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    Clinical Trial Results:
    A Phase Ib/IIa study of combination therapy with Gemcitabine and Atu027 in subjects with locally advanced or metastatic pancreatic adenocarcinoma

    Summary
    EudraCT number
    		 2012-004429-26
    Trial protocol
    		 DE  
    Global end of trial date
    05 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2017
    First version publication date
    16 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Atu027-I-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Silence Therpeutics GmbH
    Sponsor organisation address
    Robert-Rössle-Str. 10, Berlin, Germany, 13125
    Public contact
    Mike Khan, PhD, Silence Therapeutics GmbH Robert-Rössle-Str. 10, 13125 Berlin, +49 30 9489 2800,
    Scientific contact
    Mike Khan, PhD, Silence Therapeutics GmbH Robert-Rössle-Str. 10, 13125 Berlin, +49 30 9489 2800,
    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
    08 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to evaluate the safety and pharmacokinetics of Atu027 when used in combination with gemcitabine in subjects with locally advanced or metastatic pancreatic adenocarcinoma.
    Protection of trial subjects
    A lead-in safety period was installed for this study enrolling three subjects with non-pancreatic cancer for whom conventional treatment options had failed. Subjects of this safety cohort were to be treated in a 28-day cycle with Atu027 twice weekly for four weeks and gemcitabine once weekly for the first three weeks. Subjects of the safety cohort were included consecutively at 2-week intervals. If one of the subjects in the safety cohort experienced an unacceptable toxicity, the safety cohort was to be expanded to six subjects. If one of these additional three subjects experienced an unacceptable toxicity, the study was to be stopped. After all subjects finished one 28-day cycle, safety data were to be reviewed by a data safety monitoring board (DSMB). If no safety concerns were observed, subjects with locally advanced or metastatic pancreatic adenocarcinoma were to be enrolled into the treatment period and subjects of the safety cohort were to be given the opportunity to get further treatment with Atu027. In case of intolerable side effects that were judged by the investigator to be detrimental to the subject’s well-being, during the treatment period, treatment was to be stopped. These subjects were not to be withdrawn from the study (End of Treatment and Follow-up visits were performed).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Mar 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    9
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment started on 27-Mar-2013 with the first patient of the safety cohort and ended on 08-Jul-2014 with the last patient included in the treatment period.

    Pre-assignment
    Screening details
    		 26 subjects with locally advanced or metastatic pancreatic adenocarcinoma were screened for the treatment period, out of which two were screening failures, and 24 subjects got randomised for treatment. One subject was a screening failure post randomisation, therefore, 23 subjects received treatment.

    Period 1
    Period 1 title
    Treatment cohort
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm 1: Atu027 once weekly
    Arm description
    		 Arm 1 of the treament period received 0.253 mg/kg Atu027 administered i.v. and gemcitabine 1,000 mg/m² (doses could have been reduced based on toxicity) once weekly for three consecutive weeks in 28-day treatment cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atu027
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatments were administered in 28-day treatment cycles: 0.253 mg/kg Atu027 were administered i.v. once weekly for three consecutive weeks. The Atu027 dose for the first treatment of Cycle 1 was calculated with the body weight measured at Baseline. At least at the beginning of each following cycle, the dose was adjusted if there was a change in body weight of 10% or greater compared to the latest weight used for dose calculation.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatments were administered in 28-day treatment cycles: gemcitabine 1,000 mg/m² (doses could have been reduced based on toxicity) was administered once weekly for three consecutive weeks. The gemcitabine dose for Cycle 1 was calculated with Dubois formula with the body surface area evaluated at Baseline. Gemcitabine was given at 1,000 mg/m² by 30-minute i.v. infusion. Dosage modifications at each cycle or within a cycle were applied based upon the actual body weight or on the grade of toxicity experienced by the subject and were done according to the SmPC.

    Arm title
    		 Arm 2: Atu027 twice weekly
    Arm description
    		 Arm 2 of the treatment period received 0.253 mg/kg Atu027 administered i.v. twice weekly for four consecutive weeks and gemcitabine 1,000 mg/m² (doses could have been reduced based on toxicity) once weekly for three consecutive weeks in 28-day treatment cycles. Each combination cycle was followed by a gemcitabine-monotherapy cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atu027
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatments were administered in 28-day treatment cycles: 0.253 mg/kg Atu027 were administered i.v. twice weekly for four consecutive weeks followed by a 28-day cycle with no Atu027 treatment. The Atu027 dose for the first treatment of Cycle 1 was calculated with the body weight measured at Baseline. At least at the beginning of each following cycle, the dose was adjusted if there was a change in body weight of 10% or greater compared to the latest weight used for dose calculation.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatments were administered in 28-day treatment cycles: gemcitabine 1,000 mg/m² (doses could have been reduced based on toxicity) was administered once weekly for three consecutive weeks. Each combination cycle was followed by a gemcitabine-monotherapy cycle. The gemcitabine dose for Cycle 1 was calculated with Dubois formula with the body surface area evaluated at Baseline. Gemcitabine was given at 1,000 mg/m² by 30-minute i.v. infusion. Dosage modifications with each cycle or within a cycle were applied based upon the actual body weight or on the grade of toxicity experienced by the subject and were done according to the SmPC.

    Arm title
    		 Total
    Arm description
    		 All patients of Arm 1 and all patients of Arm 2 who received Atu027 and gemcitabine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atu027
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatments were administered in 28-day treatment cycles: 0.253 mg/kg Atu027 were administered i.v. once weekly for three consecutive weeks or twice weekly for four consecutive weeks followed by 4 weeks of no Atu027 treatment. The Atu027 dose for the first treatment of Cycle 1 was calculated with the body weight measured at Baseline. At least at the beginning of each following cycle, the dose was adjusted if there was a change in body weight of 10% or greater compared to the latest weight used for dose calculation.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatments were administered in 28-day treatment cycles: gemcitabine1,000 mg/m² (doses could have been reduced based on toxicity) was administered once weekly for three consecutive weeks. For patients receiving Atu027 twice weekly, each combination cycle was followed by a gemcitabine-monotherapy cycle. The gemcitabine dose for Cycle 1 was calculated with Dubois formula with the body surface area evaluated at Baseline. Gemcitabine was given at 1,000 mg/m² by 30-minute i.v. infusion. Dosage modifications at each cycle or within a cycle were applied based upon the actual body weight or on the grade of toxicity experienced by the subject and were done according to the SmPC.

    Number of subjects in period 1
    		Arm 1: Atu027 once weekly Arm 2: Atu027 twice weekly Total
    Started
    11
    12
    23
    Completed
    6
    7
    13
    Not completed
    5
    5
    10
         Consent withdrawn by subject
    2
    -
    2
         Death
    3
    3
    6
         Lost to follow-up
    -
    2
    2
    Period 2
    Period 2 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1: Atu027 once weekly FU
    Arm description
    		 Follow up of Arm 1 for safety for a further year without study medication.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Arm 2: Atu027 twice weekly FU
    Arm description
    		 Follow up of Arm 2 for safety for a further year without study medication.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Arm 1: Atu027 once weekly FU Arm 2: Atu027 twice weekly FU
    Started
    6
    7
    Completed
    1
    1
    Not completed
    5
    6
         Consent withdrawn by subject
    1
    1
         Death
    4
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment cohort
    Reporting group description
    		 23 subjects were randomised to two treatment arms and received either Atu027 once weekly and Gemcitabine once weekly, or Atu027 twice weekly and Gemcitagine once weekly.

    Reporting group values
    		 Treatment cohort Total
    Number of subjects
    		 23 23
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 14 14
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 9 9
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 7 7
        ECOG 1
    		 16 16
    Subject analysis sets

    Subject analysis set title
    PK analysis set - Atu027 once weekly
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    4 subjects of Arm 1 who received Atu027 once weekly.

    Subject analysis set title
    PK analysis set - Atu027 twice weekly
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    3 subjects of the safety cohort plus 4 subjects of Arm 2 who all received Atu027 twice weekly.

    Subject analysis sets values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects
    4
    7
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    2
    2
        From 65-84 years
    2
    5
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    2
    5
        Male
    2
    2
    ECOG performance status
    Units: Subjects
        ECOG 0
        ECOG 1

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: Atu027 once weekly
    Reporting group description
    		 Arm 1 of the treament period received 0.253 mg/kg Atu027 administered i.v. and gemcitabine 1,000 mg/m² (doses could have been reduced based on toxicity) once weekly for three consecutive weeks in 28-day treatment cycles.

    Reporting group title
    Arm 2: Atu027 twice weekly
    Reporting group description
    		 Arm 2 of the treatment period received 0.253 mg/kg Atu027 administered i.v. twice weekly for four consecutive weeks and gemcitabine 1,000 mg/m² (doses could have been reduced based on toxicity) once weekly for three consecutive weeks in 28-day treatment cycles. Each combination cycle was followed by a gemcitabine-monotherapy cycle.

    Reporting group title
    Total
    Reporting group description
    		 All patients of Arm 1 and all patients of Arm 2 who received Atu027 and gemcitabine.
    Reporting group title
    Arm 1: Atu027 once weekly FU
    Reporting group description
    		 Follow up of Arm 1 for safety for a further year without study medication.

    Reporting group title
    Arm 2: Atu027 twice weekly FU
    Reporting group description
    		 Follow up of Arm 2 for safety for a further year without study medication.

    Subject analysis set title
    PK analysis set - Atu027 once weekly
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    4 subjects of Arm 1 who received Atu027 once weekly.

    Subject analysis set title
    PK analysis set - Atu027 twice weekly
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    3 subjects of the safety cohort plus 4 subjects of Arm 2 who all received Atu027 twice weekly.

    Primary: PK Atu027siRNA - Cmax

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    End point title
    		 PK Atu027siRNA - Cmax [1]
    End point description
    The maximum serum concentration that Atu027siRNA achieved after it has been administrated and before administration of the next dose.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [2]
    7
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Atu027 First Administration
    142.33 ± 10.7
    130.44 ± 32.1
        Atu027 Sixth Administration
    146.27 ± 35.2
    152.16 ± 32.6
    Notes
    [2] - 1st Admin: samples of 4 subjects were available. 6th Admin: samples of 2 subjects were available.
    No statistical analyses for this end point

    Primary: PK Atu027siRNA - tmax

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    End point title
    		 PK Atu027siRNA - tmax [3]
    End point description
    The time taken to reach the maximum concentration of Atu027siRNA.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [4]
    7
    Units: hour
    median (full range (min-max))
        Atu027 First Administration
    4.25 (4 to 4.5)
    4 (1 to 4.5)
        Atu027 Sixth Administration
    4 (4 to 4)
    4 (2 to 4.5)
    Notes
    [4] - 1st (6th) Admin: samples of 4 (2) subjects were available. Infusion took place over 4 hours.
    No statistical analyses for this end point

    Primary: PK Atu027siRNA - AUClast

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    End point title
    		 PK Atu027siRNA - AUClast [5]
    End point description
    Area under the plasma concentration time curve from zero to the time of last measurable conentration for Atu027siRNA.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [6]
    7
    Units: ng x h/mL
    geometric mean (geometric coefficient of variation)
        Atu027 First adeministration
    902.4 ± 42.9
    801.7 ± 27.6
        Atu027 Sixth Administration
    1297.9 ± 33.6
    1037.4 ± 31.9
    Notes
    [6] - 1st Admin: samples of 4 subjects were available. 6th Admin: samples of 2 subjects were available.
    No statistical analyses for this end point

    Primary: PK AtuFect01 - Cmax

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    End point title
    		 PK AtuFect01 - Cmax [7]
    End point description
    The maximum serum concentration that AtuFect01 achieved after it has been administrated and before administration of the next dose.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [8]
    7
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Atu027 First Administration
    6824 ± 15.4
    6775.1 ± 13.6
        Atu027 Sixth Administration
    6841.8 ± 21.2
    9990.9 ± 13.2
    Notes
    [8] - 1st Admin: samples of 4 subjects were available. 6th Admin: samples of 2 subjects were available.
    No statistical analyses for this end point

    Primary: PK AtuFect01 - tmax

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    End point title
    		 PK AtuFect01 - tmax [9]
    End point description
    The time taken to reach the maximum concentration of AtuFect01.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [10]
    7
    Units: hour
    median (full range (min-max))
        Atu027 First Administration
    6.2 (4.5 to 8)
    6 (4.5 to 8)
        Atu027 Sixth Administration
    6.9 (6 to 7.8)
    4.5 (4.5 to 8)
    Notes
    [10] - 1st Admin: samples of 4 subjects were available. 6th Admin: samples of 2 subjects were available.
    No statistical analyses for this end point

    Primary: PK AtuFect01 - AUClast

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    End point title
    		 PK AtuFect01 - AUClast [11]
    End point description
    Area under the plasma concentration time curve from zero to the time of last measurable conentration for AtuFect01.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [12]
    7
    Units: h x ng/mL
    geometric mean (geometric coefficient of variation)
        Atu027 First Administration
    116200 ± 20.8
    123375 ± 12.9
        Atu027 Sixth Administration
    120551 ± 27.7
    182571 ± 19
    Notes
    [12] - 1st Admin: samples of 4 subjects were available. 6th Admin: samples of 2 subjects were available.
    No statistical analyses for this end point

    Primary: PK Lipid DPyPE - Cmax

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    End point title
    		 PK Lipid DPyPE - Cmax [13]
    End point description
    The maximum serum concentration that Lipid DPyPE achieved after it has been administrated and before administration of the next dose.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [14]
    7
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Atu027 First Administration
    5848.1 ± 12.9
    5521.5 ± 17.1
        Atu027 Sixth Administration
    5347.7 ± 16.1
    7675 ± 20.7
    Notes
    [14] - 1st Admin: samples of 4 subjects were available. 6th Admin: samples of 2 subjects were available.
    No statistical analyses for this end point

    Primary: PK Lipid DPyPE - tmax

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    End point title
    		 PK Lipid DPyPE - tmax [15]
    End point description
    The time taken to reach the maximum concentration of Lipid DPyPE.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [16]
    7
    Units: hour
    median (full range (min-max))
        Atu027 First Administration
    4.5 (4 to 8)
    4.5 (4 to 8)
        Atu027 Sixth Administration
    7.9 (7.8 to 8)
    4.5 (4.5 to 7.6)
    Notes
    [16] - 1st Admin: samples of 4 subjects were available. 6th Admin: samples of 2 subjects were available.
    No statistical analyses for this end point

    Primary: PK Lipid DPyPE - AUClast

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    End point title
    		 PK Lipid DPyPE - AUClast [17]
    End point description
    Area under the plasma concentration time curve from zero to the time of last measurable conentration for Lipid DPyPE.
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 PK analysis set - Atu027 once weekly PK analysis set - Atu027 twice weekly
    Number of subjects analysed
    4 [18]
    7
    Units: h x ng/mL
    geometric mean (geometric coefficient of variation)
        Atu027 First Administration
    95237 ± 12.7
    98685 ± 15.3
        Atu027 Sixth Administration
    93996 ± 21.1
    136133 ± 19.5
    Notes
    [18] - 1st Admin: samples of 4 subjects were available. 6th Admin: samples of 2 subjects were available.
    No statistical analyses for this end point

    Primary: Number of adverse events

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    End point title
    		 Number of adverse events [19]
    End point description
    End point type
    Primary
    End point timeframe
    Adverse events were reported from Baseline until 5 weeks after end of treatment or premature termination.
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 Arm 1: Atu027 once weekly Arm 2: Atu027 twice weekly Total
    Number of subjects analysed
    11
    12
    23
    Units: adverse events
    116
    147
    263
    No statistical analyses for this end point

    Primary: Number of subjects with adverse events

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    End point title
    		 Number of subjects with adverse events [20]
    End point description
    End point type
    Primary
    End point timeframe
    Adverse events were reported from Baseline until 5 weeks after end of treatment or premature termination.
    Notes
    [20] - 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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 Arm 1: Atu027 once weekly Arm 2: Atu027 twice weekly Total
    Number of subjects analysed
    11
    12
    23
    Units: subject
    11
    11
    22
    No statistical analyses for this end point

    Primary: Number of adverse events related to Atu027

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    End point title
    		 Number of adverse events related to Atu027 [21]
    End point description
    End point type
    Primary
    End point timeframe
    Adverse events were reported from Baseline until 5 weeks after end of treatment or premature termination.
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 Arm 1: Atu027 once weekly Arm 2: Atu027 twice weekly Total
    Number of subjects analysed
    11
    12
    23
    Units: adverse events
    25
    24
    49
    No statistical analyses for this end point

    Primary: Number of subjects with adverse events related to Atu027

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    End point title
    		 Number of subjects with adverse events related to Atu027 [22]
    End point description
    End point type
    Primary
    End point timeframe
    Adverse events were reported from Baseline until 5 weeks after end of treatment or premature termination.
    Notes
    [22] - 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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 Arm 1: Atu027 once weekly Arm 2: Atu027 twice weekly Total
    Number of subjects analysed
    11
    12
    23
    Units: subject
    5
    7
    12
    No statistical analyses for this end point

    Primary: Number of serious adverse events

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    End point title
    		 Number of serious adverse events [23]
    End point description
    End point type
    Primary
    End point timeframe
    Adverse events were reported from Baseline until 5 weeks after end of treatment or premature termination.
    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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 Arm 1: Atu027 once weekly Arm 2: Atu027 twice weekly Total
    Number of subjects analysed
    11
    12
    23
    Units: adverse events
    13
    10
    23
    No statistical analyses for this end point

    Primary: Number of subjects with serious adverse events

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    End point title
    		 Number of subjects with serious adverse events [24]
    End point description
    End point type
    Primary
    End point timeframe
    Adverse events were reported from Baseline until 5 weeks after end of treatment or premature termination.
    Notes
    [24] - 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 analyses was planned for this Phase Ib/IIa clinical study.
    End point values
    		 Arm 1: Atu027 once weekly Arm 2: Atu027 twice weekly Total
    Number of subjects analysed
    11
    12
    23
    Units: subject
    9
    7
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from Baseline until 5 weeks after end of treatment or premature termination.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    Safety period
    Reporting group description
    		 The three subjects of the safety cohort with non-pancreatic cancer and for whom conventional treatment options had failed were treated for one 28-day treatment cycle with 0.253 mg/kg Atu027 i.v. twice weekly for four weeks and gemcitabine 1,000 mg/m2 (doses could have been reduced based on toxicity) once weekly for the first three weeks.

    Reporting group title
    Treatment period: Arm 1: Atu027 once weekly
    Reporting group description
    		 Arm 1 of the treament period received 0.253 mg/kg Atu027 administered i.v. and gemcitabine 1,000 mg/m² (doses could have been reduced based on toxicity) once weekly for three consecutive weeks in 28-day treatment cycles.

    Reporting group title
    Treatment period: Arm 2: Atu027 twice weekly
    Reporting group description
    		 Arm 2 of the treatment period received 0.253 mg/kg Atu027 administered i.v. twice weekly for four consecutive weeks and gemcitabine 1,000 mg/m² (doses could have been reduced based on toxicity) once weekly for three consecutive weeks in 28-day treatment cycles. Each combination cycle was followed by a gemcitabine-monotherapy cycle.

    Serious adverse events
    		 Safety period Treatment period: Arm 1: Atu027 once weekly Treatment period: Arm 2: Atu027 twice weekly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    9 / 11 (81.82%)
    7 / 12 (58.33%)
         number of deaths (all causes)
    0
    3
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
    Tumour pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         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 disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 12 (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
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device occlusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (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
    Extravasation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (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
    multi-organ failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (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
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (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
    Infections and infestations
    Biliary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 12 (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
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         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: 0%
    Non-serious adverse events
    		 Safety period Treatment period: Arm 1: Atu027 once weekly Treatment period: Arm 2: Atu027 twice weekly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    11 / 11 (100.00%)
    11 / 12 (91.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Vasculitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    5 / 11 (45.45%)
    5 / 12 (41.67%)
         occurrences all number
    2
    7
    7
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    5
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Localised oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    5 / 12 (41.67%)
         occurrences all number
    0
    4
    7
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Apathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Emotional distress
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Panic attack
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 11 (27.27%)
    4 / 12 (33.33%)
         occurrences all number
    1
    8
    7
    White blood cell count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    2
    Platelet count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 11 (27.27%)
    8 / 12 (66.67%)
         occurrences all number
    1
    7
    13
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood creatine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    0
    2
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    0
    3
    2
    Protein total decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    2
    Laceration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Rib fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Skull fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 11 (27.27%)
    6 / 12 (50.00%)
         occurrences all number
    1
    4
    8
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    1
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Vestibular disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    1
    Abdominal hernia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Faecal vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Gastric haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Haematemesis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Impaired gastric emptying
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Melaena
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 11 (45.45%)
    7 / 12 (58.33%)
         occurrences all number
    0
    5
    8
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    5 / 12 (41.67%)
         occurrences all number
    0
    3
    5
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    0
    3
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Mucosal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Postoperative wound infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Prostate infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    0
    2
    3
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    0
    4
    4
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2013
    The following changes were introduced before subject enrolment: • The inclusion and exclusion criteria for the safety period were adapted to those for the main part except for those referring to the primary indication. • The criteria for subject withdrawal were revised. • Expected toxicities under treatment with gemcitabine and Atu027 and the management of toxicities attributable to gemcitabine or Atu027 were included. Increased blood lipase and fatigue were the most common Atu027-related adverse events in the phase I study. In this study these were expected due to the underlying disease. However, grade 3 fatigue and a severe increase in lipase values were considered unacceptable and dosing with Atu027 was to be adjusted. Lipase values were to be monitored closely. • Information on the calculation of doses of gemcitabine and Atu027 was added. • The measurement of blood urea nitrogen was deleted because separate urea and creatinine measurements were assumed to be sufficient for the evaluation of renal function. • Disease response was to be evaluated based on the clinical judgment of the investigator at the end of treatment/premature termination (EOT/PT) visit, 5 weeks after EOT/PT, and during the 1-year follow up. • A time window for the EoT/PT visit was included. • Concomitant medications were only to be documented until the EoT/PT visit instead of up to FU Visit 1. • Further corrections and adaptations for consistency were made.
    27 Aug 2013
    • Introduction of an electronic SAE reporting system. • Deletion of study visits: in Arm 2, visits at Days 1, 8, 15, 22, and 25 in cycles in which only gemcitabine was administered were deleted. All safety assessments initially planned to be performed at Day 1 were therefore rescheduled to Day 4. • Formal change: corrections of the RECIST Version (an incorrect version was erroneously referenced in protocol version 2.0).
    12 May 2014
    • The name of the company was changed to Silence Therapeutics GmbH. All references were adjusted accordingly. • Exclusion criterion #2 was changed from haemoglobin A1c (HbA1c) > or = 7% to haemoglobinA1c (HbA1c) > or = 8% to allow more subjects to be treated with Atu027. The lower value was still considered prudent to avoid any suitable subject being unnecessarily denied therapy. • A footnote was added stating that for the 12-lead ECG at Baseline, data from the subject’s medical record (within the last 7 days) may be used. • Clarified that the safety laboratory is to be done within 24 hours before the start of gemcitabine/Atu027. • Clarified that the investigator could make the dose adjustment for Atu027 earlier on his own discretion (during the cycle or in case the weight changed less than 10 %). This change was done to clarify that the dose can always be adjusted to the actual weight. • Clarified that the dose of gemcitabine was added stating that the dose should be adjusted to the actual body weight.

    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
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