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    Clinical Trial Results:
    A Phase II multicenter study comparing the efficacy of the oral angionenesis inhibitor nintedanib with the intravenous cytotoxis compound ifosfamide for treatment of patients with advanced metastatic soft tissue sarcoma after failure of systemic non-oxazaphosporine-based first line chemotherapy for inoperable disease "ANITA"

    Summary
    EudraCT number
    		 2016-002093-12
    Trial protocol
    		 BE   GB   PL   NL   ES   LT  
    Global end of trial date
    13 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2022
    First version publication date
    19 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1506-STBSG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02808247
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    EORTC
    Sponsor organisation address
    Avenue E Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Clinical Operations Department, European Organisation for the Research and, 0032 27741345, regulatory@eortc.org
    Scientific contact
    Clinical Operations Department, European Organisation for the Research and, 0032 27741345, regulatory@eortc.org
    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
    18 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to evaluate whether nintedanib given as second-line therapy for advanced, inoperable and/or metastatic STS prolongs progression-free survival when compared with ifosfamide.
    Protection of trial subjects
    The responsible investigator ensure that this study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol had been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-goodclinicalpractice_ en.pdf). The protocol was approved by the competent ethics committee(s) as required
    Background therapy
    		 Ifosfamide 3 g/m2 intravenously on days 1, 2 and 3 every 21 days for up to a maximum of 6 cycles.
    Evidence for comparator
    		 Investigational arm: Nintedanib 200 mg twice daily orally.
    Actual start date of recruitment
    26 Jul 2017
    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: 10
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Switzerland: 2
    Worldwide total number of subjects
    80
    EEA total number of subjects
    67
    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)
    53
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 80 patients were randomized (40 pts per arm) between July 26, 2017 and November 21, 2019 by 18 institutions in 8 countries.

    Pre-assignment
    Screening details
    		 • Histologically proven advanced, inoperable (medical or surgical) and/or metastatic malignant STS of intermediate or high grade, • One line of previous systemic chemotherapy for advanced, inoperable and/or metastatic malignant STS. • No active brain metastases

    Period 1
    Period 1 title
    Enrolled (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ifosfamide
    Arm description
    		 Ifosfamide 3 g/m2 intravenously on days 1, 2 and 3 every 21 days for up to a maximum of 6 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion, Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ifosfamide 3 g/m2 intravenously on days 1, 2 and 3 every 21 days for up to a maximum of 6 cycles.

    Arm title
    		 Nintedanib
    Arm description
    		 Nintedanib 200 mg twice daily orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Nintedanib 200 mg twice daily orally.

    Number of subjects in period 1
    		Ifosfamide Nintedanib
    Started
    40
    40
    Completed
    38
    39
    Not completed
    2
    1
         Consent withdrawn by subject
    2
    -
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ifosfamide
    Reporting group description
    		 Ifosfamide 3 g/m2 intravenously on days 1, 2 and 3 every 21 days for up to a maximum of 6 cycles.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Nintedanib 200 mg twice daily orally.

    Reporting group values
    		 Ifosfamide Nintedanib Total
    Number of subjects
    		 40 40 80
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 27 26 53
        From 65-84 years
    		 13 14 27
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 23 20 43
        Male
    		 17 20 37
    Performance status
    WHO performance status
    Units: Subjects
        Cat 0
    		 22 20 42
        Cat 1
    		 14 19 33
        Cat 2
    		 3 1 4
        Missing
    		 1 0 1
    Tumor Type
    Units: Subjects
        Liposarcoma
    		 11 11 22
        Fibroblastic sarcoma
    		 4 5 9
        Leiomyosarcoma
    		 17 14 31
        Vascular Tumours
    		 2 1 3
        Tumors of uncertain differentiation
    		 1 2 3
        MPNST
    		 2 3 5
        Undifferentiated / unclassified sarcoma
    		 3 3 6
        Other
    		 0 1 1
    Tumor grade
    Units: Subjects
        Low
    		 1 0 1
        Intermediate
    		 13 19 32
        High
    		 23 20 43
        Not assessable
    		 3 1 4
    Tumor size
    Units: mm
        median (inter-quartile range (Q1-Q3))
    		 72.5 (45 to 137.5) 94 (65 to 142.5) -

    End points

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    End points reporting groups
    Reporting group title
    Ifosfamide
    Reporting group description
    		 Ifosfamide 3 g/m2 intravenously on days 1, 2 and 3 every 21 days for up to a maximum of 6 cycles.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Nintedanib 200 mg twice daily orally.

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    Progression-free survival will be measured from the date of randomization until the date of first documented progression or death, whichever occurs first. Patients who are alive without evidence of progression at their last radiological assessment will be censored at that date. As per the clinical evaluation schedule, radiological follow-up was to be discontinued after starting a new treatment in the absence of progression. When this occurs, follow-up was censored at the date of starting new treatment. Note that death after starting new treatment is still considered an event for this endpoint.
    End point type
    Primary
    End point timeframe
    Progression-free survival will be measured from the date of randomization until the date of first documented progression or death, whichever occurs first.
    End point values
    		 Ifosfamide Nintedanib
    Number of subjects analysed
    40
    40
    Units: months
        median (confidence interval 95%)
    4.4 (2.9 to 6.7)
    2.5 (1.5 to 3.4)
    Attachments
    		 Progression free survival
    Statistical analysis title
    		 Primary analysis of progression free survival
    Comparison groups
    Nintedanib v Ifosfamide
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.56
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 2.13
    Notes
    [1] - From a Cox proportional hazards adjusted for stratification factors tumor grade and histology

    Secondary: Progression free rate at 12 weeks

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    End point title
    		 Progression free rate at 12 weeks
    End point description
    Patients achieving RECIST 1.1 CR, PR or SD at the 12 week disease assessment will be considered a success for this endpoint. All other conditions, e.g. no available imaging, RECIST 1.1 progression prior to or at week 12, non-evaluable assessments, switching to new anti-tumor treatment in the absence of documented progression, or early death will be counted as a failure. Note that when an assessment was performed later than the foreseen time window of 12 weeks, but before and after was documented as a stable disease (or response), then the 12 week assessment was not considered a failure for this analysis.
    End point type
    Secondary
    End point timeframe
    Patients achieving RECIST 1.1 CR, PR or SD at the 12 week disease assessment will be considered a success for this endpoint.
    End point values
    		 Ifosfamide Nintedanib
    Number of subjects analysed
    40
    40
    Units: subjects
        No
    22
    26
        Yes
    18
    14
    Statistical analysis title
    		 Interim analysis
    Statistical analysis description
    Decision rule: If less than 19 out of these 36 patients on nintedanib are progression-free at the 12 week assessment, the trial will stop early. Otherwise, the trial will continue as planned. Note that if more than 17 failures are observed in the nintedanib arm, the trial should be stopped.
    Comparison groups
    Nintedanib v Ifosfamide
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 > 0.1 [3]
    Method
    		 Decision rule based on A'Hern design
    Parameter type
    		 Binomial estimate and exact 80% CI
    Point estimate
    0.35
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.249
         upper limit
    		 0.463
    Notes
    [2] - This interim look originates from a single arm, single stage A’Hern design with type I and II error fixed at alpha = 0.1 and beta = 0.15, testing the null hypothesis H0: P ≤ 40% versus HA: P > 40%. The decision rule is computed under the alternative hypothesis that P = 60%. The analysis is done in the Nintedanib arm only.
    [3] - Decision rule: If less than 19 out of the first 36 patients on nintedanib are progression-free at the 12 week assessment, the trial will stop early. Otherwise, the trial will continue as planned. Therefore this trial was closed for futility

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) was computed from the date of start of treatment to the date of death (due to any cause). Patients alive at the time of analysis will be censored at the date of last follow-up.
    End point values
    		 Ifosfamide Nintedanib
    Number of subjects analysed
    40
    40
    Units: Months
        median (confidence interval 95%)
    24.1 (10.9 to 100)
    13.7 (9.4 to 23.4)
    Attachments
    		 Untitled (Filename: 1506_OS.pdf)
    Statistical analysis title
    		 Overall survival
    Comparison groups
    Ifosfamide v Nintedanib
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.111 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 3.06
    Notes
    [4] - Cox Proportional hazards model adjusted for stratification factors tumor grade and histology

    Secondary: Best response

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    End point title
    		 Best response
    End point description
    End point type
    Secondary
    End point timeframe
    Best response observed on treatment
    End point values
    		 Ifosfamide Nintedanib
    Number of subjects analysed
    40
    40
    Units: subjects
        Partial response
    2
    2
        Stable disease
    23
    18
        Progressive disease
    10
    19
        Early death
    2
    0
        Not evaluable
    3
    1
    No statistical analyses for this end point

    Secondary: Time on nintedanib treatment

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    End point title
    		 Time on nintedanib treatment [5]
    End point description
    computed from the date of start of treatment to the date of discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. Patients alive and still on protocol treatment at the time of the analysis will be censored at the date of last known treatment administration.
    End point type
    Secondary
    End point timeframe
    computed from the date of start of treatment to the date of discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is only valid in one arm, i.e. in the arm of patients who received nintedanib treatment
    End point values
    		 Nintedanib
    Number of subjects analysed
    40
    Units: Months
        median (confidence interval 95%)
    2.5 (1.4 to 3.4)
    Attachments
    		 Untitled (Filename: 1506_ntrt.jpeg)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events, laboratory and physical abnormalities were collected till 90 days after the end of treatment. For SAEs: all SAEs till 30 days after end of treatment; afterwards, only related SA
    Adverse event reporting additional description
    AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs has not been collected specifically, all AEs will be reported in non-SAE section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Ifosfamide
    Reporting group description
    		 Ifosfamide

    Reporting group title
    Nintedanib
    Reporting group description
    		 Nintedanib

    Serious adverse events
    		 Ifosfamide Nintedanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 38 (42.11%)
    8 / 39 (20.51%)
         number of deaths (all causes)
    18
    24
         number of deaths resulting from adverse events
    0
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ENCEPHALOPATHY
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUDDEN DEATH
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STENOSIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY EMBOLISM
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ANAL ABSCESS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BILIARY TRACT INFECTION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOCALISED INFECTION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ifosfamide Nintedanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 38 (86.84%)
    35 / 39 (89.74%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOR PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Vascular disorders
    HYPERTENSION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    7 / 38 (18.42%)
    15 / 39 (38.46%)
         occurrences all number
    12
    35
    HYPOTENSION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    LYMPHEDEMA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    PHLEBITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    THROMBOEMBOLIC EVENT
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 39 (5.13%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    FATIGUE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    22 / 38 (57.89%)
    18 / 39 (46.15%)
         occurrences all number
    41
    30
    FEVER
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 38 (10.53%)
    3 / 39 (7.69%)
         occurrences all number
    4
    3
    FLU LIKE SYMPTOMS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    1
    2
    LOCALIZED EDEMA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    MALAISE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    NON-CARDIAC CHEST PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 39 (10.26%)
         occurrences all number
    5
    5
    PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    SUDDEN DEATH NOS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    BRONCHIAL INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    COUGH
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 39 (5.13%)
         occurrences all number
    2
    4
    DYSPNEA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 39 (10.26%)
         occurrences all number
    5
    6
    HICCUPS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    HOARSENESS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    RESPIRATORY, THORACIC-OTHER-HAEMOPTYSIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    UPPER RESPIRATORY INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    VOICE ALTERATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Psychiatric disorders
    DEPRESSION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    INSOMNIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    PSYCHIATRIC DISORDERS - OTHER: PSYCHOLOGIC DISTRES
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Investigations
    ELECTROCARDIOGRAM QT CORRECTED INTERVAL PROLONGED
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    WEIGHT LOSS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 38 (15.79%)
    6 / 39 (15.38%)
         occurrences all number
    7
    8
    Cardiac disorders
    ATRIAL FIBRILLATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    MYOCARDIAL INFARCTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    PALPITATIONS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    DEPRESSION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    DIZZINESS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    DYSGEUSIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    6 / 39 (15.38%)
         occurrences all number
    1
    6
    ENCEPHALOPATHY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    9 / 38 (23.68%)
    0 / 39 (0.00%)
         occurrences all number
    15
    0
    HEADACHE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    HICCUPS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    PARESTHESIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    PERIPHERAL MOTOR NEUROPATHY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    PERIPHERAL SENSORY NEUROPATHY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    SYNCOPE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    ANEMIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    8 / 38 (21.05%)
    1 / 39 (2.56%)
         occurrences all number
    19
    3
    BLOOD&LYMPHATIC SYSTEM DISORDERS:MEDULLAR TOXICITY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    FEBRILE NEUTROPENIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    5 / 38 (13.16%)
    0 / 39 (0.00%)
         occurrences all number
    7
    0
    INFECTIONS AND INFESTATIONS-OTHER: BLOOD INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    PANCYTOPENIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    BLURRED VISION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    CONJUNCTIVITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    ABDOMINAL PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 39 (10.26%)
         occurrences all number
    7
    6
    ANAL HEMORRHAGE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    BLOATING
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    CONSTIPATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    11 / 38 (28.95%)
    4 / 39 (10.26%)
         occurrences all number
    18
    7
    DIARRHEA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 38 (15.79%)
    14 / 39 (35.90%)
         occurrences all number
    9
    31
    DRY MOUTH
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    ESOPHAGEAL PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 39 (2.56%)
         occurrences all number
    4
    1
    FLATULENCE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    3
    GASTROESOPHAGEAL REFLUX DISEASE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    MUCOSITIS ORAL
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 39 (7.69%)
         occurrences all number
    2
    3
    NAUSEA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    17 / 38 (44.74%)
    10 / 39 (25.64%)
         occurrences all number
    38
    13
    SMALL INTESTINAL OBSTRUCTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    SMALL INTESTINAL PERFORATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    VOMITING
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    11 / 38 (28.95%)
    7 / 39 (17.95%)
         occurrences all number
    19
    12
    Hepatobiliary disorders
    BILE DUCT STENOSIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    HEPATIC INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    PORTAL HYPERTENSION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    ALOPECIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    5 / 38 (13.16%)
    0 / 39 (0.00%)
         occurrences all number
    6
    0
    DRY SKIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    PRURITUS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    5 / 38 (13.16%)
    0 / 39 (0.00%)
         occurrences all number
    6
    0
    RENAL&URINARY DISORDERS-OTHER: RENAL TUBULOPATHY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    URINARY FREQUENCY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    URINARY TRACT PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    BACK PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    1
    3
    BONE PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    BUTTOCK PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    CHEST WALL PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    GENERALIZED MUSCLE WEAKNESS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    MUSCULOSKELETAL &CONNECTIVE TIS.DIS.RCALF SWELLING
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    MUSCULOSKELETAL&CONNECTIVE TISSUE DISORDER
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    MUSCULOSKELETAL&CONNECTIVE TISSUE DISORDER-GROIN P
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    MYALGIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    PAIN IN EXTREMITY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 38 (10.53%)
    6 / 39 (15.38%)
         occurrences all number
    4
    7
    Infections and infestations
    BILIARY TRACT INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    BRONCHIAL INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    INFECTIONS AND INFESTATIONS - PLASTRON RIGHT FOSSA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    INFECTIONS AND INFESTATIONS-OTHER: SIGMOIDITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    INFECTIONS AND INFESTATIONS-OTHER:HERPES LABIALIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    LIP INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    LUNG INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    MUCOSAL INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    PERITONITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    SEPSIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    UPPER RESPIRATORY INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    URINARY TRACT INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    WOUND INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    ACIDOSIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    ANOREXIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    14 / 38 (36.84%)
    7 / 39 (17.95%)
         occurrences all number
    19
    11
    HYPERGLYCEMIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    HYPOGLYCEMIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    HYPOKALEMIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    HYPOPHOSPHATEMIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    As the study was closed for futility, there is limited follow-up data for QoL, HE and long term endpoints such as overall survival

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34062484
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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