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    Clinical Trial Results:
    A Randomized, Multicenter, Phase III Trial of Trabectedin (Yondelis) versus Doxorubicin-based Chemotherapy as First-Line Therapy in Patients with Translocation-Related Sarcomas (TRS)

    Summary
    EudraCT number
    2008-002326-11
    Trial protocol
    FR   DE   ES   GB   IT  
    Global end of trial date
    20 Aug 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ET-C-002-07
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00796120
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharma Mar, S.A.
    Sponsor organisation address
    Av de los Reyes 1, Poligono Industrial La Mina , Colmenar Viejo, Madrid, Spain, 28770
    Public contact
    Clinical Development Department of PharmaMar´s Oncology, Business Unit., Pharma Mar, S.A., +34 918466000, clinicaltrials@pharmamar.com
    Scientific contact
    Clinical Development Department of PharmaMar´s Oncology, Business Unit., Pharma Mar, S.A., +34 918466000, clinicaltrials@pharmamar.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Aug 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy and safety of trabectedin compared to standard doxorubicin in participants with advanced translocation-related sarcomas (cancer of connective tissue cells) (TRS).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and was consistent with the Good Clinical Practice (GCP) and applicable regulatory requirements. Safety was evaluated by clinical examination, including vital signs, assessment of Adverse Events (AEs), changes in laboratory parameters (blood counts, clinical chemistry including liver function tests), and other tests that could be necessary.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Nov 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 53
    Worldwide total number of subjects
    121
    EEA total number of subjects
    68
    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)
    103
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 121 patients were randomized; out of them, 88 were evaluable for the primary efficacy analysis (51 in Arm A, trabectedin, and 37 in Arm B, DXCT). Efficacy population included all participants randomly assigned to either treatment arm with externally confirmed pathological and molecular diagnosis of translocation-related sarcomas (TRS).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Trabectedin
    Arm description
    Trabectedin 1.5 milligram per square meter (mg/m^2) given as 24-hour continuous intravenous infusion every 3 weeks until disease progression.
    Arm type
    Experimental

    Investigational medicinal product name
    Trabectedin
    Investigational medicinal product code
    Other name
    YONDELIS
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trabectedin 1.5 milligram per square meter (mg/m^2) given as 24-hour continuous intravenous infusion every 3 weeks until disease progression.

    Arm title
    DXCT
    Arm description
    DXCT = Doxorubicin based chemotherapy Doxorubicin (as a monotherapy) 75 mg per m^2 will be given intravenously every 3 weeks or Doxorubicin 60 mg per m^2 will be given intravenously every 3 weeks along with ifosfamide 6 to 9 gram (g)/m^2 every 3 weeks until disease progression.
    Arm type
    Experimental

    Investigational medicinal product name
    Doxorubicin/Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Doxorubicin (as a monotherapy) 75 or 60 mg per m^2 will be given intravenously every 3 weeks.

    Number of subjects in period 1
    Trabectedin DXCT
    Started
    61
    60
    Treated
    61
    57
    Completed
    0
    0
    Not completed
    61
    60
         Progressive disease
             22
             13
         Randomized but not treated
             -
             3
         Physician decision
             16
             17
         Other causes
             6
             17
         death
             3
             -
         Consent withdrawn by subject
             3
             4
         Treatment-related AEs
             11
             6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trabectedin
    Reporting group description
    Trabectedin 1.5 milligram per square meter (mg/m^2) given as 24-hour continuous intravenous infusion every 3 weeks until disease progression.

    Reporting group title
    DXCT
    Reporting group description
    DXCT = Doxorubicin based chemotherapy Doxorubicin (as a monotherapy) 75 mg per m^2 will be given intravenously every 3 weeks or Doxorubicin 60 mg per m^2 will be given intravenously every 3 weeks along with ifosfamide 6 to 9 gram (g)/m^2 every 3 weeks until disease progression.

    Reporting group values
    Trabectedin DXCT Total
    Number of subjects
    61 60 121
    Age, Customized
    Units: participants
        >=18 to <=49 years
    33 30 63
        >=50 to <=65 years
    19 21 40
        >=65 years
    9 9 18
    Age continuous
    Units: years
        median (full range (min-max))
    47 (19 to 78) 49 (19 to 78) -
    Gender, Male/Female
    Units: participants
        Female
    25 22 47
        Male
    36 38 74
    Race
    Units: Subjects
        Caucasian
    53 54 107
        Black
    3 4 7
        Asian/oriental
    2 0 2
        Other
    2 2 4
        Unk
    1 0 1
    ECOG PS
    Eastern Cooperative Oncology Group performance status
    Units: Subjects
        PS 0
    28 29 57
        PS 1
    32 30 62
        PS 2
    1 1 2
    Tumor diagnosis (investigator)
    A comparison of tumor diagnosis per central pathology review compared to per investigators’ classification
    Units: Subjects
        MRCL
    28 28 56
        Other TRS
    33 32 65
    Tumor diagnosis (external pathology review)
    A comparison of tumor diagnosis per central pathology review compared to per investigators’ classification
    Units: Subjects
        MRCL
    23 17 40
        Other TRS
    28 20 48
        Not confirmed
    10 23 33
    Primary tumor site
    Units: Subjects
        Lower extremity
    39 37 76
        Trunk/abdominal wall
    2 10 12
        Upper extremity
    8 1 9
        Face and neck
    2 1 3
        Other
    10 11 21
    Disease at study entry
    Units: Subjects
        Locally advanced
    18 13 31
        Metastatic
    43 47 90
    Tumor stage at diagnosis
    Units: Subjects
        Stage I
    3 4 7
        Stage II
    9 10 19
        Stage III
    13 14 27
        Stage IV
    21 18 39
        Unknown
    15 14 29
    Signs and symptoms
    Units: Subjects
        0 signs and symptoms
    19 20 39
        1 signs and symptoms
    12 10 22
        2 signs and symptoms
    11 9 20
        >=3 signs and symptoms
    19 21 40
    Time from diagnosis to randomization
    Units: months
        median (full range (min-max))
    10.3 (0.5 to 186.8) 8.2 (0.1 to 309.7) -
    Time from unresectable locally advanced disease to randomization
    Units: months
        median (full range (min-max))
    0.7 (0 to 6.4) 0.8 (0 to 2.3) -
    Time from metastatic disease to randomization
    Units: months
        median (full range (min-max))
    2.2 (0 to 50.7) 1.6 (0.1 to 249.6) -
    Time from last progression date before study to randomization
    Units: months
        median (full range (min-max))
    0.7 (0 to 3.2) 0.6 (0 to 3.1) -
    Sites of disease
    Units: No. of sites
        median (full range (min-max))
    2 (1 to 8) 2 (1 to 5) -
    Signs and symptoms
    Units: Number
        median (full range (min-max))
    1 (0 to 7) 2 (0 to 29) -
    WBC
    white blood cells
    Units: x10^9/l
        median (full range (min-max))
    6.7 (4 to 17.5) 7.2 (2.8 to 14) -
    Hemoglobin
    Units: g/dl
        median (full range (min-max))
    13.7 (9.2 to 17.7) 13.3 (9 to 15.7) -
    Hematocrit
    Units: percentage
        median (full range (min-max))
    40.8 (29.7 to 51) 39 (27.5 to 50.3) -
    Neutrophils
    Units: x10^9/l
        median (full range (min-max))
    4.2 (2.2 to 13.5) 4.8 (2 to 11.9) -
    Lymphocytes
    Units: x10^9/l
        median (full range (min-max))
    1.7 (0.4 to 3) 1.7 (0.3 to 3.9) -
    Platelets
    Units: x10^9/l
        median (full range (min-max))
    254 (113 to 597) 275.5 (140 to 836) -
    ALT
    Units: ULN
        median (full range (min-max))
    0.5 (0.1 to 2.5) 0.5 (0.2 to 1.7) -
    AP
    Units: ULN
        median (full range (min-max))
    0.7 (0.3 to 1.4) 0.7 (0.4 to 1.6) -
    AST
    Units: ULN
        median (full range (min-max))
    0.6 (0.2 to 1.5) 0.6 (0.3 to 1.7) -
    CPK
    Units: ULN
        median (full range (min-max))
    0.5 (0.1 to 2.3) 0.4 (0.1 to 2) -
    Creatinine
    Units: ULN
        median (full range (min-max))
    0.6 (0.3 to 1) 0.6 (0.4 to 1.1) -
    Total bilirubin
    Units: ULN
        median (full range (min-max))
    0.4 (0.1 to 1.2) 0.4 (0.2 to 1.3) -
    Albumin
    Units: g/dl
        median (full range (min-max))
    4.2 (2.6 to 5) 4.2 (2.5 to 4.8) -
    Glucose
    Units: mmol/l
        median (full range (min-max))
    5.5 (3.6 to 17.9) 5.3 (2.4 to 11.9) -

    End points

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    End points reporting groups
    Reporting group title
    Trabectedin
    Reporting group description
    Trabectedin 1.5 milligram per square meter (mg/m^2) given as 24-hour continuous intravenous infusion every 3 weeks until disease progression.

    Reporting group title
    DXCT
    Reporting group description
    DXCT = Doxorubicin based chemotherapy Doxorubicin (as a monotherapy) 75 mg per m^2 will be given intravenously every 3 weeks or Doxorubicin 60 mg per m^2 will be given intravenously every 3 weeks along with ifosfamide 6 to 9 gram (g)/m^2 every 3 weeks until disease progression.

    Primary: Progression - Free Survival (PFS)

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    End point title
    Progression - Free Survival (PFS)
    End point description
    Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progressive disease (PD) or death (regardless of the cause of death)
    End point type
    Primary
    End point timeframe
    Every 6 weeks from randomization during the first 9 months and thereafter, every 9 weeks
    End point values
    Trabectedin DXCT
    Number of subjects analysed
    51
    37
    Units: months
        median (confidence interval 95%)
    19.6 (5.7 to 32.3)
    8.3 (7.1 to 25)
    Attachments
    Progression-free survival
    Statistical analysis title
    Progression-free survival
    Comparison groups
    Trabectedin v DXCT
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8391 [1]
    Method
    Log-rank test stratified
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.879
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.425
         upper limit
    1.817
    Notes
    [1] - HR: Arm A (trabectedin) compared to Arm B (DXCT). HR and p-value determined by Log-rank test stratified.

    Secondary: 6-month Progression - Free Survival

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    End point title
    6-month Progression - Free Survival
    End point description
    Percentage of participants survived for 6 months from the start of study treatment without progression of disease. Progression of the disease was associated with increasing symptoms, including pain from new or progressing lesions. Delay in disease progression generally represents a clinical benefit to the participant.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Trabectedin DXCT
    Number of subjects analysed
    51
    37
    Units: percentage of participants
        number (confidence interval 95%)
    66.7 (50.6 to 82.8)
    78.3 (64 to 92.5)
    No statistical analyses for this end point

    Secondary: Percentage of participants with Objective Response

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    End point title
    Percentage of participants with Objective Response
    End point description
    Tumor response was assessed according to RECIST criteria: Partial Response (PR)=at least 30% reduction in the sum of the longest dimensions (LD) of all target lesions in reference to the baseline sum LD, Complete Response (CR) =Disappearance of all non-target lesions. Percentage of participants with objective tumor response was determined by the number of participants with PR or CR divided by the total number of response-evaluable participants.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks during first 9 months of the study and thereafter every 9 weeks
    End point values
    Trabectedin DXCT
    Number of subjects analysed
    51
    37
    Units: percentage of participants
        number (confidence interval 95%)
    5.9 (1.2 to 16.2)
    27 (13.8 to 44.1)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival defined as time from the date of randomization to the date of death. For participants who were alive at the time of analysis, overall survival was censored at the last contact date. Upper limit of confirdence interval value '99999' signifies that Upper limit of confidence interval was not reached because of high censorship rate that is smaller number of events.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of Study (2008 to 2014)
    End point values
    Trabectedin DXCT
    Number of subjects analysed
    51
    37
    Units: months
        median (confidence interval 95%)
    46.6 (27.5 to 99999)
    33.5 (21.6 to 99999)
    Attachments
    Overall survival
    Statistical analysis title
    Overall survival
    Comparison groups
    Trabectedin v DXCT
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4348 [2]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.785
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.427
         upper limit
    1.441
    Notes
    [2] - Arm A (trabectedin) compared to Arm B (DXCT). HR and p-value determined by Cox regression

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time frame for AE
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Trabectedin
    Reporting group description
    Trabectedin 1.5 milligram per square meter (mg/m^2) given as 24-hour continuous intravenous infusion every 3 weeks until disease progression.

    Reporting group title
    DXCT
    Reporting group description
    DXCT = Doxorubicin based chemotherapy Doxorubicin (as a monotherapy) 75 mg per m^2 will be given intravenously every 3 weeks or Doxorubicin 60 mg per m^2 will be given intravenously every 3 weeks along with ifosfamide 6 to 9 gram (g)/m^2 every 3 weeks until disease progression.

    Serious adverse events
    Trabectedin DXCT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 61 (40.98%)
    16 / 57 (28.07%)
         number of deaths (all causes)
    33
    33
         number of deaths resulting from adverse events
    4
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (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 discomfort
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site extravasation
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood CPK increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 61 (1.64%)
    7 / 57 (12.28%)
         occurrences causally related to treatment / all
    1 / 1
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dyspraxia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope vasovagal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 57 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver injury
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis viral
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal bacteremia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Trabectedin DXCT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 61 (100.00%)
    57 / 57 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 57 (0.00%)
         occurrences all number
    16
    0
    Hypertension
         subjects affected / exposed
    7 / 61 (11.48%)
    0 / 57 (0.00%)
         occurrences all number
    23
    0
    Hypotension
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 57 (5.26%)
         occurrences all number
    2
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    34 / 61 (55.74%)
    32 / 57 (56.14%)
         occurrences all number
    170
    107
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    3 / 61 (4.92%)
    3 / 57 (5.26%)
         occurrences all number
    8
    3
    Fatigue
         subjects affected / exposed
    45 / 61 (73.77%)
    43 / 57 (75.44%)
         occurrences all number
    322
    140
    Mass
         subjects affected / exposed
    11 / 61 (18.03%)
    5 / 57 (8.77%)
         occurrences all number
    93
    24
    Mucosal inflammation
         subjects affected / exposed
    4 / 61 (6.56%)
    15 / 57 (26.32%)
         occurrences all number
    6
    41
    Oedema peripheral
         subjects affected / exposed
    18 / 61 (29.51%)
    6 / 57 (10.53%)
         occurrences all number
    98
    24
    Pyrexia
         subjects affected / exposed
    10 / 61 (16.39%)
    11 / 57 (19.30%)
         occurrences all number
    12
    17
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 61 (9.84%)
    4 / 57 (7.02%)
         occurrences all number
    27
    11
    Insomnia
         subjects affected / exposed
    13 / 61 (21.31%)
    6 / 57 (10.53%)
         occurrences all number
    52
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 61 (31.15%)
    1 / 57 (1.75%)
         occurrences all number
    50
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 61 (9.84%)
    0 / 57 (0.00%)
         occurrences all number
    29
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 61 (14.75%)
    0 / 57 (0.00%)
         occurrences all number
    15
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 61 (9.84%)
    0 / 57 (0.00%)
         occurrences all number
    36
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 57 (1.75%)
         occurrences all number
    4
    1
    Weight decreased
         subjects affected / exposed
    4 / 61 (6.56%)
    8 / 57 (14.04%)
         occurrences all number
    19
    17
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 57 (7.02%)
         occurrences all number
    7
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 61 (18.03%)
    13 / 57 (22.81%)
         occurrences all number
    31
    25
    Neutropenia
         subjects affected / exposed
    29 / 61 (47.54%)
    15 / 57 (26.32%)
         occurrences all number
    98
    31
    Thrombocytopenia
         subjects affected / exposed
    9 / 61 (14.75%)
    2 / 57 (3.51%)
         occurrences all number
    29
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 61 (16.39%)
    10 / 57 (17.54%)
         occurrences all number
    31
    21
    Dyspnoea
         subjects affected / exposed
    12 / 61 (19.67%)
    6 / 57 (10.53%)
         occurrences all number
    72
    17
    Hiccups
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 57 (7.02%)
         occurrences all number
    0
    4
    Pharyngolaryngeal pain
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 57 (3.51%)
         occurrences all number
    6
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 61 (8.20%)
    7 / 57 (12.28%)
         occurrences all number
    9
    14
    Headache
         subjects affected / exposed
    13 / 61 (21.31%)
    14 / 57 (24.56%)
         occurrences all number
    58
    30
    Dysgeusia
         subjects affected / exposed
    4 / 61 (6.56%)
    6 / 57 (10.53%)
         occurrences all number
    21
    10
    Neuropathy peripheral
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 57 (0.00%)
         occurrences all number
    10
    0
    Paraesthesia
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 57 (5.26%)
         occurrences all number
    4
    5
    Tremor
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 57 (5.26%)
         occurrences all number
    1
    6
    Eye disorders
    Eye irritation
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    0
    11
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 57 (3.51%)
         occurrences all number
    22
    5
    Abdominal pain
         subjects affected / exposed
    8 / 61 (13.11%)
    7 / 57 (12.28%)
         occurrences all number
    32
    11
    Abdominal pain upper
         subjects affected / exposed
    8 / 61 (13.11%)
    5 / 57 (8.77%)
         occurrences all number
    20
    7
    Constipation
         subjects affected / exposed
    27 / 61 (44.26%)
    16 / 57 (28.07%)
         occurrences all number
    142
    54
    Diarrhoea
         subjects affected / exposed
    15 / 61 (24.59%)
    15 / 57 (26.32%)
         occurrences all number
    26
    42
    Dyspepsia
         subjects affected / exposed
    8 / 61 (13.11%)
    7 / 57 (12.28%)
         occurrences all number
    64
    23
    Dry mouth
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 57 (5.26%)
         occurrences all number
    10
    4
    Haemorrhoids
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 57 (7.02%)
         occurrences all number
    1
    15
    Nausea
         subjects affected / exposed
    46 / 61 (75.41%)
    39 / 57 (68.42%)
         occurrences all number
    255
    146
    Stomatitis
         subjects affected / exposed
    1 / 61 (1.64%)
    6 / 57 (10.53%)
         occurrences all number
    1
    23
    Oral pain
         subjects affected / exposed
    0 / 61 (0.00%)
    10 / 57 (17.54%)
         occurrences all number
    0
    16
    Vomiting
         subjects affected / exposed
    29 / 61 (47.54%)
    16 / 57 (28.07%)
         occurrences all number
    104
    38
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    0
    5
    Alopecia
         subjects affected / exposed
    2 / 61 (3.28%)
    25 / 57 (43.86%)
         occurrences all number
    7
    129
    Rash
         subjects affected / exposed
    4 / 61 (6.56%)
    6 / 57 (10.53%)
         occurrences all number
    29
    13
    Scar
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 57 (3.51%)
         occurrences all number
    24
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 61 (8.20%)
    7 / 57 (12.28%)
         occurrences all number
    22
    12
    Joint range of motion decreased
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 57 (1.75%)
         occurrences all number
    10
    6
    Back pain
         subjects affected / exposed
    8 / 61 (13.11%)
    9 / 57 (15.79%)
         occurrences all number
    30
    28
    Musculoskeletal pain
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 57 (1.75%)
         occurrences all number
    13
    4
    Muscle spasms
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 57 (5.26%)
         occurrences all number
    7
    11
    Myalgia
         subjects affected / exposed
    7 / 61 (11.48%)
    2 / 57 (3.51%)
         occurrences all number
    24
    4
    Pain in extremity
         subjects affected / exposed
    6 / 61 (9.84%)
    3 / 57 (5.26%)
         occurrences all number
    28
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    20 / 61 (32.79%)
    15 / 57 (26.32%)
         occurrences all number
    60
    50
    Hypocalcaemia
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 57 (7.02%)
         occurrences all number
    14
    6
    Dehydration
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 57 (7.02%)
         occurrences all number
    3
    4
    Hypokalaemia
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 57 (7.02%)
         occurrences all number
    6
    5
    Infections and infestations
    Catheter related infection
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 57 (0.00%)
         occurrences all number
    11
    0
    Candidiasis
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    0
    5
    Urinary tract infection
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 57 (5.26%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2008
    This substantial protocol amendment incorporated changes to clarify patient inclusion criteria and to avoid inconsistencies or discrepancies through the document regarding dose adjustment guidance, as follows: 1) potential misinterpretation was avoided by erasing a coma in a sentence describing patient inclusion requirements, and 2) the scheme of ifosfamide consecutive reductions was corrected according to the initial dose range for ifosfamide administration. Additionally, the time of prophylactic dexamethasone before trabectedin administration was adjusted to 30 min, to be in concordance to the Summary of Product Characteristics specifications
    30 Oct 2008
    This substantial protocol amendment included changes with respect to: 1) issues affecting the medical management of alveolar rhabdomyosarcoma patients, which led to the exclusion of this subgroup from the study population; 2) a better definition of the study termination (clinical cutoff) period was required; 3) to clarify the reference document for evaluation of AEs in patients under treatment with investigational drugs; 4) to better explain the measures taken for international transfers of personal data, and 5) other changes and additions have been included to disambiguate some unclear statements.
    11 Mar 2009
    This substantial protocol amendment included changes with respect to: 1) inclusion criteria: to add progressive disease prior to study entry as well as to allow inclusion of patients with Gilbert’s syndrome with total bilirubin > ULN; 2) to modify the frequency of tumor assessments in order to allow close monitoring of disease response to treatment but to decrease the exposure to irradiation of patients; 3) to clarify the times for confirmation of tumor response; 4) some changes in hematology laboratory test schedule in case of neutropenia to make it less restrictive and more practical; 5) to update information on concomitant therapy according to more recent reports of toxicity; 6) to update the study contacts, and 7) minor changes to eliminate grammatical errors and to clarify ambiguous statements in the Time and Events Schedule Table.
    29 Apr 2010
    This substantial protocol amendment included changes with respect to: 1) the wording of inclusion criterion No.3 was changed to clarify that recruitment was restricted to only those patients who had any of the tumor subtypes listed in this criterion [in the particular case of endometrial stromal sarcoma, only patients with low grade disease were allowed to enter the study, as translocation t(7;17)(p15;p21) has been found associated with this variant]; 2) a new inclusion criteria (No.5) was added stating that patients had to have measurable disease as defined by RECIST v.1.0; 3) in the case of alveolar soft part sarcoma, due to the absence of available probe to perform FISH, patients with externally confirmed pathological diagnosis of this subtype were also allowed to be included in the efficacy population; 4) some clarifications were added with respect to AEs/SAEs reporting, including guidelines to report laboratory disorders, exclusion of disease progression as an AE, and rewording of sentences about deaths in SAE reporting, and 5) other changes, including update of study contacts, the number of investigational sites, and the planned enrollment period.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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