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    Clinical Trial Results:
    Lurbinectedin Monotherapy in Patients with Progressive Malignant Pleural Mesothelioma. A Multicenter, Single-arm Phase II Trial

    Summary
    EudraCT number
    		 2017-001016-11
    Trial protocol
    		 IT  
    Global end of trial date
    22 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Sep 2022
    First version publication date
    28 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK17/16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03213301
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer Research (SAKK), +41 31 508 41 51, sakkcc@sakk.ch
    Scientific contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer Research (SAKK), +41 31 508 41 51, sakkcc@sakk.ch
    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
    11 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess efficacy and safety of lurbinectedin monotherapy in patients with progressive malignant mesothelioma
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 All patients received standard antiemetic prophylaxis 30 minutes before each lurbinectedin treatment infusion, as follows: (i) Corticosteroids (dexamethasone i.v. at least 8 mg or equivalent; if institutional standard antiemetic dose is higher, institutional dose is allowed), (ii) Serotonin (5-HT3) antagonists (ondansetron at least 8 mg i.v. or equivalent). If necessary, during treatment and in addition to the above, the duration of treatment with 5-HT3 antagonists and/or dexamethasone could be extended. Additional antiemetic agents (with the exception of aprepitant or equivalents) could be administered as appropriate.
    Evidence for comparator
    		 N/A; single arm study
    Actual start date of recruitment
    06 Oct 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
    Italy: 17
    Country: Number of subjects enrolled
    Switzerland: 25
    Worldwide total number of subjects
    42
    EEA total number of subjects
    17
    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)
    10
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment phase started September 28th, 2017 and was completed October 25th, 2018 after recruitment of 42 out of 39 planned patients. Twenty-five patients were enrolled at six sites in Switzerland and 17 patients at three sites in Italy.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was enrolled.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Lurbinectedin - Treatment arm
    Arm description
    		 Lurbinectedin, 3.2 mg/m2 by intravenous infusion on day one every three weeks (q3w) until disease progression, unacceptable toxicity or patient’s withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lurbinectedin
    Investigational medicinal product code
    Other name
    Zepsyre, Zepzelca, PM01183
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3.2 mg/m2 by intravenous infusion on day one every three weeks (q3w)

    Number of subjects in period 1
    		Lurbinectedin - Treatment arm
    Started
    42
    Completed
    42
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Lurbinectedin - Treatment arm
    Arm description
    		 Lurbinectedin, 3.2 mg/m2 by intravenous infusion on day one every three weeks (q3w) until disease progression, unacceptable toxicity or patient’s withdrawal of consent. After treatment discontinuation patients were followed up for up to two years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lurbinectedin
    Investigational medicinal product code
    Other name
    Zepsyre, Zepzelca, PM01183
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3.2 mg/m2 by intravenous infusion on day one every three weeks (q3w)

    Number of subjects in period 2
    		Lurbinectedin - Treatment arm
    Started
    42
    Completed
    0
    Not completed
    42
         Physician decision
    2
         Consent withdrawn by subject
    7
         Treatment delay >6 weeks
    1
         Progressive disease
    32

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lurbinectedin - Treatment arm
    Reporting group description
    		 Lurbinectedin, 3.2 mg/m2 by intravenous infusion on day one every three weeks (q3w) until disease progression, unacceptable toxicity or patient’s withdrawal of consent.

    Reporting group values
    		 Lurbinectedin - Treatment arm Total
    Number of subjects
    		 42 42
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 10 10
        From 65-84 years
    		 32 32
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 35 35

    End points

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    End points reporting groups
    Reporting group title
    Lurbinectedin - Treatment arm
    Reporting group description
    		 Lurbinectedin, 3.2 mg/m2 by intravenous infusion on day one every three weeks (q3w) until disease progression, unacceptable toxicity or patient’s withdrawal of consent.
    Reporting group title
    Lurbinectedin - Treatment arm
    Reporting group description
    		 Lurbinectedin, 3.2 mg/m2 by intravenous infusion on day one every three weeks (q3w) until disease progression, unacceptable toxicity or patient’s withdrawal of consent. After treatment discontinuation patients were followed up for up to two years.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Defined as all patients who received at least one dose of trial treatment, excluding patients with major eligibility violations.

    Subject analysis set title
    PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Defined as a subset of patients of the FAS population excluding patients with major protocol violations.

    Subject analysis set title
    FAS | Subgroup Immunotherapy - Prior Immunotherapy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in FAS receiving prior immunotherapy.

    Subject analysis set title
    FAS | Subgroup Immunotherapy - No Prior Immunotherapy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in FAS receiving no prior immunotherapy.

    Subject analysis set title
    PPS | Subgroup Immunotherapy - Prior Immunotherapy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in PPS receiving prior immunotherapy.

    Subject analysis set title
    PPS | Subgroup Immunotherapy - No prior Immunotherapy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in PPS receiving no prior immunotherapy.

    Subject analysis set title
    FAS | Subgroup Histological type - Epithelioid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in FAS with histological type at initial diagnosis = Epithelioid

    Subject analysis set title
    FAS | Subgroup Histological type - Non-Epithelioid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in FAS with histological type at initial diagnosis = Non-epithelioid

    Subject analysis set title
    PPS | Subgroup Histological type - Epithelioid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in PPS with histological type at initial diagnosis = Epithelioid

    Subject analysis set title
    PPS | Subgroup Histological type - Non-epithelioid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in PPS with histological type at initial diagnosis = Non-epithelioid

    Subject analysis set title
    FAS | Subgroup Prior PT-Pemetrexed - <6 months
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in FAS with prior platinum-pemetrexed chemotherapy in <6 months

    Subject analysis set title
    FAS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in FAS with prior platinum-pemetrexed chemotherapy in ≥6 months

    Subject analysis set title
    PPS | Subgroup Prior PT-Pemetrexed - <6 months
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in PPS with prior platinum-pemetrexed chemotherapy in <6 months

    Subject analysis set title
    PPS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in PPS with prior platinum-pemetrexed chemotherapy in ≥6 months

    Subject analysis set title
    FAS | Subgroup Subsequent treatment received
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in FAS starting subsequent systemic further treatment.

    Subject analysis set title
    FAS | Subgroup Subsequent treatment not received
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in FAS not starting subsequent systemic further treatment.

    Subject analysis set title
    PPS | Subgroup Subsequent treatment received
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in PPS starting subsequent systemic further treatment.

    Subject analysis set title
    PPS | Subgroup Subsequent treatment not received
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients in PPS not starting subsequent systemic further treatment.

    Primary: PE || Progression-free survival (PFS) at 12 weeks

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    End point title
    		 PE || Progression-free survival (PFS) at 12 weeks [1]
    End point description
    PFS is defined as time from registration to one of the following events, whichever occurs first: (i) Relapse or progression according to the modified RECIST criteria for malignant pleural mesothelioma (ii) Death due to any cause. Patients not experiencing an event will be censored at the date of last evaluable tumor assessment before starting a subsequent treatment, if any. p-value for FAS = 0.015; p-value for PPS = 0.024
    End point type
    Primary
    End point timeframe
    PFS at 12 +/- 2 weeks.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was a single arm study, no comparison groups were available. However, the null hypothesis was rejected as the lower of the 90%CI of the primary endpoint calculated using the uniformly minimum variance unbiased estimator (UMVUE) was over 35% (null hypothesis).
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: % patients with PFS
        number (confidence interval 90%)
    52.4 (38.7 to 63.6)
    51.6 (37.5 to 62.7)
    No statistical analyses for this end point

    Secondary: SE || Progression-free survival

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    End point title
    		 SE || Progression-free survival
    End point description
    Kaplan-Meier analysis. Number of events 39/42 (FAS) and 38/41 (PPS), respectively.
    End point type
    Secondary
    End point timeframe
    From registration until death or progressive disease (PD).
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: Progression-free survival (months)
        median (confidence interval 95%)
    4.1 (2.6 to 5.5)
    3.4 (2.6 to 5.5)
    No statistical analyses for this end point

    Secondary: SE || Objective Response

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    End point title
    		 SE || Objective Response
    End point description
    CR - Complete response; PR - Partial response
    End point type
    Secondary
    End point timeframe
    From registration until CR or PR.
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: % patients with CR or PR
        number (confidence interval 95%)
    4.8 (0.6 to 16.2)
    4.9 (0.6 to 16.5)
    No statistical analyses for this end point

    Secondary: SE || Disease control (DC) at 12 weeks

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    End point title
    		 SE || Disease control (DC) at 12 weeks
    End point description
    Disease control defined as CR (complete response), PR (partial response) or SD (stable disease) at week 12. (FAS: CR=1; PR=1; SD=20); (FAS: CR=1; PR=1; SD=19)
    End point type
    Secondary
    End point timeframe
    At 12 weeks.
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: % patients with DC
        number (confidence interval 95%)
    52.4 (36.4 to 68.0)
    51.2 (35.1 to 67.1)
    No statistical analyses for this end point

    Secondary: SE || Duration of disease control

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    End point title
    		 SE || Duration of disease control
    End point description
    Kaplan-Meier analysis of duration of DC. (FAS: 20 events [1 death, 19 PD]), (PPS: 20 events [1 death, 19 PD])
    End point type
    Secondary
    End point timeframe
    From registration until death or progressive disease.
    End point values
    		 FAS PPS
    Number of subjects analysed
    20 [2]
    20 [3]
    Units: Duration of DC (months)
        number (confidence interval 95%)
    6.6 (5.2 to 7.4)
    6.6 (5.2 to 7.4)
    Notes
    [2] - 20 patients with DC at 12 weeks.
    [3] - 20 patients with DC at 12 weeks.
    No statistical analyses for this end point

    Secondary: SE || Overall survival (OS)

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    End point title
    		 SE || Overall survival (OS)
    End point description
    Median follow-up time =32.8 months (95%CI: 28.5 – 39.0). (FAS 36/42 events [deaths]); (FAS 35/41 events [deaths])
    End point type
    Secondary
    End point timeframe
    From registration until death.
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: OS (months)
        median (confidence interval 95%)
    11.5 (8.8 to 13.9)
    11.9 (8.5 to 14.7)
    No statistical analyses for this end point

    Secondary: SE || Overall survival - OS at fixed timepoints

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    End point title
    		 SE || Overall survival - OS at fixed timepoints
    End point description
    Estimates of OS rate at 3, 6, 9 and 12 months.
    End point type
    Secondary
    End point timeframe
    At 3, 6, 9, 12 months.
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: % patients
    number (confidence interval 95%)
        3 months
    95.2 (82.3 to 98.8)
    95.1 (85.2 to 98.4)
        6 months
    73.8 (57.7 to 84.6)
    73.2 (59.8 to 82.7)
        9 months
    64.3 (47.9 to 76.7)
    63.4 (49.7 to 74.3)
        12 months
    47.6 (32.1 to 61.6)
    48.8 (35.5 to 60.8)
    No statistical analyses for this end point

    Secondary: SE || Time to treatment failure (TTF)

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    End point title
    		 SE || Time to treatment failure (TTF)
    End point description
    Kaplan-Meier Analysis of time to treatment failure from registration. (FAS: 42 events; PPS: 41 events)
    End point type
    Secondary
    End point timeframe
    From registration until end of treatment due to any reason.
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: Time to treatment failure (months)
        median (confidence interval 95%)
    2.5 (0.9 to 3.6)
    2.3 (0.9 to 3.8)
    No statistical analyses for this end point

    Other pre-specified: PE || Progression-free survival (PFS) at 12 weeks - Subgroup analyses

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    End point title
    		 PE || Progression-free survival (PFS) at 12 weeks - Subgroup analyses
    End point description
    PFS as defined before. Subgroup analyses.
    End point type
    Other pre-specified
    End point timeframe
    PFS at 12 +/- 2 weeks.
    End point values
    		 FAS | Subgroup Immunotherapy - Prior Immunotherapy FAS | Subgroup Immunotherapy - No Prior Immunotherapy PPS | Subgroup Immunotherapy - Prior Immunotherapy PPS | Subgroup Immunotherapy - No prior Immunotherapy FAS | Subgroup Histological type - Epithelioid FAS | Subgroup Histological type - Non-Epithelioid PPS | Subgroup Histological type - Epithelioid PPS | Subgroup Histological type - Non-epithelioid FAS | Subgroup Prior PT-Pemetrexed - <6 months FAS | Subgroup Prior PT-Pemetrexed - ≥6 months PPS | Subgroup Prior PT-Pemetrexed - <6 months PPS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects analysed
    10
    32
    9
    32
    33
    9
    33
    8
    14
    28
    11
    27
    Units: % patients with PFS
        number (confidence interval 95%)
    70 (32.9 to 89.2)
    61.4 (42.1 to 75.9)
    66.7 (28.2 to 87.8)
    61.4 (42.1 to 75.9)
    63.6 (44.9 to 77.5)
    62.5 (22.9 to 86.1)
    63.6 (44.9 to 77.5)
    57.1 (17.2 to 83.7)
    53.8 (24.8 to 76.0)
    67.9 (47.3 to 81.8)
    53.8 (24.8 to 76.0)
    66.7 (45.7 to 81.1)
    Statistical analysis title
    		 Subgroup analysis Immunotherapy (FAS)
    Statistical analysis description
    The 12-week PFS rate between categories were compared using the Kaplan-Meier estimator at 12 weeks.
    Comparison groups
    FAS | Subgroup Immunotherapy - Prior Immunotherapy v FAS | Subgroup Immunotherapy - No Prior Immunotherapy
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.628
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Immunotherapy (PPS)
    Statistical analysis description
    The 12-week PFS rate between categories were compared using the Kaplan-Meier estimator at 12 weeks.
    Comparison groups
    PPS | Subgroup Immunotherapy - Prior Immunotherapy v PPS | Subgroup Immunotherapy - No prior Immunotherapy
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.775
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Histological type (FAS)
    Statistical analysis description
    The 12-week PFS rate between categories were compared using the Kaplan-Meier estimator at 12 weeks.
    Comparison groups
    FAS | Subgroup Histological type - Epithelioid v FAS | Subgroup Histological type - Non-Epithelioid
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.952
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Histological type (PPS)
    Statistical analysis description
    The 12-week PFS rate between categories were compared using the Kaplan-Meier estimator at 12 weeks.
    Comparison groups
    PPS | Subgroup Histological type - Epithelioid v PPS | Subgroup Histological type - Non-epithelioid
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.744
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Prior Pt-Pemetrexed (FAS)
    Statistical analysis description
    The 12-week PFS rate between categories were compared using the Kaplan-Meier estimator at 12 weeks.
    Comparison groups
    FAS | Subgroup Prior PT-Pemetrexed - <6 months v FAS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.381
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Prior Pt-Pemetrexed (PPS)
    Statistical analysis description
    The 12-week PFS rate between categories were compared using the Kaplan-Meier estimator at 12 weeks.
    Comparison groups
    PPS | Subgroup Prior PT-Pemetrexed - <6 months v PPS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.428
    Method
    		 Logrank
    Confidence interval

    Other pre-specified: PE || Progression-free survival (PFS) at 12 weeks

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    End point title
    		 PE || Progression-free survival (PFS) at 12 weeks
    End point description
    PFS as defined before. Using Kaplan Meier Estimator.
    End point type
    Other pre-specified
    End point timeframe
    At 12 weeks.
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: % patients with PFS
        number (confidence interval 90%)
    63.5 (49.7 to 74.4)
    62.5 (48.6 to 73.7)
    No statistical analyses for this end point

    Other pre-specified: SE || Progression-free survival - PFS at fixed timepoints

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    End point title
    		 SE || Progression-free survival - PFS at fixed timepoints
    End point description
    Kaplan-Meier analysis.
    End point type
    Other pre-specified
    End point timeframe
    At 3, 6, 9, 12 months.
    End point values
    		 FAS PPS
    Number of subjects analysed
    42
    41
    Units: % patietnts with PFS
    number (confidence interval 95%)
        3 months
    58.4 (41.8 to 71.7)
    57.3 (43.4 to 69.0)
        6 months
    30.5 (17.1 to 44.9)
    31.3 (19.6 to 43.6)
        9 months
    12.7 (4.7 to 24.9)
    13.0 (5.8 to 23.3)
        12 months
    3.4 (0.3 to 14.1)
    3.5 (0.5 to 12.0)
    No statistical analyses for this end point

    Other pre-specified: SE || Progression-free survival - Subgroup analyses

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    End point title
    		 SE || Progression-free survival - Subgroup analyses
    End point description
    Kaplan-Meier analysis for subgroups.
    End point type
    Other pre-specified
    End point timeframe
    From registration until death or progressive disease (PD).
    End point values
    		 FAS | Subgroup Immunotherapy - Prior Immunotherapy FAS | Subgroup Immunotherapy - No Prior Immunotherapy PPS | Subgroup Immunotherapy - Prior Immunotherapy PPS | Subgroup Immunotherapy - No prior Immunotherapy FAS | Subgroup Histological type - Epithelioid FAS | Subgroup Histological type - Non-Epithelioid PPS | Subgroup Histological type - Epithelioid PPS | Subgroup Histological type - Non-epithelioid FAS | Subgroup Prior PT-Pemetrexed - <6 months FAS | Subgroup Prior PT-Pemetrexed - ≥6 months PPS | Subgroup Prior PT-Pemetrexed - <6 months PPS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects analysed
    10
    32
    9
    32
    33
    9
    33
    8
    14
    28
    14
    27
    Units: Progression-free survival (months)
        number (confidence interval 95%)
    3.2 (1.4 to 5.8)
    4.1 (2.3 to 6.4)
    3.2 (1.4 to 5.8)
    4.1 (2.3 to 6.4)
    4.1 (2.5 to 6.4)
    3.7 (1.1 to 5.5)
    4.1 (2.5 to 6.4)
    3.2 (1.1 to 5.5)
    3.0 (1.3 to 5.5)
    4.3 (2.6 to 6.6)
    3.0 (1.3 to 5.5)
    4.4 (2.5 to 6.6)
    Statistical analysis title
    		 Subgroup analysis Immunotherapy (FAS)
    Statistical analysis description
    Comparisons of PFS between subgroups were investigated using the log rank test.
    Comparison groups
    FAS | Subgroup Immunotherapy - Prior Immunotherapy v FAS | Subgroup Immunotherapy - No Prior Immunotherapy
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.508
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Immunotherapy (PPS)
    Statistical analysis description
    Comparisons of PFS between subgroups were investigated using the log rank test.
    Comparison groups
    PPS | Subgroup Immunotherapy - Prior Immunotherapy v PPS | Subgroup Immunotherapy - No prior Immunotherapy
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.555
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Histological type (FAS)
    Statistical analysis description
    Comparisons of PFS between subgroups were investigated using the log rank test.
    Comparison groups
    FAS | Subgroup Histological type - Epithelioid v FAS | Subgroup Histological type - Non-Epithelioid
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.986
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Histological type (PPS)
    Statistical analysis description
    Comparisons of PFS between subgroups were investigated using the log rank test.
    Comparison groups
    PPS | Subgroup Histological type - Epithelioid v PPS | Subgroup Histological type - Non-epithelioid
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.916
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Prior Pt-Pemetrexed (FAS)
    Statistical analysis description
    Comparisons of PFS between subgroups were investigated using the log rank test.
    Comparison groups
    FAS | Subgroup Prior PT-Pemetrexed - <6 months v FAS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.402
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Prior Pt-Pemetrexed (PPS)
    Statistical analysis description
    Comparisons of PFS between subgroups were investigated using the log rank test.
    Comparison groups
    PPS | Subgroup Prior PT-Pemetrexed - <6 months v PPS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.387
    Method
    		 Logrank
    Confidence interval

    Other pre-specified: SE || Overall survival - Subgroup analyses

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    End point title
    		 SE || Overall survival - Subgroup analyses
    End point description
    Kaplan-Meier analyses for subgroups.
    End point type
    Other pre-specified
    End point timeframe
    From registration until death.
    End point values
    		 FAS | Subgroup Immunotherapy - Prior Immunotherapy FAS | Subgroup Immunotherapy - No Prior Immunotherapy PPS | Subgroup Immunotherapy - Prior Immunotherapy PPS | Subgroup Immunotherapy - No prior Immunotherapy FAS | Subgroup Histological type - Epithelioid FAS | Subgroup Histological type - Non-Epithelioid PPS | Subgroup Histological type - Epithelioid PPS | Subgroup Histological type - Non-epithelioid FAS | Subgroup Prior PT-Pemetrexed - <6 months FAS | Subgroup Prior PT-Pemetrexed - ≥6 months PPS | Subgroup Prior PT-Pemetrexed - <6 months PPS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects analysed
    10
    32
    9
    32
    33
    9
    33
    8
    14
    28
    14
    27
    Units: Overall survival (months)
        median (confidence interval 95%)
    10.8 (2.5 to 13.3)
    12.0 (8.1 to 22.4)
    11.1 (2.5 to 14.7)
    12.0 (8.1 to 22.4)
    12.4 (8.1 to 15.5)
    10.0 (2.9 to 30.9)
    12.4 (8.1 to 15.5)
    9.8 (2.9 to 30.9)
    8.8 (3.2 to 11.1)
    14.2 (10.0 to 22.4)
    8.8 (3.2 to 11.1)
    14.7 (8.8 to 22.5)
    Statistical analysis title
    		 Subgroup analysis Immunotherapy (FAS)
    Statistical analysis description
    Comparisons of OS between subgroups were investigated using the log rank test.
    Comparison groups
    FAS | Subgroup Immunotherapy - Prior Immunotherapy v FAS | Subgroup Immunotherapy - No Prior Immunotherapy
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.063
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Immunotherapy (PPS)
    Statistical analysis description
    Comparisons of OS between subgroups were investigated using the log rank test.
    Comparison groups
    PPS | Subgroup Immunotherapy - Prior Immunotherapy v PPS | Subgroup Immunotherapy - No prior Immunotherapy
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.075
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Histological type (FAS)
    Statistical analysis description
    Comparisons of OS between subgroups were investigated using the log rank test.
    Comparison groups
    FAS | Subgroup Histological type - Non-Epithelioid v FAS | Subgroup Histological type - Epithelioid
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.385
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Histological type (PPS)
    Statistical analysis description
    Comparisons of OS between subgroups were investigated using the log rank test.
    Comparison groups
    PPS | Subgroup Histological type - Epithelioid v PPS | Subgroup Histological type - Non-epithelioid
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.478
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Prior Pt-Pemetrexed (FAS)
    Statistical analysis description
    Comparisons of OS between subgroups were investigated using the log rank test.
    Comparison groups
    FAS | Subgroup Prior PT-Pemetrexed - <6 months v FAS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.003
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Subgroup analysis Prior Pt-Pemetrexed (PPS)
    Statistical analysis description
    Comparisons of OS between subgroups were investigated using the log rank test.
    Comparison groups
    PPS | Subgroup Prior PT-Pemetrexed - <6 months v PPS | Subgroup Prior PT-Pemetrexed - ≥6 months
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.003
    Method
    		 Logrank
    Confidence interval

    Other pre-specified: SE || Overall survival - Subgroup analysis Subsequent treatment

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    End point title
    		 SE || Overall survival - Subgroup analysis Subsequent treatment
    End point description
    Subgroup analysis for patients starting further systemic treatment.
    End point type
    Other pre-specified
    End point timeframe
    From registration until death.
    End point values
    		 FAS | Subgroup Subsequent treatment received FAS | Subgroup Subsequent treatment not received PPS | Subgroup Subsequent treatment received PPS | Subgroup Subsequent treatment not received
    Number of subjects analysed
    28
    14
    28
    13
    Units: Number of patients
    28
    14
    28
    13
    Statistical analysis title
    		 Hazard ratio (OS / Subsequent treatment) - FAS
    Statistical analysis description
    Effect of systemic subsequent treatment on OS.
    Comparison groups
    FAS | Subgroup Subsequent treatment received v FAS | Subgroup Subsequent treatment not received
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.699
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.851
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.375
         upper limit
    		 1.931
    Statistical analysis title
    		 Hazard ratio (OS / Subsequent treatment) - PPS
    Statistical analysis description
    Effect of systemic subsequent treatment on OS.
    Comparison groups
    PPS | Subgroup Subsequent treatment received v PPS | Subgroup Subsequent treatment not received
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.84
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.917
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.396
         upper limit
    		 2.123

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From registration up to 30 days after last dose of study medication or until the start of a new antitumor therapy, whichever occured first.
    Adverse event reporting additional description
    Recording during the follow-up period, except for new malignancies or congenital abnormalities, only for events with possible relationship to the study drug. Safety was assessed with the safety set, defined as all patients who took at least one dose of the trial treatment after registration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Safety analysis set
    Reporting group description
    		 Safety set, defined as all patients who took at least one dose of the trial treatment after registration.

    Serious adverse events
    		 Safety analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 42 (21.43%)
         number of deaths (all causes)
    36
         number of deaths resulting from adverse events
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdiaphragmatic abscess
    Additional description: Sub-diaphragmatic fluid collection
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 42 (100.00%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    14 / 42 (33.33%)
         occurrences all number
    24
    Weight decreased
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 42 (23.81%)
         occurrences all number
    12
    Blood bilirubin increased
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    4
    Blood creatinine increased
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    8
    Lymphocyte count decreased
         subjects affected / exposed
    23 / 42 (54.76%)
         occurrences all number
    23
    Blood urea increased
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    6
    White blood cell count decreased
         subjects affected / exposed
    12 / 42 (28.57%)
         occurrences all number
    17
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    10
    Superficial vein thrombosis
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 42 (42.86%)
         occurrences all number
    26
    Thrombocytopenia
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    10
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    32 / 42 (76.19%)
         occurrences all number
    38
    Pyrexia
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    10
    Non-cardiac chest pain
         subjects affected / exposed
    7 / 42 (16.67%)
         occurrences all number
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    6
    Constipation
         subjects affected / exposed
    12 / 42 (28.57%)
         occurrences all number
    21
    Diarrhoea
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    7
    Dysphagia
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    5
    Stomatitis
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    25 / 42 (59.52%)
         occurrences all number
    36
    Vomiting
         subjects affected / exposed
    11 / 42 (26.19%)
         occurrences all number
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 42 (26.19%)
         occurrences all number
    13
    Dyspnoea
         subjects affected / exposed
    12 / 42 (28.57%)
         occurrences all number
    15
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    10 / 42 (23.81%)
         occurrences all number
    10
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 42 (33.33%)
         occurrences all number
    16
    Hyperkalaemia
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    6
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    7
    Hypomagnesaemia
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    5

    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.
    n/a
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    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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