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    Clinical Trial Results:
    A Multicenter Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer.

    Summary
    EudraCT number
    		 2011-006108-11
    Trial protocol
    		 ES  
    Global end of trial date
    27 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2020
    First version publication date
    18 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PM1183-B-003-11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01525589
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharma Mar, S.A.
    Sponsor organisation address
    Avenida de los Reyes, 1 Polígono Industrial "La Mina", Colmenar Viejo, Madrid, Spain, 28770
    Public contact
    Clinical Development Department of PharmaMar´s Oncology, Business Unit., Pharma Mar, S.A., 34 91846 60 00, clinicaltrials@pharmamar.com
    Scientific contact
    Clinical Development Department of PharmaMar´s Oncology, Business Unit., Pharma Mar, S.A., 34 91846 60 00, 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
    03 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the antitumor activity of PM01183 in terms of overall response rate (ORR) according to RECIST vs 1.1 in each cohort of metastatic breast cancer (MBC) patients.
    Protection of trial subjects
    The study was in compliance with ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 All patients received standard antiemetic prophylactic medication at least 30 minutes before each administration of lurbinectedin, as follows: • Corticosteroids (dexamethasone i.v. or equivalent at institutional standard antiemetic doses). • Serotonin (5-HT3) antagonists (ondansetron 8 mg i.v. or equivalent). If necessary and in addition to the above, any of the following could apply: • Administration of 10 mg of metoclopramide (or equivalent) every eight hours. • Extended treatment with 5-HT3 antagonists and/or dexamethasone. Aprepitant and directly related agents (e.g., fosaprepitant) were forbidden. For the purpose of safety evaluations, an optimal prophylaxis was defined as any of the aforementioned allowed medications at their respectively maximum dose.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 2012
    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: 51
    Country: Number of subjects enrolled
    United States: 60
    Worldwide total number of subjects
    111
    EEA total number of subjects
    51
    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)
    100
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was included on 27JUN12 and the first study treatment administration was on 28JUN12. The cutoff date for the results was 24OCT18. A total of 111 patients were included in the 3 cohorts of the study: 56 in Cohort A (BRCA+), 20 in Cohort A1 (BRCA+/PARPi), 35 in Cohort B (Unselected).

    Pre-assignment
    Screening details
    		 Women 18-75 years;signed ICF;diagnosis of MBC;No more than three prior chemotherapy;ECOG PS 0-1;Adequate major organ function;Washout periods prior to D1 of Cycle 1

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A (BRCA+)
    Arm description
    		 Patients with known deleterious BRCA1/2 mutation status at study entry.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lurbinectedin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Lurbinectedin was administered over a minimum total volume of 100 mL of solution for infusion (either on 5% glucose or 0.9% sodium chloride), through a central catheter, or over a minimum total volume of 250 mL if administered through a peripheral line, always over 1h at a fixed infusion rate. Patients received lurbinectedin i.v. as a 1h infusion on D1 q3wk, at one of two starting doses: - Patients included under protocol v1.0 v2.0 received lurbinectedin at a starting dose of 7.0 mg FD. - Patients included from protocol v3.0 onwards received lurbinectedin at a starting dose of 3.5 mg/m2. Dose did not exceed 7.0 mg. As a result, patients in Cohort A were treated at a starting dose of 7.0 mg FD or 3.5 mg/m2, and all patients in Cohort B were treated at a starting dose of 7.0 mg FD. Recruitment into Cohort A1 started after implementation of substantial amendment No. 3 (8MAR16); therefore, all patients in Cohort A1 were treated at a starting dose of 3.5 mg/m2.

    Arm title
    		 Cohort A1 (BRCA+/PARPi)
    Arm description
    		 Patients with known deleterious BRCA1/2 mutation status and prior treatment with PARPi.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lurbinectedin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Lurbinectedin was administered over a minimum total volume of 100 mL of solution for infusion (either on 5% glucose or 0.9% sodium chloride), through a central catheter, or over a minimum total volume of 250 mL if administered through a peripheral line, always over 1h at a fixed infusion rate. Patients received lurbinectedin i.v. as a 1h infusion on D1 q3wk, at one of two starting doses: - Patients included under protocol v1.0 v2.0 received lurbinectedin at a starting dose of 7.0 mg FD. - Patients included from protocol v3.0 onwards received lurbinectedin at a starting dose of 3.5 mg/m2. Dose did not exceed 7.0 mg. As a result, patients in Cohort A were treated at a starting dose of 7.0 mg FD or 3.5 mg/m2, and all patients in Cohort B were treated at a starting dose of 7.0 mg FD. Recruitment into Cohort A1 started after implementation of substantial amendment No. 3 (8MAR16); therefore, all patients in Cohort A1 were treated at a starting dose of 3.5 mg/m2.

    Arm title
    		 Cohort B (Unselected)
    Arm description
    		 Patients without known deleterious BRCA1/2 mutation status at study entry, i.e., either: - Patients known to have no deleterious BRCA1/2 mutations (BRCA−), or - Patients whose BRCA 1/2 mutation status was unknown (BRCA-UK). BRCA1/2 germline mutation status would be assessed in all patients in this subgroup responding to lurbinectedin treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lurbinectedin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Lurbinectedin was administered over a minimum total volume of 100 mL of solution for infusion (either on 5% glucose or 0.9% sodium chloride), through a central catheter, or over a minimum total volume of 250 mL if administered through a peripheral line, always over 1h at a fixed infusion rate. Patients received lurbinectedin i.v. as a 1h infusion on D1 q3wk, at one of two starting doses: - Patients included under protocol v1.0 v2.0 received lurbinectedin at a starting dose of 7.0 mg FD. - Patients included from protocol v3.0 onwards received lurbinectedin at a starting dose of 3.5 mg/m2. Dose did not exceed 7.0 mg. As a result, patients in Cohort A were treated at a starting dose of 7.0 mg FD or 3.5 mg/m2, and all patients in Cohort B were treated at a starting dose of 7.0 mg FD. Recruitment into Cohort A1 started after implementation of substantial amendment No. 3 (8MAR16); therefore, all patients in Cohort A1 were treated at a starting dose of 3.5 mg/m2.

    Number of subjects in period 1
    		Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Started
    56
    20
    35
    Completed
    0
    0
    0
    Not completed
    56
    20
    35
         Physician decision
    4
    2
    2
         Consent withdrawn by subject
    -
    1
    -
         Treatment-related AE
    1
    1
    2
         Non-treatment-related AE
    1
    -
    -
         Death (due to toxicity)
    -
    -
    1
         Other reasons
    -
    1
    -
         Never treated
    2
    -
    -
         Progressive disease
    48
    15
    29
         Death (non-treatment-related)
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A (BRCA+)
    Reporting group description
    		 Patients with known deleterious BRCA1/2 mutation status at study entry.

    Reporting group title
    Cohort A1 (BRCA+/PARPi)
    Reporting group description
    		 Patients with known deleterious BRCA1/2 mutation status and prior treatment with PARPi.

    Reporting group title
    Cohort B (Unselected)
    Reporting group description
    		 Patients without known deleterious BRCA1/2 mutation status at study entry, i.e., either: - Patients known to have no deleterious BRCA1/2 mutations (BRCA−), or - Patients whose BRCA 1/2 mutation status was unknown (BRCA-UK). BRCA1/2 germline mutation status would be assessed in all patients in this subgroup responding to lurbinectedin treatment.

    Reporting group values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected) Total
    Number of subjects
    		 56 20 35 111
    Age categorical
    Units: Subjects
        18-40
    		 24 8 6 38
        41-64
    		 27 11 24 62
        >=65
    		 5 1 5 11
    Age continuous
    Units: years
        median (full range (min-max))
    		 42.5 (30 to 73) 45.0 (31 to 66) 52.0 (32 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 56 20 35 111
        Male
    		 0 0 0 0
    Race
    Units: Subjects
        Caucasian
    		 50 16 32 98
        Black
    		 2 0 1 3
        Asian
    		 1 1 0 2
        Hispanic
    		 2 1 2 5
        Unknown
    		 1 2 0 3
    ECOG PS
    ECOG PS, Eastern Cooperative Oncology Group performance status
    Units: Subjects
        PS 0
    		 32 10 22 64
        PS 1
    		 24 10 13 47
    Sites of disease at diagnosis
    Units: Subjects
        Left breast
    		 26 11 18 55
        Right breast
    		 28 9 15 52
        Bilateral
    		 2 0 2 4
    Histology type at diagnosis
    Units: Subjects
        Ductal carcinoma
    		 54 20 34 108
        Lobular carcinoma
    		 2 0 0 2
        Lobular and ductal carcinoma
    		 0 0 1 1
    Histology grade at diagnosis
    Units: Subjects
        Well differentiated
    		 3 0 1 4
        Moderately differentiated
    		 10 8 13 31
        Poorly differentiated
    		 31 11 17 59
        Unknown
    		 12 1 4 17
    Stage at diagnosis
    Units: Subjects
        Stage I
    		 9 3 0 12
        Stage II
    		 26 9 13 48
        Stage III
    		 16 6 19 41
        Stage IV
    		 5 2 3 10
    BRCA deleterious mutation
    Units: Subjects
        BRCA1
    		 33 10 0 43
        BRCA2
    		 23 9 0 32
        Both
    		 0 1 0 1
        Not applicable
    		 0 0 35 35
    Hormonal status
    Units: Subjects
        Triple negative
    		 33 7 17 57
        ER and/or PR positive and HER2 negative
    		 21 12 14 47
        ER and/or PR positive and HER2 positive
    		 2 1 3 6
        ER and PR negative and HER2 positive
    		 0 0 1 1
    Sites at baseline
    Units: Subjects
        <3 sites
    		 23 7 21 51
        ≥3 sites
    		 33 13 14 60
    Prior surgery
    Units: Subjects
        Yes
    		 53 19 34 106
        No
    		 3 1 1 5
    Prior radiotherapy
    Units: Subjects
        Yes
    		 44 18 32 94
        No
    		 12 2 3 17
    Weight
    Units: kg
        median (full range (min-max))
    		 69.2 (48.4 to 107.3) 59.8 (48.5 to 98.8) 71.7 (43.0 to 153.6) -
    Height
    Units: cm
        median (full range (min-max))
    		 162.5 (150.0 to 178.0) 161.0 (148.0 to 173.0) 161.0 (147.0 to 171.0) -
    BSA
    BSA, body surface area
    Units: m2
        median (full range (min-max))
    		 1.72 (1.47 to 2.12) 1.63 (1.48 to 2.05) 1.75 (1.36 to 2.41) -
    Albumin
    Units: g/dL
        median (full range (min-max))
    		 4.1 (3.3 to 4.9) 4.1 (3.6 to 4.8) 4.0 (3.4 to 4.6) -
    Number of sites at baseline
    Units: Number of sites
        median (full range (min-max))
    		 3.0 (1 to 7) 3.0 (1 to 6) 2.0 (1 to 6) -
    Time from first diagnosis to registration
    Units: months
        median (full range (min-max))
    		 44.0 (0.9 to 170.3) 55.7 (11.5 to 337.3) 47.0 (5.0 to 177.3) -
    Time from metastatic disease to registration
    Units: months
        median (full range (min-max))
    		 12.5 (0.4 to 129.8) 26.1 (8.4 to 98.2) 13.8 (2.5 to 110.9) -
    Time from last progression before study entry
    Units: weeks
        median (full range (min-max))
    		 2.9 (0.0 to 15.6) 3.2 (0.9 to 14.0) 3.0 (0.7 to 8.1) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort A (BRCA+)
    Reporting group description
    		 Patients with known deleterious BRCA1/2 mutation status at study entry.

    Reporting group title
    Cohort A1 (BRCA+/PARPi)
    Reporting group description
    		 Patients with known deleterious BRCA1/2 mutation status and prior treatment with PARPi.

    Reporting group title
    Cohort B (Unselected)
    Reporting group description
    		 Patients without known deleterious BRCA1/2 mutation status at study entry, i.e., either: - Patients known to have no deleterious BRCA1/2 mutations (BRCA−), or - Patients whose BRCA 1/2 mutation status was unknown (BRCA-UK). BRCA1/2 germline mutation status would be assessed in all patients in this subgroup responding to lurbinectedin treatment.

    Primary: Overall Response Rate

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    End point title
    		 Overall Response Rate [1]
    End point description
    Overall Response Rate (ORR) in the population evaluable for efficacy according to RECIST v.1.1. ORR was defined as the percentage of patients with a confirmed response, either CR or PR, according to the RECIST v.1.1.
    End point type
    Primary
    End point timeframe
    Overall period
    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: No comparative design. Multicenter, open-label, exploratory, phase II clinical trial to evaluate the efficacy and safety of lurbinectedin in previously treated patients with MBC. Three cohorts of MBC patients were prospectively evaluated.
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [2]
    20
    34 [3]
    Units: percent
        median (confidence interval 95%)
    40.7 (27.6 to 55.0)
    5.0 (0.1 to 24.9)
    8.8 (1.9 to 23.7)
    Notes
    [2] - Two patients never treated
    [3] - 1 patient due to lack of post-baseline tumor assessments
    No statistical analyses for this end point

    Primary: Overall Response

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    End point title
    		 Overall Response [4]
    End point description
    Overall Response Rate (ORR) in the population evaluable for efficacy according to RECIST v.1.1. ORR was defined as the percentage of patients with a confirmed response, either CR or PR, according to the RECIST v.1.1. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; TF, treatment failure
    End point type
    Primary
    End point timeframe
    Overall period
    Notes
    [4] - 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: No comparative design. Multicenter, open-label, exploratory, phase II clinical trial to evaluate the efficacy and safety of lurbinectedin in previously treated patients with MBC. Three cohorts of MBC patients were prospectively evaluated.
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [5]
    20
    34 [6]
    Units: subjects
        CR
    2
    0
    0
        PR
    20
    1
    3
        SD
    24
    9
    17
        PD
    8
    10
    13
        TF
    0
    0
    1
    Notes
    [5] - 2 patients never treated
    [6] - 1 patient due to lack of post-baseline tumor assessments
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response (DoR), defined as the time between the date when the response criteria (PR or CR, whichever was first reached) were fulfilled to the first date when disease progression (PD), recurrence or death was documented. 000, 999: not reached
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    22 [7]
    1 [8]
    3 [9]
    Units: months
        median (confidence interval 95%)
    6.3 (3.4 to 12.7)
    2.7 (000 to 999)
    3.6 (2.1 to 16.1)
    Notes
    [7] - 22 responder patients
    [8] - 1 responder patients
    [9] - 3 responder patients
    Statistical analysis title
    		 Differences between groups
    Comparison groups
    Cohort A (BRCA+) v Cohort A1 (BRCA+/PARPi) v Cohort B (Unselected)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0909
    Method
    		 Logrank
    Confidence interval

    Secondary: Duration of response rate at 6 months

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    End point title
    		 Duration of response rate at 6 months
    End point description
    Duration of response (DoR), defined as the time between the date when the response criteria (PR or CR, whichever was first reached) were fulfilled to the first date when disease progression (PD), recurrence or death was documented.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    22 [10]
    1 [11]
    3 [12]
    Units: percent
        number (confidence interval 95%)
    53.1 (31.8 to 74.4)
    0 (0 to 999)
    33.3 (0 to 86.7)
    Notes
    [10] - 22 responder patients
    [11] - 1 responder patients
    [12] - 3 responder patients
    No statistical analyses for this end point

    Secondary: Duration of response rate at 12 months

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    End point title
    		 Duration of response rate at 12 months
    End point description
    Duration of response (DoR), defined as the time between the date when the response criteria (PR or CR, whichever was first reached) were fulfilled to the first date when disease progression (PD), recurrence or death was documented.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    22 [13]
    1 [14]
    3 [15]
    Units: percent
        number (confidence interval 95%)
    33.8 (13.5 to 54.1)
    0 (0 to 999)
    33.3 (0 to 86.7)
    Notes
    [13] - 22 responder patients
    [14] - 1 responder patients
    [15] - 3 responder patients
    No statistical analyses for this end point

    Secondary: Clinical benefit rate

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    End point title
    		 Clinical benefit rate
    End point description
    Clinical benefit, defined as the percentage of patients with ORR or SD lasting over three months (SD >3 months).
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [16]
    20
    34 [17]
    Units: percent
        number (confidence interval 95%)
    61.1 (46.9 to 74.1)
    40.0 (19.1 to 63.9)
    32.4 (17.4 to 50.5)
    Notes
    [16] - 2 patients never treated
    [17] - 1 patient due to lack of post-baseline tumor assessments
    No statistical analyses for this end point

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Progression-free survival (PFS), defined as the period of time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [18]
    20
    34 [19]
    Units: months
        median (confidence interval 95%)
    4.6 (3.0 to 6.2)
    1.4 (1.3 to 3.9)
    2.5 (1.3 to 3.4)
    Notes
    [18] - 2 patients never treated
    [19] - 1 patient due to lack of post-baseline tumor assessments
    Statistical analysis title
    		 Differences between groups
    Comparison groups
    Cohort A1 (BRCA+/PARPi) v Cohort B (Unselected) v Cohort A (BRCA+)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Logrank
    Confidence interval

    Secondary: Progression-free survival at 3 months

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    End point title
    		 Progression-free survival at 3 months
    End point description
    Progression-free survival (PFS), defined as the period of time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [20]
    20
    34 [21]
    Units: percent
        number (confidence interval 95%)
    63.5 (50.4 to 76.6)
    42.5 (20.3 to 64.7)
    35.5 (18.9 to 52.1)
    Notes
    [20] - 2 patients never treated
    [21] - 1 patient due to lack of post-baseline tumor assessments
    No statistical analyses for this end point

    Secondary: Progression-free survival at 6 months

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    End point title
    		 Progression-free survival at 6 months
    End point description
    Progression-free survival (PFS), defined as the period of time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [22]
    20
    34 [23]
    Units: percent
        number (confidence interval 95%)
    37.6 (24.2 to 50.9)
    21.3 (2.8 to 39.7)
    11.1 (0 to 22.6)
    Notes
    [22] - 2 patients never treated
    [23] - 1 patient due to lack of post-baseline tumor assessments
    No statistical analyses for this end point

    Secondary: Progression-free survival at 12 months

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    End point title
    		 Progression-free survival at 12 months
    End point description
    Progression-free survival (PFS), defined as the period of time from the date of first infusion to the date of PD, death (due to any cause), or last tumor evaluation.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [24]
    20
    34 [25]
    Units: percent
        number (confidence interval 95%)
    20.5 (9.1 to 31.9)
    0 (0 to 0)
    3.7 (0 to 10.7)
    Notes
    [24] - 2 patients never treated
    [25] - 1 patient due to lack of post-baseline tumor assessments
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival (OS), defined as the time from the date of first infusion to the date of death or last contact
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [26]
    20
    34 [27]
    Units: months
        median (confidence interval 95%)
    18.6 (10.9 to 22.8)
    8.1 (4.6 to 14.6)
    12.1 (6.6 to 17.9)
    Notes
    [26] - 2 patients never treated
    [27] - 1 patient due to lack of post-baseline tumor assessments
    Statistical analysis title
    		 Differences between groups
    Comparison groups
    Cohort A (BRCA+) v Cohort A1 (BRCA+/PARPi) v Cohort B (Unselected)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0561
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall survival rate at 12 months

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    End point title
    		 Overall survival rate at 12 months
    End point description
    Overall survival (OS), defined as the time from the date of first infusion to the date of death or last contact.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [28]
    20
    34 [29]
    Units: percent
        number (confidence interval 95%)
    62.5 (49.0 to 75.9)
    29.7 (7.9 to 51.5)
    55.4 (37.9 to 73.0)
    Notes
    [28] - 2 patients never treated
    [29] - 1 patient due to lack of post-baseline tumor assessments
    No statistical analyses for this end point

    Secondary: Overall survival rate at 18 months

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    End point title
    		 Overall survival rate at 18 months
    End point description
    Overall survival (OS), defined as the time from the date of first infusion to the date of death or last contact.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Number of subjects analysed
    54 [30]
    20
    34 [31]
    Units: percent
        number (confidence interval 95%)
    53.4 (39.2 to 67.5)
    22.3 (1.6 to 42.9)
    27.7 (11.5 to 43.9)
    Notes
    [30] - 2 patients never treated
    [31] - 1 patient due to lack of post-baseline tumor assessments
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Cohort A (BRCA+)
    Reporting group description
    		 Patients with known deleterious BRCA1/2 mutation status at study entry.

    Reporting group title
    Cohort A1 (BRCA+/PARPi)
    Reporting group description
    		 Patients with known deleterious BRCA1/2 mutation status and prior treatment with PARPi.

    Reporting group title
    Cohort B (Unselected)
    Reporting group description
    		 Patients without known deleterious BRCA1/2 mutation status at study entry, i.e., either: - Patients known to have no deleterious BRCA1/2 mutations (BRCA−), or - Patients whose BRCA 1/2 mutation status was unknown (BRCA-UK). BRCA1/2 germline mutation status would be assessed in all patients in this subgroup responding to lurbinectedin treatment.

    Serious adverse events
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 54 (25.93%)
    5 / 20 (25.00%)
    8 / 35 (22.86%)
         number of deaths (all causes)
    40
    13
    30
         number of deaths resulting from adverse events
    1
    0
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site erythema
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug interaction
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutropenia
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Medication error
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 54 (12.96%)
    2 / 20 (10.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    6 / 54 (11.11%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Myelitis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A (BRCA+) Cohort A1 (BRCA+/PARPi) Cohort B (Unselected)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 54 (100.00%)
    20 / 20 (100.00%)
    34 / 35 (97.14%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    1
    Hot flush
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 20 (10.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    2
    Lymphoedema
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 20 (0.00%)
    4 / 35 (11.43%)
         occurrences all number
    5
    0
    5
    Phlebitis
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 20 (10.00%)
    2 / 35 (5.71%)
         occurrences all number
    5
    3
    2
    Flushing
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 20 (10.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    2
    1
    Fatigue
         subjects affected / exposed
    48 / 54 (88.89%)
    10 / 20 (50.00%)
    30 / 35 (85.71%)
         occurrences all number
    195
    21
    66
    Gait disturbance
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    3
    0
    2
    Influenza like illness
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    4
    0
    1
    Infusion site pain
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    13 / 54 (24.07%)
    1 / 20 (5.00%)
    2 / 35 (5.71%)
         occurrences all number
    15
    1
    2
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    2
    4
    0
    Oedema
         subjects affected / exposed
    5 / 54 (9.26%)
    2 / 20 (10.00%)
    4 / 35 (11.43%)
         occurrences all number
    13
    2
    5
    Pain
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    4
    0
    1
    Pyrexia
         subjects affected / exposed
    8 / 54 (14.81%)
    4 / 20 (20.00%)
    6 / 35 (17.14%)
         occurrences all number
    10
    5
    16
    Chest discomfort
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 20 (10.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    3
    0
    Localised oedema
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    2
    1
    0
    Pelvic pain
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 54 (29.63%)
    2 / 20 (10.00%)
    6 / 35 (17.14%)
         occurrences all number
    21
    2
    9
    Dyspnoea
         subjects affected / exposed
    11 / 54 (20.37%)
    5 / 20 (25.00%)
    8 / 35 (22.86%)
         occurrences all number
    12
    11
    12
    Nasal congestion
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    0
    Pleural effusion
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    2
    Pulmonary embolism
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 54 (14.81%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    9
    0
    2
    Depression
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    3
    0
    2
    Insomnia
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 20 (10.00%)
    1 / 35 (2.86%)
         occurrences all number
    4
    2
    1
    Investigations
    Neutropenia
         subjects affected / exposed
    24 / 54 (44.44%)
    11 / 20 (55.00%)
    7 / 35 (20.00%)
         occurrences all number
    48
    15
    9
    Alanine aminotransferase
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 20 (10.00%)
    1 / 35 (2.86%)
         occurrences all number
    3
    5
    1
    Aspartate aminotransferase
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Breath sounds abnormal
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    1
    2
    Weight decreased
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 20 (10.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    2
    Platelet count decreased
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    2
    Injury, poisoning and procedural complications
    fall
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    2
    1
    0
    Lower limb fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    5 / 54 (9.26%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    8
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 54 (12.96%)
    2 / 20 (10.00%)
    3 / 35 (8.57%)
         occurrences all number
    9
    3
    4
    Dysgeusia
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 20 (10.00%)
    0 / 35 (0.00%)
         occurrences all number
    8
    2
    0
    Headache
         subjects affected / exposed
    16 / 54 (29.63%)
    6 / 20 (30.00%)
    5 / 35 (14.29%)
         occurrences all number
    29
    10
    5
    Neuralgia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    1
    Neuropathy peripheral
         subjects affected / exposed
    6 / 54 (11.11%)
    1 / 20 (5.00%)
    2 / 35 (5.71%)
         occurrences all number
    6
    1
    2
    Tremor
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 54 (24.07%)
    2 / 20 (10.00%)
    6 / 35 (17.14%)
         occurrences all number
    16
    3
    10
    Febrile neutropenia
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    4
    0
    0
    Neutropenia
         subjects affected / exposed
    24 / 54 (44.44%)
    11 / 20 (55.00%)
    7 / 35 (20.00%)
         occurrences all number
    48
    15
    9
    Thrombocytopenia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 54 (20.37%)
    5 / 20 (25.00%)
    7 / 35 (20.00%)
         occurrences all number
    25
    6
    12
    Constipation
         subjects affected / exposed
    23 / 54 (42.59%)
    9 / 20 (45.00%)
    9 / 35 (25.71%)
         occurrences all number
    32
    17
    17
    Diarrhoea
         subjects affected / exposed
    16 / 54 (29.63%)
    4 / 20 (20.00%)
    5 / 35 (14.29%)
         occurrences all number
    23
    7
    6
    Dyspepsia
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 20 (5.00%)
    2 / 35 (5.71%)
         occurrences all number
    3
    1
    3
    Nausea
         subjects affected / exposed
    43 / 54 (79.63%)
    15 / 20 (75.00%)
    20 / 35 (57.14%)
         occurrences all number
    123
    23
    37
    Odynophagia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    2
    1
    Vomiting
         subjects affected / exposed
    23 / 54 (42.59%)
    7 / 20 (35.00%)
    10 / 35 (28.57%)
         occurrences all number
    48
    9
    13
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatomegaly
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    0
    Dry skin
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    4
    0
    2
    Erythema
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    3
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    2
    Rash
         subjects affected / exposed
    8 / 54 (14.81%)
    1 / 20 (5.00%)
    2 / 35 (5.71%)
         occurrences all number
    10
    1
    2
    Skin hyperpigmentation
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    2
    Pollakiuria
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 54 (7.41%)
    4 / 20 (20.00%)
    3 / 35 (8.57%)
         occurrences all number
    6
    6
    3
    Back pain
         subjects affected / exposed
    7 / 54 (12.96%)
    2 / 20 (10.00%)
    4 / 35 (11.43%)
         occurrences all number
    9
    5
    5
    Bone pain
         subjects affected / exposed
    8 / 54 (14.81%)
    2 / 20 (10.00%)
    2 / 35 (5.71%)
         occurrences all number
    10
    2
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    3
    0
    1
    Myalgia
         subjects affected / exposed
    5 / 54 (9.26%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    9
    0
    1
    Neck pain
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    2
    Pain in extremity
         subjects affected / exposed
    6 / 54 (11.11%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    8
    0
    2
    Pain in jaw
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    9 / 54 (16.67%)
    2 / 20 (10.00%)
    4 / 35 (11.43%)
         occurrences all number
    10
    2
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    3
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    5
    2
    1
    Pharyngitis
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 20 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 20 (5.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    1
    2
    Urinary tract infection
         subjects affected / exposed
    6 / 54 (11.11%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    9
    1
    1
    Candidiasis of trachea
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Klebsiella infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    2
    0
    Sputum purulent
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 20 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 54 (27.78%)
    6 / 20 (30.00%)
    5 / 35 (14.29%)
         occurrences all number
    20
    7
    9
    Dehydration
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    3
    3
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 20 (5.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 20 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2013
    The following changes were implemented in this amendment: • The BRCA mutation assessment was added to the screening procedures for those candidates to be enrolled into the trial whose BRCA status was unknown and there was high suspicion of being BRCA-mutated. This was done in accordance with the National Comprehensive Cancer Network (NCCN) criteria for consideration of BRCA1/2 genetic testing. • The frequency of hematological tests in the event of febrile neutropenia of any grade, grade 4 neutropenia and/or grade 4 thrombocytopenia was changed, so that they had to be conducted at least every 48-72 hours until recovery to at least grade 2. • A statement was added to clarify that the Sponsor could request the study sites to provide the imaging tests conducted on the patients during the clinical trial, for evaluation. • Information on the laboratories for PGx analyses was updated, and a statement was added to clarify that polymorphisms and mutational status of genes involved in DNA repair mechanisms, or related to the mechanism of action of lurbinectedin or to the disease, could also be analyzed if relevant. • Information on the laboratory responsible for the BRCA1/2 mutation analysis was added. • A typographic mistake was corrected.
    28 Oct 2014
    The following changes were implemented: • Lurbinectedin dosing was modified from a fixed dose to a BSA-based dose. This conservative approach was adopted following a logistic regression analysis of data from the first 64 patients enrolled in this trial, which found a statistically significant relationship between BSA and the possibility of developing grade 3/4 neutropenia while on treatment with lurbinectedin at 7.0 mg FD on Day 1 q3wk. Patients with lower BSA values were found to be at highest risk. This dose adjustment was expected to reduce the incidence of grade 3/4 neutropenia, which at the time was the most common lurbinectedin toxicity observed so far. • Some eligibility criteria were revised: - The prior requirement that BRCA+ MBC patients had to have received at least one prior chemotherapy-containing line for advanced disease to be included in the study was removed. - The prior requirement that patients liver metastases had to have ALT and AST values ≤5.0 x ULN to be included in the study was removed. - Patients previously treated with PARPi were no longer allowed to be included in the study. - A clarification was added to allow the inclusion of patients with in situ melanoma. • A clarification was added to specify that use of aprepitant and directly related compounds (e.g., fosaprepitant) was forbidden. • Primary G-CSF prophylaxis remained limited but could be permitted on a caseby-case basis. • The planned study duration was updated to include a longer enrolment period to reflect recruitment rates at the time. • The follow-up period and the schedule after end of treatment were clarified. • Safety reporting contact details were updated. • Preclinical information about lurbinectedin drug-drug interactions was updated. • Appendix 4, which listed commonly used medications known to be CYP2C8- and CYP3A4-substrates, was replaced with a list of CYP1/CYP2/CYP3 inhibitors, inducers and substrates. • New version of the WMA Declaration of Helsinki
    08 Mar 2016
    The following changes were implemented in this amendment: • A new cohort (Cohort A1) was implemented to evaluate lurbinectedin specifically in BRCA+ MBC patients previously treated with PARPi. These patients had been excluded from this study following the implementation of substantial amendment No. 2 (see Section 9.8.2). However, this decision was reverted owing to the increasing relevance of PARPi in the treatment of MBC. Evaluation of more BRCA+ MBC patients previously treated with PARPi was further justified to determine if tumor cell resistance mechanisms might affect the antitumor activity of lurbinectedin, and to establish if the ORR difference observed in Cohort A between patients previously treated or not with PARPi might be explained by other variables (e.g., number of prior treatment lines, best response to last treatment or to PARPi, patient characteristics, etc.). • The PGx substudy was amended to make it mandatory for patients included in the new cohort (it had been optional for patients in Cohorts A and B). Hence, patients in Cohort A1 were asked to undergo a tumor biopsy at study entry to evaluate potential biomarkers of resistance/sensitivity to lurbinectedin after PARPi administration. This was in addition to the archived diagnostic sample (if available). • The planned study duration was updated to include a longer enrollment period. • References to R1 of the ICH Topic E6 Guideline for Good Clinical Practice were removed, in anticipation of a new revised version of the document. • Study contact information was updated.

    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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