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    Clinical Trial Results:
    Phase III Randomized Clinical Trial of Lurbinectedin (PM01183) versus Pegylated Liposomal Doxorubicin or Topotecan in Patients with Platinum-resistant Ovarian Cancer (CORAIL Trial)

    Summary
    EudraCT number
    		 2014-005251-39
    Trial protocol
    		 HU   ES   CZ   AT   BE   GB   FR   DE   IT  
    Global end of trial date
    12 Oct 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Mar 2020
    First version publication date
    17 Oct 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    The report was reviewed for compliance to FDA technical documentation requirements for submission of clinical reports forming part of a NDA for marketing approval in the USA. The safety results were also presented as one group of the ISS and when compared to the prior ones it was found that it was necessary to adjust some computation algorithms for some variables in order to achieve consistency with the ISS results. In addition, some errors were detected in the analysis.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PM1183-C-004-14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 Developtment, Department of PharmaMar´s Oncology., Business Unit., Pharmamar, S.A., 34 918466000, clinicaltrials@pharmamar.com
    Scientific contact
    Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit., Pharmamar, S.A., 34 918466000, clinicaltrials@pharmamar.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine a difference in progression-free-survival (PFS) between lurbinectedin (PM01183) and pegylated liposomal doxorubicin (PLD) or topotecan in platinum-resistant ovarian cancer patients according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
    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 the following standard antiemetic prophylaxis before each treatment infusion: • Corticosteroids (dexamethasone i.v. at least 8 mg or equivalent, or at institutional standard antiemetic doses). • Serotonin (5-HT3) antagonists (ondansetron at least 8 mg i.v. or equivalent). If necessary, in addition to the above, the duration of treatment with 5-HT3 antagonists and/or dexamethasone could be extended. Additional antiemetic agents could be administered as appropriate. Aprepitant and equivalent agents (e.g., fosaprepitant) were forbidden in patients treated with lurbinectedin. For the purpose of safety evaluations, an optimal prophylaxis was defined as all the aforementioned allowed medications at their respectively maximum dose.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 22
    Country: Number of subjects enrolled
    Spain: 86
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 40
    Country: Number of subjects enrolled
    Bulgaria: 10
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    Italy: 94
    Country: Number of subjects enrolled
    United States: 79
    Country: Number of subjects enrolled
    Serbia: 9
    Worldwide total number of subjects
    442
    EEA total number of subjects
    354
    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)
    267
    From 65 to 84 years
    172
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 First randomization/first study treatment administration took place on 26JUN2015. The cutoff date for results was 12OCT2018. 534 patients were screened; 442 were randomized at 83 sites/12 countries. 10 patients did not receive the study treatment.

    Pre-assignment
    Screening details
    		 IC;Age≥18 years;confirmed diagnosis of unresectable epithelial ovarian, fallopian tube or primary peritoneal cancer;Platinum-resistant disease;ECOG PS≤2;Adequate hematological, renal, metabolic, and hepatic function

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lurbinectedin
    Arm description
    		 3.2 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks = one treatment cycle) through peripheral or central lines. A minimum total volume of 100 mL, diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lurbinectedin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3.2 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks = one treatment cycle) through peripheral or central lines. A minimum total volume of 100 mL, diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL

    Arm title
    		 Control (PLD or topotecan)
    Arm description
    		 Patients randomized to the Control arm were assigned to receive PLD if they had previously been treated with topotecan, or to receive topotecan if they had previously been treated with PLD. However, if the number of patients randomized to either PLD or topotecan reached 60% (i.e., 126 patients) of the total number of patients expected in the Control Arm, then the treatment of choice in the Control Arm would be restricted to the less frequent control drug until the end of accrual
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PLD
    Investigational medicinal product code
    Other name
    Pegylated Liposomal Doxorubicin
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 i.v. on Day 1 q4wk (four weeks = one treatment cycle), at an initial rate of 1 mg/min through peripheral or central lines. If no infusion reactions were observed, the rate of infusion could be increased to complete the administration of the drug over one hour. Total PLD doses >90 mg and ≤90 mg had to be diluted in 500 and 250 mL of 5% glucose solution for infusion, respectively

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    i.v. as a 30-min infusion on Days 1-5 q3wk (three weeks = one treatment cycle) at the following doses: - 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min. - 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min. - 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min. Topotecan was administered through peripheral or central lines, and was diluted in a minimum of 50 mL of 0.9% sodium chloride or 5% glucose solution for infusion. Skipped doses of topotecan were not replaced.

    Number of subjects in period 1
    		Lurbinectedin Control (PLD or topotecan)
    Started
    221
    221
    Completed
    0
    0
    Not completed
    221
    221
         Consent withdrawn by subject
    14
    16
         Physician decision
    8
    17
         Treatment-related AE
    10
    14
         Symptomatic deterioration
    13
    19
         Death
    11
    3
         Other
    3
    1
         Non-treatment-related AE
    8
    8
         Progressive disease
    152
    135
         Not treated
    2
    8

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Lurbinectedin
    Reporting group description
    		 3.2 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks = one treatment cycle) through peripheral or central lines. A minimum total volume of 100 mL, diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL

    Reporting group title
    Control (PLD or topotecan)
    Reporting group description
    		 Patients randomized to the Control arm were assigned to receive PLD if they had previously been treated with topotecan, or to receive topotecan if they had previously been treated with PLD. However, if the number of patients randomized to either PLD or topotecan reached 60% (i.e., 126 patients) of the total number of patients expected in the Control Arm, then the treatment of choice in the Control Arm would be restricted to the less frequent control drug until the end of accrual

    Reporting group values
    		 Lurbinectedin Control (PLD or topotecan) Total
    Number of subjects
    		 221 221 442
    Age categorical
    Units: Subjects
        18-49 years
    		 21 35 56
        50-64 years
    		 105 106 211
        ≥65 years
    		 95 80 175
    Age continuous
    Units: years
        median (full range (min-max))
    		 63.0 (25 to 85) 59.0 (28 to 87) -
    Gender categorical
    Units: Subjects
        Female
    		 221 221 442
        Male
    		 0 0 0
    BMI
    BMI, body mass index
    Units: Subjects
        ≤20 kg/m^2
    		 26 37 63
        20-25 kg/m^2
    		 82 84 166
        25-30 kg/m^2
    		 62 51 113
        >30 kg/m^2
    		 50 49 99
        Unknown
    		 1 0 1
    Race
    Some countries like France did not allow to collect race information by ethical reasons
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 2 3 5
        Black or African American
    		 6 2 8
        White
    		 192 201 393
        Other
    		 2 2 4
        Not applicable
    		 19 12 31
    ECOG PS
    ECOG PS, Eastern Cooperative Oncology Group performance status
    Units: Subjects
        PS 0
    		 126 123 249
        PS 1
    		 87 94 181
        PS 2
    		 8 4 12
    Primary site
    Units: Subjects
        Ovarian
    		 196 195 391
        Fallopian
    		 11 13 24
        Peritoneal
    		 14 13 27
    Histology type
    Units: Subjects
        Serous/Papillary
    		 181 199 380
        Endometrioid
    		 14 6 20
        Clear cell
    		 10 12 22
        Mucinous
    		 3 1 4
        Other
    		 13 3 16
    Histologic grade
    Units: Subjects
        Well differentiated
    		 16 15 31
        Moderately differentiated
    		 21 24 45
        Poorly differentiated/Undifferentiated
    		 154 143 297
        Unknown
    		 30 39 69
    BRCA status
    Units: Subjects
        BRCA1
    		 10 8 18
        BRCA2
    		 4 3 7
        Not mutated
    		 64 61 125
        Unknown
    		 143 149 292
    Intestinal sub-occlusion
    Units: Subjects
        Yes
    		 9 10 19
        No
    		 212 211 423
    Clinically evident ascites
    Units: Subjects
        Yes
    		 35 39 74
        No
    		 186 182 368
    Radiological presence of ascites
    Units: Subjects
        Yes
    		 59 71 130
        No
    		 162 150 312
    Prior radiotherapy
    Units: Subjects
        Yes
    		 6 5 11
        No
    		 215 216 431
    Prior Cytoreductive surgery
    Units: Subjects
        Yes
    		 198 204 402
        No
    		 23 17 40
    Other prior surgical procedures
    Units: Subjects
        Yes
    		 86 81 167
        No
    		 135 140 275
    Weight
    Units: Kg
        median (full range (min-max))
    		 65.8 (37.0 to 125.0) 63.0 (39.0 to 142.8) -
    Height
    Units: cm
        median (full range (min-max))
    		 161.0 (147 to 177) 161.0 (144 to 183) -
    BSA
    BSA, body surface area
    Units: m^2
        median (full range (min-max))
    		 1.7 (1.3 to 2.4) 1.7 (1.3 to 2.4) -
    BMI
    BMI, body mass index
    Units: kg/m^2
        median (full range (min-max))
    		 25.1 (15.0 to 47.9) 24.7 (14.5 to 56.5) -
    First diagnosis to randomization
    Units: months
        median (full range (min-max))
    		 23.4 (7 to 294) 20.7 (4 to 184) -
    Sites involved
    Units: number of sites
        median (full range (min-max))
    		 2.0 (1 to 5) 2.0 (1 to 7) -
    Subject analysis sets

    Subject analysis set title
    PLD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients randomized to the Control arm were assigned to receive PLD

    Subject analysis set title
    Topotecan
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients randomized to the Control arm were assigned to receive topotecan

    Subject analysis sets values
    		 PLD Topotecan
    Number of subjects
    127
    94
    Age categorical
    Units: Subjects
        18-49 years
    18
    17
        50-64 years
    61
    45
        ≥65 years
    48
    32
    Age continuous
    Units: years
        median (full range (min-max))
    59.0 (28 to 87)
    59.5 (31 to 80)
    Gender categorical
    Units: Subjects
        Female
    127
    94
        Male
    0
    0
    BMI
    BMI, body mass index
    Units: Subjects
        ≤20 kg/m^2
    23
    14
        20-25 kg/m^2
    42
    42
        25-30 kg/m^2
    35
    16
        >30 kg/m^2
    27
    22
        Unknown
    0
    0
    Race
    Some countries like France did not allow to collect race information by ethical reasons
    Units: Subjects
        American Indian or Alaska Native
    1
    0
        Asian
    3
    0
        Black or African American
    1
    1
        White
    116
    85
        Other
    2
    0
        Not applicable
    4
    8
    ECOG PS
    ECOG PS, Eastern Cooperative Oncology Group performance status
    Units: Subjects
        PS 0
    77
    46
        PS 1
    47
    47
        PS 2
    3
    1
    Primary site
    Units: Subjects
        Ovarian
    115
    80
        Fallopian
    6
    7
        Peritoneal
    6
    7
    Histology type
    Units: Subjects
        Serous/Papillary
    111
    88
        Endometrioid
    3
    3
        Clear cell
    10
    2
        Mucinous
    1
    0
        Other
    2
    1
    Histologic grade
    Units: Subjects
        Well differentiated
    7
    8
        Moderately differentiated
    12
    12
        Poorly differentiated/Undifferentiated
    85
    58
        Unknown
    23
    16
    BRCA status
    Units: Subjects
        BRCA1
    5
    3
        BRCA2
    1
    2
        Not mutated
    28
    33
        Unknown
    93
    56
    Intestinal sub-occlusion
    Units: Subjects
        Yes
    5
    5
        No
    122
    89
    Clinically evident ascites
    Units: Subjects
        Yes
    25
    14
        No
    102
    80
    Radiological presence of ascites
    Units: Subjects
        Yes
    41
    30
        No
    86
    64
    Prior radiotherapy
    Units: Subjects
        Yes
    2
    3
        No
    125
    91
    Prior Cytoreductive surgery
    Units: Subjects
        Yes
    114
    90
        No
    13
    4
    Other prior surgical procedures
    Units: Subjects
        Yes
    50
    31
        No
    77
    63
    Weight
    Units: Kg
        median (full range (min-max))
    63.2 (39.0 to 142.8)
    62.5 (40.0 to 114.7)
    Height
    Units: cm
        median (full range (min-max))
    161.0 (144 to 183)
    161.5 (145 to 175)
    BSA
    BSA, body surface area
    Units: m^2
        median (full range (min-max))
    1.7 (1.3 to 2.4)
    1.7 (1.4 to 2.4)
    BMI
    BMI, body mass index
    Units: kg/m^2
        median (full range (min-max))
    24.9 (15.9 to 56.5)
    24.2 (14.5 to 43.1)
    First diagnosis to randomization
    Units: months
        median (full range (min-max))
    14.9 (4 to 184)
    26.8 (4 to 103)
    Sites involved
    Units: number of sites
        median (full range (min-max))
    2.0 (1 to 7)
    3.0 (1 to 7)

    End points

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    End points reporting groups
    Reporting group title
    Lurbinectedin
    Reporting group description
    		 3.2 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks = one treatment cycle) through peripheral or central lines. A minimum total volume of 100 mL, diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL

    Reporting group title
    Control (PLD or topotecan)
    Reporting group description
    		 Patients randomized to the Control arm were assigned to receive PLD if they had previously been treated with topotecan, or to receive topotecan if they had previously been treated with PLD. However, if the number of patients randomized to either PLD or topotecan reached 60% (i.e., 126 patients) of the total number of patients expected in the Control Arm, then the treatment of choice in the Control Arm would be restricted to the less frequent control drug until the end of accrual

    Subject analysis set title
    PLD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients randomized to the Control arm were assigned to receive PLD

    Subject analysis set title
    Topotecan
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients randomized to the Control arm were assigned to receive topotecan

    Primary: Progression-free Survival by Independent Review Committee

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    End point title
    		 Progression-free Survival by Independent Review Committee
    End point description
    End point type
    Primary
    End point timeframe
    Overall period
    End point values
    		 Lurbinectedin Control (PLD or topotecan)
    Number of subjects analysed
    221 [1]
    221 [2]
    Units: months
        median (confidence interval 95%)
    3.5 (2.1 to 3.7)
    3.6 (2.7 to 3.8)
    Notes
    [1] - Events (%): 180 (81.4)
    [2] - Events (%): 158 (71.5)
    Statistical analysis title
    		 PFS between treatments
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6294
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.854
         upper limit
    		 1.309
    Statistical analysis title
    		 PFS (%) at 6 months
    Statistical analysis description
    PFS (%) at 6 months: Lurbinectedin: 24.3 (18.4-30.7) Control: 27.5 (20.9-34.4)
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5032
    Method
    		 Normal approximation
    Confidence interval
    Statistical analysis title
    		 PFS (%) at 12 months
    Statistical analysis description
    PFS (%) at 12 months: Lurbinectedin: 8.3 (4.7-13.3) Control: 7.0 (3.3-12.5)
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6742
    Method
    		 Normal approximation
    Confidence interval

    Secondary: Progression-free Survival by Investigator’s Assessment

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    End point title
    		 Progression-free Survival by Investigator’s Assessment
    End point description
    PFS, progression-free survival
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Lurbinectedin Control (PLD or topotecan)
    Number of subjects analysed
    221 [3]
    221 [4]
    Units: months
        median (confidence interval 95%)
    3.7 (3.6 to 3.9)
    3.7 (3.5 to 4.0)
    Notes
    [3] - Events (%): 194 (87.8)
    [4] - Events (%): 179 (81.0)
    Statistical analysis title
    		 PFS between treatments
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7673
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.987
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.805
         upper limit
    		 1.209
    Statistical analysis title
    		 PFS (%) at 6 months
    Statistical analysis description
    PFS (%) at 6 months (95% CI) Lurbinectedin: 29.0 (22.8-35.4) Control: 27.4 (21.3-33.9)
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7385
    Method
    		 Normal approximation
    Confidence interval
    Statistical analysis title
    		 PFS (%) at 12 months
    Statistical analysis description
    PFS (%) at 12 months (95% CI) Lurbinectedin: 8.2 (4.8-12.7) Control: 7.5 (4.2-12.2)
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8245
    Method
    		 Normal approximation
    Confidence interval

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Lurbinectedin Control (PLD or topotecan)
    Number of subjects analysed
    221 [5]
    221 [6]
    Units: months
        median (confidence interval 95%)
    11.4 (9.0 to 14.2)
    10.9 (9.3 to 12.5)
    Notes
    [5] - Events (%): 170 (76.9)
    [6] - Events (%): 168 (76.0)
    Statistical analysis title
    		 OS (%) between treatments
    Statistical analysis description
    OS, Overall survival
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8021
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.956
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.772
         upper limit
    		 1.183
    Statistical analysis title
    		 OS (%) at 12 months
    Statistical analysis description
    OS (%) at 12 months (95% CI): Lurbinectedin: 48.2 (41.3-54.8) Control: 45.3 (38.4-52.0)
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5515
    Method
    		 Normal approximation
    Confidence interval
    Statistical analysis title
    		 OS (%) at 24 months
    Statistical analysis description
    OS (%) at 24 months (95% CI): Lurbinectedin: 22.3 (16.8-28.2) Control: 22.7 (17.1-28.7)
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9253
    Method
    		 Normal approximation
    Confidence interval

    Secondary: Response Rate by Independent Review Committee

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    End point title
    		 Response Rate by Independent Review Committee
    End point description
    CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Lurbinectedin Control (PLD or topotecan)
    Number of subjects analysed
    221
    221
    Units: subjects
        CR
    3
    3
        PR
    29
    25
        SD
    90
    97
        PD
    83
    72
        Unknown
    16
    24
    Statistical analysis title
    		 Overall response rate
    Statistical analysis description
    ORR, n (%) 95% CI Lurbinectedin: 32 (14.5) [10.1-19.8] Control: 28 (12.7) [8.6-17.8]
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6772
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Response Rate by Investigator’s Assessment

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    End point title
    		 Response Rate by Investigator’s Assessment
    End point description
    CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Lurbinectedin Control (PLD or topotecan)
    Number of subjects analysed
    221
    221
    Units: subjects
        CR
    3
    2
        PR
    32
    35
        SD
    107
    94
        PD
    63
    68
        Unknown
    16
    22
    Statistical analysis title
    		 Overall response rate
    Statistical analysis description
    ORR, n (%) 95% CI Lurbinectedin: 35 (15.8) [11.3-21.3] Control: 37 (16.7) [12.1-22.3]
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8976
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Duration of Response by Independent Review Committee

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    End point title
    		 Duration of Response by Independent Review Committee
    End point description
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Lurbinectedin Control (PLD or topotecan)
    Number of subjects analysed
    32
    28
    Units: months
        median (confidence interval 95%)
    4.0 (1.9 to 5.7)
    3.7 (3.6 to 7.2)
    Statistical analysis title
    		 Duration of response between treatments
    Comparison groups
    Control (PLD or topotecan) v Lurbinectedin
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2631
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.406
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.769
         upper limit
    		 2.569

    Secondary: Duration of Response by Investigator’s Assessment

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    End point title
    		 Duration of Response by Investigator’s Assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Lurbinectedin Control (PLD or topotecan)
    Number of subjects analysed
    35
    37
    Units: months
        median (confidence interval 95%)
    4.3 (3.6 to 5.8)
    3.7 (3.2 to 5.6)
    Statistical analysis title
    		 Duration of response between treatments
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8276
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.743

    Secondary: Best Response according to Tumor Marker Evaluation (CA-125)

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    End point title
    		 Best Response according to Tumor Marker Evaluation (CA-125)
    End point description
    CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Lurbinectedin Control (PLD or topotecan)
    Number of subjects analysed
    173
    165
    Units: subjects
        CR
    13
    3
        PR
    33
    29
        SD
    95
    94
        PD
    17
    16
        Unknown
    15
    23
    Statistical analysis title
    		 ORR by CA-125
    Statistical analysis description
    ORR by CA-125, n (%) 95% CI Lurbinectedin: 46 (26.6) [20.2-33.8] Control: 32 (19.4) [13.7-26.3]
    Comparison groups
    Lurbinectedin v Control (PLD or topotecan)
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1231
    Method
    		 Fisher exact
    Confidence interval

    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
    20.0
    Reporting groups
    Reporting group title
    Lurbinectedin
    Reporting group description
    		 3.2 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks = one treatment cycle) through peripheral or central lines. A minimum total volume of 100 mL, diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL

    Reporting group title
    Control (PLD or topotecan)
    Reporting group description
    		 Patients randomized to the Control arm were assigned to receive PLD if they had previously been treated with topotecan, or to receive topotecan if they had previously been treated with PLD. However, if the number of patients randomized to either PLD or topotecan reached 60% (i.e., 126 patients) of the total number of patients expected in the Control Arm, then the treatment of choice in the Control Arm would be restricted to the less frequent control drug until the end of accrual

    Serious adverse events
    		 Lurbinectedin Control (PLD or topotecan)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 219 (42.01%)
    85 / 213 (39.91%)
         number of deaths (all causes)
    170
    171
         number of deaths resulting from adverse events
    6
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    2 / 219 (0.91%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Phlebitis
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    2 / 219 (0.91%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 219 (0.91%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 219 (0.46%)
    4 / 213 (1.88%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 219 (1.37%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vessel puncture site haematoma
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 219 (0.00%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 219 (0.91%)
    4 / 213 (1.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 219 (1.37%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 219 (1.37%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    3 / 219 (1.37%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiorespiratory arrest
         subjects affected / exposed
    3 / 219 (1.37%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    2 / 219 (0.91%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 219 (3.65%)
    12 / 213 (5.63%)
         occurrences causally related to treatment / all
    11 / 14
    17 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    14 / 219 (6.39%)
    12 / 213 (5.63%)
         occurrences causally related to treatment / all
    12 / 14
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leucopenia
         subjects affected / exposed
    3 / 219 (1.37%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    11 / 219 (5.02%)
    13 / 213 (6.10%)
         occurrences causally related to treatment / all
    14 / 14
    13 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    9 / 219 (4.11%)
    11 / 213 (5.16%)
         occurrences causally related to treatment / all
    9 / 9
    20 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    6 / 219 (2.74%)
    6 / 213 (2.82%)
         occurrences causally related to treatment / all
    0 / 8
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    4 / 219 (1.83%)
    7 / 213 (3.29%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 219 (0.91%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    24 / 219 (10.96%)
    21 / 213 (9.86%)
         occurrences causally related to treatment / all
    1 / 32
    0 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Nausea
         subjects affected / exposed
    7 / 219 (3.20%)
    4 / 213 (1.88%)
         occurrences causally related to treatment / all
    5 / 8
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 219 (4.57%)
    4 / 213 (1.88%)
         occurrences causally related to treatment / all
    8 / 10
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 219 (0.00%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hydronephrosis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 219 (2.28%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Septic shock
         subjects affected / exposed
    1 / 219 (0.46%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 219 (1.83%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    4 / 219 (1.83%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperclycemia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminemia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 219 (0.46%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 219 (0.91%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lurbinectedin Control (PLD or topotecan)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    212 / 219 (96.80%)
    211 / 213 (99.06%)
    Investigations
    Weight decreased
         subjects affected / exposed
    10 / 219 (4.57%)
    14 / 213 (6.57%)
         occurrences all number
    14
    16
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 219 (5.48%)
    4 / 213 (1.88%)
         occurrences all number
    22
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 219 (11.87%)
    9 / 213 (4.23%)
         occurrences all number
    36
    10
    Neuropathy peripheral
         subjects affected / exposed
    19 / 219 (8.68%)
    15 / 213 (7.04%)
         occurrences all number
    32
    20
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    57 / 219 (26.03%)
    77 / 213 (36.15%)
         occurrences all number
    155
    201
    Leucopenia
         subjects affected / exposed
    23 / 219 (10.50%)
    21 / 213 (9.86%)
         occurrences all number
    39
    38
    Neutropenia
         subjects affected / exposed
    73 / 219 (33.33%)
    89 / 213 (41.78%)
         occurrences all number
    167
    211
    Thrombocytopenia
         subjects affected / exposed
    20 / 219 (9.13%)
    39 / 213 (18.31%)
         occurrences all number
    46
    77
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    133 / 219 (60.73%)
    113 / 213 (53.05%)
         occurrences all number
    328
    206
    Mucosal inflammation
         subjects affected / exposed
    22 / 219 (10.05%)
    68 / 213 (31.92%)
         occurrences all number
    26
    145
    Oedema
         subjects affected / exposed
    25 / 219 (11.42%)
    13 / 213 (6.10%)
         occurrences all number
    32
    15
    Pyrexia
         subjects affected / exposed
    25 / 219 (11.42%)
    33 / 213 (15.49%)
         occurrences all number
    29
    40
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    12 / 219 (5.48%)
    10 / 213 (4.69%)
         occurrences all number
    16
    12
    Abdominal pain
         subjects affected / exposed
    74 / 219 (33.79%)
    52 / 213 (24.41%)
         occurrences all number
    145
    73
    Ascites
         subjects affected / exposed
    14 / 219 (6.39%)
    21 / 213 (9.86%)
         occurrences all number
    15
    43
    Constipation
         subjects affected / exposed
    72 / 219 (32.88%)
    61 / 213 (28.64%)
         occurrences all number
    118
    84
    Diarrhoea
         subjects affected / exposed
    45 / 219 (20.55%)
    35 / 213 (16.43%)
         occurrences all number
    71
    58
    Nausea
         subjects affected / exposed
    156 / 219 (71.23%)
    92 / 213 (43.19%)
         occurrences all number
    390
    169
    Dyspepsia
         subjects affected / exposed
    14 / 219 (6.39%)
    15 / 213 (7.04%)
         occurrences all number
    16
    16
    Vomiting
         subjects affected / exposed
    87 / 219 (39.73%)
    58 / 213 (27.23%)
         occurrences all number
    196
    88
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 219 (7.76%)
    26 / 213 (12.21%)
         occurrences all number
    19
    33
    Dyspnoea
         subjects affected / exposed
    29 / 219 (13.24%)
    23 / 213 (10.80%)
         occurrences all number
    37
    34
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 219 (2.28%)
    30 / 213 (14.08%)
         occurrences all number
    5
    33
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 219 (1.37%)
    51 / 213 (23.94%)
         occurrences all number
    3
    98
    Rash
         subjects affected / exposed
    8 / 219 (3.65%)
    14 / 213 (6.57%)
         occurrences all number
    9
    25
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    22 / 219 (10.05%)
    10 / 213 (4.69%)
         occurrences all number
    23
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 219 (6.85%)
    5 / 213 (2.35%)
         occurrences all number
    20
    7
    Back pain
         subjects affected / exposed
    13 / 219 (5.94%)
    19 / 213 (8.92%)
         occurrences all number
    17
    22
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 219 (5.02%)
    20 / 213 (9.39%)
         occurrences all number
    14
    21
    Urinary tract infection
         subjects affected / exposed
    21 / 219 (9.59%)
    15 / 213 (7.04%)
         occurrences all number
    25
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    51 / 219 (23.29%)
    47 / 213 (22.07%)
         occurrences all number
    81
    69
    Hypokalaemia
         subjects affected / exposed
    15 / 219 (6.85%)
    15 / 213 (7.04%)
         occurrences all number
    26
    28

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2015
    This amendment resulted in a local version (v.1.1) of the study protocol that was only implemented in France and included the following changes: • Following a request by French Health Authorities, patients with AP levels between 2.5 and 5 × ULN were not allowed to be included into the study. • As a result of the merger between Zeltia, S.A and Pharma Mar, S.A., Sociedad Unipersonal, the Sponsor shall now be referred to as Pharma Mar, S.A, without further reference to “Sociedad Unipersonal”.

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

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