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    Clinical Trial Results:
    An Open, Randomized, Multicenter Study in Patients with Recurrent Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer to Compare the Efficacy and Safety of paclitaxel (micellar) nanoparticles and paclitaxel(Cremophor® EL)

    Summary
    EudraCT number
    		 2008-002668-32
    Trial protocol
    		 SE   BE   CZ   HU   LV   SK   LT   DK   BG   FI  
    Global end of trial date
    07 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Mar 2017
    First version publication date
    08 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OAS-07OVA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00989131
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oasmia Pharmaceutical
    Sponsor organisation address
    Vallongatan 1, Uppsala, Sweden, 75228
    Public contact
    Clinical Development, Oasmia Pharmaceutical, 46 505440, margareta.eriksson@oasmia.com
    Scientific contact
    Clinical Development, Oasmia Pharmaceutical, 46 505440, margareta.eriksson@oasmia.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
    28 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To show non-inferiority of the experimental treatment and the control treatment in terms of progression free survival (PFS) using CT scans according to Response Criteria in Solid Tumours, RECIST ver 1.0. • To show non-inferiority of the experimental treatment and the control treatment in terms of overall survivial (OS) • To show safety and tolerability in the two study arms
    Protection of trial subjects
    - Investigators were allowed to withdraw patients at any time, other therapy may be a reason - In case of reactions towards carboplatin patients it was possible to continue on monotherapy with paclitaxel
    Background therapy
    		 Combination therapy was used. Carboplatin was administered 30 minutes after Paclical/Taxol administration was ended.
    Evidence for comparator
    		 Paclitaxel has been used for more than 20 years for treatment of different forms of cancer. Taxol in combination with cisplatin is authorised for the treatment of ovarian cancer, but due to safety issues with cisplatin, carboplatin is recommended standard first-line chemotherapy rteatment in ovarian cancer (Gynecological Cancer Intergroup, GCIG 2005). Patients are usually re-reated with platinum and taxane therapy at their first and second relapse. Thus, paclitaxel as Taxol in combination with carboplatin was thus chosen as the comparator.
    Actual start date of recruitment
    21 Jan 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Bulgaria: 40
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Latvia: 46
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Belarus: 107
    Country: Number of subjects enrolled
    Croatia: 9
    Country: Number of subjects enrolled
    Romania: 17
    Country: Number of subjects enrolled
    Russian Federation: 348
    Country: Number of subjects enrolled
    Serbia: 26
    Country: Number of subjects enrolled
    Ukraine: 102
    Worldwide total number of subjects
    789
    EEA total number of subjects
    206
    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)
    655
    From 65 to 84 years
    134
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study inclusion and exclusion criteria were assessed during the screening period, i.e. up to 6 weeks before randomisation and after patients gave their consent. Recruitment was initated in each country/at each site after respective legal and ethical approvals. First patients were recruited in Russia in Jan 2009 and randomised in Feb 2009.

    Pre-assignment
    Screening details
    		 Platinum-sensitive patients with relapsing ovarian cancer, >6 m after end of 1st /2nd line chemoterapy, CA 125 >2xUNL at two occasions before inclusion, life expectancy >12 weeks, lab criteria to ensure safety of patients, tumours of other origin not allowed. 865 screened , 789 randomized. Most common screenfailures: CA125 <2xUNL, relapse <6 m

    Pre-assignment period milestones
    Number of subjects started
    		 865 [1]
    Intermediate milestone: Number of subjects
    Randomization: 789
    Number of subjects completed
    		 789

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 7
    Reason: Number of subjects
    		 Lost of follow up: 1
    Reason: Number of subjects
    		 Inclusion/Exclusion criteria failures: 60
    Reason: Number of subjects
    		 Missing reason: 8
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In this reported data the pre-assignment period is equal to the enrollment period (=screening period) and number of patients enrolled worlwide are the number of patients randomized world wide. Thus, there are more patients in the beginning of the pre-assignment period (= screened) than actually randomized (= enrolled).
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open study design when related to allocation to treatment arm. Assessments of CT Scans for PSF was made centrally and blinded. The tumour marker CA 125 was analysed in serum samples at a central lab in a blinded manner. The personnel at these labs did not have access to clinical data entered by sites or the patient's treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Paclical
    Arm description
    		 Patients received the study drug under investigation, Paclical , 250 mg/m2, intravenous infusion, followed by intravenous infusion of carboplatin, 5-6 AUC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel (micellar)
    Investigational medicinal product code
    Other name
    Apealea
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclical was administred at 250mg/m2 body-surface area as one hour intravenous infusion, followed by carboplatin 5-6 AUC at least 30 minutes after end of the Paclical administration. In total six treatment cycles with three weeks intervals. Each vial contained 60 mg of lyophilized powder of Paclical for reconstitution before use. Acetate Ringer's solution or Lactated Ringer's Solution should be used for reconstitution. 60 ml of the solution for reconstitution was injected to each Paclical vial (concentration of the concentrate = 1mg/ml), after reconstitution of enough number of vials for one patient the exact dosing volume of the 1 mg/ml concentrate of Paclical required for the patient was injected into an empty sterile infusion bag. The infusion bag was protected from daylight during the infusion by using a cover.

    Arm title
    		 Taxol
    Arm description
    		 Patients received the control drug paclitaxel, Cremophor EL (Taxol), 175 mg/m2, intravenous infusion, followed by intravenous infusion of carboplatin, 5-6 AUC.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Taxol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Taxol was administred at 175mg/m2 body surface area as three-hour intravenous infusion, followed by carboplatin 5-6 AUC at least 30 minutes after end of the Paclical administration, in total six treatment cycles with three weeks interval. The concentrate for solution for infusion of Taxol has a paclitaxel concentration of 6 mg/ml. The concentrate was diluted before use according to local Summary Product Characteristics.

    Number of subjects in period 1
    		Paclical Taxol
    Started
    397
    392
    Completed
    292
    311
    Not completed
    105
    81
         Missing data of reason
    3
    -
         Consent withdrawn by subject
    30
    25
         Physician decision
    24
    12
         Adverse event, non-fatal
    8
    6
         Other illness that prevented further treatment wit
    2
    -
         Other illness that prevented further treatment
    -
    2
         Progression not confirmed in central assessment
    27
    28
         Lost to follow-up
    6
    7
         Protocol deviation
    5
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paclical
    Reporting group description
    		 Patients received the study drug under investigation, Paclical , 250 mg/m2, intravenous infusion, followed by intravenous infusion of carboplatin, 5-6 AUC.

    Reporting group title
    Taxol
    Reporting group description
    		 Patients received the control drug paclitaxel, Cremophor EL (Taxol), 175 mg/m2, intravenous infusion, followed by intravenous infusion of carboplatin, 5-6 AUC.

    Reporting group values
    		 Paclical Taxol Total
    Number of subjects
    		 397 392 789
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 334 321 655
        From 65-84 years
    		 63 71 134
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        geometric mean (full range (min-max))
    		 56 (26 to 81) 56 (27 to 81) -
    Gender categorical
    Units: Subjects
        Female
    		 397 392 789
        Male
    		 0 0 0
    Tumour type
    Number of patient with either epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer.
    Units: Subjects
        Epithelial ovarian cancer
    		 386 369 755
        Primary peritoneal cancer
    		 4 10 14
        Fallopian tube cancer
    		 7 13 20
    Initial tumour stage
    Tumour stage according to FIGO classification.
    Units: Subjects
        Stage IA
    		 7 5 12
        Stage IB
    		 7 10 17
        Stage IC
    		 25 21 46
        Stage IIA
    		 9 17 26
        Stage IIB
    		 8 11 19
        Stage IIC
    		 26 11 37
        Stage IIIA
    		 40 34 74
        Stage IIIB
    		 34 25 59
        Stage IIIC
    		 183 192 375
        Stage IV
    		 58 65 123
        Missing
    		 0 1 1
    Platinum-free interval
    Number of patients within platinum intervals, between last chemotherapy including platinum therapy and randomisation.
    Units: Subjects
        6-12 months
    		 159 169 328
        12-24 months
    		 121 132 253
        >24 months
    		 110 90 200
        Missing
    		 7 1 8
    ECOG performance score
    Units: Subjects
        Normal activity
    		 202 203 405
        Symptomatic but ambulatory self-care
    		 181 182 363
        Ambulatory >50% of the time
    		 14 7 21
        Ambulatory 50% or less of time, need nursing care
    		 0 0 0
        Bedridden, may need hospitalization
    		 0 0 0
    Body surface area (BSA)
    Calculated based on weight and height of each patient.
    Units: BSA (m2)
        geometric mean (standard deviation)
    		 1.8 ( 0.2 ) 1.8 ( 0.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Paclical
    Reporting group description
    		 Patients received the study drug under investigation, Paclical , 250 mg/m2, intravenous infusion, followed by intravenous infusion of carboplatin, 5-6 AUC.

    Reporting group title
    Taxol
    Reporting group description
    		 Patients received the control drug paclitaxel, Cremophor EL (Taxol), 175 mg/m2, intravenous infusion, followed by intravenous infusion of carboplatin, 5-6 AUC.

    Subject analysis set title
    Intention-to-treat (ITT), Paclical arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Same as Reporting group population. The ITT consists of all patients randomised to the Paclical arm regardless whether they received any study drug or not. This population was used to check the robustness of the efficacy data analysed on the per-protocol populations.

    Subject analysis set title
    Intention-to-treat (ITT), Taxol arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Same as Reporting group population. The ITT consists of all patients randomised to the Taxol arm regardless whether they received any study drug or not. This population was used to check the robustness of the efficacy data analysed on the per-protocol populations.

    Subject analysis set title
    Per-protocol Paclical arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The sub-set of the intention-to-treat (ITT) Paclical arm population who received 6 treatment cycles of Paclical and had no major violation.

    Subject analysis set title
    Per-protocol Taxol arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The sub-set of the intention-to-treat (ITT) Taxol arm population who received 6 treatment cycles of Taxol and had no major violation.

    Subject analysis set title
    Safety population Paclical arm
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in the Paclical arm who received at least one dose of study treatment.

    Subject analysis set title
    Safety population Taxol arm
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in theTaxol arm who received at least one dose of study treatment.

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Primary
    End point timeframe
    Time in months from date of randomisation to date of progression based on CT scan assessment as confirmed by the central lab, or time to date of Death of any cause. CT scan assessment according to RECIST version 1.0.
    End point values
    		 Intention-to-treat (ITT), Paclical arm Intention-to-treat (ITT), Taxol arm Per-protocol Paclical arm Per-protocol Taxol arm
    Number of subjects analysed
    397
    392
    311
    333
    Units: months
        median (confidence interval 95%)
    10.2 (10.1 to 10.6)
    10 (9.7 to 10.2)
    10.3 (10.1 to 10.7)
    10.1 (9.9 to 10.2)
    Statistical analysis title
    		 Non-inferiority testing of primary endpoint - PFS
    Comparison groups
    Per-protocol Paclical arm v Per-protocol Taxol arm
    Number of subjects included in analysis
    644
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.094
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.03
    Notes
    [1] - Non-inferiority margin is 1.2. Non-inferiority is established if the upper limit of the one sided 95% confidence interval of the hazard ratio of the two compared groups is lower than 1.2.
    Statistical analysis title
    		 Hazard ratio of PFS in ITT
    Statistical analysis description
    To investigate the robustness of PFS results assessed in the per-protocol population.
    Comparison groups
    Intention-to-treat (ITT), Paclical arm v Intention-to-treat (ITT), Taxol arm
    Number of subjects included in analysis
    789
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.055
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1
    Notes
    [2] - Cox propotion hazards models was used to estimate the hazard ratio between the two groups.

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    The long term follow-up of 3 years after the date of global end of study was to collect data for the OS analysis. The statistics of OS data was received 18 Oct 2016.
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) is defined as the time between randomisation and date of death of any cause.
    End point values
    		 Intention-to-treat (ITT), Paclical arm Intention-to-treat (ITT), Taxol arm Per-protocol Paclical arm Per-protocol Taxol arm
    Number of subjects analysed
    397
    392
    311
    333
    Units: months
        median (confidence interval 95%)
    23.8 (21.5 to 26.9)
    23.5 (21.2 to 26.2)
    25.7 (22.9 to 28.1)
    24.8 (21.7 to 27.1)
    Statistical analysis title
    		 Non-inferiority testing of secondary endpoint - OS
    Comparison groups
    Per-protocol Paclical arm v Per-protocol Taxol arm
    Number of subjects included in analysis
    644
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.62
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.16
    Notes
    [3] - Non-inferiority margin is 1.185. Non-inferiority of OS (i.e. reject the null hypothesis for OS) is established if the upper limit of the one-sided 95% confidence interval of the hazard ratio of the two treatment groups is lower than 1.185.
    Statistical analysis title
    		 Hazard ratio of OS in ITT
    Statistical analysis description
    To investigate the robustness of OS results assessed in the per-protocol population.
    Comparison groups
    Intention-to-treat (ITT), Taxol arm v Intention-to-treat (ITT), Paclical arm
    Number of subjects included in analysis
    789
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.851 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.22
    Notes
    [4] - Cox propotion hazards models was used to estimate the hazard ratio between the two groups.

    Secondary: Hypersensitivity reactions (HR) during treatment

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    End point title
    		 Hypersensitivity reactions (HR) during treatment
    End point description
    Number of patients with at least one hypersensitivity reaction, based on British Columbia Cancer Agency. In the Statistical analysis plan amendment dated 8 May 2014 it was clarified that the objective to show superiority of the experimental treatment over the control treatment in terms of the incidence and severity of hypersensitivity reactions was discarded for the regulatory submission in Europe. Results from the interim analysis clearly showed that due to intense pre-medication before the infusion of Taxol, it was not possible to show superiority of the experimental treatment over the control treatment. A test for superiority was thus not performed.
    End point type
    Secondary
    End point timeframe
    Assessed during infusion of Paclical/Taxol/Carboplatin and directly after the respective infusion.
    End point values
    		 Safety population Paclical arm Safety population Taxol arm
    Number of subjects analysed
    391
    391
    Units: Number of patients with HR
        Patients with no HR
    331
    342
        Patients with mild HR
    32
    28
        Patients with moderate HR
    21
    17
        Patients with severe HR
    7
    4
        Patients with at least 1 HR related to paclitaxel
    20
    26
        Patients with at least 1 HR related to carboplatin
    47
    29
    Statistical analysis title
    		 Test of difference in HR between study arms
    Statistical analysis description
    The incidence of HR is counted as number of patients with at least one HR reaction.
    Comparison groups
    Safety population Taxol arm v Safety population Paclical arm
    Number of subjects included in analysis
    782
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.255
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 Incidence of HR related to paclitaxel
    Comparison groups
    Safety population Taxol arm v Safety population Paclical arm
    Number of subjects included in analysis
    782
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.3672
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - Test of the difference between groups in incidence of HR related to paclitaxel, i.e. either Paclical or Taxol.
    Statistical analysis title
    		 Incidence of HR related to carboplatin
    Comparison groups
    Safety population Paclical arm v Safety population Taxol arm
    Number of subjects included in analysis
    782
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.03
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - Test of the difference between groups in incidence of HR related to carboplatin.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse event reporting started Day 1 Cycle 1 and ended when patient left the study.
    Adverse event reporting additional description
    In the data-output for this study AEs were categorised as All AEs (non-serious AEs+ SAEs) and SAEs. Thus, non-serious adverse events (NSAE) can not be reported here. Due to how EudraCT works the number of patients with NSAEs has to be set = 0, even if there were non-serious adverse events in the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Safety Paclical arm
    Reporting group description
    		 The safety population consists of all patients in the Paclical arm who received at least one dose of Paclical. Date of death, due to any cause was an end-point in the study. Therefore, only deaths related to an adverse event is reported here, not deaths as a result of disease progression.

    Reporting group title
    Safety Taxol arm
    Reporting group description
    		 The safety population consists of all patients in the Taxol arm who received at least one dose of Taxol. Date of death, due to any cause was an end-point in the study. Therefore, only deaths related to an adverse event is reported here, not deaths as a result of disease progression.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: In the data-output for this study AEs were categorised and presented as All AEs (non-serious AEs+ SAEs) and SAEs. Thus, there are no summaries available for non-serious adverse events as per specific AE term.
    Serious adverse events
    		 Safety Paclical arm Safety Taxol arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    160 / 391 (40.92%)
    106 / 391 (27.11%)
         number of deaths (all causes)
    10
    5
         number of deaths resulting from adverse events
    10
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Paraneoplastic syndrome
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Allergic respiratory symptom
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulomary artery thrombosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (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
    Femur fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         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 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenia febrile
         subjects affected / exposed
    13 / 391 (3.32%)
    6 / 391 (1.53%)
         occurrences causally related to treatment / all
    13 / 13
    6 / 6
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    10 / 391 (2.56%)
    5 / 391 (1.28%)
         occurrences causally related to treatment / all
    16 / 16
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematotoxicity
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (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
    20 / 391 (5.12%)
    7 / 391 (1.79%)
         occurrences causally related to treatment / all
    23 / 23
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    110 / 391 (28.13%)
    74 / 391 (18.93%)
         occurrences causally related to treatment / all
    210 / 210
    113 / 113
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    8 / 391 (2.05%)
    8 / 391 (2.05%)
         occurrences causally related to treatment / all
    9 / 9
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Anaemia
         subjects affected / exposed
    16 / 391 (4.09%)
    11 / 391 (2.81%)
         occurrences causally related to treatment / all
    18 / 18
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 391 (1.02%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal functional disorder
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periproctitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (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 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         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 / 391 (0.26%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholesystitis chronic
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Rash generalised
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin discolouration
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (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 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site cellulitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 391 (0.26%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 391 (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
    1 / 391 (0.26%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety Paclical arm Safety Taxol arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 391 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2008
    Protocol amendment of 5 Nov 2008 was implemented before any patient was randomized in the study. This amendment was only submitted to authorities and ethics committees in Sweden, Russia and Ukraine as the original study protocol was submitted only to these countries at the time of this amendment. For the other countries the texts in amendment 1 were included in the first study protocol submitted. The following items were the major changes, completely or partly in the protocol amendment dated 5 Nov, 2008: • A central reading of CT scans was introduced • The study committees were reduced from four to two • Inclusion criterion 1 and 3 were modified to better agree with clinical practise and to avoid ambiguity • The procedure of assessing hypersensitivity is clarified • The Adverse Event reporting period was changed to better capture AEs related to study treatment All changes were made either in order to clarify the procedures of the study or to improve its conduct.
    02 Feb 2010
    The background for the protocol amendment of 2 Feb, 2010 was the need to prolong the follow up period to exceed to study period of 12 months as written in the original study protocol. The prolongation was decided to achieve enough events for the statistical power in the PFS analysis.
    14 Feb 2011
    The protocol is aimed for submission to EMA. However, the amendment of 14 Feb 2011 was written to facilitate a future submission for a market application to FDA. The main changes were the emphasis on evaluating PFS by using CT scan and the definition of overall survival as a secondary endpoint. The frequency of CT scans was increased during the follow-up period to increase the sensitivity in the evaluation of PFS. Apart from this, the changes to the conduct of the study were minor.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Feb 2011
    The interruption in recruiting patients was due to manufactoring proboblems of Paclical 60 mg vials.
    17 May 2011

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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