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    Clinical Trial Results:
    Maintenance therapy with trabectedin versus observation after first line treatment with doxorubicin of patients with advanced or metastatic soft tissue sarcoma

    Summary
    EudraCT number
    		 2016-003535-38
    Trial protocol
    		 DE   GB   NL   PL   ES   FR   CY   IT  
    Global end of trial date
    05 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jan 2021
    First version publication date
    28 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1447-STBSG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02929394
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    EORTC
    Sponsor organisation address
    Avenue E. Mounier 83, Bruxelles, Belgium, 1200
    Public contact
    Clinical Operations Department, European Organisation for the Research and treatment of Cancer, 0032 27741013, regulatory@eortc.be
    Scientific contact
    Clinical Operations Department, European Organisation for the Research and treatment of Cancer, 0032 27741013, regulatory@eortc.be
    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
    08 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to evaluate whether maintenance trabectedin given after 6 cycles of doxorubicin first-line therapy for advanced or metastatic STS prolongs progression-free survival (PFS) as compared to an observational approach.
    Protection of trial subjects
    The responsible investigator ensures 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 has been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    France: 10
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    8
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 13 patients were registered by 6 institutions between 17/Nov/2017 and 29/Aug/2018.

    Pre-assignment
    Screening details
    		 Age 18 yo WHO PS ≤ 1 adequate bone marrow, liver and renal function. No prior exposure to trabectedin. Histologically proven locally advanced or metastatic high grade STS (excluding histologies insensitive to chemotherapy). Non-progressive disease after 6 cycles of first-line chemotherapy with doxorubicin.

    Pre-assignment period milestones
    Number of subjects started
    		 13
    Number of subjects completed
    		 13

    Period 1
    Period 1 title
    Overall period - Full patient population
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - Trabectedin maintenance
    Arm description
    		 Treatment should start within 3 days from randomization. Trabectedin was administered on day 1 every 4 weeks at the dose of 1.2 mg/m2 body surface area, administered as an intravenous infusion over 24 hours. Trabectedin (trade name Yondelis®) was supplied by PharmaMar free of charge. Trabectedin was provided as a sterile lyophilized powder for reconstitution in solution for infusion in strength of 1 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TRABECTEDIN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Trabectedin was provided as a sterile lyophilized powder for reconstitution in solution for infusion in strength of 1 mg. Trabectedin was administered on day 1 every 4 weeks at the dose of 1.2 mg/m2 body surface area, administered as an intravenous infusion over 24 hours.

    Arm title
    		 Arm B - Observational
    Arm description
    		 Observation through clinical and radiological follow-up until disease progression (RECIST 1.1). Patients could receive commercial trabectedin after progression in Arm B as second line treatment as per investigator's decision.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Arm A - Trabectedin maintenance Arm B - Observational
    Started
    7
    6
    Completed
    0
    1
    Not completed
    7
    5
         Toxicity
    5
    -
         Symptomatic deterioration
    1
    1
         Patient's decision (not related to toxicity)
    -
    1
         Progression of disease/death due to PD
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - Trabectedin maintenance
    Reporting group description
    		 Treatment should start within 3 days from randomization. Trabectedin was administered on day 1 every 4 weeks at the dose of 1.2 mg/m2 body surface area, administered as an intravenous infusion over 24 hours. Trabectedin (trade name Yondelis®) was supplied by PharmaMar free of charge. Trabectedin was provided as a sterile lyophilized powder for reconstitution in solution for infusion in strength of 1 mg.

    Reporting group title
    Arm B - Observational
    Reporting group description
    		 Observation through clinical and radiological follow-up until disease progression (RECIST 1.1). Patients could receive commercial trabectedin after progression in Arm B as second line treatment as per investigator's decision.

    Reporting group values
    		 Arm A - Trabectedin maintenance Arm B - Observational Total
    Number of subjects
    		 7 6 13
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 3 8
        From 65-84 years
    		 2 3 5
    Age continuous
    Units: years
        median (full range (min-max))
    		 61 (34 to 70) 64 (45 to 74) -
    Gender categorical
    Units: Subjects
        Female
    		 5 2 7
        Male
    		 2 4 6
    WHO performance status (PS)
    Units: Subjects
        WHO PS = 0
    		 2 2 4
        WHO PS = 1
    		 5 4 9
    A first line chemotherapy with Doxorubicin (6 cycles)
    Units: Subjects
        Yes
    		 7 6 13
    Previous treatment - Dose of Doxorubicin (mg/m²)
    Units: (mg/m²)
        median (full range (min-max))
    		 75.0 (50.0 to 75.0) 75.0 (60.0 to 75.0) -
    Subject analysis sets

    Subject analysis set title
    Overall - full patient population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Considers all 13 patients randomised.

    Subject analysis sets values
    		 Overall - full patient population
    Number of subjects
    13
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    8
        From 65-84 years
    5
    Age continuous
    Units: years
        median (full range (min-max))
    62 (34 to 74)
    Gender categorical
    Units: Subjects
        Female
    7
        Male
    6
    WHO performance status (PS)
    Units: Subjects
        WHO PS = 0
    4
        WHO PS = 1
    9
    A first line chemotherapy with Doxorubicin (6 cycles)
    Units: Subjects
        Yes
    13
    Previous treatment - Dose of Doxorubicin (mg/m²)
    Units: (mg/m²)
        median (full range (min-max))
    75.0 (50.0 to 75.0)

    End points

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    End points reporting groups
    Reporting group title
    Arm A - Trabectedin maintenance
    Reporting group description
    		 Treatment should start within 3 days from randomization. Trabectedin was administered on day 1 every 4 weeks at the dose of 1.2 mg/m2 body surface area, administered as an intravenous infusion over 24 hours. Trabectedin (trade name Yondelis®) was supplied by PharmaMar free of charge. Trabectedin was provided as a sterile lyophilized powder for reconstitution in solution for infusion in strength of 1 mg.

    Reporting group title
    Arm B - Observational
    Reporting group description
    		 Observation through clinical and radiological follow-up until disease progression (RECIST 1.1). Patients could receive commercial trabectedin after progression in Arm B as second line treatment as per investigator's decision.

    Subject analysis set title
    Overall - full patient population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Considers all 13 patients randomised.

    Primary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    PFS was estimated by the Kaplan-Meier method. Median PFS was provided with it's 95% confidence interval. Patients who were alive without evidence of progression and who did not start a new antitumoral treatment in the absence of progression were censored at the date of their last radiological assessment.
    End point type
    Primary
    End point timeframe
    Progression-free survival was measured from the date of randomization until the date of the first documented disease progression, start of new antitumoral treatment in the absence of documented disease progression, or death, whichever occurs first.
    End point values
    		 Arm A - Trabectedin maintenance Arm B - Observational
    Number of subjects analysed
    7
    6
    Units: Months
        median (confidence interval 95%)
    11.3 (6.5 to 19.0)
    5.4 (1.4 to 14.7)
    Attachments
    		 PFS - Since randomization
    Statistical analysis title
    		 Kaplan-Meier
    Statistical analysis description
    There were only 13 patients available in the study (the study was closed for recruitment for poor accrual) so it is not justifiable to make statistical analysis. For the "Parameter estimate" Section, median PFS (and 95% CI) for Trabectedin Arm were described in order to avoid an error in the system.
    Comparison groups
    Arm A - Trabectedin maintenance v Arm B - Observational
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Median PFS estimate
    Point estimate
    11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.5
         upper limit
    		 19
    Notes
    [1] - Progression-free survival was estimated by the Kaplan-Meier method. The median survival time and its associated 95% CI was provided. For the "Parameter estimate" Section, median PFS (and 95% CI) for Trabectedin Arm were described in order to avoid an error in the system.

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall survival was estimated by the Kaplan-Meier method. The median survival time and its associated 95% CI was provided.
    End point type
    Secondary
    End point timeframe
    Overall survival was measured from the date of randomization to the date of death, whatever the cause of death. Patients who were alive were censored at the date of their last follow-up.
    End point values
    		 Arm A - Trabectedin maintenance Arm B - Observational
    Number of subjects analysed
    7
    6
    Units: Months
        median (confidence interval 95%)
    9999 (15.3 to 9999)
    9999 (5.3 to 9999)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) - Since Doxorubicin

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    End point title
    		 Progression-free survival (PFS) - Since Doxorubicin
    End point description
    PFS was estimated by the Kaplan-Meier method. Median PFS was provided with it's 95% confidence interval.
    End point type
    Secondary
    End point timeframe
    PFS was measured from the date of starting first-line Doxorubicin treatment.
    End point values
    		 Arm A - Trabectedin maintenance Arm B - Observational
    Number of subjects analysed
    7
    6
    Units: Months
        median (confidence interval 95%)
    16.6 (11.0 to 24.2)
    10.0 (6.6 to 19.5)
    Attachments
    		 PFS - Since Doxorubicin
    No statistical analyses for this end point

    Secondary: Overall survival - since Doxorubicin start

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    End point title
    		 Overall survival - since Doxorubicin start
    End point description
    Overall survival was estimated by the Kaplan-Meier method. The median survival time and its associated 95% CI was provided.
    End point type
    Secondary
    End point timeframe
    OS was measured from the date of starting first-line Doxorubicin treatment.
    End point values
    		 Arm A - Trabectedin maintenance Arm B - Observational
    Number of subjects analysed
    7
    6
    Units: Months
        median (confidence interval 95%)
    9999 (20.6 to 9999)
    9999 (9.9 to 9999)
    Attachments
    		 OS - since Doxorubicin
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start from randomization up to 30 days after administration of the last dose.
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items. (2 AEs are reported as "other" and are not reported as not available from the list of SOC). Both AEs and SAEs are evaluated using CTC grading.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Treatment should start within 3 days from randomization. Trabectedin was administered on day 1 every 4 weeks at the dose of 1.2 mg/m2 body surface area, administered as an intravenous infusion over 24 hours. Trabectedin (trade name Yondelis®) was supplied by PharmaMar free of charge. Trabectedin was provided as a sterile lyophilized powder for reconstitution in solution for infusion in strength

    Serious adverse events
    		 Arm A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 7 (57.14%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Vascular disorders
    ARTERIAL STENOSIS
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    CARDIAC FAILURE
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PLEURAL EFFUSION
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    ASPARTATE AMINOTRANSFERASE INCREASED
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    3
    CPK INCREASED
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    7
    CREATININE INCREASED
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    EJECTION FRACTION DECREASED
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    LYMPHOCYTE COUNT DECREASED
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    NEUTROPHIL COUNT DECREASED
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    8
    WHITE BLOOD CELL DECREASED
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEVROMA
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Cardiac disorders
    CARDIAC DISORDERS - OTHER, ARTERIAL STENOSIS
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    HEART FAILURE
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Nervous system disorders
    DYSGEUSIA
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    ANEMIA
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    4
    General disorders and administration site conditions
    EDEMA LIMBS
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    FATIGUE
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 7 (42.86%)
         occurrences all number
    4
    FEVER
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Gastrointestinal disorders
    ABDOMINAL PAIN
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    3
    DIARRHEA
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    DRY MOUTH
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    MUCOSITIS ORAL
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    NAUSEA
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 7 (42.86%)
         occurrences all number
    3
    VOMITING
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    BONE PAIN
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    INFLAMMATORY LEGS
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    PAIN IN EXTREMITY
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    ANOREXIA
    alternative dictionary used: CTCAE 4
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Mar 2017
    The protocol and patient information sheet have been updated according to the VHP comments: - Contraceptive methods considered to be highly effective, listed in the protocol, are now in line with Clinical Trial Facilitation group (CTFG) guidance. - A definition of women of childbearing potential has been included. - According to the Trabectedin SmPC, a note for advice on the possibility of ovules/sperm conservation has been added in the inclusion criteria. - It has been clarified that protocol waivers are not acceptable. A new section 16.4 regarding protocol and GCP compliance has been added as well. - Complete blood counts must be performed weekly for the first two cycles. This amendment has been discussed and agreed by the study team and study coordinator.

    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.
    Despite many efforts from all the parties involved, only few patients (13 patients in total) were recruited. The study was closed for recruitment on 10/08/2018 for poor accrual but two patients were included after that because they consented earlier.
    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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