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    Clinical Trial Results:
    A PROSPECTIVE RANDOMIZED, OPEN-LABEL PHASE 2 STUDY OF IMMUNE CHECKPOINT INHIBITION, NIVOLUMAB WITH OR WITHOUT IPILIMUMAB IN COMBINATION WITH RADIATION THERAPY IN PRETREATED PATIENTS WITH METASTATIC PANCREATIC CANCER OR BILIARY TRACT CANCER

    Summary
    EudraCT number
    		 2016-001883-12
    Trial protocol
    		 DK  
    Global end of trial date
    09 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Nov 2023
    First version publication date
    08 Nov 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GI1616
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02866383
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Herlev and Gentofte Hospital, Department of Oncology
    Sponsor organisation address
    Borgmester Ib Juuls Vej 1, Herlev, Denmark, 2730
    Public contact
    Principal investigator Inna Chen, Oncology dept. Herlev & Gentofte Hospital, +45 38682898, inna.chen@regionh.dk
    Scientific contact
    Principal investigator Inna Chen, Oncology dept. Herlev & Gentofte Hospital, +45 38682898, inna.chen@regionh.dk
    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
    09 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical benefit rate of immune checkpoint inhibition,ipilimumab and/or nivolumab in combination with RT
    Protection of trial subjects
    Patients that signed informed consent and fulfilling eligibility criteria were included. Continued monitoring of standard safety parameters during treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Nov 2016
    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
    Denmark: 145
    Worldwide total number of subjects
    145
    EEA total number of subjects
    145
    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)
    75
    From 65 to 84 years
    70
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was open for recruitment of patients with pancreatic cancer from November 2016 to November 2019. Recruitment of patients with biliary tract cancer was open from September 2018 to January 2022. All patients are recruited at a single site: Copenhagen University Hospital - Herlev and Gentofte in Denmark

    Pre-assignment
    Screening details
    		 Eligible patients were ≥ 18 years with metastatic pancreatic or biliary tract cancer, who had received >=1 line of prior systemic chemotherape, ECOG PS 0-1, mGPS >=1, with at least two tumor lesions (one amenable to radiotherapy and one qualified as measureable per RECIST 1.1) and adequate organ and hematologic function

    Period 1
    Period 1 title
    Protocol Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    NB separate randomisation to one of the treatment arms for the 2 patient groups, i.e. pancreatic cancer (PC) and biliary tract cancer (BTC). For each arm Simon 2 stage design was used to decide if arm should contiue recruitment. For PC both arms contiuned recruitment in stage 2, whereas for BTC treatment in arm A (SBRT + Nivolumab) was discontinued at stage 1 -thereafter recruitment continued for BTC arm B (SBRT + Nivolumab+ Ipilimumab) without randomisation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab
    Arm description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administrated at 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT and then every 2 weeks (q2w), for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Arm title
    		 Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab
    Arm description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w and iplimumab1 mg/kg q6w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administrated at 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT and then every 2 weeks (q2w), for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab was administrated at 1 mg/kg over 90 minutes as an IV infusion on day 1 (30 min after completion of nivolumab infusion) and then every 6 weeks (q6w), for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Arm title
    		 Biliary Tract Cancer Arm A: SBRT + Nivolumab
    Arm description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administrated at 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT and then every 2 weeks (q2w), for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Arm title
    		 Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Arm description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w and ipilimumab 1 mg/kg q6w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was administrated at 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT and then every 2 weeks (q2w), for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab was administrated at 1 mg/kg over 90 minutes as an IV infusion on day 1 (30 min after completion of nivolumab infusion) and then every 6 weeks (q6w), for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Number of subjects in period 1
    		Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Started
    41
    43
    19
    42
    Completed
    38
    38
    19
    35
    Not completed
    3
    5
    0
    7
         Adverse event, serious fatal
    -
    -
    -
    2
         Adverse event, non-fatal
    1
    3
    -
    5
         Death from malignant disease under study
    2
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pancreatic Cancer Arm A: SBRT + Nivolumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w and iplimumab1 mg/kg q6w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Biliary Tract Cancer Arm A: SBRT + Nivolumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w and ipilimumab 1 mg/kg q6w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group values
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab Total
    Number of subjects
    		 41 43 19 42 145
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 25 18 8 24 75
        From 65-84 years
    		 16 25 11 18 70
    Age continuous
    Units: years
        median (full range (min-max))
    		 63 (37 to 80) 66 (35 to 79) 66 (46 to 76) 59 (34 to 81) -
    Gender categorical
    Units: Subjects
        Female
    		 19 21 11 23 74
        Male
    		 22 22 8 19 71
    ECOG Performance status
    Units: Subjects
        PS 0
    		 21 20 9 24 74
        PS 1
    		 20 23 10 18 71
    Prior resection of primary tumor
    Units: Subjects
        Yes
    		 10 9 4 9 32
        No
    		 31 34 15 33 113
    Number of metastatic sites
    Units: Subjects
        =1
    		 13 11 7 6 37
        =2
    		 17 17 4 14 52
        >=3
    		 11 15 8 22 56
    Number of previous treatment lines
    Units: Subjects
        =1
    		 19 21 17 30 87
        =>2
    		 22 22 2 12 58

    End points

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    End points reporting groups
    Reporting group title
    Pancreatic Cancer Arm A: SBRT + Nivolumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w and iplimumab1 mg/kg q6w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Biliary Tract Cancer Arm A: SBRT + Nivolumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w and ipilimumab 1 mg/kg q6w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Primary: Clinical Benefit Rate

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    End point title
    		 Clinical Benefit Rate [1]
    End point description
    clinical benefit rate (CBR), defined as the percentage of patients with stable disease (SD), partial response (PR), or complete response (CR) according to RECIST 1.1
    End point type
    Primary
    End point timeframe
    Tumor assessements were performed every 8 weeks until progression
    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: The study includes 2 patient populations analysed independently. Within each population, the study was not designed to compare treatment arms A and B, but each arm had the same Simon two-stage design to evaluate efficacy/recommendation for further investigation of the treatment.
    End point values
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Number of subjects analysed
    41
    43
    19
    42
    Units: percent
        number (confidence interval 95%)
    17.1 (8 to 30.6)
    37.2 (24 to 52.1)
    10.5 (1.3 to 33.1)
    31 (17.6 to 47.1)
    No statistical analyses for this end point

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Objective response rate (ORR), defined as the percentage of patients with partial response (PR), or complete response (CR) according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    Tumor assessments were done every 8 weeks until progression of disease
    End point values
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Number of subjects analysed
    41
    43
    19
    42
    Units: percent
        number (confidence interval 95%)
    2.4 (0.3 to 10.8)
    14 (6 to 26.5)
    0 (0 to 17.6)
    11.9 (4 to 25.6)
    No statistical analyses for this end point

    Secondary: Best overall response

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    End point title
    		 Best overall response
    End point description
    End point type
    Secondary
    End point timeframe
    Tumor assessments were done every 8 weeks until progression of disease
    End point values
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Number of subjects analysed
    41
    43
    19
    42
    Units: subjects
        Partial response
    1
    6
    0
    5
        Stable disease
    6
    10
    2
    8
        Progressive disease
    28
    23
    17
    23
        Not evaluable/no post-baseline assessment
    6
    4
    0
    6
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    PFS is the time from randomisation to radiological progression or death
    End point type
    Secondary
    End point timeframe
    time from randomisation to radiological progression or death
    End point values
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Number of subjects analysed
    41
    43
    19
    42
    Units: months
        median (confidence interval 95%)
    1.7 (1.7 to 1.8)
    1.6 (1.6 to 2.8)
    1.7 (1.6 to 1.9)
    1.7 (1.6 to 1.8)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Time from randomisation to death
    End point values
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Number of subjects analysed
    41
    43
    19
    42
    Units: months
        median (confidence interval 95%)
    3.8 (3.1 to 5.8)
    3.8 (2.8 to 6.5)
    4.7 (3.8 to 8.5)
    5.4 (3.8 to 8.8)
    No statistical analyses for this end point

    Secondary: OS rate at 1 year

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    End point title
    		 OS rate at 1 year
    End point description
    End point type
    Secondary
    End point timeframe
    1 year from randomisation
    End point values
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Number of subjects analysed
    41
    43
    19
    42
    Units: percent
        number (confidence interval 95%)
    7.3 (2.5 to 21.8)
    14 (6.6 to 29.3)
    5.1 (0.4 to 21.4)
    16.7 (7.3 to 29.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE were collected from initiation of study treatment until 100 days after discontinuation of dosing or until starting a new anti-neoplastic therapy (whichever occured first)
    Adverse event reporting additional description
    For non-serious AE section, only AEs with causal relationship to treatment (AR) are listed (numbers includes subjects/occurences reported as SARs as well).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Pancreatic Cancer Arm A: SBRT + Nivolumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w and iplimumab1 mg/kg q6w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Biliary Tract Cancer Arm A: SBRT + Nivolumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Reporting group title
    Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Reporting group description
    		 Patients received SBRT of 15 Gy to a single primary or metastatic lesion administered on day 1 of the first cycle, followed by nivolumab 3 mg/kg q2w and ipilimumab 1 mg/kg q6w for a maximum of 52 weeks or until disease progression (PD), unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator’s judgment

    Serious adverse events
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 41 (43.90%)
    24 / 43 (55.81%)
    4 / 19 (21.05%)
    16 / 42 (38.10%)
         number of deaths (all causes)
    40
    40
    19
    38
         number of deaths resulting from adverse events
    0
    1
    0
    2
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    thromboembolic event
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Back pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    tumor fever
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Haematoma
    Additional description: liver haematoma after biopsy
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 41 (12.20%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 43 (6.98%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary tract infection
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    erythroderma
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Liver abscess
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection unknown focus
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    3 / 19 (15.79%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine abscess
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 43 (6.98%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    myelomeningoradiculitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pancreatic Cancer Arm A: SBRT + Nivolumab Pancreatic Cancer Arm B: SBRT + Nivolumab + Ipilimumab Biliary Tract Cancer Arm A: SBRT + Nivolumab Biliary Tract Cancer Arm B: SBRT + Nivolumab +Ipilimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 41 (100.00%)
    41 / 43 (95.35%)
    19 / 19 (100.00%)
    42 / 42 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 43 (9.30%)
    0 / 19 (0.00%)
    7 / 42 (16.67%)
         occurrences all number
    5
    9
    0
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 41 (9.76%)
    4 / 43 (9.30%)
    0 / 19 (0.00%)
    8 / 42 (19.05%)
         occurrences all number
    9
    10
    0
    12
    Alkaline phosphatase increased
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 43 (6.98%)
    0 / 19 (0.00%)
    5 / 42 (11.90%)
         occurrences all number
    5
    4
    0
    9
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    2
    Blood TSH increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    1
    0
    4
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    9 / 41 (21.95%)
    8 / 43 (18.60%)
    2 / 19 (10.53%)
    4 / 42 (9.52%)
         occurrences all number
    13
    13
    2
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 41 (7.32%)
    6 / 43 (13.95%)
    1 / 19 (5.26%)
    4 / 42 (9.52%)
         occurrences all number
    3
    11
    1
    4
    Headache
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 43 (9.30%)
    1 / 19 (5.26%)
    3 / 42 (7.14%)
         occurrences all number
    3
    12
    1
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 41 (29.27%)
    14 / 43 (32.56%)
    5 / 19 (26.32%)
    19 / 42 (45.24%)
         occurrences all number
    19
    25
    8
    30
    Fever
         subjects affected / exposed
    2 / 41 (4.88%)
    10 / 43 (23.26%)
    2 / 19 (10.53%)
    4 / 42 (9.52%)
         occurrences all number
    3
    13
    2
    4
    Chills
         subjects affected / exposed
    8 / 41 (19.51%)
    6 / 43 (13.95%)
    0 / 19 (0.00%)
    6 / 42 (14.29%)
         occurrences all number
    9
    7
    0
    7
    Pain
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    4
    3
    0
    4
    Flu like symptoms
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    1
    2
    0
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 43 (6.98%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 43 (6.98%)
    1 / 19 (5.26%)
    5 / 42 (11.90%)
         occurrences all number
    3
    6
    1
    6
    Dry mouth
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 43 (6.98%)
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    6
    1
    0
    Nausea
         subjects affected / exposed
    9 / 41 (21.95%)
    14 / 43 (32.56%)
    4 / 19 (21.05%)
    12 / 42 (28.57%)
         occurrences all number
    11
    26
    6
    14
    Vomiting
         subjects affected / exposed
    2 / 41 (4.88%)
    7 / 43 (16.28%)
    1 / 19 (5.26%)
    6 / 42 (14.29%)
         occurrences all number
    2
    9
    1
    10
    Diarrhoea
         subjects affected / exposed
    16 / 41 (39.02%)
    15 / 43 (34.88%)
    4 / 19 (21.05%)
    13 / 42 (30.95%)
         occurrences all number
    18
    38
    5
    18
    Colitis
         subjects affected / exposed
    2 / 41 (4.88%)
    5 / 43 (11.63%)
    1 / 19 (5.26%)
    4 / 42 (9.52%)
         occurrences all number
    2
    12
    1
    8
    Pancreatitis
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    3
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    1
    1
    0
    5
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    2
    0
    3
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 43 (6.98%)
    1 / 19 (5.26%)
    4 / 42 (9.52%)
         occurrences all number
    1
    5
    1
    5
    Pruritus
         subjects affected / exposed
    10 / 41 (24.39%)
    14 / 43 (32.56%)
    2 / 19 (10.53%)
    19 / 42 (45.24%)
         occurrences all number
    11
    25
    3
    35
    Rash
         subjects affected / exposed
    8 / 41 (19.51%)
    9 / 43 (20.93%)
    0 / 19 (0.00%)
    19 / 42 (45.24%)
         occurrences all number
    11
    19
    0
    28
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 43 (11.63%)
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    2
    8
    0
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 43 (6.98%)
    0 / 19 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Thyroiditis
         subjects affected / exposed
    7 / 41 (17.07%)
    13 / 43 (30.23%)
    7 / 19 (36.84%)
    9 / 42 (21.43%)
         occurrences all number
    10
    18
    7
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 41 (7.32%)
    12 / 43 (27.91%)
    5 / 19 (26.32%)
    12 / 42 (28.57%)
         occurrences all number
    7
    25
    5
    18
    Myalgia
         subjects affected / exposed
    5 / 41 (12.20%)
    7 / 43 (16.28%)
    1 / 19 (5.26%)
    6 / 42 (14.29%)
         occurrences all number
    7
    13
    1
    10
    Back pain
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 43 (6.98%)
    2 / 19 (10.53%)
    3 / 42 (7.14%)
         occurrences all number
    3
    4
    2
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    6 / 41 (14.63%)
    11 / 43 (25.58%)
    2 / 19 (10.53%)
    6 / 42 (14.29%)
         occurrences all number
    9
    13
    2
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2016
    Added biopsy at time of progressive disease, if feasible
    26 Mar 2018
    - expansion of the trial to patients with metastatic biliary tract cancer. Both target population to have their separate Arm A and Arm B, and Simon 2-stage design for each arm. Analyses for the two target populations to be done independently from each other.
    04 Dec 2018
    - Added fecal samples for tranlational research - Adjustment of study time lines
    03 Nov 2019
    Added Olink analysis in translational research.
    12 Mar 2021
    -Arm A for biliary tract cancer discontinued at the end of stage 1 according to Simon-2 stage design. - added intratumor microbiome and immune cell gene-expression profiling for translational research

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35476508
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