment n°5 of 9 July 2018 (non-VHP procedure, the date refers to the date of preparation of the text submitted to all national coordinating centres): 1. Update of the safety reference documents (SPC) of Vincristine an irinotecan ; with changes having an impact on the conduct of the study and the safety of patients 2. Changes in the protocol: - addition of a secondary objective to estimate the relative treatment effect of VIT compared to VI in terms of objective response rate (ORR), PFS and OS, in order to anticipate the future design of FarRMS trial ; statistical considerations are updated according to this new objective - update of the protocol to make it compliant with the new safety reference documents of vincristine and irinotecan - update of Pharmacovigilance guidelines according to the recent french legislation (SAE must be reported immediately) and new sponsor procedures
    24 Jun 2019
    International amendment n°6 of 24-June-2019 (non-VHP procedure): Changes in the protocol: - Removal of a withdrawal criterion: “Local therapy after 2nd cycle of study treatment”, in line with Steering Committee recommendations to perform analysis on local treatment received after VI/VIT, in order to explain the much larger effect of VIT compared to VI on overall survival than progression-free survival. - Clarification of the Last Visit of the Last Subject (LVLS) timepoint, defined as the last VI/VIT administration followed by 6 months to have relevant data in terms of response after 2 cycles ; in this way, the study end date corresponds to the last database export, and is the same all across countries.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34343032
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri May 02 19:19:43 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA