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    Clinical Trial Results:
    A Phase I/II Study to Evaluate Safety and Efficacy of DCVAC/LuCa Added to Standard First Line Chemotherapy with Carboplatin and Paclitaxel +/- Immune Enhancers (Interferon-alpha and Hydroxychloroquine) vs Chemotherapy alone in Patients with Stage IV Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2014-003084-37
    Trial protocol
    		 CZ   SK  
    Global end of trial date
    22 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Aug 2022
    First version publication date
    28 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SLU01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02470468
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SCTbio a.s. (formerly SOTIO a.s.)
    Sponsor organisation address
    Jankovcova 1518/2, Prague, Czechia, 170 00
    Public contact
    Clinical trials, SCTbio a.s. (formerly SOTIO a.s.), +420 224 175 111, clinicaltrial@sotio.com
    Scientific contact
    Clinical trials, SCTbio a.s. (formerly SOTIO a.s.), +420 224 175 111, 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 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective in protocol versions 1.0, 1.1, 2.0, and 3.0 was to compare the efficacy of DCVAC/LuCa together with chemotherapy with/without immune enhancers vs. chemotherapy alone in patients with stage IV non-small cell lung cancer (NSCLC), as measured by progression-free survival (PFS). The primary objective in protocol versions 4.0, 5.0, and 6.0 was to compare the efficacy of DCVAC/LuCa together with chemotherapy without immune enhancers vs. chemotherapy alone in patients with stage IV NSCLC, as measured by overall survival (OS).
    Protection of trial subjects
    Not applicable
    Background therapy
    		 Paclitaxel 175 mg/m2 intravenously over 3 hours followed by carboplatin area under the curve (AUC) 6 mg/mL per minute intravenously over 15-30 minutes
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Czech Republic: 107
    Worldwide total number of subjects
    112
    EEA total number of subjects
    112
    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)
    44
    From 65 to 84 years
    68
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Fifteen sites in the Czech Republic and 2 sites in Slovakia screened at least 1 patient. Patients: Screened: 129 Randomized: 112 Analyzed for efficacy: 107 Analyzed for safety: 101

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Patients in this arm received DCVAC/LuCa subcutaneously every 3 weeks for the first 5 doses and then every 6 weeks in up to a total of 15 doses. DCVAC/LuCa was administered concurrently with chemotherapy (carboplatin and paclitaxel) for 3 to 5 cycles on day 15 (±3 days), starting from the second chemotherapy cycle. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DCVAC/LuCa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of approximately 1×10e7 autologous dendritic cells

    Arm title
    		 Group B
    Arm description
    		 Patients in this arm received DCVAC/LuCa subcutaneously every 3 weeks for the first 5 doses and then every 6 weeks in up to a total of 15 doses. DCVAC/LuCa was administered concurrently with chemotherapy (carboplatin and paclitaxel) for 3 to 5 cycles on day 15 (±3 days), starting from the second chemotherapy cycle. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator. Patients also received pegylated IFN-α2b and hydroxychloroquine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DCVAC/LuCa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of approximately 1×10e7 autologous dendritic cells

    Investigational medicinal product name
    Pegylated IFN-α2b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegylated IFN-α2b, 1 µg/kg, was divided into 2 doses and administered subcutaneously within a 10 cm radius from the DCVAC/LuCa injection site after each administration of DCVAC/LuCa.

    Investigational medicinal product name
    Hydroxychloroquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Hydroxychloroquine was administered as 2 doses of 400 mg orally daily on a continuous basis for 7 consecutive days starting 1 day after each administration of DCVAC/LuCa.

    Arm title
    		 Group C
    Arm description
    		 Patients in this arm received chemotherapy (carboplatin and paclitaxel) alone. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Group A Group B Group C
    Started
    45
    29
    38
    Completed
    40
    28
    36
    Not completed
    5
    1
    2
         Adverse event, serious fatal
    1
    -
    -
         Consent withdrawn by subject
    -
    1
    1
         Leukapheresis failure
    2
    -
    -
         Start of new anticancer treatment
    -
    -
    1
         DCVAC/LuCa production failure
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Patients in this arm received DCVAC/LuCa subcutaneously every 3 weeks for the first 5 doses and then every 6 weeks in up to a total of 15 doses. DCVAC/LuCa was administered concurrently with chemotherapy (carboplatin and paclitaxel) for 3 to 5 cycles on day 15 (±3 days), starting from the second chemotherapy cycle. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator.

    Reporting group title
    Group B
    Reporting group description
    		 Patients in this arm received DCVAC/LuCa subcutaneously every 3 weeks for the first 5 doses and then every 6 weeks in up to a total of 15 doses. DCVAC/LuCa was administered concurrently with chemotherapy (carboplatin and paclitaxel) for 3 to 5 cycles on day 15 (±3 days), starting from the second chemotherapy cycle. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator. Patients also received pegylated IFN-α2b and hydroxychloroquine.

    Reporting group title
    Group C
    Reporting group description
    		 Patients in this arm received chemotherapy (carboplatin and paclitaxel) alone. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator.

    Reporting group values
    		 Group A Group B Group C Total
    Number of subjects
    		 45 29 38 112
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 13 11 20 44
        From 65-84 years
    		 32 18 18 68
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 14 8 10 32
        Male
    		 31 21 28 80

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Patients in this arm received DCVAC/LuCa subcutaneously every 3 weeks for the first 5 doses and then every 6 weeks in up to a total of 15 doses. DCVAC/LuCa was administered concurrently with chemotherapy (carboplatin and paclitaxel) for 3 to 5 cycles on day 15 (±3 days), starting from the second chemotherapy cycle. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator.

    Reporting group title
    Group B
    Reporting group description
    		 Patients in this arm received DCVAC/LuCa subcutaneously every 3 weeks for the first 5 doses and then every 6 weeks in up to a total of 15 doses. DCVAC/LuCa was administered concurrently with chemotherapy (carboplatin and paclitaxel) for 3 to 5 cycles on day 15 (±3 days), starting from the second chemotherapy cycle. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator. Patients also received pegylated IFN-α2b and hydroxychloroquine.

    Reporting group title
    Group C
    Reporting group description
    		 Patients in this arm received chemotherapy (carboplatin and paclitaxel) alone. A total of 4 cycles of chemotherapy were to be administered to all patients. Patients with stable disease, partial response, or complete response could continue chemotherapy for up to a total of 6 cycles at the discretion of the investigator.

    Primary: Overall survival, modified intention-to-treat population

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    End point title
    		 Overall survival, modified intention-to-treat population
    End point description
    All randomized patients regardless of whether they received treatment or not, except patients who did not start DCVAC/LuCa treatment due to leukapheresis or DCVAC/LuCa production failure
    End point type
    Primary
    End point timeframe
    From the date of randomization to the date of death due to any cause or to the end of the study on 22-Nov-2021
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    40
    29
    38
    Units: Days
        median (inter-quartile range (Q1-Q3))
    471.0 (253.0 to 721.0)
    443.0 (166.0 to 604.0)
    359.0 (151.0 to 476.0)
    Statistical analysis title
    		 Primary
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0065
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.83

    Primary: Overall survival, per protocol population

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    End point title
    		 Overall survival, per protocol population
    End point description
    All randomized patients who received at least one cycle of chemotherapy and, for Group A and Group B, one dose of DCVAC/LuCa and, for Group B, one dose of one of immune enhancers, and did not have any major protocol deviation (protocol violation)
    End point type
    Primary
    End point timeframe
    From the date of randomization to the date of death due to any cause or to the end of the study on 22-Nov-2021
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    33
    26
    28
    Units: Days
        median (inter-quartile range (Q1-Q3))
    499.0 (278.0 to 721.0)
    458.0 (173.0 to 604.0)
    367.0 (243.5 to 476.5)
    Statistical analysis title
    		 Supportive
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0116
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.87

    Secondary: Progression-free survival, modified intention-to-treat population

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    End point title
    		 Progression-free survival, modified intention-to-treat population
    End point description
    All randomized patients regardless of whether they received treatment or not, except patients who did not start DCVAC/LuCa treatment due to leukapheresis or DCVAC/LuCa production failure
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the date of an event defined as the first progression or death due to any cause or to the cut-off date of 21-Nov-2018
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    40
    29
    38
    Units: Days
        median (inter-quartile range (Q1-Q3))
    205.0 (164.0 to 282.0)
    182.0 (135.0 to 232.0)
    171.0 (90.0 to 230.0)
    Statistical analysis title
    		 Secondary
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0334
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.97

    Secondary: Progression-free survival, per protocol population

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    End point title
    		 Progression-free survival, per protocol population
    End point description
    All randomized patients who received at least one cycle of chemotherapy and, for Group A and Group B, one dose of DCVAC/LuCa and, for Group B, one dose of one of the immune enhancers, and did not have any major protocol deviation (protocol violation)
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the date of an event defined as the first progression or death due to any cause or to the cut-off date of 21-Nov-2018
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    33
    26
    28
    Units: Days
        median (inter-quartile range (Q1-Q3))
    225.0 (176.0 to 282.0)
    184.5 (136.0 to 232.0)
    180.0 (92.0 to 268.0)
    Statistical analysis title
    		 Secondary
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0587
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.03

    Secondary: Objective response rate, modified intention-to-treat

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    End point title
    		 Objective response rate, modified intention-to-treat
    End point description
    All randomized patients regardless of whether they received treatment or not, except patients who did not start DCVAC/LuCa treatment due to leukapheresis or DCVAC/LuCa production failure
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the cut-off date of 21-Nov-2018
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    40
    29
    38
    Units: Percentage
        number (confidence interval 95%)
    45 (29.3 to 61.5)
    42.3 (23.4 to 63.1)
    34.3 (19.1 to 52.2)
    No statistical analyses for this end point

    Secondary: Objective response rate, per protocol population

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    End point title
    		 Objective response rate, per protocol population
    End point description
    All randomized patients who received at least one cycle of chemotherapy and, for Group A and Group B, one dose of DCVAC/LuCa and, for Group B, one dose of one of the immune enhancers, and did not have any major protocol deviation (protocol violation)
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the cut-off date of 21-Nov-2018
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    33
    26
    28
    Units: Percentage
        number (confidence interval 95%)
    54.5 (36.4 to 71.9)
    47.8 (26.8 to 69.4)
    46.2 (26.6 to 66.6)
    No statistical analyses for this end point

    Secondary: Duration of response, modified intention-to-treat population

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    End point title
    		 Duration of response, modified intention-to-treat population
    End point description
    All randomized patients regardless of whether they received treatment or not, except patients who did not start DCVAC/LuCa treatment due to leukapheresis or DCVAC/LuCa production failure
    End point type
    Secondary
    End point timeframe
    From the date of complete/partial response to disease progression or death or the cut-off date of 21-Nov-2018
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    40
    29
    38
    Units: Days
        median (inter-quartile range (Q1-Q3))
    102.0 (78.0 to 276.0)
    108.0 (44.0 to 181.0)
    89.5 (48.0 to 239.5)
    Statistical analysis title
    		 Secondary
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2539
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.39

    Secondary: Duration of response, per protocol population

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    End point title
    		 Duration of response, per protocol population
    End point description
    All randomized patients who received at least one cycle of chemotherapy and, for Group A and Group B, one dose of DCVAC/LuCa and, for Group B, one dose of one of the immune enhancers, and did not have any major protocol deviation (protocol violation)
    End point type
    Secondary
    End point timeframe
    From the date of complete/partial response to disease progression or death or the cut-off date of 21-Nov-2018
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    33
    26
    28
    Units: Days
        median (inter-quartile range (Q1-Q3))
    102.0 (78.0 to 276.0)
    108.0 (44.0 to 181.0)
    89.5 (48.0 to 239.5)
    Statistical analysis title
    		 Secondary
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2539
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.39

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs): started/worsened at/after start of study treatment and before 30 days after study treatment end; related serious AEs, AEs of special interest: collected beyond 30 days after study treatment end; deaths: consent signature to study end
    Adverse event reporting additional description
    Only treatment-emergent AEs (TEAEs) were analyzed (see the definition above); the tables include information on TEAEs, serious TEAEs, and all deaths; causality was assessed by investigators; disease progression or AEs related to disease progression were reported as AEs but not as SAEs (regardless of outcome or seriousness criteria)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Patients in this arm received DCVAC/LuCa subcutaneously every 3 weeks for the first 5 doses and then every 6 weeks in up to a total of 15 doses. DCVAC/LuCa was to be administered concurrently with chemotherapy (carboplatin and paclitaxel) for 3 to 5 cycles on day 15 (±3 days) during each cycle and was to start during the second cycle of chemotherapy.

    Reporting group title
    Group B
    Reporting group description
    		 Patients in this arm received DCVAC/LuCa subcutaneously every 3 weeks for the first 5 doses and then every 6 weeks in up to a total of 15 doses. DCVAC/LuCa was to be administered concurrently with chemotherapy (carboplatin and paclitaxel) for 3 to 5 cycles on day 15 (±3 days) during each cycle and was to start during the second cycle of chemotherapy. Pegylated IFN-α2b, 1 µg/kg, was to be divided into 2 doses and administered to patients in Group B subcutaneously within a 10 cm radius from the injection site of DCVAC/LuCa after each DCVAC/LuCa administration. Hydroxychloroquine was to be administered to patients in Group B in 2 doses of 400 mg orally daily on a continuous basis for 7 consecutive days starting 1 day after each dosing of DCVAC/LuCa.

    Reporting group title
    Group C
    Reporting group description
    		 Chemotherapy (carboplatin and paclitaxel) alone

    Serious adverse events
    		 Group A Group B Group C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 40 (32.50%)
    13 / 27 (48.15%)
    9 / 34 (26.47%)
         number of deaths (all causes)
    9
    9
    2
         number of deaths resulting from adverse events
    9
    9
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pericardial effusion malignant
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural pneumothorax
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Demyelinating polyneuropathy
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer haemorrhage
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A Group B Group C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 40 (97.50%)
    27 / 27 (100.00%)
    33 / 34 (97.06%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 27 (7.41%)
    1 / 34 (2.94%)
         occurrences all number
    1
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 27 (14.81%)
    1 / 34 (2.94%)
         occurrences all number
    1
    4
    1
    Chills
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 27 (14.81%)
    0 / 34 (0.00%)
         occurrences all number
    1
    4
    0
    Fatigue
         subjects affected / exposed
    16 / 40 (40.00%)
    5 / 27 (18.52%)
    7 / 34 (20.59%)
         occurrences all number
    16
    5
    7
    General physical health deterioration
         subjects affected / exposed
    7 / 40 (17.50%)
    3 / 27 (11.11%)
    0 / 34 (0.00%)
         occurrences all number
    7
    3
    0
    Influenza like illness
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences all number
    2
    2
    0
    Immune system disorders
    Pyrexia
         subjects affected / exposed
    2 / 40 (5.00%)
    6 / 27 (22.22%)
    2 / 34 (5.88%)
         occurrences all number
    2
    6
    2
    Hypersensitivity
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 27 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    3
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 27 (14.81%)
    1 / 34 (2.94%)
         occurrences all number
    4
    4
    1
    Dysphonia
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    Dyspnoea
         subjects affected / exposed
    5 / 40 (12.50%)
    4 / 27 (14.81%)
    1 / 34 (2.94%)
         occurrences all number
    5
    4
    1
    Pleural effusion
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 27 (11.11%)
    0 / 34 (0.00%)
         occurrences all number
    4
    3
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 27 (7.41%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Depression
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 27 (7.41%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Insomnia
         subjects affected / exposed
    6 / 40 (15.00%)
    1 / 27 (3.70%)
    1 / 34 (2.94%)
         occurrences all number
    6
    1
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 27 (7.41%)
    2 / 34 (5.88%)
         occurrences all number
    4
    2
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 27 (7.41%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences all number
    2
    2
    0
    Neuropathy peripheral
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 27 (7.41%)
    2 / 34 (5.88%)
         occurrences all number
    4
    2
    2
    Paraesthesia
         subjects affected / exposed
    11 / 40 (27.50%)
    7 / 27 (25.93%)
    6 / 34 (17.65%)
         occurrences all number
    11
    7
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 27 (7.41%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    2
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    20 / 40 (50.00%)
    8 / 27 (29.63%)
    7 / 34 (20.59%)
         occurrences all number
    20
    8
    7
    Anaemia
         subjects affected / exposed
    12 / 40 (30.00%)
    11 / 27 (40.74%)
    11 / 34 (32.35%)
         occurrences all number
    12
    11
    11
    Leukopenia
         subjects affected / exposed
    6 / 40 (15.00%)
    3 / 27 (11.11%)
    4 / 34 (11.76%)
         occurrences all number
    6
    3
    4
    Thrombocytopenia
         subjects affected / exposed
    10 / 40 (25.00%)
    12 / 27 (44.44%)
    10 / 34 (29.41%)
         occurrences all number
    10
    12
    10
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 40 (0.00%)
    4 / 27 (14.81%)
    1 / 34 (2.94%)
         occurrences all number
    0
    4
    1
    Constipation
         subjects affected / exposed
    8 / 40 (20.00%)
    1 / 27 (3.70%)
    2 / 34 (5.88%)
         occurrences all number
    8
    1
    2
    Diarrhoea
         subjects affected / exposed
    7 / 40 (17.50%)
    5 / 27 (18.52%)
    3 / 34 (8.82%)
         occurrences all number
    7
    5
    3
    Nausea
         subjects affected / exposed
    9 / 40 (22.50%)
    12 / 27 (44.44%)
    6 / 34 (17.65%)
         occurrences all number
    9
    12
    6
    Vomiting
         subjects affected / exposed
    8 / 40 (20.00%)
    5 / 27 (18.52%)
    8 / 34 (23.53%)
         occurrences all number
    8
    5
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 40 (25.00%)
    8 / 27 (29.63%)
    14 / 34 (41.18%)
         occurrences all number
    10
    8
    14
    Alopecia totalis
         subjects affected / exposed
    5 / 40 (12.50%)
    5 / 27 (18.52%)
    1 / 34 (2.94%)
         occurrences all number
    5
    5
    1
    Pruritus
         subjects affected / exposed
    0 / 40 (0.00%)
    4 / 27 (14.81%)
    0 / 34 (0.00%)
         occurrences all number
    0
    4
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 27 (7.41%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 40 (20.00%)
    4 / 27 (14.81%)
    7 / 34 (20.59%)
         occurrences all number
    8
    4
    7
    Back pain
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 27 (0.00%)
    5 / 34 (14.71%)
         occurrences all number
    4
    0
    5
    Bone pain
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Myalgia
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 27 (3.70%)
    3 / 34 (8.82%)
         occurrences all number
    4
    1
    3
    Pain in extremity
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 27 (11.11%)
    4 / 34 (11.76%)
         occurrences all number
    4
    3
    4
    Spinal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 40 (12.50%)
    1 / 27 (3.70%)
    0 / 34 (0.00%)
         occurrences all number
    5
    1
    0
    Candida infection
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 27 (7.41%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 27 (7.41%)
    1 / 34 (2.94%)
         occurrences all number
    3
    2
    1
    Viral infection
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 27 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 40 (22.50%)
    9 / 27 (33.33%)
    6 / 34 (17.65%)
         occurrences all number
    9
    9
    6
    Dehydration
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 27 (11.11%)
    1 / 34 (2.94%)
         occurrences all number
    2
    3
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 27 (11.11%)
    2 / 34 (5.88%)
         occurrences all number
    2
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2014
    Non-substantial changes: - The reason for the update was to delete country specification of the trial, as it was decided to extend the trial to other countries - Linguistic corrections or rewording
    26 May 2016
    Substantial changes: - Addition of population with large cell carcinoma - Update of timing of the primary efficacy analysis due to prolonged recruitment - Update of estimated study duration from 36 to 48 months resulting from prolonged patient recruitment - Update of wording of inclusion criteria to clarify requirement for recovery from toxicity - Addition of sections and wording to allow patient replacement and addition of patients in case of leukapheresis failures, to reach a total of 105 evaluable patients - Update of wording on prohibited medications to better reflect current practices - Addition of acceptable time window for the EoT visit - Clarification on timing of research samples collection in patients with disease progression - Clarification that CT scan is not needed at the EoT visit in case of prior documented progression - Clarification wording on censoring patients in case of protocol violations Non-substantial change: - Clarifications and correction of typos
    28 Jul 2016
    Substantial change: - Omission of Group B
    14 Aug 2017
    Substantial changes: - Omission of Group B in the analysis (except for safety tables and listings) - Changing the primary endpoint from PFS to OS - Due to harmonization with other studies, time from randomization is used in the analyses (and not time from the initiation of chemotherapy as in the previous protocol versions)
    09 Oct 2018
    Substantial change: - Addition of exploratory research on predictive and prognostic biomarkers, which requires the collection of archived tissue samples after obtaining appropriate informed consent from all randomized patients regardless of the protocol version according to which they were randomized
    19 Nov 2018
    Substantial change: - Study extension by 3 years to collect additional survival data for ongoing patients Non-substantial change: - Clarification of the timing of statistical analyses

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34284344
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