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    Clinical Trial Results:
    Evaluation of immunological effects of the RANKL-inhibitor Denosumab when administered concurrently with PD1-blocking antibodies (Nivolumab, Pembrolizumab) in patients with metastatic malignant melanoma with bone involvement

    Summary
    EudraCT number
    		 2016-001925-15
    Trial protocol
    		 DE  
    Global end of trial date
    30 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jun 2023
    First version publication date
    22 Jun 2023
    Other versions
    Summary report(s)
    		 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    ISS20159321
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS: DRKS00016064
    Sponsors
    Sponsor organisation name
    Alcedis GmbH
    Sponsor organisation address
    Winchesterstraße 3, Gießen, Germany, 35394
    Public contact
    Universitätsklinik für Dermatologie, Johannes Wesling Klinikum Minden, +49 5717904500, ralf.gutzmer@muehlenkreiskliniken.de
    Scientific contact
    Universitätsklinik für Dermatologie, Johannes Wesling Klinikum Minden, +49 5717904500, ralf.gutzmer@muehlenkreiskliniken.de
    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
    26 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This phase IV study aims to investigate possible immunologic and biologic effects of the concurrent administration of PD-1 blocking antibodies and denosumab as primary endpoint by evaluating peripheral blood mononuclear cells (PBMC, esp. activated T-cells), chemokines, and cytokines (e.g., interferon gamma): 1) Dynamic changes in the numbers of central memory, effector memory, and/or effector T-cells in the circulating blood (based on expression of CD45RA, CD45RO, CCR7, CD62L, and TCF-1). 2) Dynamic changes in the concentration of cytokines and chemokines present in circulating blood.
    Protection of trial subjects
    Patients had to met the inclusion and exclusion criteria. Pregnant or breast-feeding women are excluded. Women of childbearing potential and male patients with partners of childbearing potential had to use a highly effective form of contraception. There was no preferrred enrolment of men or women. The treatment should be conducted exactly as described in the protocol. Any protocol deviations were reported. criteria for premature treatment discontinuation of study patients were specified in the protocol. The study was conducted in accordance with the 2013 Declaration of Helsinki (Fortaleza, Brazil, 2013). The recommendations of Good Clinical Practice, valid since 17 January 1997, were met.
    Background therapy
    		 Prior therapy with CTLA4-inhibitor or PD1-inhibitor or denosumab for distant metastatic disease as well as any other concurrent medical treatments for metastatic disease such as targeted therapies or chemotherapies was not allowed. Treatments in the adjuvant setting were allowed in case treatment was discontinued at least 4 weeks before inclusion in this study. All permitted therapies specified in the SmPCs of the used study drugs could be administered during study treatment to assist in the management of pain, infection and other complications of the underlying malignancy. Relevant prior and concomitant medications were documented in the eCRF.
    Evidence for comparator
    		 Since this was a single arm trial, no comparators were used.
    Actual start date of recruitment
    16 Apr 2019
    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
    Germany: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    14
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Upon obtaining signed informed consent, screening evaluation were performed to confirm eligibilty and to obtain baseline data. Between 16 April 2019 (first patient in) and 18 February 2021 (last patient in), 17 patients were registered by 4 German university clinics.

    Pre-assignment
    Screening details
    		 The investigators selected patients according to the inclusion / exclusion criteria after informing the patient written and orally about the study and after the patient had signed the informed consent. There was no preferred enrolment of men or women. Baseline examinations should be performed within 28 days before study treatment.

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

    Arms
    Arm title
    		 PD-1 and denosumab
    Arm description
    		 Patients were treated with nivolumab, either alone or in combination with ipilimumab, or pembrolizumab and denosumab according to the respective SmPCs.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab treatment was performed according to SmPC. At the time of the latest final protocol version (V2.0 dated 25 JUNE 2019), nivolumab was approved for the treatment of metastatic melanoma as monotherapy (either 240 mg every 2 weeks or 480 mg every 4 weeks) or in combination with ipilimumab (1 mg/kg nivolumab + 3 mg/kg ipilimumab every 3 weeks for 4 dose cycles followed by nivolumab monotherapy (either 240 mg every 2 weeks or 480 mg every 4 weeks)).

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was used according to the SmPC. At the time of the latest final protocol version (V2.0 dated 25 JUNE 2019), pembrolizumab was approved as monotherapy for patients with metastatic melanoma with either 200 mg pembrolizumab every 3 weeks or 400 mg pembrolizumab every 6 weeks.

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab was administered according to the SmPC. At the time of the latest final protocol version (V2.0 dated 25 JUNE 2019), ipilimumab was approved for the treatment of metastatic melanoma in combination with nivolumab (1 mg/kg nivolumab + 3 mg/kg ipilimumab every 3 weeks for 4 dose cycles followed by nivolumab monotherapy (either 240 mg every 2 weeks or 480 mg every 4 weeks)).

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    Other name
    Xgeva
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Denosumab was admninistered according to the SmPC. At the time of the latest final protocol version (V2.0 dated 25 JUNE 2019), denosumab was applied as a subcutaneous injection of 120 mg every 4 weeks. Supplementation of at least 500 mg calcium and 400 IU vitamin D daily was required for all patients, unless hypercalcaemia was present.

    Number of subjects in period 1
    		PD-1 and denosumab
    Started
    17
    Completed
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PD-1 and denosumab
    Reporting group description
    		 Patients were treated with nivolumab, either alone or in combination with ipilimumab, or pembrolizumab and denosumab according to the respective SmPCs.

    Reporting group values
    		 PD-1 and denosumab Total
    Number of subjects
    		 17 17
    Age categorical
    Units: Subjects
    Age continuous
    Patients aged 18 years or older could be enrolled. There was no maximum age limit. Age was calculated as Year of screening minus Year of birth.
    Units: years
        median (full range (min-max))
    		 52 (34 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 9 9
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who received at least one treatment administration of PD-1 blocking antibodies and denosumab

    Subject analysis set title
    mPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Modified per protocol. Patients who received the study therapy of PD-1 blocking antibody and denosumab at least twice and are evaluable for disease, i.e., have a RECIST staging after baseline or clear medical progression, which makes a staging unnecessary per investigator decision.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who received the study therapy of PD-1 blocking antibody and denosumab for at least 12 weeks

    Subject analysis sets values
    		 ITT mPP PP
    Number of subjects
    17
    14
    8
    Age categorical
    Units: Subjects
    Age continuous
    Patients aged 18 years or older could be enrolled. There was no maximum age limit. Age was calculated as Year of screening minus Year of birth.
    Units: years
        median (full range (min-max))
    52 (34 to 78)
    49.5 (34 to 78)
    51 (35 to 76)
    Gender categorical
    Units: Subjects
        Female
    8
    7
    4
        Male
    9
    7
    4

    End points

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    End points reporting groups
    Reporting group title
    PD-1 and denosumab
    Reporting group description
    		 Patients were treated with nivolumab, either alone or in combination with ipilimumab, or pembrolizumab and denosumab according to the respective SmPCs.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who received at least one treatment administration of PD-1 blocking antibodies and denosumab

    Subject analysis set title
    mPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Modified per protocol. Patients who received the study therapy of PD-1 blocking antibody and denosumab at least twice and are evaluable for disease, i.e., have a RECIST staging after baseline or clear medical progression, which makes a staging unnecessary per investigator decision.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who received the study therapy of PD-1 blocking antibody and denosumab for at least 12 weeks

    Primary: Dynamic changes in the numbers of central memory T-cells in circulating blood (PBMC)

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    End point title
    		 Dynamic changes in the numbers of central memory T-cells in circulating blood (PBMC) [1]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [2]
    Units: % of CD3+
    arithmetic mean (standard deviation)
        baseline
    14.44 ( 9.07 )
        Week 4
    12.19 ( 6.71 )
        Week 12
    6.59 ( 7.50 )
        Week 24
    9.07 ( 7.72 )
    Notes
    [2] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes in the numbers of activated T-cells in circulating blood (PBMC)

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    End point title
    		 Dynamic changes in the numbers of activated T-cells in circulating blood (PBMC) [3]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    13 [4]
    Units: % of CD3+
    arithmetic mean (standard deviation)
        baseline
    2.93 ( 6.29 )
        Week 4
    1.58 ( 2.53 )
        Week 12
    0.32 ( 0.68 )
        Week 24
    1.3 ( 3.01 )
    Notes
    [4] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes in the numbers of cytotoxic T-cells in circulating blood (PBMC)

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    End point title
    		 Dynamic changes in the numbers of cytotoxic T-cells in circulating blood (PBMC) [5]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [6]
    Units: % of CD3+
    arithmetic mean (standard deviation)
        Baseline
    31.75 ( 11.01 )
        Week 4
    35.01 ( 15.84 )
        Week 12
    51.61 ( 18.09 )
        Week 24
    57.16 ( 17.71 )
    Notes
    [6] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes in the numbers of naive T-cells events in circulating blood (PBMC)

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    End point title
    		 Dynamic changes in the numbers of naive T-cells events in circulating blood (PBMC) [7]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [8]
    Units: % of CD3+
    arithmetic mean (standard deviation)
        Baseline
    15.5 ( 9.77 )
        Week 4
    14.52 ( 11.85 )
        Week 12
    9.42 ( 12.52 )
        Week 24
    3.95 ( 4.33 )
    Notes
    [8] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes in Tcm/Tscm (CD3+ TCF1+) in circulating blood (PMBC)

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    End point title
    		 Dynamic changes in Tcm/Tscm (CD3+ TCF1+) in circulating blood (PMBC) [9]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    13 [10]
    Units: % of CD3+]
    arithmetic mean (standard deviation)
        Baseline
    67.56 ( 24.9 )
        Week 4
    51.0 ( 25.84 )
        Week 12
    44.1 ( 29.2 )
        Week 24
    44.54 ( 30.62 )
    Notes
    [10] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes of Interferon-γ in circulating blood (serum)

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    End point title
    		 Dynamic changes of Interferon-γ in circulating blood (serum) [11]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [12]
    Units: pg/ml
    arithmetic mean (standard deviation)
        Baseline
    19.11 ( 24.40 )
        Week 4
    101.71 ( 143.64 )
        Week 12
    12.82 ( 8.87 )
        Week 24
    40.91 ( 65.97 )
    Notes
    [12] - Number of analyzed patients decreased pover time
    No statistical analyses for this end point

    Primary: Dynamic changes of TNF-α in circulating blood (serum)

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    End point title
    		 Dynamic changes of TNF-α in circulating blood (serum) [13]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [14]
    Units: pg/ml
    arithmetic mean (standard deviation)
        Baseline
    1.56 ( 0.90 )
        Week 4
    4.33 ( 3.31 )
        Week 12
    2.37 ( 1.46 )
        Week 24
    2.31 ( 2.30 )
    Notes
    [14] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes of IL-6 in circulating blood (serum)

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    End point title
    		 Dynamic changes of IL-6 in circulating blood (serum) [15]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [16]
    Units: pg/ml
    arithmetic mean (standard deviation)
        Baseline
    4.54 ( 7.17 )
        Week 4
    9.60 ( 17.51 )
        Week 12
    4.64 ( 6.68 )
        Week 24
    1.66 ( 1.15 )
    Notes
    [16] - Number of patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes of IL-8 in circulating blood (serum)

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    End point title
    		 Dynamic changes of IL-8 in circulating blood (serum) [17]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [18]
    Units: pg/ml
    arithmetic mean (standard deviation)
        Baseline
    68.59 ( 105.60 )
        Week 4
    110.94 ( 148.97 )
        Week 12
    53.39 ( 43.95 )
        Week 24
    49.27 ( 41.50 )
    Notes
    [18] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes of IL-12/IL-23p40 in circulating blood (serum)

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    End point title
    		 Dynamic changes of IL-12/IL-23p40 in circulating blood (serum) [19]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [20]
    Units: pg/ml
    arithmetic mean (standard deviation)
        Baseline
    154.61 ( 75.42 )
        Week 4
    317.83 ( 144.13 )
        Week 12
    160.95 ( 128.06 )
        Week 24
    146.13 ( 121.70 )
    Notes
    [20] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes of IL-27 in circulating blood (serum)

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    End point title
    		 Dynamic changes of IL-27 in circulating blood (serum) [21]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [22]
    Units: pg/ml
    arithmetic mean (standard deviation)
        Baseline
    2263.03 ( 1210.58 )
        Week 4
    4222.37 ( 2639.11 )
        Week 12
    2799.77 ( 1424.88 )
        Week 24
    2405.34 ( 1573.00 )
    Notes
    [22] - Number of analyzed patients decreased over time
    No statistical analyses for this end point

    Primary: Dynamic changes of IP-10 in circulating blood (serum)

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    End point title
    		 Dynamic changes of IP-10 in circulating blood (serum) [23]
    End point description
    20 ml of heparinized blood and 2 x 7,5 ml of blood (preferably using EDTA-tubes and serum separator tubes) for the preparation of plasma and serum, respectively, were obtained from each study patient at baseline and after 4, 12 and 24 weeks of study duration for immunological monitoring. Samples were analyzed in a central biomarker laboratory (Universität Duisburg/Essen).
    End point type
    Primary
    End point timeframe
    From baseline until end of study (= 24 weeks after initiation of therapy)
    Notes
    [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to low sample number
    End point values
    		 ITT
    Number of subjects analysed
    14 [24]
    Units: pg/ml
    arithmetic mean (standard deviation)
        Baseline
    492.73 ( 296.99 )
        Week 4
    2613.65 ( 1581.41 )
        Week 12
    1050.06 ( 593.80 )
        Week 24
    1543.13 ( 1916.20 )
    Notes
    [24] - Number of patients decreased over time
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) at week 12

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    End point title
    		 Overall response rate (ORR) at week 12
    End point description
    Response was assessed according to RECIST 1.1 criteria by the investigator
    End point type
    Secondary
    End point timeframe
    12 weeks after start of treatment with concurrent PD-1 and RANKL inhibition
    End point values
    		 ITT mPP PP
    Number of subjects analysed
    15
    13
    7
    Units: Patients
    2
    1
    0
    No statistical analyses for this end point

    Secondary: ORR at week 24

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    End point title
    		 ORR at week 24
    End point description
    Response was assessed according to RECIST 1.1 criteria by the investigator
    End point type
    Secondary
    End point timeframe
    24 weeks after start of treatment with concurrent PD-1 and RANKL inhibition
    End point values
    		 ITT mPP PP
    Number of subjects analysed
    14
    12
    8
    Units: patients
    2
    1
    1
    No statistical analyses for this end point

    Secondary: Response rate of bone metastases

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    End point title
    		 Response rate of bone metastases
    End point description
    Best response during the 24 weeks study period was used for determination of response rate of bone metastases (size and number). Response was determined by the investigator according to RECIST 1.1 and by bone scans.
    End point type
    Secondary
    End point timeframe
    From start of treatment with concurrent PD-1 and RANKL inhibition up to 24 weeks
    End point values
    		 ITT mPP PP
    Number of subjects analysed
    14
    12
    8
    Units: Number of Patients
    9
    8
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first study drug application (for AEs) or from date of informed consent (for SAEs) until regular end (day 169 after start of study treatment) or, in case of premature therapy discontinuation, 30 days after last administration of study drugs
    Adverse event reporting additional description
    All AEs including start date, end date, treatment of AE, outcome, relatedness and seriousness had to be recorded in the eCRF. Relatedness of the AE to study drugs was determined by the investigator. Due to the definition of the safety population, only SAEs which occurred after start of study treatment are listed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Safety set
    Reporting group description
    		 All patients who received at least one treatment administration = ITT population

    Serious adverse events
    		 Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 17 (76.47%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    1
    General disorders and administration site conditions
    General disorders and administration site conditions - Other, specify: Progressive Disease
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions - Other, specify: Nephritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions - Other, specify: Immune-related hepatitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial stricture
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Heart Failure
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Nervous system disorders - Other, specify: neurological deficits left leg
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders - Other, specify: immune related ileitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, specify: immune related hepatitis
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders - Other, specify: autoimmune hepatitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders - Other, specify: Panniculitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders - Other, specify: immune related tubulointerstitial nephritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Endocrine disorders
    Endocrine disorders - Other, specify: Morbus Basedow
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders - Other, specify: autoimmune Thyreoiditis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
         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
    		 Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Vascular disorders
    Lymphedema
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hot flashes
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    7
    Fever
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    5
    Flu like symptoms
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: Sprained right ankle
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: decreased sensibility in the
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: heartburn
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: Cytokine-release Syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: Cholecystolithiasis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: Sludge in the distal ductus h
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: joint pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: difficulties swallowing
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: Migraine
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: decreased hemaglobin
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: suspicion of immune related h
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: thrombophlebitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: lipase decreased
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: immune related hepatitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: hordeolum
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: suspicion of immune related p
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: infarct pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: segmental artery embolisms bi
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: stomatitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions - Other, specify: immune related thyreoditis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Immune system disorders - Other, specify: immune-related hepatitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Hoarseness
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Sore throat
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 17 (47.06%)
         occurrences all number
    23
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 17 (52.94%)
         occurrences all number
    24
    Blood bilirubin increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    CPK increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Creatinine increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    GGT increased
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    9
    Lipase increased
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    8
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    6
    Lymphocyte count increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    Serum amylase increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Atrial fibrillation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Chest pain - cardiac
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Cardiac disorders - Other, specify: tachyarrhtyhmia absoluta
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nervous system disorders - Other, specify: worsening of sciatica
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Seizure
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    7
    Blood and lymphatic system disorders - Other, specify: increased CRP
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Blood and lymphatic system disorders - Other, specify: increased Alkalische Phosphatase
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Blood and lymphatic system disorders - Other, specify: Iron deficiency anemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: increased GammaGT
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    3
    Blood and lymphatic system disorders - Other, specify: decreased Calcium
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Blood and lymphatic system disorders - Other, specify: Folic acid deficiency
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: hypoproteinemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: increased Lipase
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: lipase decreased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: increased LDH
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: creatine kinase increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Blood and lymphatic system disorders - Other, specify: Thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: Serum amylase decreased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Eosinophilia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: lymphopenia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders - Other, specify: lipaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    5
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Middle ear inflammation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Vision decreased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Eye disorders - Other, specify: vitreous body clouding left eye
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Eye disorders - Other, specify: mouches volantes
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Colitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Diarrhea
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    7
    Dry mouth
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders - Other, specify: autoimmune colitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Oral pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Stomach pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, specify: Suspected of Hepatitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pain of skin
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Rash maculo-papular
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders - Other, specify: Erysipel
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders - Other, specify: Exanthema
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders - Other, specify: itching
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders - Other, specify: subcutaneous nodus left Sublavicular
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal and urinary disorders - Other, specify: Enterococcus faecalis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Renal and urinary disorders - Other, specify: suspicion of urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hypothyroidism
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    3
    Endocrine disorders - Other, specify: subacute thyroiditis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Muscle cramp
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Infections and infestations
    Lip infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Mucosal infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Thrush
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Urinary tract infection
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hypoalbuminemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Hypocalcemia
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    5
    Hyponatremia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Hypophosphatemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2019
    In a first amendment of the study protocol, endpoints were widened to dynamic changes of cells, inclusion and exclusion criteria were adapted to more common medical standards for the addressed indication (e.g., the planned therapy with PD-1 blocking antibodies was opened by including the combination of nivolumab and ipilimumab), the number of clinic visits was adapted to the treatment schedules, and it was clarified that the study represents a hypotheses-generating approach as there was no prespecified hypothesis.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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