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    Clinical Trial Results:
    A randomized, open-label, three-arm, multi-center Phase II clinical trial evaluating effect of addition of DCVAC/OvCa to first line standard chemotherapy (carboplatin and paclitaxel) in women with newly diagnosed epithelial ovarian carcinoma

    Summary
    EudraCT number
    		 2013-001322-26
    Trial protocol
    		 DE   CZ   PL  
    Global end of trial date
    18 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Mar 2022
    First version publication date
    13 Mar 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SOV01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02107937
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SOTIO a.s.
    Sponsor organisation address
    Jankovcova 1518/2, Prague, Czechia,
    Public contact
    Clinical Trials SOTIO, SOTIO a.s., +420 224175111, clinicaltrial@sotio.com
    Scientific contact
    Clinical Trials SOTIO, SOTIO a.s., +420 224175111, clinicaltrial@sotio.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
    21 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    PRIMARY OBJECTIVE To explore the effect of adding DCVAC/OvCa to standard of care (SoC) chemotherapy on progression-free survival (PFS) measured at 2 years after randomization in women with epithelial ovarian cancer who have undergone debulking surgery SECONDARY OBJECTIVES • Proportion of patients staying in remission at 6 months after the last dose of first-line chemotherapy • Proportion of patients staying in remission at 12 months after the last dose of first-line chemotherapy • Biological progression-free interval (PFIBIO) • Immunological response • Proportion of patients requiring second-line chemotherapy • Time to second-line chemotherapy • Overall survival (OS)
    Protection of trial subjects
    Not applicable
    Background therapy
    		 All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 1 week after leukapheresis for patients in treatment groups A and B or within 2 weeks after randomization for patients in treatment group C. In Part 1, eligible patients were centrally randomized to 3 groups (1:1:1) within 3 weeks after surgery to receive DCVAC/OvCa with SoC chemotherapy (treatment group A), DCVAC/OvCa after SoC chemotherapy (treatment group B), or SoC chemotherapy alone (treatment group C). In Part 2, eligible patients were centrally randomized to 2 groups (2:1) within 3 weeks after surgery to receive DCVAC/OvCa after SoC chemotherapy (treatment group B) or SoC chemotherapy alone (treatment group C). With the exception of safety, the 2 trial parts could not be analysed together. Part 1 is reported here. Part 2 was exploratory and is not reported here. The number of patients enrolled worldwide had to be increased artificially by 1000 to allow input of safety results due to the fact that with the exception of safety, the 2 trial parts could not be analysed together. Therefore, the safety population includes both Part 1 and Part 2 combined and the number of patients is higher than the actual number of worldwide enrolled patients. The artificial 1000 patients were added to the demographic group of adults (18-64 years).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czechia: 1097
    Country: Number of subjects enrolled
    Poland: 2
    Worldwide total number of subjects
    1099
    EEA total number of subjects
    1099
    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)
    1070
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The number of subjects enrolled was increased artificially by 1000 to allow input of safety results which included both Part 1 and Part 2 patients.

    Pre-assignment
    Screening details
    		 Twenty investigational sites participated in the study, of which 3 sites did not initiate any screening process (2 in Poland and 1 in Germany). 15 sites screened at least 1 patient: 11 in the Czech Republic, 2 in Poland and 2 in Germany (no patient has been randomized in Germany).

    Period 1
    Period 1 title
    Part 1 (main trial) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment group A
    Arm description
    		 Parallel DCVAC/OvCa Patients were to receive up to 10 doses of DCVAC/OvCa (approximately 1x10e7 autologous DCs) with SoC therapy. The first 5 doses were to be administered at 3-week intervals, followed by dosing at 6-week intervals. All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 1 week after leukapheresis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DCVAC/OvCa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    An aliquot of approximately 1×10e7 activated autologous DCs (DCVAC/OvCa) was to be thawed and diluted with 4 mL of pre-cooled saline solution (0.9% NaCl) in an injection syringe to a total volume of 5 mL. DCVAC/OvCa was to be administered subcutaneously to the inguinal and axillary lymph node areas (2.5 mL per injection) within 30 minutes after dilution.

    Arm title
    		 Treatment group B
    Arm description
    		 Sequential DCVAC/OvCa Patients were to receive up to 10 doses of DCVAC/OvCa (approximately 1x10e7 autologous DCs) after SoC therapy. The first 5 doses were to be administered at 3-week intervals, followed by dosing at 6-week intervals. All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 1 week after leukapheresis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DCVAC/OvCa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    An aliquot of approximately 1×10e7 activated autologous DCs (DCVAC/OvCa) was to be thawed and diluted with 4 mL of pre-cooled saline solution (0.9% NaCl) in an injection syringe to a total volume of 5 mL. DCVAC/OvCa was to be administered subcutaneously to the inguinal and axillary lymph node areas (2.5 mL per injection) within 30 minutes after dilution.

    Arm title
    		 Treatment group C
    Arm description
    		 Standard of care All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 2 weeks after randomization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DCVAC/OvCa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    An aliquot of approximately 1×10e7 activated autologous DCs (DCVAC/OvCa) was to be thawed and diluted with 4 mL of pre-cooled saline solution (0.9% NaCl) in an injection syringe to a total volume of 5 mL. DCVAC/OvCa was to be administered subcutaneously to the inguinal and axillary lymph node areas (2.5 mL per injection) within 30 minutes after dilution.

    Number of subjects in period 1 [1]
    		Treatment group A Treatment group B Treatment group C
    Started
    34
    34
    31
    Completed
    28
    28
    30
    Not completed
    6
    6
    1
         Consent withdrawn by subject
    1
    -
    -
         Physician decision
    1
    -
    -
         Treatment not initiated (manufacture failure)
    3
    2
    -
         Adverse event, non-fatal
    -
    1
    -
         Death
    1
    1
    -
         Treatment not initiated
    -
    -
    1
         Leukapheresis not initiated
    -
    2
    -
    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 number of patients enrolled worldwide had to be increased artificially by 1000 to allow input of safety results due to the fact that with the exception of safety, the 2 trial parts could not be analysed together. Therefore, the safety population includes both Part 1 and Part 2 combined and the number of patients is higher than the actual number of worldwide enrolled patients.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment group A
    Reporting group description
    		 Parallel DCVAC/OvCa Patients were to receive up to 10 doses of DCVAC/OvCa (approximately 1x10e7 autologous DCs) with SoC therapy. The first 5 doses were to be administered at 3-week intervals, followed by dosing at 6-week intervals. All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 1 week after leukapheresis.

    Reporting group title
    Treatment group B
    Reporting group description
    		 Sequential DCVAC/OvCa Patients were to receive up to 10 doses of DCVAC/OvCa (approximately 1x10e7 autologous DCs) after SoC therapy. The first 5 doses were to be administered at 3-week intervals, followed by dosing at 6-week intervals. All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 1 week after leukapheresis.

    Reporting group title
    Treatment group C
    Reporting group description
    		 Standard of care All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 2 weeks after randomization.

    Reporting group values
    		 Treatment group A Treatment group B Treatment group C Total
    Number of subjects
    		 34 34 31 99
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 23 25 22 70
        From 65-84 years
    		 11 9 9 29
    Gender categorical
    Units: Subjects
        Female
    		 34 34 31 99
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Treatment group A
    Reporting group description
    		 Parallel DCVAC/OvCa Patients were to receive up to 10 doses of DCVAC/OvCa (approximately 1x10e7 autologous DCs) with SoC therapy. The first 5 doses were to be administered at 3-week intervals, followed by dosing at 6-week intervals. All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 1 week after leukapheresis.

    Reporting group title
    Treatment group B
    Reporting group description
    		 Sequential DCVAC/OvCa Patients were to receive up to 10 doses of DCVAC/OvCa (approximately 1x10e7 autologous DCs) after SoC therapy. The first 5 doses were to be administered at 3-week intervals, followed by dosing at 6-week intervals. All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 1 week after leukapheresis.

    Reporting group title
    Treatment group C
    Reporting group description
    		 Standard of care All patients were to receive SoC chemotherapy (paclitaxel 175 mg/m2 intravenous over 3 hours followed by carboplatin area under the concentration time curve 5-7 intravenous over 30-60 minutes) given at 3-week intervals (±3 days) for 6 cycles, starting within 2 weeks after randomization.

    Primary: Progression-free survival at 2 yrs after randomization (mITT)

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    End point title
    		 Progression-free survival at 2 yrs after randomization (mITT)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Primary
    End point timeframe
    From the time from randomization to documented disease progression or death from any cause, whichever occurs earlier
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    31
    29
    30
    Units: month
        median (confidence interval 95%)
    20.3 (15.7 to 1000)
    1000 (24.6 to 1000)
    21.4 (12.6 to 1000)
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.9483
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 2
    Notes
    [1] - Logrank
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0336
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.96
    Notes
    [2] - Logrank

    Primary: Progression-free survival at 2 yrs after randomization (PP)

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    End point title
    		 Progression-free survival at 2 yrs after randomization (PP)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Primary
    End point timeframe
    From the time from randomization to documented disease progression or death from any cause, whichever occurs earlier
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    28
    27
    30
    Units: month
        median (confidence interval 95%)
    20.3 (15.7 to 1000)
    1000 (24.6 to 1000)
    21.4 (12.6 to 1000)
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group C v Treatment group A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.8726
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.95
    Notes
    [3] - Logrank
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0081
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.77
    Notes
    [4] - Logrank

    Secondary: Proportion of patients staying in remission at 6 months after the last dose of first-line SoC (mITT)

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    End point title
    		 Proportion of patients staying in remission at 6 months after the last dose of first-line SoC (mITT)
    End point description
    End point type
    Secondary
    End point timeframe
    From the last dose of first-line SoC until the last dose of first-line chemotherapy + 6 months
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    31
    29
    30
    Units: percent
        number (not applicable)
    80.6
    96.6
    83.3
    No statistical analyses for this end point

    Secondary: Proportion of patients staying in remission at 6 months after the last dose of first-line SoC (PP)

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    End point title
    		 Proportion of patients staying in remission at 6 months after the last dose of first-line SoC (PP)
    End point description
    End point type
    Secondary
    End point timeframe
    From the last dose of first-line SoC until the last dose of first-line chemotherapy + 6 months
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    28
    27
    30
    Units: percent
        number (not applicable)
    85.7
    100
    83.3
    No statistical analyses for this end point

    Secondary: Proportion of patients staying in remission at 12 months after the last dose of first-line SoC (mITT)

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    End point title
    		 Proportion of patients staying in remission at 12 months after the last dose of first-line SoC (mITT)
    End point description
    End point type
    Secondary
    End point timeframe
    From the last dose of first-line SoC until the last dose of first-line chemotherapy + 12 months
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    31
    29
    30
    Units: percent
        number (not applicable)
    64.5
    79.3
    56.7
    No statistical analyses for this end point

    Secondary: Proportion of patients staying in remission at 12 months after the last dose of first-line SoC (PP)

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    End point title
    		 Proportion of patients staying in remission at 12 months after the last dose of first-line SoC (PP)
    End point description
    End point type
    Secondary
    End point timeframe
    From the last dose of first-line SoC until the last dose of first-line chemotherapy + 12 months
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    28
    27
    30
    Units: percent
        number (not applicable)
    67.9
    85.2
    56.7
    No statistical analyses for this end point

    Secondary: Biological progression-free interval defined by increasing CA 125 levels (mITT)

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    End point title
    		 Biological progression-free interval defined by increasing CA 125 levels (mITT)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Secondary
    End point timeframe
    From randomization till progression in CA 125 according to GCIG criteria
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    31
    29
    30
    Units: month
        median (confidence interval 95%)
    1000 (1000 to 1000)
    1000 (1000 to 1000)
    1000 (1000 to 1000)
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.9055
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 6.31
    Notes
    [5] - Logrank
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.3704
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 3.87
    Notes
    [6] - Logrank

    Secondary: Biological progression-free interval defined by increasing CA 125 levels (PP)

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    End point title
    		 Biological progression-free interval defined by increasing CA 125 levels (PP)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Secondary
    End point timeframe
    From randomization till progression in CA 125 according to GCIG criteria
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    28
    27
    30
    Units: month
        median (confidence interval 95%)
    1000 (1000 to 1000)
    1000 (1000 to 1000)
    1000 (1000 to 1000)
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.9455
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 6.64
    Notes
    [7] - Logrank
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.3704
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 3.87
    Notes
    [8] - Logrank

    Secondary: Immunological response

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    End point title
    		 Immunological response
    End point description
    A significant increase in CD56+ NK cells and a similar trend toward higher percentage of CD8+ T cells was detected in the peripheral blood of patients with low baseline levels of CD8+ from tissue samples in treatment groups A and B compared to patients with low baseline levels of CD8+ from tissue samples in treatment group C. The differences in relative number increases of CD16+/56+ NK cells, HLA-DR+, CD3+ T cells, and CD8+ T cells counts became more significant with time. A significant decrease in relative numbers of CD19+ B cells in patients with low baseline levels of CD8+ from tissue samples in treatment groups A and B compared to patients with low baseline levels of CD8+ from tissue samples in treatment group C was observed.
    End point type
    Secondary
    End point timeframe
    From randomization till week 104 of treatment
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    31 [9]
    29 [10]
    28 [11]
    Units: Not applicable
    1000
    1000
    1000
    Notes
    [9] - 28 patients in the PP population
    [10] - 27 patients in the PP population
    [11] - 28 patients in the PP population
    No statistical analyses for this end point

    Secondary: Proportion of patients requiring second-line chemotherapy (mITT)

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    End point title
    		 Proportion of patients requiring second-line chemotherapy (mITT)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization until the end of survival follow-up
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    31
    29
    30
    Units: percent
        number (not applicable)
    64.5
    62.1
    60.0
    No statistical analyses for this end point

    Secondary: Proportion of patients requiring second-line chemotherapy (PP)

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    End point title
    		 Proportion of patients requiring second-line chemotherapy (PP)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization until the first administration of further-line therapy
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    28
    27
    30
    Units: percent
        number (not applicable)
    64.3
    59.3
    60.0
    No statistical analyses for this end point

    Secondary: Proportion of patients requiring second-line chemotherapy (ITT)

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    End point title
    		 Proportion of patients requiring second-line chemotherapy (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization until the first administration of further-line therapy
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    34
    32
    31
    Units: percent
        number (not applicable)
    61.8
    56.3
    58.1
    No statistical analyses for this end point

    Secondary: Time to second-line chemotherapy (mITT)

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    End point title
    		 Time to second-line chemotherapy (mITT)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Secondary
    End point timeframe
    From randomization until the first administration of further-line therapy
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    31
    29
    30
    Units: month
        median (confidence interval 95%)
    24.1 (18.3 to 63.3)
    43.9 (32.5 to 1000)
    27.4 (20.7 to 1000)
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.5191
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 2.33
    Notes
    [12] - Logrank
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.5817
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.6
    Notes
    [13] - Logrank

    Secondary: Time to second-line chemotherapy (PP)

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    End point title
    		 Time to second-line chemotherapy (PP)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of survival follow-up
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    28
    27
    30
    Units: month
        median (confidence interval 95%)
    27.9 (18.3 to 63.3)
    51.8 (34.4 to 1000)
    27.4 (20.7 to 1000)
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.6863
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 2.2
    Notes
    [14] - Logrank
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.3871
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.46
    Notes
    [15] - Logrank

    Secondary: Time to second-line chemotherapy (ITT)

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    End point title
    		 Time to second-line chemotherapy (ITT)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of survival follow-up
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    34
    32
    31
    Units: month
        median (confidence interval 95%)
    24.1 (18.3 to 63.3)
    43.9 (32.5 to 1000)
    29.0 (21.4 to 1000)
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.7032
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.7
    Notes
    [16] - Logrank
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.4388
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 2.41
    Notes
    [17] - Logrank

    Secondary: Overall survival (mITT)

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    End point title
    		 Overall survival (mITT)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Secondary
    End point timeframe
    From randomization till death due to any cause
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    31
    29
    30
    Units: month
        median (confidence interval 95%)
    1000 (59.0 to 1000)
    1000 (69.1 to 1000)
    1000 (34.9 to 1000)
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.7491
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.86
    Notes
    [18] - Logrank
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.264
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.41
    Notes
    [19] - Logrank

    Secondary: Overall survival (PP)

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    End point title
    		 Overall survival (PP)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Secondary
    End point timeframe
    From randomization till death due to any cause
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    28
    27
    30
    Units: month
        median (confidence interval 95%)
    1000 (61.1 to 1000)
    1000 (70.4 to 1000)
    1000 (34.9 to 1000)
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.1299
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 1.22
    Notes
    [20] - Logrank
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.593
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.75
    Notes
    [21] - Logrank

    Secondary: Overall survival (ITT)

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    End point title
    		 Overall survival (ITT)
    End point description
    In case the value/percentile cannot be estimated due to a low number of events, 1000 is used, meaning Not available.
    End point type
    Secondary
    End point timeframe
    From randomization till death due to any cause
    End point values
    		 Treatment group A Treatment group B Treatment group C
    Number of subjects analysed
    34
    32
    31
    Units: month
        median (confidence interval 95%)
    1000 (42.9 to 1000)
    1000 (65.4 to 1000)
    1000 (34.9 to 1000)
    Statistical analysis title
    		 Sequential DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group B v Treatment group C
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.6087
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.73
    Notes
    [22] - Logrank
    Statistical analysis title
    		 Parallel DCVAC/OvCa vs. SoC only
    Comparison groups
    Treatment group A v Treatment group C
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.9739
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 2.07
    Notes
    [23] - Logrank

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were to be reported since subjects´ signature of ICF/study entry until 30 days after the last administration of IMP (arms A and B) or the last dose of SoC first-line chemotherapy (arm C).
    Adverse event reporting additional description
    If there was no IMP administration in patient randomized to group A or B and the patient is prematurely discontinued from the study due to any reason (i.e. before the first application of DCVAC/OvCa), the reporting period for AEs/SAEs ends with the date when decision for premature withdrawal from the study was taken.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 The safety (SAF) population consisted of all subjects who received at least one dose of chemotherapy or DCVAC/OvCa. The SAF and mITT populations differ in term of patients in arms A and B. In case patient from arm A or B received at least one dose of chemotherapy but did not initiate DCVAC/OvCa treatment (e.g. DCVAC/OvCa manufacturing failure), the patient is part of the SAF population but not of the mITT population.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 130 (34.62%)
         number of deaths (all causes)
    40
         number of deaths resulting from adverse events
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Breast fibrosis
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea at rest
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Incisional hernia
         subjects affected / exposed
    3 / 130 (2.31%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Vaginal cuff dehiscence
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    8 / 130 (6.15%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    8 / 130 (6.15%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 130 (2.31%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Subileus
         subjects affected / exposed
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 130 (2.31%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Pyelocaliectasis
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infected lymphocele
         subjects affected / exposed
    4 / 130 (3.08%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 130 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Anal abscess
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Folliculitis
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    perirectal a
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Retroperitoneal abscess
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Small intestine gangrene
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic alkalosis
         subjects affected / exposed
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    121 / 130 (93.08%)
    Investigations
    Weight decreased
         subjects affected / exposed
    10 / 130 (7.69%)
         occurrences all number
    10
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    15 / 130 (11.54%)
         occurrences all number
    15
    Paraesthesia
         subjects affected / exposed
    40 / 130 (30.77%)
         occurrences all number
    45
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    59 / 130 (45.38%)
         occurrences all number
    109
    Anaemia
         subjects affected / exposed
    50 / 130 (38.46%)
         occurrences all number
    73
    Thrombocytopenia
         subjects affected / exposed
    36 / 130 (27.69%)
         occurrences all number
    59
    Leukopenia
         subjects affected / exposed
    22 / 130 (16.92%)
         occurrences all number
    48
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 130 (13.85%)
         occurrences all number
    22
    Pyrexia
         subjects affected / exposed
    14 / 130 (10.77%)
         occurrences all number
    18
    Pain
         subjects affected / exposed
    8 / 130 (6.15%)
         occurrences all number
    8
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    10 / 130 (7.69%)
         occurrences all number
    14
    Hypersensitivity
         subjects affected / exposed
    10 / 130 (7.69%)
         occurrences all number
    14
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    37 / 130 (28.46%)
         occurrences all number
    58
    Constipation
         subjects affected / exposed
    14 / 130 (10.77%)
         occurrences all number
    16
    Abdominal pain
         subjects affected / exposed
    8 / 130 (6.15%)
         occurrences all number
    8
    Vomiting
         subjects affected / exposed
    13 / 130 (10.00%)
         occurrences all number
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 130 (4.62%)
         occurrences all number
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    13 / 130 (10.00%)
         occurrences all number
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 130 (5.38%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 130 (16.92%)
         occurrences all number
    28
    Pain in extremity
         subjects affected / exposed
    9 / 130 (6.92%)
         occurrences all number
    13
    Myalgia
         subjects affected / exposed
    6 / 130 (4.62%)
         occurrences all number
    6
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    11 / 130 (8.46%)
         occurrences all number
    11
    Nasopharyngitis
         subjects affected / exposed
    10 / 130 (7.69%)
         occurrences all number
    12
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    11 / 130 (8.46%)
         occurrences all number
    12
    Decreased appetite
         subjects affected / exposed
    8 / 130 (6.15%)
         occurrences all number
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2013
    • Specification of the DCVAC/OvCa application sites (groin and axillary areas) • Specification of SoC chemotherapy toxicity management based on institutional standards or applicable oncology guidelines • Added information regarding the use of historical CT/MRI scans obtained prior to study entry • Specification of pre-treatment assessments of infection
    01 Nov 2013
    • Specification of methods of contraception (exclusion criterion 13) • Added justification for the dose of DCVAC/OvCa to be administered • Added definition of slow progressive disease • Added information about the continuation of DCVAC/OvCa administration after disease progression • Specification that not only the medications must be recorded, but also the doses taken/administered • Specification of the exclusion criterion for post-surgery residual disease with lesion(s)>1 cm (exclusion criterion 4) • Specification of procedures for discontinuation • Elimination of blood samples for research and immunology assessment in treatment period 2 • Added information regarding using historical heart and lung X-ray scans obtained prior to study entry
    14 Feb 2014
    • Conditional prolongation of screening up to 42 days, under specified conditions • Specification of follow-up including the definition of the EoT visit, efficacy follow-up and survival follow-up • Specification of methods of contraception (exclusion criterion 13) • Change in the AE reporting period (30 days after the EoT visit) • Added condition for patients’ replacement • Added calculation of the sample size
    16 Jul 2014
    • Change in the study design • Chest X-ray may be replaced by CT of thorax at the investigator’s decision • Withdrawal of central reading for the evaluation of patients’ eligibility • Specification that pregnant women must pass the EoT visit • Correction in follow-up procedures in Table 1 • Independent blinded radiologist evaluates sensitive analyses of PFS and ORR • This is the last submitted and approved version of this protocol for Germany; the study was locally closed in Germany on 30-Jun-2017, before the Protocol was amended to version 5.0
    04 Aug 2017
    • Change of Chief Medical Officer
    10 Nov 2017
    • Changing the number of DCVAC/OvCa doses administered to the additional patients enrolled as per Protocol versions 5.1 onwards from up to 10 to up to 15 doses (i.e., all available doses for a patient) • Immunology assessments for additional patients as per Protocol versions 5.1 onwards reduced to TSH testing only, other laboratory tests will not be done (additional patients only)
    23 Jul 2018
    • Consolidation of the CZ and PL protocols • Cancellation of interim analyses • Final PFS analysis 2 years after the last patient randomized • Final survival analysis 5 years after randomization of the last patient or when at least 50% of maturity is reached, whichever occurs earlier • Exclusion criterion 7 amended to prevent Protocol violation and/or losing patients from final analysis • Data on OS status and further-line therapy collected for all randomized patients • Tumor assessment – change in wording • Wording adjusted to be in line with the changes

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Trial Part 1 and trial Part 2 could not be analysed together due to differences in treatment duration, which would introduce bias. As Part 2 is considered to be exploratory, only Part 1 is reported.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34294416
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