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    Clinical Trial Results:
    A Randomized-Controlled Three-arm Phase II Study of Lurbinectedin (PM01183) Alone or In Combination with Gemcitabine and a control arm with Docetaxel as Second-Line Treatment in Unresectable Non-Small Cell Lung Cancer (NSCLC) Patients.

    Summary
    EudraCT number
    2013-000548-25
    Trial protocol
    ES   IT   BE   FR  
    Global end of trial date
    24 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Oct 2018
    First version publication date
    24 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PM1183-B-004-13
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01951157
    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 91846 60 00, clinicaltrials@pharmamar.com
    Scientific contact
    Clinical Developtment Department of PharmaMar´s Oncology, Business Unit., Pharmamar, S.A, 34 91846 60 00, clinicaltrials@pharmamar.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the antitumor activity as progression-freesurvival at four months (PFS4) of PM01183 alone or in combination with gemcitabine as second-line treatment in unresectable NSCLC patients, using single agent docetaxel as a reference in the control arm as current standard of care.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    All patients treated in PM01183-containing arms (Arms B or C) will receive standard antiemetic prophylaxis, according to American Society of Clinical Oncology (ASCO) guidelines before each treatment administration, as follows: - Corticosteroids (i.v. dexamethasone or equivalent, at institutional standard antiemetic doses). - Serotonin (5-HT3) antagonists (8 mg i.v. ondansetron or equivalent). If necessary, in addition to the above, 10 mg metoclopramide every eight hours could be administered orally, or the duration of treatment with 5-HT3 antagonists and/or dexamethasone could be extended (depending on the Investigator’s own criteria). Prophylactic antiemetic medication for the docetaxel arm (Arm A) will follow institutional guidelines. In addition, these patients have to receive 8 mg oral dexamethasone every 12-hours starting the night before docetaxel administration, for a total of six consecutive doses.
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Italy: 32
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    69
    EEA total number of subjects
    67
    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)
    38
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    69 patients were enrolled between 11/09/2013 and 2/10/2015 at 13 centers. 68 patients were treated: 22 in Arm A, 21 in Arm B, and 25 in Arm C. The first dose of the first cycle was administered on 17/09/2013 and the last dose of the last cycle was administered on 3/11/2016. The last patient, last follow-up was on 26/11/2016

    Pre-assignment
    Screening details
    Voluntary written IC;Histologically/cytologically confirmed unresectable NSCLC;failed one prior line of CT-based therapy for unresectable disease;Age 18-75 years;ECOG PS≤1;Adequate hematological, renal, metabolic and hepatic function;three weeks since the last prior therapy;Washout period for radiotherapy;Pregnancy/contraception.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A
    Arm description
    Docetaxel 75 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk
    Arm type
    Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Docetaxel
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk

    Arm title
    Arm B
    Arm description
    In the first protocol version, PM01183 7 mg Flat dose, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles After protocol amedment 3, PM01183 3.2 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles
    Arm type
    Experimental

    Investigational medicinal product name
    PM01183
    Investigational medicinal product code
    PM01183
    Other name
    Lurbinectedin,Zepsyre
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the first protocol version, PM01183 7 mg Flat dose, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles After protocol amedment 3, PM01183 3.2 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles

    Arm title
    Arm C
    Arm description
    Gemcitabine 800 mg/m2, 30-min i.v. infusion, immediately followed by PM01183 3.0 mg Flat dose, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles (in the first protocol version) or PM01183 1.6 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles (after protocol amedment 3)
    Arm type
    Experimental

    Investigational medicinal product name
    PM01183
    Investigational medicinal product code
    PM01183
    Other name
    Lurbinectedin,Zepsyre
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the first protocol version, PM01183 3.0 mg Flat dose, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles After protocol amedment 3, PM01183 1.6 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Gemcitabine
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 800 mg/m2, 30-min i.v. infusion

    Number of subjects in period 1
    Arm A Arm B Arm C
    Started
    22
    22
    25
    Completed
    0
    0
    0
    Not completed
    22
    22
    25
         Progressive disease
    12
    13
    10
         Treatment-unrelated AE
    1
    -
    3
         Study termination
    -
    -
    1
         Physician decision
    5
    3
    2
         Non-treatmentrelated death
    2
    2
    2
         No treated
    -
    1
    -
         Treatment-related AE
    2
    -
    4
         Consent withdrawn by subject
    -
    1
    3
         Treatment-related death
    -
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    Docetaxel 75 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk

    Reporting group title
    Arm B
    Reporting group description
    In the first protocol version, PM01183 7 mg Flat dose, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles After protocol amedment 3, PM01183 3.2 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles

    Reporting group title
    Arm C
    Reporting group description
    Gemcitabine 800 mg/m2, 30-min i.v. infusion, immediately followed by PM01183 3.0 mg Flat dose, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles (in the first protocol version) or PM01183 1.6 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles (after protocol amedment 3)

    Reporting group values
    Arm A Arm B Arm C Total
    Number of subjects
    22 22 25 69
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    15 10 13 38
        From 65-84 years
    7 12 12 31
    Age continuous
    Units: years
        median (full range (min-max))
    61.5 (49 to 72) 65.0 (46 to 74) 64.0 (41 to 75) -
    Gender categorical
    Units: Subjects
        Female
    5 5 9 19
        Male
    17 17 16 50
    ECOG PS
    ECOG PS, Eastern Cooperative Oncology Group performance status
    Units: Subjects
        PS 0
    6 11 10 27
        PS 1
    16 11 15 42
    Race
    Units: Subjects
        Caucasian
    21 22 25 68
        Unknown
    1 0 0 1
    Histology type
    Units: Subjects
        Non-squamous-cell
    17 18 19 54
        Squamous-cell
    4 4 6 14
        Not specified
    1 0 0 1
    Histology grade
    Units: Subjects
        Well differentiated
    0 1 0 1
        Moderately differentiated
    2 5 1 8
        Poorly differentiated
    7 3 9 19
        Unknown
    13 13 15 41
    Stage at diagnosis
    Units: Subjects
        Early
    1 1 2 4
        Locally advanced
    4 7 4 15
        Metastatic
    15 14 18 47
        Unknown
    2 0 1 3
    Stage at study entry
    Units: Subjects
        Locally advanced
    1 0 2 3
        Metastatic
    21 22 23 66
    Surgery
    Units: Subjects
        Yes
    3 5 3 11
        No
    19 17 22 58
    Radiotherapy
    Units: Subjects
        Yes
    9 10 10 29
        No
    13 12 15 40
    Prior chemotherapy
    Number of prior lines
    Units: Subjects
        1 line
    19 21 23 63
        2 lines
    3 1 2 6
    Best response to last prior platinum based chemotherapy
    NA, not applicable; PD, progressive disease; PR, partial response; SD, stable disease; UK, unknown
    Units: Subjects
        PR
    11 11 9 31
        SD
    5 8 10 23
        PD
    5 3 5 13
        NA
    1 0 0 1
        UK
    0 0 1 1
    Weight
    Units: Kg
        median (full range (min-max))
    70.5 (45.0 to 90.8) 74.0 (39.0 to 124.0) 77.0 (40.0 to 136.0) -
    BSA
    BSA, body surface area
    Units: m2
        median (full range (min-max))
    1.8 (1.4 to 2.1) 1.9 (1.4 to 2.3) 1.9 (1.3 to 2.5) -
    Signs and symptoms per patient
    Units: Signs and symptoms
        median (full range (min-max))
    1 (0 to 4) 1 (0 to 4) 1 (0 to 5) -
    Albumin
    Units: g/dL
        median (full range (min-max))
    4.3 (3.1 to 4.7) 3.9 (3.2 to 5.0) 4.0 (3.3 to 4.8) -
    Alpha-1-acid glycoprotein
    Units: mg/dL
        median (full range (min-max))
    172 (144 to 251) 141 (65 to 243) 159 (57 to 247) -
    Time from first diagnosis to first infusion
    Units: months
        median (full range (min-max))
    8.0 (2.4 to 48.0) 11.4 (3.3 to 42.7) 9.2 (1.9 to 109.3) -
    Number of sites involved at baseline
    Units: sites
        median (full range (min-max))
    3 (1 to 6) 3 (1 to 6) 3 (1 to 6) -
    Platinum-free interval
    Units: months
        median (full range (min-max))
    3.5 (1.0 to 16.3) 5.6 (0.7 to 36.8) 3.9 (1.0 to 20.8) -
    PFS to last prior line
    PFS, progression-free survival
    Units: months
        median (full range (min-max))
    5.7 (0.1 to 18.2) 6.7 (1.1 to 36.9) 5.4 (1.1 to 17.4) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    Docetaxel 75 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk

    Reporting group title
    Arm B
    Reporting group description
    In the first protocol version, PM01183 7 mg Flat dose, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles After protocol amedment 3, PM01183 3.2 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles

    Reporting group title
    Arm C
    Reporting group description
    Gemcitabine 800 mg/m2, 30-min i.v. infusion, immediately followed by PM01183 3.0 mg Flat dose, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles (in the first protocol version) or PM01183 1.6 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles (after protocol amedment 3)

    Primary: Progression-free survival at four months

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    End point title
    Progression-free survival at four months [1]
    End point description
    The primary analysis of efficacy was based on the percentage of patients who were alive and progression-free at 16 weeks (~4 months) after randomization.
    End point type
    Primary
    End point timeframe
    16 weeks (~4 months) after randomization
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The exact binomial estimator and its 95%CI was used. A pre-planned Bayesian supportive analysis test comparing PFS4 was performed. The Bayes quadratic loss estimator following a noninformative prior distribution and their 95% credible region were: -A: 29.2% 95%CI(13.2, 48.4) -B: 19.0% 95%CI(5.7, 37.9) -C: 28.0% 95%CI(12.6, 46.7) The three 95% confidence intervals overlap when comparing the PFS4 Bayesian estimator, then statistically significant differences were not found in PFS4
    End point values
    Arm A Arm B Arm C
    Number of subjects analysed
    22
    19 [2]
    23 [3]
    Units: percent
        number (confidence interval 95%)
    27.3 (10.7 to 50.2)
    15.8 (3.4 to 39.6)
    26.1 (10.2 to 48.4)
    Notes
    [2] - 1 no treated, 1 no tumour assesment, 1 major protocol desviation
    [3] - 2 no tumour assesment
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    Overall Response Rate
    End point description
    Objective response per RECIST v.1.1 PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease; TF, treatment failure (defined as symptomatic deterioration or death due to progression or treatment discontinuation due to any treatment-related toxicity occurred before any appropriate tumor assessments had been performed).
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Arm A Arm B Arm C
    Number of subjects analysed
    22
    19 [4]
    23 [5]
    Units: subjects
        PR
    2
    0
    4
        SD
    10
    7
    11
        PD
    8
    8
    6
        TF
    2
    4
    2
    Notes
    [4] - 1 no treated, 1 no tumour assesment, 1 major protocol desviation
    [5] - 2 no tumour assesment
    No statistical analyses for this end point

    Secondary: Response rate

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    End point title
    Response rate
    End point description
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Arm A Arm B Arm C
    Number of subjects analysed
    22
    19 [6]
    23 [7]
    Units: percent
        number (confidence interval 95%)
    9.1 (1.1 to 29.2)
    0 (0 to 17.6)
    17.4 (5.0 to 38.8)
    Notes
    [6] - 1 no treated, 1 no tumour assesment, 1 major protocol desviation
    [7] - 2 no tumour assesment
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response [8]
    End point description
    Duration of response (DR) was defined as the time from the date when the response criteria (PR or CR, whichever was reached first) were fulfilled, to the first date when PD, recurrence or death was documented. 999, Not applicable No patients with CR or PR to treatment as per the RECIST v.1.1 criteria were found in Arm B.
    End point type
    Secondary
    End point timeframe
    Overall period
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No patients with CR or PR to treatment as per the RECIST v.1.1 criteria were found in Arm B.
    End point values
    Arm A Arm C
    Number of subjects analysed
    22
    23 [9]
    Units: months
        median (confidence interval 95%)
    1.2 (0.8 to 1.6)
    6.1 (2.0 to 999)
    Notes
    [9] - 2 no tumour assesment
    Statistical analysis title
    Kaplan meier analysis and log rank test
    Statistical analysis description
    A statistically significant longer median DR was observed for Arm C compared to Arm A (6.1 months vs. 1.2 months; p=0.0177)
    Comparison groups
    Arm C v Arm A
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0177
    Method
    Logrank
    Confidence interval

    Secondary: Progression-free survival

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    End point title
    Progression-free survival
    End point description
    PFS rate at six months (PFS6) was 18.2% (95% CI, 2.1–34.3%) in Arm A, 16.7% (95% CI, 0–33.9%) in Arm B, and 17.5% (95% CI, 0–35.2%) in Arm C. PFS, progression-free survival; PFS6, progression-free survival rate at six months.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Arm A Arm B Arm C
    Number of subjects analysed
    22
    19 [10]
    23 [11]
    Units: months
        median (confidence interval 95%)
    3.1 (1.8 to 4.0)
    1.9 (1.5 to 3.0)
    3.3 (1.9 to 5.7)
    Notes
    [10] - 1 no treated, 1 no tumour assesment, 1 major protocol desviation
    [11] - 2 no tumour assesment
    Statistical analysis title
    Progression-free survival
    Statistical analysis description
    No statistically significant difference was detected among the three study arms in terms of median PFS
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3873
    Method
    Logrank
    Confidence interval

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival at 1 year (OS12) was 38.4% (95% CI, 17.6–59.2%) in Arm A; 27.9% (95% CI, 7.1–48.6%) in Arm B; and 17.4% (95% CI, 1.9–32.9%) in Arm C 999, Not applicable
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Arm A Arm B Arm C
    Number of subjects analysed
    22
    19 [12]
    23 [13]
    Units: months
        median (confidence interval 95%)
    9.4 (3.1 to 999)
    5.5 (3.0 to 8.0)
    7.2 (4.5 to 10.6)
    Notes
    [12] - 1 no treated, 1 no tumour assesment, 1 major protocol desviation
    [13] - 2 no tumour assesment
    Statistical analysis title
    Overall survival
    Statistical analysis description
    No statistically significant difference was detected among the three study arms in terms of median OS
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3526
    Method
    Logrank
    Confidence interval

    Secondary: Quality of Life

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    End point title
    Quality of Life
    End point description
    The mean QoL scores self-reported by patients using the Lung Cancer Symptom Scale (LCSS) at baseline and after the start of the therapy in visits 3 or 6 (+/- 1 visit) and visit 9 for those patients in maintenance therapy. Higher LCSS scores indicate more severe problems. Total score was calculated as the mean of the total scores of all nine patient items 000 or 999, Not applicable
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    Arm A Arm B Arm C
    Number of subjects analysed
    22
    20
    25
    Units: points
    arithmetic mean (confidence interval 95%)
        Baseline
    27.2 (18.4 to 36.1)
    36.4 (25.0 to 47.7)
    38.1 (27.7 to 48.5)
        Cycle 3
    29.5 (14.5 to 44.5)
    32.2 (19.5 to 44.9)
    36.4 (25.4 to 47.5)
        Cycle 6
    24.3 (17.4 to 31.1)
    55.4 (000 to 999)
    35.4 (-11.7 to 82.5)
        Cycle 9
    999 (999 to 999)
    38.1 (-74.8 to 151.1)
    999 (999 to 999)
    Statistical analysis title
    Wilcoxon signed rankstest repeat analysis
    Statistical analysis description
    Changes in QoL scores over time were calculated and tested for statistical significance by means of Wilcoxon signed ranks test repeat-measure analyses of variance.
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9026 [14]
    Method
    Wilcoxon signed ranks test repeat analys
    Confidence interval
    Notes
    [14] - Arm A p-value=0.9026; Arm B p-value=0.9862; Arm C p-value=0.8057

    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
    16.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    Docetaxel 75 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk

    Reporting group title
    Arm B
    Reporting group description
    PM01183 3.2 mg/m2, 1-h i.v. infusion (at a fixed rate), on D1, q3wk, up to 6 cycles

    Reporting group title
    Arm C
    Reporting group description
    Gemcitabine 800 mg/m2, 30-min i.v. infusion, immediately followed by PM01183 1.6 mg/m2, 1-h i.v. infusion, both on D1 and D8, q3wk, up to 6 cycles

    Serious adverse events
    Arm A Arm B Arm C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 22 (54.55%)
    9 / 21 (42.86%)
    18 / 25 (72.00%)
         number of deaths (all causes)
    14
    17
    21
         number of deaths resulting from adverse events
    2
    4
    2
    Vascular disorders
    Shock
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Asthenia/Fatigue
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 21 (14.29%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    3 / 25 (12.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    3 / 25 (12.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oesophagobronchial fistula
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Necrotising fasciitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 21 (0.00%)
    4 / 25 (16.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candida pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A Arm B Arm C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 22 (95.45%)
    20 / 21 (95.24%)
    25 / 25 (100.00%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    2 / 25 (8.00%)
         occurrences all number
    0
    6
    3
    Hypertension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    3
    Hypotension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Asthenia/Fatigue
         subjects affected / exposed
    16 / 22 (72.73%)
    16 / 21 (76.19%)
    17 / 25 (68.00%)
         occurrences all number
    30
    32
    35
    Influenza like illness
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    4 / 22 (18.18%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    4
    0
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 22 (18.18%)
    2 / 21 (9.52%)
    5 / 25 (20.00%)
         occurrences all number
    5
    3
    7
    Pyrexia
         subjects affected / exposed
    7 / 22 (31.82%)
    5 / 21 (23.81%)
    7 / 25 (28.00%)
         occurrences all number
    10
    8
    14
    Chest pain
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    3 / 25 (12.00%)
         occurrences all number
    0
    2
    3
    General physical health deterioration
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Injection site reaction
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    0 / 25 (0.00%)
         occurrences all number
    1
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    2
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    3 / 25 (12.00%)
         occurrences all number
    0
    4
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    0
    0
    5
    Weight decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 22 (13.64%)
    7 / 21 (33.33%)
    15 / 25 (60.00%)
         occurrences all number
    4
    11
    29
    Neutropenia
         subjects affected / exposed
    4 / 22 (18.18%)
    3 / 21 (14.29%)
    13 / 25 (52.00%)
         occurrences all number
    4
    8
    21
    Thrombocytopenia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    1
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 22 (36.36%)
    5 / 21 (23.81%)
    4 / 25 (16.00%)
         occurrences all number
    13
    7
    4
    Dyspnoea
         subjects affected / exposed
    8 / 22 (36.36%)
    5 / 21 (23.81%)
    7 / 25 (28.00%)
         occurrences all number
    11
    7
    9
    Haemoptysis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    4
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    1
    0
    3
    Headache
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    0
    Neuropathy peripheral
         subjects affected / exposed
    4 / 22 (18.18%)
    1 / 21 (4.76%)
    2 / 25 (8.00%)
         occurrences all number
    4
    1
    5
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 22 (13.64%)
    5 / 21 (23.81%)
    6 / 25 (24.00%)
         occurrences all number
    3
    6
    7
    Diarrhoea
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 21 (14.29%)
    4 / 25 (16.00%)
         occurrences all number
    5
    4
    10
    Nausea
         subjects affected / exposed
    2 / 22 (9.09%)
    6 / 21 (28.57%)
    13 / 25 (52.00%)
         occurrences all number
    2
    7
    23
    Stomatitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    1
    0
    4
    Vomiting
         subjects affected / exposed
    2 / 22 (9.09%)
    8 / 21 (38.10%)
    6 / 25 (24.00%)
         occurrences all number
    4
    10
    13
    Abdominal distension
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Dysphagia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 21 (28.57%)
    3 / 25 (12.00%)
         occurrences all number
    0
    7
    4
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    2
    0
    1
    Rash
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    3
    5
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    2
    0
    3
    Back pain
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 21 (14.29%)
    0 / 25 (0.00%)
         occurrences all number
    2
    4
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    Myalgia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    6
    0
    2
    Pain in extremity
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 21 (14.29%)
    3 / 25 (12.00%)
         occurrences all number
    1
    3
    3
    Muscle spasms
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 22 (9.09%)
    10 / 21 (47.62%)
    8 / 25 (32.00%)
         occurrences all number
    2
    13
    10
    Hypokalaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 21 (14.29%)
    1 / 25 (4.00%)
         occurrences all number
    3
    3
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    Lung infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    0
    1
    Folliculitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 May 2013
    The protocol amendment included the following main changes: 1) Gene-expression profiling (GEP) was done in circulating tumor and invasive cell (CTIC)-enriched fractions purified from an additional blood sample collected from patients who consented to the PGx sub-study and used to determine a PGx model of PM01183 in NSCLC. 2) The restriction to include only patients with measurable disease was removed (inclusion criterion #5) and patients with non-measurable disease as defined by RECIST v 1.1 were allowed in the trial. 3) The exclusion criterion #7 was modified to clarify that patients who have previously received gemcitabine treatment were eligible.
    02 Oct 2013
    The protocol amendment included the following main changes: 1) The duration of the docetaxel infusion was changed from 30 minutes to one hour, in accordance with the drug’s Summary of Product Characteristics. 2) The exclusion criterion #8 was modified to clarify that both women and men must agree to use a medically acceptable method of contraception (i.e., intrauterine device [IUD], oral contraceptive, subdermal implant, double barrier and/or complete abstinence [non-periodic]) throughout the treatment period and for 6 months after treatment discontinuation.
    09 Apr 2015
    1) Due to data from a pooled analysis of phase II single-agent trials suggesting that grade 3/4 neutropenia and thrombocytopenia could be more frequent in patients with lower BSA values, the dose of PM01183 was adjusted according to BSA. In consequence, the PM01183 starting dose for the combination arm (Arm C) was changed to 1.6 mg/m2. In addition, in order to improve tolerability, the singleagent PM01183 starting dose was reduced by 20% from the original PM01183 RD of 4.0 mg/m2 (or 7 mg FD) found in the FiH trial (PM1183-A-001-08) (23). Therefore, the starting PM01183 dose in Arm B of this trial was changed to 3.2 mg/m2. In addition, a clarification as to the capping of BSA-adjusted PM01183 dose at a BSA of 2.0 m2 and the rounding of the dose to the first decimal point was included. Furthermore, the maintenance dose in arms B and C was changed from 5.0 mg FD to 2.6 mg/m2 2) EC #6.b #6.c were modified to clarify that all patients at study entry were required to have ALT and AST ≤ 3.0 x ULN and total bilirubin had to be within the normal range 3) IC #7 was modified to clarify the time lapse between completion of any prior radiotherapy and study entry. Therefore, patients who received a total dose of radiation≥30Gy needed to complete a 4-week period between the end of radiotherapy and study entry, whereas those who received a total dose of radiation<30Gy only needed to complete a 2-week period before entering the study 4) EC #1d was modified to clarify the diagnostic tests accepted for the diagnosis of chronic active hepatitis B and C 5) The secondary prophylactic treatment with G-CSF has been clarified for the different study arms 6) The restriction in the use of aprepitant was expanded to any directly-related compound 7) Planned end-of-study date was extended to 18 months after accrual of the last evaluable patient 8) The Appendix 5 of the protocol was updated with the most recent version of the Declaration of Helsinki

    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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