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    Clinical Trial Results:
    A Randomized, Open-Label, Multicenter, Phase 3 Study of Rovalpituzumab Tesirine Compared with Topotecan for Subjects with Advanced or Metastatic DLL3high Small Cell Lung Cancer (SCLC) who have First Disease Progression During or Following Front-Line Platinum-Based Chemotherapy (TAHOE)

    Summary
    EudraCT number
    		 2016-003726-17
    Trial protocol
    		 DK   SE   PT   GB   CZ   DE   HU   BE   LV   NL   GR   BG   PL   FR   ES   HR   IT   RO  
    Global end of trial date
    12 Feb 2020

    Results information
    Results version number
    		 v1
    This version publication date
    14 Feb 2021
    First version publication date
    14 Feb 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    M16-289
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03061812
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road,, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.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
    12 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are to assess if treatment with rovalpituzumab tesirine improves overall survival (OS) compared to topotecan in subjects with advanced or metastatic delta-like protein 3 high (DLL3high) SCLC who have first disease progression during or following frontline platinum based chemotherapy.
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Apr 2017
    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
    Australia: 17
    Country: Number of subjects enrolled
    Belarus: 1
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 22
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Greece: 22
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Japan: 35
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    Latvia: 9
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    Serbia: 6
    Country: Number of subjects enrolled
    Singapore: 5
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Taiwan: 10
    Country: Number of subjects enrolled
    Turkey: 21
    Country: Number of subjects enrolled
    Ukraine: 9
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 43
    Worldwide total number of subjects
    444
    EEA total number of subjects
    221
    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)
    245
    From 65 to 84 years
    196
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The collection of tumor material for DLL3 testing was done at any time after the informed consent is signed and prior to randomization. Screening procedures and radiographic assessments (computed tomography scan or magnetic resonance imaging) were performed within 28 days prior to randomization.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Topotecan
    Arm description
    		 Topotecan given as an intravenous (IV) infusion over 30 minutes at a dose of 1.5 mg/m^2 on Days 1 to 5 of each 21-day cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Topotecan was given as an IV infusion over 30 minutes at a dose of 1.5 mg/m^2 on Days 1 to 5 of 21-day cycle.

    Arm title
    		 Rovalpituzumab Tesirine
    Arm description
    		 Rovalpituzumab tesirine IV administration (dosing based on actual body weight) on Day 1 of a 42-day cycle for 2 cycles, with up to 2 additional cycles permitted. Dexamethasone coadministered orally (PO) twice daily at a dose of 8 mg on Day -1, Day 1, and Day 2 of each 42-day cycle in which rovalpituzumab tesirine is administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rovalpituzumab tesirine
    Investigational medicinal product code
    Other name
    Rova-T
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rovalpituzumab tesirine will be given by IV infusion over approximately 30 minutes (window 20 – 45 minutes), adjusted to participant tolerability, at a dose of 0.3 mg/kg on Day 1 of a 42-Day cycle for 2 cycles.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone dosing occurred such that there were approximately 12-hours (i.e., 10 – 14 hours) between AM and PM doses. The first dose of the dexamethasone on the day of dosing was at least 30 minutes but no more than 4 hours prior to the rovalpituzumab tesirine infusion.

    Number of subjects in period 1
    		Topotecan Rovalpituzumab Tesirine
    Started
    148
    296
    Completed
    148
    296

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Topotecan
    Reporting group description
    		 Topotecan given as an intravenous (IV) infusion over 30 minutes at a dose of 1.5 mg/m^2 on Days 1 to 5 of each 21-day cycle.

    Reporting group title
    Rovalpituzumab Tesirine
    Reporting group description
    		 Rovalpituzumab tesirine IV administration (dosing based on actual body weight) on Day 1 of a 42-day cycle for 2 cycles, with up to 2 additional cycles permitted. Dexamethasone coadministered orally (PO) twice daily at a dose of 8 mg on Day -1, Day 1, and Day 2 of each 42-day cycle in which rovalpituzumab tesirine is administered.

    Reporting group values
    		 Topotecan Rovalpituzumab Tesirine Total
    Number of subjects
    		 148 296 444
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.4 ( 8.72 ) 63.0 ( 8.57 ) -
    Gender categorical
    Units: Subjects
        Female
    		 62 105 167
        Male
    		 86 191 277
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 23 57 80
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 2 0 2
        White
    		 122 236 358
        More than one race
    		 0 2 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 9 11
        Not Hispanic or Latino
    		 146 287 433

    End points

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    End points reporting groups
    Reporting group title
    Topotecan
    Reporting group description
    		 Topotecan given as an intravenous (IV) infusion over 30 minutes at a dose of 1.5 mg/m^2 on Days 1 to 5 of each 21-day cycle.

    Reporting group title
    Rovalpituzumab Tesirine
    Reporting group description
    		 Rovalpituzumab tesirine IV administration (dosing based on actual body weight) on Day 1 of a 42-day cycle for 2 cycles, with up to 2 additional cycles permitted. Dexamethasone coadministered orally (PO) twice daily at a dose of 8 mg on Day -1, Day 1, and Day 2 of each 42-day cycle in which rovalpituzumab tesirine is administered.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from the date of randomization to the date of death from any cause. Participants were censored at the last date they were documented alive. After the End of treatment, survival information was collected at approximately 6-week intervals (or as requested by sponsor to support data analysis) continuing until the endpoint of death, the participant became lost to follow-up, AbbVie terminated the study, or until 12 February 2020. Calculated using the Kaplan-Meier product-limit method.
    End point type
    Primary
    End point timeframe
    From randomization until the end of study; median time on follow-up was 20 and 20.6 months for the topotecan and rovalpituzumab tesirine arms, respectively.
    End point values
    		 Topotecan Rovalpituzumab Tesirine
    Number of subjects analysed
    148 [1]
    296 [2]
    Units: months
        median (confidence interval 95%)
    8.57 (7.69 to 10.12)
    6.34 (5.55 to 7.33)
    Notes
    [1] - randomized participants
    [2] - randomized participants
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio calculated using a Cox proportional hazards regression model, with treatment and randomization stratification factors as covariates.
    Comparison groups
    Topotecan v Rovalpituzumab Tesirine
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0051 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.17
         upper limit
    		 1.82
    Notes
    [3] - Two-sided p-value stratified by the randomization stratification factors.

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is defined as the number of months from the date of randomization until the date of first progression or the date of a participant's death, whichever occurs first. If a participant neither experienced disease progression nor died, then the participant's data were censored at the last date of radiographic assessment that they were documented to be progression free. Calculated using the Kaplan-Meier product-limit method. Radiographic tumor assessments for response were conducted by CT scanning according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Progressive Disease (PD) was defined as at least a 20% increase in the size of target lesions and an absolute increase of at least 5 mm taking as reference the smallest lesion size recorded since the treatment started (baseline or after), or the appearance of one or more new lesions.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of study; median time on follow-up was 20 and 20.6 months for the topotecan and rovalpituzumab tesirine arms, respectively.
    End point values
    		 Topotecan Rovalpituzumab Tesirine
    Number of subjects analysed
    148 [4]
    296 [5]
    Units: months
        median (confidence interval 95%)
    4.27 (3.75 to 5.42)
    3.02 (2.86 to 3.61)
    Notes
    [4] - randomized participants
    [5] - randomized participants
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio calculated using a Cox proportional hazards regression model, with treatment and randomization stratification factors as covariates.
    Comparison groups
    Topotecan v Rovalpituzumab Tesirine
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.22
         upper limit
    		 1.87
    Notes
    [6] - Two-sided p-value stratified by the randomization stratification factors.

    Secondary: Change From Baseline of the Physical Functioning Scale Score in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative Care (EORTC QLQ-C15-PAL) at Week 7

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    End point title
    		 Change From Baseline of the Physical Functioning Scale Score in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative Care (EORTC QLQ-C15-PAL) at Week 7
    End point description
    The EORTC QLQ-C15-PAL is an abbreviated 15-item version of the EORTC core quality of life questionnaire (EORTC QLQ-C30) developed for use in palliative care. The score of 'physical functioning scale' score ranges from 0 (very poor) to 100 (excellent).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 7
    End point values
    		 Topotecan Rovalpituzumab Tesirine
    Number of subjects analysed
    93 [7]
    217 [8]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -7.16 (-11.95 to -2.36)
    -7.66 (-11.31 to -4.01)
    Notes
    [7] - Randomized participants with an assessment at baseline and Week 7.
    [8] - Randomized participants with an assessment at baseline and Week 7.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Topotecan v Rovalpituzumab Tesirine
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.66
         upper limit
    		 4.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.62

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST version 1.1. Radiographic tumor assessments for response were conducted by CT scanning, and assessed from the date of randomization until disease progression or death, whichever came first. Any participant who did not meet CR or PR, including those who did not have post-baseline radiological assessments were considered non-responders. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    End point type
    Secondary
    End point timeframe
    Radiographic tumor assessments were conducted at baseline, every 6 weeks for 30 weeks, then every 9 weeks until progression or death; median time on follow-up was 20 and 20.6 months for the topotecan and rovalpituzumab tesirine arms, respectively.
    End point values
    		 Topotecan Rovalpituzumab Tesirine
    Number of subjects analysed
    129 [9]
    287 [10]
    Units: percentage of participants
        number (confidence interval 95%)
    20.9 (14.27 to 28.97)
    14.6 (10.75 to 19.26)
    Notes
    [9] - Randomized participants with measurable disease at baseline.
    [10] - Randomized participants with measurable disease at baseline.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Topotecan v Rovalpituzumab Tesirine
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3352 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.18
    Notes
    [11] - Stratified by the randomization stratification factors.

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    CBR is defined as percentage of participants whose best overall response is CR, PR, or stable disease (SD) according to RECIST version 1.1. Radiographic tumor assessments for response were conducted by CT scanning, and assessed from the date of randomization until disease progression or death, whichever came first. Any participant who did not meet CR, PR, or SD, including those who did not have post-baseline radiological assessments were considered as experiencing no clinical benefit. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
    End point type
    Secondary
    End point timeframe
    Radiographic tumor assessments were conducted at baseline, every 6 weeks for 30 weeks, then every 9 weeks until progression or death; median time on follow-up was 20 and 20.6 months for the topotecan and rovalpituzumab tesirine arms, respectively.
    End point values
    		 Topotecan Rovalpituzumab Tesirine
    Number of subjects analysed
    129 [12]
    287 [13]
    Units: percentage of participants
        number (confidence interval 95%)
    43.4 (34.71 to 52.42)
    35.9 (30.34 to 41.74)
    Notes
    [12] - Randomized participants with measurable disease at baseline.
    [13] - Randomized participants with measurable disease at baseline.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Topotecan v Rovalpituzumab Tesirine
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0358 [14]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.12
    Notes
    [14] - Stratified by the randomization stratification factors.

    Secondary: Duration of Objective Response (DOR)

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    End point title
    		 Duration of Objective Response (DOR)
    End point description
    DOR is defined as the time between the date of first response (CR or PR, whichever is recorded first) to the date of the first documented tumor progression (per RECIST version 1.1) or death due to any cause, whichever comes first. Radiographic tumor assessments for response were conducted by CT scanning, and assessed from the date of randomization until disease progression or death, whichever came first. Any participant who did not meet CR or PR, including those who did not have post-baseline radiological assessments were considered non-responders. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    End point type
    Secondary
    End point timeframe
    Radiographic tumor assessments were conducted at baseline, every 6 weeks for 30 weeks, then every 9 weeks until progression or death; median time on follow-up was 20 and 20.6 months for the topotecan and rovalpituzumab tesirine arms, respectively.
    End point values
    		 Topotecan Rovalpituzumab Tesirine
    Number of subjects analysed
    27 [15]
    42 [16]
    Units: months
        number (confidence interval 95%)
    4.86 (3.94 to 7.85)
    3.52 (2.76 to 4.17)
    Notes
    [15] - Randomized participants with measurable disease at baseline, and a response.
    [16] - Randomized participants with measurable disease at baseline, and a response.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Deaths are reported from enrollment to the end of study; median time on follow-up was 20 and 20.6 months for the topotecan and rovalpituzumab tesirine arms, respectively.
    Adverse event reporting additional description
    Treatment-emergent adverse events and serious adverse events were collected from first dose of study drug until 70 days after the last dose of study drug; mean duration on study drug was 14.8 weeks and 11.3 weeks for the topotecan and rovalpituzumab tesirine arms, respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Topotecan
    Reporting group description
    		 Topotecan given as an intravenous (IV) infusion over 30 minutes at a dose of 1.5 mg/m^2 on Days 1 to 5 of each 21-day cycle.

    Reporting group title
    Rovalpituzumab Tesirine
    Reporting group description
    		 Rovalpituzumab tesirine IV administration (dosing based on actual body weight) on Day 1 of a 42-day cycle for 2 cycles, with up to 2 additional cycles permitted. Dexamethasone coadministered orally (PO) twice daily at a dose of 8 mg on Day -1, Day 1, and Day 2 of each 42-day cycle in which rovalpituzumab tesirine is administered.

    Serious adverse events
    		 Topotecan Rovalpituzumab Tesirine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 129 (57.36%)
    160 / 287 (55.75%)
         number of deaths (all causes)
    104
    254
         number of deaths resulting from adverse events
    28
    64
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    CANCER PAIN
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL NEOPLASM
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTED NEOPLASM
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG NEOPLASM
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    MALIGNANT NEOPLASM OF SPINAL CORD
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALIGNANT NEOPLASM PROGRESSION
         subjects affected / exposed
    17 / 129 (13.18%)
    30 / 287 (10.45%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 32
         deaths causally related to treatment / all
    0 / 17
    0 / 26
    METASTASES TO MENINGES
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    NEOPLASM MALIGNANT
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    NEOPLASM PROGRESSION
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    NON-SMALL CELL LUNG CANCER
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SMALL CELL LUNG CANCER
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    SMALL CELL LUNG CANCER METASTATIC
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR NECROSIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR PAIN
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SUPERIOR VENA CAVA SYNDROME
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CHEST PAIN
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    DISEASE PROGRESSION
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    FACE OEDEMA
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 129 (0.00%)
    6 / 287 (2.09%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    6 / 129 (4.65%)
    8 / 287 (2.79%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 10
         deaths causally related to treatment / all
    0 / 3
    0 / 6
    MALAISE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYSEROSITIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    3 / 129 (2.33%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEROSITIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE LUNG INJURY
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASTHMA
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ATELECTASIS
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 129 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 129 (0.00%)
    16 / 287 (5.57%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    DYSPNOEA AT REST
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 129 (0.00%)
    17 / 287 (5.92%)
         occurrences causally related to treatment / all
    0 / 0
    13 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURISY
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    1 / 129 (0.78%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY FIBROSIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PULMONARY HAEMORRHAGE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    RESPIRATORY DISTRESS
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 129 (0.78%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    2 / 129 (1.55%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CULTURE URINE POSITIVE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL CONDITION ABNORMAL
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    LIPASE INCREASED
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (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
    CONTUSION
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EYELID CONTUSION
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEAT STROKE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THERMAL BURN
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    APLASIA
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARRHYTHMIA
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARDIAC TAMPONADE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ATAXIA
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CERVICAL CORD COMPRESSION
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLIC STROKE
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERALISED TONIC-CLONIC SEIZURE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    2 / 129 (1.55%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRACRANIAL PRESSURE INCREASED
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    INTRAVENTRICULAR HAEMORRHAGE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MEMORY IMPAIRMENT
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NERVOUS SYSTEM DISORDER
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SOMNOLENCE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    4 / 129 (3.10%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    11 / 129 (8.53%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    12 / 13
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HAEMATOTOXICITY
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    6 / 129 (4.65%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    10 / 129 (7.75%)
    5 / 287 (1.74%)
         occurrences causally related to treatment / all
    10 / 10
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 129 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBILEUS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLANGITIS
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLESTASIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FAILURE
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    JAUNDICE CHOLESTATIC
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    ADRENAL INSUFFICIENCY
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOPOROSIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    BRONCHITIS
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CANDIDA INFECTION
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (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 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 129 (0.00%)
    5 / 287 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ABSCESS
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORCHITIS
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    6 / 129 (4.65%)
    19 / 287 (6.62%)
         occurrences causally related to treatment / all
    3 / 6
    4 / 26
         deaths causally related to treatment / all
    0 / 0
    2 / 7
    PNEUMONIA NECROTISING
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY SYNCYTIAL VIRUS INFECTION
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION VIRAL
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SALMONELLOSIS
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    CACHEXIA
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    DECREASED APPETITE
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS INADEQUATE CONTROL
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    3 / 129 (2.33%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Topotecan Rovalpituzumab Tesirine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    118 / 129 (91.47%)
    245 / 287 (85.37%)
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    4 / 129 (3.10%)
    16 / 287 (5.57%)
         occurrences all number
    6
    16
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    21 / 129 (16.28%)
    36 / 287 (12.54%)
         occurrences all number
    28
    47
    CHEST PAIN
         subjects affected / exposed
    4 / 129 (3.10%)
    18 / 287 (6.27%)
         occurrences all number
    4
    19
    FATIGUE
         subjects affected / exposed
    35 / 129 (27.13%)
    65 / 287 (22.65%)
         occurrences all number
    47
    85
    OEDEMA PERIPHERAL
         subjects affected / exposed
    11 / 129 (8.53%)
    51 / 287 (17.77%)
         occurrences all number
    14
    58
    PYREXIA
         subjects affected / exposed
    6 / 129 (4.65%)
    16 / 287 (5.57%)
         occurrences all number
    9
    18
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    16 / 129 (12.40%)
    42 / 287 (14.63%)
         occurrences all number
    19
    45
    DYSPNOEA
         subjects affected / exposed
    25 / 129 (19.38%)
    56 / 287 (19.51%)
         occurrences all number
    28
    69
    EPISTAXIS
         subjects affected / exposed
    14 / 129 (10.85%)
    9 / 287 (3.14%)
         occurrences all number
    16
    11
    PLEURAL EFFUSION
         subjects affected / exposed
    5 / 129 (3.88%)
    65 / 287 (22.65%)
         occurrences all number
    6
    72
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    9 / 129 (6.98%)
    15 / 287 (5.23%)
         occurrences all number
    9
    17
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 129 (0.78%)
    18 / 287 (6.27%)
         occurrences all number
    3
    31
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 129 (2.33%)
    20 / 287 (6.97%)
         occurrences all number
    4
    34
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    12 / 129 (9.30%)
    1 / 287 (0.35%)
         occurrences all number
    20
    1
    PLATELET COUNT DECREASED
         subjects affected / exposed
    7 / 129 (5.43%)
    9 / 287 (3.14%)
         occurrences all number
    13
    11
    WEIGHT DECREASED
         subjects affected / exposed
    7 / 129 (5.43%)
    18 / 287 (6.27%)
         occurrences all number
    7
    22
    Cardiac disorders
    PERICARDIAL EFFUSION
         subjects affected / exposed
    3 / 129 (2.33%)
    56 / 287 (19.51%)
         occurrences all number
    3
    58
    Nervous system disorders
    DYSGEUSIA
         subjects affected / exposed
    7 / 129 (5.43%)
    6 / 287 (2.09%)
         occurrences all number
    8
    6
    HEADACHE
         subjects affected / exposed
    11 / 129 (8.53%)
    20 / 287 (6.97%)
         occurrences all number
    14
    21
    PARAESTHESIA
         subjects affected / exposed
    7 / 129 (5.43%)
    0 / 287 (0.00%)
         occurrences all number
    7
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    75 / 129 (58.14%)
    42 / 287 (14.63%)
         occurrences all number
    136
    53
    LEUKOPENIA
         subjects affected / exposed
    25 / 129 (19.38%)
    4 / 287 (1.39%)
         occurrences all number
    80
    8
    NEUTROPENIA
         subjects affected / exposed
    50 / 129 (38.76%)
    14 / 287 (4.88%)
         occurrences all number
    136
    20
    THROMBOCYTOPENIA
         subjects affected / exposed
    45 / 129 (34.88%)
    39 / 287 (13.59%)
         occurrences all number
    94
    75
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    11 / 129 (8.53%)
    21 / 287 (7.32%)
         occurrences all number
    11
    25
    CONSTIPATION
         subjects affected / exposed
    29 / 129 (22.48%)
    33 / 287 (11.50%)
         occurrences all number
    36
    35
    DIARRHOEA
         subjects affected / exposed
    25 / 129 (19.38%)
    20 / 287 (6.97%)
         occurrences all number
    29
    24
    NAUSEA
         subjects affected / exposed
    40 / 129 (31.01%)
    65 / 287 (22.65%)
         occurrences all number
    58
    77
    VOMITING
         subjects affected / exposed
    17 / 129 (13.18%)
    30 / 287 (10.45%)
         occurrences all number
    20
    35
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    20 / 129 (15.50%)
    3 / 287 (1.05%)
         occurrences all number
    24
    3
    ERYTHEMA
         subjects affected / exposed
    0 / 129 (0.00%)
    16 / 287 (5.57%)
         occurrences all number
    0
    22
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    0 / 129 (0.00%)
    46 / 287 (16.03%)
         occurrences all number
    0
    60
    RASH
         subjects affected / exposed
    1 / 129 (0.78%)
    25 / 287 (8.71%)
         occurrences all number
    1
    34
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    10 / 129 (7.75%)
    16 / 287 (5.57%)
         occurrences all number
    11
    19
    BACK PAIN
         subjects affected / exposed
    12 / 129 (9.30%)
    21 / 287 (7.32%)
         occurrences all number
    12
    22
    MYALGIA
         subjects affected / exposed
    7 / 129 (5.43%)
    7 / 287 (2.44%)
         occurrences all number
    7
    8
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    8 / 129 (6.20%)
    13 / 287 (4.53%)
         occurrences all number
    11
    13
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    35 / 129 (27.13%)
    71 / 287 (24.74%)
         occurrences all number
    47
    87
    HYPOALBUMINAEMIA
         subjects affected / exposed
    3 / 129 (2.33%)
    17 / 287 (5.92%)
         occurrences all number
    3
    18
    HYPOKALAEMIA
         subjects affected / exposed
    13 / 129 (10.08%)
    18 / 287 (6.27%)
         occurrences all number
    13
    24

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2017
    Specified that DLL3high is defined as ≥ 75% tumor cells staining positive according to the VENTANA DLL3 (SP347) IHC Assay, provided additional detail for definitive treatment for CNS disease and include subjects with stable or improved clinical status prior to randomization, provided modified exclusion windows for prior history of effusions, clarified that the corticosteroid exclusion criterion is to exclude subjects with unstable CNS metastases.
    19 May 2017
    Revised the exclusion criteria to provide additional safety parameters, clarified any prior exposure to a pyrrolobenzodiazepine- or indolinobenzodiazepine-based drug is excluded, added new criterion since the antibody is produced using these cells and there could be possible cross-reactivity in the product.
    02 Jul 2018
    Removed requirement for prospective CRAC confirmation for disease measurability to simplify patient randomization logistics and due to change of objective response rate (ORR) from primary to secondary endpoint, clarify definition of non-active CNS metastases and requirements for study entry for subjects with history of CNS metastases with complete response, added more stringent safety requirements and allowances for flexibility on dose interruptions if treatment benefits were observed, updated dose reduction guidelines incorporating information on rovalpituzumab tesirine tolerability available to date.
    08 Jan 2019
    Following the 4th safety review by the IDMC on 03 December 2018, the IDMC recommended that enrollment in the study be discontinued due to shorter OS in the rovalpituzumab tesirine arm compared with the topotecan control arm. At this point in time, 444 subjects had enrolled of the planned enrollment for the study of 600 subjects. Amendment 4 discontinued CRAC assessment of response and progression; these analyses were conducted using investigator assessment. For patients that were currently on treatment with rovalpituzumab tesirine, the IDMC recommended that sites and patients make individual decisions as to whether or not to continue treatment based on patient level response. A series of changes were made to the protocol to reflect that no further formal statistical hypothesis testing related to efficacy endpoints would be conducted, and to clarify the study duration reflecting the end of treatment no later than 04 December 2019 and survival follow up no later than 12 February 2020.

    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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