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    Clinical Trial Results:
    A RANDOMIZED DOUBLE-BLIND PHASE 3 TRIAL COMPARING VINTAFOLIDE (EC145) AND PEGYLATED LIPOSOMAL DOXORUBICIN (PLD/DOXIL®/CAELYX®) IN COMBINATION VERSUS PLD IN PARTICIPANTS WITH PLATINUM-RESISTANT OVARIAN CANCER

    Summary
    EudraCT number
    		 2011-000348-11
    Trial protocol
    		 CZ   ES   BE   PL   HU   GB  
    Global end of trial date
    02 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Sep 2018
    First version publication date
    12 Sep 2018
    Other versions
    Summary report(s)
    		 EC-FV-06 CSR Synopsis (FEB-2017)

    Trial information

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    Trial identification
    Sponsor protocol code
    EC-FV-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01170650
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Endocyte, Inc.
    Sponsor organisation address
    3000 Kent Avenue, Suite A1-100, West Lafayette, United States, 47906
    Public contact
    Christopher Jordan, Endocyte, Inc., 001 3176080769, cjordan@endocyte.com
    Scientific contact
    Christopher Jordan, Endocyte, Inc., 001 3176080769, cjordan@endocyte.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
    Interim
    Date of interim/final analysis
    17 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Compare progression-free survival (PFS), based upon investigator assessment using RECIST v 1.1 in participants with platinum-resistant ovarian cancer who receive combination therapy with vintafolide and pegylated liposomal doxorubicin (PLD) (i.e., vintafolide + PLD) with that of participants with platinum-resistant ovarian cancer who receive PLD and placebo. The primary analysis will be conducted in FR (100%) participants as determined by 99mTc-etarfolatide scan.
    Protection of trial subjects
    Preparation of the ICF is the responsibility of the investigator and must include all elements required by the International Conference on Harmonization (ICH), Good Clinical Practice (GCP), Health Insurance Portability and Accountability Act (HIPAA) or other local regulatory requirements for protection of personal information, and other applicable regulatory requirements and must adhere to the ethical principles that have their origin in the Declaration of Helsinki. The ICF will be approved and reviewed by the sponsor prior to IRB/IEC review.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 124
    Country: Number of subjects enrolled
    Canada: 77
    Country: Number of subjects enrolled
    Israel: 25
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Poland: 5
    Worldwide total number of subjects
    321
    EEA total number of subjects
    71
    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)
    203
    From 65 to 84 years
    117
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was enrolled in April 2011. <12 patients had enrolled into the study when enrollment was suspended from August 2011 through April 2012 due to an interruption in the study’s PLD supply. Once supply had been secured, enrollment increased such that ~57% of patients were enrolled within 12 months of the first planned interim analysis.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 321
    Number of subjects completed
    		 230

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Inclusion/Exclusion: 91
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Study EC-FV-06 is double-blinded in order to limit the occurrence of conscious or unconscious bias in the conduct and interpretation of the clinical trial arising from the influence which the knowledge of treatment may have on the execution of the clinical study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vintafolide + PLD
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EC145
    Investigational medicinal product code
    Other name
    Vintafolide
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2.5mg IV on days 1, 3, 5 of weeks 1 and 3 of a 28 day cycle.

    Investigational medicinal product name
    PLD
    Investigational medicinal product code
    Other name
    Doxorubicin pegylated liposomal
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    50mg/m2 IBW IV on day 1 of 28 day cycle

    Arm title
    		 Placebo + PLD
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PLD
    Investigational medicinal product code
    Other name
    Doxorubicin pegylated liposomal
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    50mg/m2 IBW IV on day 1 of 28 day cycle

    Number of subjects in period 1 [1]
    		Vintafolide + PLD Placebo + PLD
    Started
    143
    87
    Completed
    143
    87
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The baseline period data include only those who completed the treatment whereas the worldwide number enrolled includes all patients enrolled.
    Period 2
    Period 2 title
    First Interim Analysis
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vintafolide + PLD
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EC145
    Investigational medicinal product code
    Other name
    Vintafolide
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2.5mg IV on days 1, 3, 5 of weeks 1 and 3 of a 28 day cycle.

    Investigational medicinal product name
    PLD
    Investigational medicinal product code
    Other name
    Doxorubicin pegylated liposomal
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    50mg/m2 IBW IV on day 1 of 28 day cycle

    Arm title
    		 Placebo + PLD
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PLD
    Investigational medicinal product code
    Other name
    Doxorubicin pegylated liposomal
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    50mg/m2 IBW IV on day 1 of 28 day cycle

    Number of subjects in period 2
    		Vintafolide + PLD Placebo + PLD
    Started
    143
    87
    Completed
    143
    87

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vintafolide + PLD
    Reporting group description
    		 -

    Reporting group title
    Placebo + PLD
    Reporting group description
    		 -

    Reporting group values
    		 Vintafolide + PLD Placebo + PLD Total
    Number of subjects
    		 143 87 230
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.8 ± 9.99 61.0 ± 10.64 -
    Gender categorical
    Units: Subjects
        Female
    		 143 87 230
        Male
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 14 10 24
        Black/African American
    		 8 0 8
        White
    		 121 75 196
        Unknown
    		 0 1 1
    ECOG
    Units: Subjects
        00
    		 71 51 122
        01
    		 72 36 108
    Type of Cancer
    Units: Subjects
        Ovarian
    		 123 73 196
        Primary Peritoneal
    		 13 12 25
        Fallopian Tube
    		 7 2 9
    Regimen
    Units: Subjects
        Primary platinum therapy only
    		 64 36 100
        Primary and secondary platinum therapy
    		 58 36 94
        Additional therapy
    		 21 15 36

    End points

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    End points reporting groups
    Reporting group title
    Vintafolide + PLD
    Reporting group description
    		 -

    Reporting group title
    Placebo + PLD
    Reporting group description
    		 -
    Reporting group title
    Vintafolide + PLD
    Reporting group description
    		 -

    Reporting group title
    Placebo + PLD
    Reporting group description
    		 -

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    End point type
    Primary
    End point timeframe
    22 April 2011 - 17 March 2014
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: Subjects
        PFS Events
    75
    35
        Progressions
    65
    28
        Deaths
    10
    7
        Censored
    68
    52
    Statistical analysis title
    		 Efficacy Analysis
    Comparison groups
    Vintafolide + PLD v Placebo + PLD
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 Regression, Cox
    Confidence interval

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    End point type
    Primary
    End point timeframe
    22 April 2011 - 17 March 2014
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: months
    median (confidence interval 95%)
        PFS Rate at 3 months
    69.4 (60.3 to 76.9)
    62.6 (49.8 to 73.0)
        PFS Rate at 6 months
    44.3 (34.3 to 53.8)
    43.1 (27.2 to 58.0)
    Statistical analysis title
    		 Efficacy Analysis
    Comparison groups
    Vintafolide + PLD v Placebo + PLD
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 Regression, Cox
    Confidence interval

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    22 April 2011 - 17 March 2014
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: Events
        Number of OS Events
    37
    22
        Number Censored
    106
    65
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    22 April 2011 - 17 March 2014
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: months
    median (confidence interval 95%)
        OS Rate at 12 months
    60.9 (48.4 to 71.2)
    58.2 (39.0 to 73.2)
        OS Rate at 18 months
    49.4 (30.3 to 66.0)
    33.9 (12.0 to 57.7)
    No statistical analyses for this end point

    Other pre-specified: Number of target lesions at study entry

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    End point title
    		 Number of target lesions at study entry
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: lesions
        median (full range (min-max))
    2.0 (1 to 5)
    2.0 (1 to 5)
    No statistical analyses for this end point

    Other pre-specified: RECIST sum of diameters at study entry

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    End point title
    		 RECIST sum of diameters at study entry
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: mm
        arithmetic mean (standard deviation)
    73.6 ± 63.05
    68.5 ± 57.28
    No statistical analyses for this end point

    Other pre-specified: RECIST sum of diameters at study entry

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    End point title
    		 RECIST sum of diameters at study entry
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: mm
        median (full range (min-max))
    61.0 (10 to 359)
    48.0 (10 to 339)
    No statistical analyses for this end point

    Other pre-specified: CA-125 Levels at study entry

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    End point title
    		 CA-125 Levels at study entry
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: U/mL
        arithmetic mean (standard deviation)
    1556.3 ± 5865.51
    808.3 ± 1352.35
    No statistical analyses for this end point

    Other pre-specified: CA-125 Levels at study entry

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    End point title
    		 CA-125 Levels at study entry
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: U/mL
        median (full range (min-max))
    248.0 (6 to 64480)
    242.0 (4 to 8634)
    No statistical analyses for this end point

    Other pre-specified: Treatment-free survival

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    End point title
    		 Treatment-free survival
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Basline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: months
        arithmetic mean (standard deviation)
    5.7 ± 4.71
    5.7 ± 3.72
    No statistical analyses for this end point

    Other pre-specified: Treatment-free survival

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    End point title
    		 Treatment-free survival
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: months
        median (full range (min-max))
    5.1 (0 to 38)
    5.3 (1 to 24)
    No statistical analyses for this end point

    Other pre-specified: Platinum-free interval

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    End point title
    		 Platinum-free interval
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    141
    84
    Units: months
        arithmetic mean (standard deviation)
    3.2 ± 1.87
    3.3 ± 1.86
    No statistical analyses for this end point

    Other pre-specified: Platinum-free interval

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    End point title
    		 Platinum-free interval
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    141
    84
    Units: months
        median (full range (min-max))
    3.7 (0 to 7)
    3.7 (0 to 6)
    No statistical analyses for this end point

    Other pre-specified: Time since initial cancer diagnosis

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    End point title
    		 Time since initial cancer diagnosis
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: months
        arithmetic mean (standard deviation)
    20.7 ± 12.09
    26.2 ± 27.69
    No statistical analyses for this end point

    Other pre-specified: Time since initial cancer diagnosis

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    End point title
    		 Time since initial cancer diagnosis
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: months
        median (full range (min-max))
    15.9 (8 to 73)
    16.0 (8 to 207)
    No statistical analyses for this end point

    Other pre-specified: Size of residual disease at the end of the primary debulking surgery or attempted debulking surgery (cm)

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    End point title
    		 Size of residual disease at the end of the primary debulking surgery or attempted debulking surgery (cm)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: Subjects
        <2.0
    95
    69
        >2.0
    21
    3
        Not Applicable
    2
    0
        Unknown
    25
    15
    No statistical analyses for this end point

    Other pre-specified: Number of target lesions at study entry

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    End point title
    		 Number of target lesions at study entry
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Vintafolide + PLD Placebo + PLD
    Number of subjects analysed
    143
    87
    Units: lesions
        arithmetic mean (standard deviation)
    2.3 ± 1.26
    2.4 ± 1.28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    22 April 2011 - 17 March 2014
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Vintafolide + PLD
    Reporting group description
    		 -

    Reporting group title
    Placebo + PLD
    Reporting group description
    		 -

    Serious adverse events
    		 Vintafolide + PLD Placebo + PLD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    79 / 189 (41.80%)
    41 / 120 (34.17%)
         number of deaths (all causes)
    5
    3
         number of deaths resulting from adverse events
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 189 (1.59%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    international normalized ratio increased
         subjects affected / exposed
    2 / 189 (1.06%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Nervous system disorders
    Brain edema
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Cerebral infarction
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Cerebral thrombosis
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 189 (2.12%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    4 / 39
    2 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Neutropenia
         subjects affected / exposed
    5 / 189 (2.65%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    5 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Anaemia
         subjects affected / exposed
    4 / 189 (2.12%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    4 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Thrombocytopenia
         subjects affected / exposed
    1 / 189 (0.53%)
    2 / 120 (1.67%)
         occurrences causally related to treatment / all
    1 / 39
    2 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 189 (2.12%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    3 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Fatigue
         subjects affected / exposed
    1 / 189 (0.53%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Sudden death
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    10 / 189 (5.29%)
    9 / 120 (7.50%)
         occurrences causally related to treatment / all
    3 / 39
    1 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Vomiting
         subjects affected / exposed
    9 / 189 (4.76%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    7 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Abdominal pain
         subjects affected / exposed
    8 / 189 (4.23%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    6 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Constipation
         subjects affected / exposed
    6 / 189 (3.17%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    5 / 39
    2 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Intestinal obstruction
         subjects affected / exposed
    6 / 189 (3.17%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Nausea
         subjects affected / exposed
    6 / 189 (3.17%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    6 / 39
    1 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Ascites
         subjects affected / exposed
    4 / 189 (2.12%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Large intestinal obstruction
         subjects affected / exposed
    4 / 189 (2.12%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Stomatitis
         subjects affected / exposed
    2 / 189 (1.06%)
    2 / 120 (1.67%)
         occurrences causally related to treatment / all
    2 / 39
    2 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Diarrhoea
         subjects affected / exposed
    3 / 189 (1.59%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 189 (1.06%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Hiatus hernia
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    7 / 189 (3.70%)
    2 / 120 (1.67%)
         occurrences causally related to treatment / all
    3 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Pleural effusion
         subjects affected / exposed
    6 / 189 (3.17%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Deep vein thrombosis
         subjects affected / exposed
    2 / 189 (1.06%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Acute respiratory failure
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Dyspnoea
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    1 / 3
    Eosinophilic pneumonia
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Aspiration Pneumonia
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    1 / 3
    Respiratory distress
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    1 / 5
    0 / 3
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    3 / 189 (1.59%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 189 (1.06%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 189 (1.06%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Urinary tract infection
         subjects affected / exposed
    0 / 189 (0.00%)
    2 / 120 (1.67%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    infectious peritonitis
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    1 / 3
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vintafolide + PLD Placebo + PLD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    186 / 189 (98.41%)
    116 / 120 (96.67%)
    Investigations
    Weight decreased
         subjects affected / exposed
    27 / 189 (14.29%)
    9 / 120 (7.50%)
         occurrences all number
    36
    36
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    19 / 189 (10.05%)
    5 / 120 (4.17%)
         occurrences all number
    24
    24
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 189 (7.94%)
    2 / 120 (1.67%)
         occurrences all number
    17
    17
    Hypotension
         subjects affected / exposed
    10 / 189 (5.29%)
    2 / 120 (1.67%)
         occurrences all number
    12
    12
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    60 / 189 (31.75%)
    19 / 120 (15.83%)
         occurrences all number
    79
    79
    Headache
         subjects affected / exposed
    46 / 189 (24.34%)
    23 / 120 (19.17%)
         occurrences all number
    69
    69
    Dizziness
         subjects affected / exposed
    32 / 189 (16.93%)
    18 / 120 (15.00%)
         occurrences all number
    50
    50
    Dysgeusia
         subjects affected / exposed
    20 / 189 (10.58%)
    10 / 120 (8.33%)
         occurrences all number
    30
    30
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    79 / 189 (41.80%)
    39 / 120 (32.50%)
         occurrences all number
    118
    118
    Anaemia
         subjects affected / exposed
    71 / 189 (37.57%)
    27 / 120 (22.50%)
         occurrences all number
    98
    98
    Thrombocytopenia
         subjects affected / exposed
    19 / 189 (10.05%)
    9 / 120 (7.50%)
         occurrences all number
    28
    28
    Leukopenia
         subjects affected / exposed
    18 / 189 (9.52%)
    6 / 120 (5.00%)
         occurrences all number
    24
    24
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    112 / 189 (59.26%)
    49 / 120 (40.83%)
         occurrences all number
    161
    161
    Asthenia
         subjects affected / exposed
    37 / 189 (19.58%)
    16 / 120 (13.33%)
         occurrences all number
    53
    53
    Pyrexia
         subjects affected / exposed
    39 / 189 (20.63%)
    10 / 120 (8.33%)
         occurrences all number
    49
    49
    Oedema peripheral
         subjects affected / exposed
    33 / 189 (17.46%)
    12 / 120 (10.00%)
         occurrences all number
    45
    45
    Chills
         subjects affected / exposed
    12 / 189 (6.35%)
    6 / 120 (5.00%)
         occurrences all number
    18
    18
    Influenza like illness
         subjects affected / exposed
    8 / 189 (4.23%)
    7 / 120 (5.83%)
         occurrences all number
    15
    15
    Pain
         subjects affected / exposed
    14 / 189 (7.41%)
    1 / 120 (0.83%)
         occurrences all number
    15
    15
    Malaise
         subjects affected / exposed
    10 / 189 (5.29%)
    4 / 120 (3.33%)
         occurrences all number
    14
    14
    Chest pain
         subjects affected / exposed
    11 / 189 (5.82%)
    2 / 120 (1.67%)
         occurrences all number
    13
    13
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    115 / 189 (60.85%)
    67 / 120 (55.83%)
         occurrences all number
    182
    182
    Stomatitis
         subjects affected / exposed
    99 / 189 (52.38%)
    54 / 120 (45.00%)
         occurrences all number
    153
    153
    Constipation
         subjects affected / exposed
    101 / 189 (53.44%)
    39 / 120 (32.50%)
         occurrences all number
    140
    140
    Abdominal pain
         subjects affected / exposed
    87 / 189 (46.03%)
    26 / 120 (21.67%)
         occurrences all number
    113
    113
    Vomiting
         subjects affected / exposed
    68 / 189 (35.98%)
    44 / 120 (36.67%)
         occurrences all number
    112
    112
    Diarrhoea
         subjects affected / exposed
    57 / 189 (30.16%)
    29 / 120 (24.17%)
         occurrences all number
    86
    86
    Dyspepsia
         subjects affected / exposed
    37 / 189 (19.58%)
    20 / 120 (16.67%)
         occurrences all number
    57
    57
    Abdominal distension
         subjects affected / exposed
    37 / 189 (19.58%)
    17 / 120 (14.17%)
         occurrences all number
    54
    54
    Abdominal pain upper
         subjects affected / exposed
    22 / 189 (11.64%)
    10 / 120 (8.33%)
         occurrences all number
    32
    32
    Small intestinal obstruction
         subjects affected / exposed
    13 / 189 (6.88%)
    10 / 120 (8.33%)
         occurrences all number
    23
    23
    Ascites
         subjects affected / exposed
    15 / 189 (7.94%)
    6 / 120 (5.00%)
         occurrences all number
    21
    21
    Abdominal pain lower
         subjects affected / exposed
    13 / 189 (6.88%)
    6 / 120 (5.00%)
         occurrences all number
    19
    19
    Dysphagia
         subjects affected / exposed
    15 / 189 (7.94%)
    3 / 120 (2.50%)
         occurrences all number
    18
    18
    Dry mouth
         subjects affected / exposed
    11 / 189 (5.82%)
    6 / 120 (5.00%)
         occurrences all number
    17
    17
    Oral pain
         subjects affected / exposed
    11 / 189 (5.82%)
    5 / 120 (4.17%)
         occurrences all number
    16
    16
    Flatulence
         subjects affected / exposed
    8 / 189 (4.23%)
    6 / 120 (5.00%)
         occurrences all number
    14
    14
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    46 / 189 (24.34%)
    9 / 120 (7.50%)
         occurrences all number
    55
    55
    Cough
         subjects affected / exposed
    30 / 189 (15.87%)
    20 / 120 (16.67%)
         occurrences all number
    50
    50
    Dysphonia
         subjects affected / exposed
    24 / 189 (12.70%)
    1 / 120 (0.83%)
         occurrences all number
    25
    25
    Oropharyngeal pain
         subjects affected / exposed
    17 / 189 (8.99%)
    4 / 120 (3.33%)
         occurrences all number
    21
    21
    Pleural effusion
         subjects affected / exposed
    14 / 189 (7.41%)
    4 / 120 (3.33%)
         occurrences all number
    18
    18
    Pulmonary embolism
         subjects affected / exposed
    10 / 189 (5.29%)
    3 / 120 (2.50%)
         occurrences all number
    13
    13
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    72 / 189 (38.10%)
    45 / 120 (37.50%)
         occurrences all number
    117
    117
    Rash
         subjects affected / exposed
    31 / 189 (16.40%)
    19 / 120 (15.83%)
         occurrences all number
    50
    50
    Alopecia
         subjects affected / exposed
    34 / 189 (17.99%)
    8 / 120 (6.67%)
         occurrences all number
    42
    34
    Skin hyperpigmentation
         subjects affected / exposed
    24 / 189 (12.70%)
    15 / 120 (12.50%)
         occurrences all number
    39
    39
    Rash maculo-papular
         subjects affected / exposed
    19 / 189 (10.05%)
    14 / 120 (11.67%)
         occurrences all number
    33
    33
    Pruritus
         subjects affected / exposed
    20 / 189 (10.58%)
    12 / 120 (10.00%)
         occurrences all number
    32
    32
    Dry skin
         subjects affected / exposed
    19 / 189 (10.05%)
    9 / 120 (7.50%)
         occurrences all number
    28
    28
    Erythema
         subjects affected / exposed
    13 / 189 (6.88%)
    7 / 120 (5.83%)
         occurrences all number
    20
    20
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    36 / 189 (19.05%)
    16 / 120 (13.33%)
         occurrences all number
    52
    52
    Anxiety
         subjects affected / exposed
    29 / 189 (15.34%)
    8 / 120 (6.67%)
         occurrences all number
    37
    37
    Depression
         subjects affected / exposed
    24 / 189 (12.70%)
    3 / 120 (2.50%)
         occurrences all number
    27
    27
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    36 / 189 (19.05%)
    17 / 120 (14.17%)
         occurrences all number
    53
    53
    Myalgia
         subjects affected / exposed
    28 / 189 (14.81%)
    11 / 120 (9.17%)
         occurrences all number
    39
    39
    Muscular weakness
         subjects affected / exposed
    31 / 189 (16.40%)
    0 / 120 (0.00%)
         occurrences all number
    31
    31
    Arthralgia
         subjects affected / exposed
    20 / 189 (10.58%)
    7 / 120 (5.83%)
         occurrences all number
    27
    27
    Pain in extremity
         subjects affected / exposed
    14 / 189 (7.41%)
    7 / 120 (5.83%)
         occurrences all number
    21
    21
    Muscle spasms
         subjects affected / exposed
    14 / 189 (7.41%)
    3 / 120 (2.50%)
         occurrences all number
    17
    17
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    23 / 189 (12.17%)
    16 / 120 (13.33%)
         occurrences all number
    39
    39
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 189 (3.17%)
    6 / 120 (5.00%)
         occurrences all number
    12
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    84 / 189 (44.44%)
    38 / 120 (31.67%)
         occurrences all number
    122
    122
    Hypomagnesaemia
         subjects affected / exposed
    21 / 189 (11.11%)
    10 / 120 (8.33%)
         occurrences all number
    31
    31
    Hypokalaemia
         subjects affected / exposed
    20 / 189 (10.58%)
    8 / 120 (6.67%)
         occurrences all number
    28
    28
    Dehydration
         subjects affected / exposed
    20 / 189 (10.58%)
    6 / 120 (5.00%)
         occurrences all number
    26
    26
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 189 (5.29%)
    3 / 120 (2.50%)
         occurrences all number
    13
    13
    Hyponatraemia
         subjects affected / exposed
    10 / 189 (5.29%)
    0 / 120 (0.00%)
         occurrences all number
    10
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2011
    Change of protocol from v1 to v3. Inclusion of section "Rationale and Justification for Quality of Life Assessments", modification of study objectives, RECIST v1.1 language added into separate appendix, addition of stratification variable based upon EC20 scan status, and modification of existing language, addition of language to section or clarification of existing language for general study design, primary and secondary endpoint definitions, analysis endpoints and populations, sample size determination, interim and final analyses and efficacy analyses.
    05 Feb 2013
    Change of protocol from v3 to v5. Change randomization from 2:1 to 1:1, folate receptor expression status nomenclatures modified, addition of use of EuroQoL EQ-5D-3L questionnaire, modification of study objectives, addition of a 4+/- day allowance for radiographic CT assessments and clarified post-baseline assessments are determined from first dose of vintafolide/placebo and/or PLD, modified inclusion and exclusion criteria, changed stratification variable based upon baseline etarfolatide scan status, updated emergency unblinding procedure, simplified QoL data collection, and modified statistical methods (changed primary objective to PFS, added hierarchical step-down testing for PFS and OS, changed sample size in FR(100%) from 256 to 350, revised interim analysis plan).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Aug 2011
    Enrollment was suspended August 2011 through April 2012 due to an interruption in the study's PLD supply.
    30 Apr 2012

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

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