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    Clinical Trial Results:
    An open-label, single-group, multicenter phase II clinical trial evaluating the effect of maintenance DCVAC/OvCa after standard of care therapy in women with first relapse of platinum-sensitive epithelial ovarian carcinoma

    Summary
    EudraCT number
    		 2017-002196-26
    Trial protocol
    		 CZ  
    Global end of trial date
    25 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SOV06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03657966
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SOTIO a.s.
    Sponsor organisation address
    Jankovcova 1518/2, Prague, Czechia, 17000
    Public contact
    Clinical Trial SOTIO, SOTIO a.s., clinicaltrial@sotio.com
    Scientific contact
    Clinical Trial SOTIO, SOTIO a.s., 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
    22 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    PRIMARY: To explore if there was any added efficacy considering time to progression (by mRECIST version 1.1) or death (PFS) by adding DCVAC/OvCa as maintenance treatment after SoC with carboplatin/gemcitabine or carboplatin/paclitaxel in women with EOC who experienced relapse >6 months after complete remission following Pt-based first-line SoC. Efficacy was to be assessed vs. a historical control patient group treated in SOV02 trial with SoC alone in those who did not have progressive disease after 6 cycles of SoC. SECONDARY: •Overall survival versus a historical control patient group treated within the SOV02 trial (SoC alone and parallel DCVAC/OvCa treatment group) •Biological progression-free interval versus a historical control patient group treated within the SOV02 trial (SoC alone and parallel DCVAC/OvCa treatment group) •Best objective response (ORR) •CA 125 response •Time to response (objective response and CA 125 response) •Immunological response •Safety
    Protection of trial subjects
    Not applicable.
    Background therapy
    		 All patients were to receive standard of care chemotherapy. For treatment with carboplatin/gemcitabine regimen, patients were to receive 1000 mg/m2 of gemcitabine as a 30-minute intravenous infusion on days 1 and 8 of 3-week cycles (with an acceptable window of ±3 days). Carboplatin (area under the curve [AUC] 4 mg/mL/min) was to be administered as an intravenous infusion (15 to 60 minutes) on day 1 of 3-week cycles (with an acceptable window of ±3 days). For treatment with carboplatin/paclitaxel regime, 175 mg/m2 of paclitaxel was to be administered intravenously in a 3-hour infusion on day 1 of 3 week cycles (with an acceptable window of ±3 days). Carboplatin (AUC 5 mg/mL/min) was to be administered intravenously as a short-term infusion (15 to 60 minutes) on day 1 of 3 week cycles (with an acceptable window of ±3 days) as a short-term infusion (15 to 60 minutes). A total of 6, 8, or 10 cycles of SoC chemotherapy were to be completed as per investigators’ decision.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czechia: 2033
    Worldwide total number of subjects
    2033
    EEA total number of subjects
    2033
    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)
    1016
    From 65 to 84 years
    1017
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 NOTE: To allow input of results of comparison with historical control groups from trial SOV02, the number of patients that started and completed trial SOV06 has been artificially increased by 2000: +1000 for age group 18-64 years and +1000 for age group 65 to 84 years.

    Pre-assignment
    Screening details
    		 5 sites screened at least 1 patient. Recruitment started on 23-Nov-2017 (first patient signed the informed consent form).

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

    Arms
    Arm title
    		 Sequential DCVAC/OvCa
    Arm description
    		 DCVAC/OvCa (approximately 1×107 autologous DCs) was to be administered at each dosing time to the patients subcutaneously. The first dose was to be administered 15 to 21 days after the last dose of SoC therapy. The first five doses of DCVAC/OvCa were to be given in 3-week intervals (with an acceptable window of ±3 days), followed by dosing at 6 week intervals (with an acceptable window of ±3 days) for a total of 15 doses. NOTE: To allow input of results of comparison with historical control groups from trial SOV02, the number of patients that started and completed trial SOV06 has been artificially increased by 2000: +1000 for age group 18-64 years and +1000 for age group 65 to 84 years.
    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) will be thawed, re-suspended in 0.9% pre-cooled saline solution to a total volume of 5 mL, and divided in two 2.5 mL injections. The two injections will be administered subcutaneously in the axillary and the opposite inguinal lymph node areas.

    Number of subjects in period 1
    		Sequential DCVAC/OvCa
    Started
    2033
    Completed
    2015
    Not completed
    18
         Consent withdrawn by subject
    2
         Death
    15
         DCVAC/OvCa manufacturing failure
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 NOTE: To allow input of results of comparison with historical control groups from trial SOV02, the number of patients that started and completed trial SOV06 has been artificially increased by 2000: +1000 for age group 18-64 years and +1000 for age group 65 to 84 years.

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 2033 2033
    Age categorical
    NOTE: To allow input of results of comparison with historical control groups from trial SOV02, the number of patients that started and completed trial SOV06 has been artificially increased by 2000: +1000 for age group 18-64 years and +1000 for age group 65 to 84 years.
    Units: Subjects
        Adults (18-64 years)
    		 1016 1016
        From 65-84 years
    		 1017 1017
    Gender categorical
    NOTE: To allow input of results of comparison with historical control groups from trial SOV02, the number of patients that started and completed trial SOV06 has been artificially increased by 2000: +1000 for age group 18-64 years and +1000 for age group 65 to 84 years.
    Units: Subjects
        Female
    		 2033 2033

    End points

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    End points reporting groups
    Reporting group title
    Sequential DCVAC/OvCa
    Reporting group description
    		 DCVAC/OvCa (approximately 1×107 autologous DCs) was to be administered at each dosing time to the patients subcutaneously. The first dose was to be administered 15 to 21 days after the last dose of SoC therapy. The first five doses of DCVAC/OvCa were to be given in 3-week intervals (with an acceptable window of ±3 days), followed by dosing at 6 week intervals (with an acceptable window of ±3 days) for a total of 15 doses. NOTE: To allow input of results of comparison with historical control groups from trial SOV02, the number of patients that started and completed trial SOV06 has been artificially increased by 2000: +1000 for age group 18-64 years and +1000 for age group 65 to 84 years.

    Subject analysis set title
    SOV02 Parallel DCVAC/OvCa (mITT population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A historical control patient group treated within the SOV02 trial with SoC chemotherapy and parallel DCVAC/OvCa.

    Subject analysis set title
    SOV02 SoC (mITT population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A historical control patient group treated within the SOV02 trial with SoC chemotherapy only.

    Primary: PFS measured according to the modified RECIST 1.1 (mITT population)

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    End point title
    		 PFS measured according to the modified RECIST 1.1 (mITT population)
    End point description
    End point type
    Primary
    End point timeframe
    From eligibility verification to the date of an event defined as the first radiological progression or death due to any cause, whichever occurs first.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    30
    26
    20
    Units: month
        median (confidence interval 95%)
    9.7 (7.7 to 13.1)
    12.4 (10.1 to 14.9)
    11.1 (7.7 to 13.1)
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.3494
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.57
    Notes
    [1] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.9361
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.9
    Notes
    [2] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.

    Primary: PFS measured according to the modified RECIST 1.1 (PP population)

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    End point title
    		 PFS measured according to the modified RECIST 1.1 (PP population)
    End point description
    End point type
    Primary
    End point timeframe
    From eligibility verification to the date of an event defined as the first radiological progression or death due to any cause, whichever occurs first.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    25
    25
    20
    Units: month
        median (confidence interval 95%)
    9.4 (7.7 to 13.8)
    13.4 (10.2 to 14.9)
    11.1 (7.7 to 13.1)
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.3138
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.76
    Notes
    [3] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.9523
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.96
    Notes
    [4] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.

    Primary: PFS measured according to the modified RECIST 1.1 (ITT population)

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    End point title
    		 PFS measured according to the modified RECIST 1.1 (ITT population)
    End point description
    End point type
    Primary
    End point timeframe
    From eligibility verification to the date of an event defined as the first radiological progression or death due to any cause, whichever occurs first.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    33
    39
    32
    Units: month
        median (confidence interval 95%)
    9.7 (7.7 to 12.6)
    11.3 (9.5 to 13.9)
    10.6 (7.7 to 12.7)
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.5723
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 2.17
    Notes
    [5] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.9347
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.81
    Notes
    [6] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.

    Secondary: Overall survival (mITT population)

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    End point title
    		 Overall survival (mITT population)
    End point description
    End point type
    Secondary
    End point timeframe
    From eligibility verification till death due to any cause.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    30 [7]
    26 [8]
    20
    Units: month
        median (confidence interval 95%)
    30 (21.3 to 1000)
    35.5 (25.6 to 1000)
    22.2 (17.2 to 36.1)
    Notes
    [7] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    [8] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.432
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 2.88
    Variability estimate
    Standard deviation
    Notes
    [9] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.1009
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 1.14
    Notes
    [10] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.

    Secondary: Overall survival (PP population)

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    End point title
    		 Overall survival (PP population)
    End point description
    End point type
    Secondary
    End point timeframe
    From eligibility verification till death due to any cause.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    25 [11]
    25 [12]
    20
    Units: month
        median (confidence interval 95%)
    30.4 (23.6 to 1000)
    35.5 (25.6 to 1000)
    22.2 (17.2 to 36.1)
    Notes
    [11] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    [12] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.6596
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 2.67
    Notes
    [13] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.0563
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 1.02
    Variability estimate
    Standard deviation
    Notes
    [14] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.

    Secondary: Overall survival (ITT population)

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    End point title
    		 Overall survival (ITT population)
    End point description
    End point type
    Secondary
    End point timeframe
    From eligibility verification till death due to any cause.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    33 [15]
    39
    32
    Units: month
        median (confidence interval 95%)
    30 (21.3 to 1000)
    29.5 (23.1 to 45)
    22.2 (17.2 to 32.5)
    Notes
    [15] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.9703
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.94
    Notes
    [16] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.034
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.95
    Notes
    [17] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.

    Secondary: Biological progression-free interval (mITT population)

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    End point title
    		 Biological progression-free interval (mITT population)
    End point description
    End point type
    Secondary
    End point timeframe
    From the date of the eligibility verification till progression in CA 125 according to GCIG criteria.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    30
    26 [18]
    20 [19]
    Units: month
        median (confidence interval 95%)
    9.9 (8.5 to 12.5)
    13.4 (11.3 to 1000)
    15.5 (9.8 to 1000)
    Notes
    [18] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    [19] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.009
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.29
         upper limit
    		 5.85
    Notes
    [20] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.0525
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 7.45
    Notes
    [21] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.

    Secondary: Biological progression-free interval (PP population)

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    End point title
    		 Biological progression-free interval (PP population)
    End point description
    End point type
    Secondary
    End point timeframe
    From the date of the eligibility verification till progression in CA 125 according to GCIG criteria.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    25
    25 [22]
    20 [23]
    Units: month
        median (confidence interval 95%)
    10.7 (8.5 to 12.6)
    13.4 (11.3 to 1000)
    15.5 (9.8 to 1000)
    Notes
    [22] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    [23] - Value 1000 in CIs means that the CI could not be calculated, therefore it is not applicable.
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.03
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 5.23
    Notes
    [24] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.1125
    Method
    		 Adjusted Cox PH model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 6.63
    Notes
    [25] - Adjusted Cox PH model. Adjustment performed on age, log (baseline CA 125) and ECOG.

    Secondary: Objective response rate (mITT population)

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    End point title
    		 Objective response rate (mITT population)
    End point description
    End point type
    Secondary
    End point timeframe
    From the start of SoC treatment until disease progression, death or end of trial treatment (SoC or DCVAC/OvCa, whichever occurred later) + 30 days, whichever occurred first.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    30
    26
    20
    Units: percent
        number (confidence interval 95%)
    70 (53.6 to 86.4)
    88.5 (76.2 to 100)
    85 (69.4 to 100)
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.0931
    Method
    		 Chi-squared
    Parameter type
    		 Difference
    Point estimate
    -18.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.9
         upper limit
    		 2
    Notes
    [26] - Difference in proportions by a Chi-squared test.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.2237
    Method
    		 Chi-squared
    Parameter type
    		 Difference
    Point estimate
    -15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.7
         upper limit
    		 7.7
    Notes
    [27] - Difference in proportions by Chi-squared test.

    Secondary: Objective response rate (PP population)

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    End point title
    		 Objective response rate (PP population)
    End point description
    End point type
    Secondary
    End point timeframe
    From the start of SoC treatment until disease progression, death or end of trial treatment (SoC or DCVAC/OvCa, whichever occurred later) + 30 days, whichever occurred first.
    End point values
    		 Sequential DCVAC/OvCa SOV02 Parallel DCVAC/OvCa (mITT population) SOV02 SoC (mITT population)
    Number of subjects analysed
    25
    25
    20
    Units: percent
        number (confidence interval 95%)
    76 (59.3 to 92.7)
    88 (75.3 to 100)
    85 (69.4 to 100)
    Statistical analysis title
    		 Main analysis vs. parallel DCVAC/OvCa
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 Parallel DCVAC/OvCa (mITT population)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 = 0.2695
    Method
    		 Chi-squared
    Parameter type
    		 Difference
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33
         upper limit
    		 9
    Notes
    [28] - Difference in proportions by a Chi-squared test.
    Statistical analysis title
    		 Main analysis vs. SoC
    Comparison groups
    Sequential DCVAC/OvCa v SOV02 SoC (mITT population)
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.4533
    Method
    		 Chi-squared
    Parameter type
    		 Difference
    Point estimate
    -9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.9
         upper limit
    		 13.9
    Notes
    [29] - Difference in proportions by a Chi-squared test.

    Secondary: Time to response according to modified RECIST 1.1 (mITT population)

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    End point title
    		 Time to response according to modified RECIST 1.1 (mITT population)
    End point description
    End point type
    Secondary
    End point timeframe
    From eligibility verification until the first objective tumor response (CR or PR).
    End point values
    		 Sequential DCVAC/OvCa
    Number of subjects analysed
    30
    Units: month
        median (confidence interval 95%)
    2.2 (2.1 to 2.5)
    No statistical analyses for this end point

    Secondary: Time to response according to modified RECIST 1.1 (PP population)

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    End point title
    		 Time to response according to modified RECIST 1.1 (PP population)
    End point description
    End point type
    Secondary
    End point timeframe
    From eligibility verification until the first objective tumor response (CR or PR).
    End point values
    		 Sequential DCVAC/OvCa
    Number of subjects analysed
    30
    Units: month
        median (confidence interval 95%)
    2.2 (2.1 to 3.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Patients exposed to DCVAC/OvCa: From the date of the patient’s signing the ICF until 30 days after the final administration of DCVAC/OvCa (SAEs with a plausible causal relationship to DCVAC/OvCa must be reported until indefinitely).
    Adverse event reporting additional description
    Patients not exposed to DCVAC/OvCa: From ICF signature until: •1 day after leukapheresis or DCVAC/OvCa manufacturing failure (before SoC therapy initiation) •30 days after the last SoC therapy cycle •following the patient’s ICF withdrawal Progression of underlying disease or AE related to progression does not need to be reported as SAE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Sequential DCVAC/OvCa
    Reporting group description
    		 DCVAC/OvCa (approximately 1×10e7 autologous DCs) was to be administered at each dosing time to the patients subcutaneously. The first dose was to be administered 15 to 21 days after the last dose of SoC therapy. The first five doses of DCVAC/OvCa were to be given in 3-week intervals (with an acceptable window of ±3 days), followed by dosing at 6 week intervals (with an acceptable window of ±3 days) for a total of 15 doses. NOTE: There were 3 TEAEs with a fatal outcome associated with the progression of underlying disease. Per protocol, progression of the underlying disease or an AE unequivocally (without doubt) related to the progression of the underlying disease, regardless of its outcome or seriousness criteria, does not need to be reported as an SAE. However, there was 1 fatal SUSAR reported (PT: Myelodysplastic syndrome) in a patient in the follow-up period as defined by the protocol. The SUSAR is recorded in the Safety Database.

    Serious adverse events
    		 Sequential DCVAC/OvCa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 32 (34.38%)
         number of deaths (all causes)
    15
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Neurotoxicity
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related sepsis
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sequential DCVAC/OvCa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 32 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    21
    General physical health deterioration
         subjects affected / exposed
    6 / 32 (18.75%)
         occurrences all number
    6
    Pain
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    10
    Pyrexia
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    6
    Cough
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    4
    Dyspnoea
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Depression
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Investigations
    Weight decreased
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    6
    Polyneuropathy
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 32 (65.63%)
         occurrences all number
    32
    Neutropenia
         subjects affected / exposed
    17 / 32 (53.13%)
         occurrences all number
    30
    Thrombocytopenia
         subjects affected / exposed
    10 / 32 (31.25%)
         occurrences all number
    15
    Leukopenia
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Leukocytosis
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Eye disorders
    Photopsia
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Cataract
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    18 / 32 (56.25%)
         occurrences all number
    41
    Diarrhoea
         subjects affected / exposed
    9 / 32 (28.13%)
         occurrences all number
    16
    Vomiting
         subjects affected / exposed
    9 / 32 (28.13%)
         occurrences all number
    13
    Abdominal pain
         subjects affected / exposed
    9 / 32 (28.13%)
         occurrences all number
    11
    Ascites
         subjects affected / exposed
    8 / 32 (25.00%)
         occurrences all number
    9
    Abdominal pain upper
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    8
    Dyspepsia
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    6
    Constipation
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    6
    Asthenia
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    6
    Abdominal discomfort
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    6
    Stomatitis
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Mechanical ileus
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Flatulence
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    7
    Hyperhidrosis
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Alopecia
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Dysuria
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    8
    Arthralgia
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    7
    Back pain
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Muscle spasms
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    8 / 32 (25.00%)
         occurrences all number
    14
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 32 (21.88%)
         occurrences all number
    8
    Nasopharyngitis
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    4
    Cystitis
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    7
    Oral herpes
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    3
    Bacteriuria
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    3
    Laryngitis
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Asymptomatic bacteriuria
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    9 / 32 (28.13%)
         occurrences all number
    21
    Hypomagnesaemia
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    6
    Decreased appetite
         subjects affected / exposed
    4 / 32 (12.50%)
         occurrences all number
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2017
    • Clarification in the statistical sections • ECOG performance status not to be measured during the survival follow-up period
    18 Dec 2017
    • The number of doses increased from up to 10 to up to 15 • Schedule of sample collection for exploratory immunological research changed to reflect the change in the number of DCVAC/OvCa doses administered per patient • Exact time points added for vital signs measured after the DCVAC/OvCa administration • Acceptable visit window added for SoC therapy and efficacy follow up period • Historical chest X ray and/or CT/MRI of the abdomen and pelvis up to 4 weeks are acceptable. • Collaboration with CEEGOG • Wording adjusted to reflect changes and to clarify meaning; minor corrections of grammar
    21 May 2019
    • Date of DCVAC/OvCa administration: tb calculated from the date of the previous DCVAC/OvCa administration • Addition of IDMC • All patients eligible at final eligibility assessment are tb followed for OS and further-line anticancer therapy • All time-to-event analyses are tb measured from eligibility verification • The control group from SOV02 trial is to include only patients who did not have PD after 6 cycles of SoC chemotherapy • Modification of the definition of ITT population, addition of mITT population, clarification of PP population • CA 125 levels are not tb considered in evaluation of non-target lesions • Response assessment is to take place after 6 cycles of SoC chemotherapy • Independent review of CT/MRI scans is to be considered in case of need for health authority interactions • CT/MRI does not take place during efficacy follow-up visits • Hematology, serum chemistry, and urinalysis tests performed at the trial site 1-3 days before the start of a treatment cycle are acceptable • Patients are to discontinue DCVAC/OvCa in case of a systemic allergic reaction to DCVAC/OvCa • The version of the MedDRA current at the time of database lock is to be used • Inclusion criterion 3: the relapse after >6 months of remission (Pt-sensitive cancer) should be radiologically confirmed up to 4 weeks prior to signing the ICF or during screening • Urine does not have to be tested only by dipstick • APTT is to be reported in seconds or ratio • Urea is to be tested and not both urea and blood urea nitrogen • CT/MRI scans are to be done at screening, every 8 weeks (± 3 days) after SoC therapy initiation, or every 8 weeks (± 3 days) from the previous CT/MRI, i.e., ideally till 104 weeks (± 3 days) after SoC therapy initiation • After confirmed disease progression after second-line SoC therapy, vascular endothelial GF inhibitors administered according to the SPC are allowed • Removal of obsolete information and changes in wording to improve readability

    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.
    To allow input of results of comparison with historical control groups from trial SOV02, the number of patients in trial SOV06 has been artificially increased by 2000: +1000 for age group 18-64 years and +1000 for age group 65-84 years.
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