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    Clinical Trial Results:
    A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in relapsed lung cancer and to evaluate biomarkers predictive for response to immune checkpoint inhibition

    Summary
    EudraCT number
    		 2016-003334-25
    Trial protocol
    		 DE  
    Global end of trial date
    20 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Feb 2025
    First version publication date
    21 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-2785
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03083691
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    Inken Terjung, University of Cologne, +49 22147898766, inken.terjung@uk-koeln.de
    Scientific contact
    Dr. Rieke Fischer, University of Cologne, +49 22147842672, rieke.fischer@uk-koeln.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cohort 1: To assess ORR when ipilimumab is added to nivolumab after progression on nivolumab monotherapy in patients relapsed with non-squamous NSCLC (second line). Note: Cohort 1 was closed for enrollment. Subjects who started screening for cohort 1 prior to stop of recruitment initiated by Coordinating PI on April 25 2019 continue to receive treatment. SCLC subjects eligible for BIOLUMA are enrolled in cohort 2b after TMB-Prescreening from October 29 2018 on. Cohort 2a: To assess ORR of the combination therapy of ipilimumab and nivolumab in patients with relapsed SCLC and non-discriminated TMB (second line). Note: Cohort 2a was closed for enrollment. SCLC Subjects eligible for BIOLUMA are enrolled in Cohort 2b after TMB-Prescreening from October 29 2018 on. Cohort 2b: To assess ORR of the combination therapy of ipilimumab and nivolumab in patients with relapsed SCLC and high TMB (second line).
    Protection of trial subjects
    The trial data including study procedures, safety results and efficacy results were extensively reviewed by the participating DMSC members on a regular basis. In the initial cohort 2 (SCLC, not TMB-discriminated), two treatment-related deaths occurred. One patient died from pneumonitis, one patient experienced a fatal course of encephalitis. Both patients did have a good tumor response within the trial. As during that time new data were presented, which indicated that the combination therapy of nivolumab and ipilimumab in SCLC patients only has beneficial effects in patients with high tumor mutation burden (23), a risk-benefit consideration lead to stop of recruitment in cohort 2. The remaining SCLC patients in the trial were treated analogous to the NSCLC patients in cohort 1. The cohort was re-opened for patients with high tumor mutation burden only (cohort 2b) and the former cohort 2 was renamed to cohort 2a for clarification reasons. In cohort 2b, one patient died due to study-procedure related complications: in order to gain a tumor biopsy, a bronchoscopy had been performed. During the procedure, the patient died from a cardiogenic shock. The patient had achieved a partial response to the study treatment. As a consequence of that fatal event, the protocol was amended (protocol amendment no.4) for cohort 2b to change tumor biopsy before study treatment from mandatory to optional.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    47
    From 65 to 84 years
    42
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment cohort 1: 05/04/2017 - 25/04/2019 Recruitment cohort 2a: 05/04/2017 - 15/12/2017 Recruitment cohort 2b: 24/10/2018 - 28/07/2022 Last Patient Out: 20/11/2023

    Pre-assignment
    Screening details
    		 Screenings: 127 patients Screening failures: 37 patients (cohort 1: 20; cohort 2a: 10; cohort 2b: 7) Reasons for screening failures: - non-fulfillment of inclusion criterion: 17 patients - fulfillment of exclusion criterion: 18 patients - withdrawal of ICF during screening: 2 patients Pre-screeenings (for cohort 2b only): 297 patients

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    As this was a single-arm, non-randomized open-label study, blinding did not apply.

    Arms
    Arm title
    		 Single arm
    Arm description
    		 Cohort 1 (non-squamous NSCLC): Treatment Part A: nivolumab 240 mg IV q2w as monotherapy; at the time of disease progression another re-biopsy; then Treatment Part B: combination therapy (nivolumab in a dose of 3 mg/kg q2w together with ipilimumab 1 mg/kg IV q6w (with a 12 days gap between last dose of nivolumab and nivolumab + ipilimumab). In case of occurrence of intolerable toxicity attributed to the combination therapy, treatment was continued with nivolumab 240 mg q2w monotherapy only. Cohort 2a (SCLC all-comer) + 2b (SCLC TMB high): Treatment Part A: nivolumab 1 mg/kg q3w together with ipilimumab 3 mg/kg q3w for a total of four doses, in case of occurrence of an AE and if AE was attributed to combination therapy, it was possible to continue treatment with Part B without completion of the four combined doses. Treatment Part B: another optional rebiopsy, then nivolumab 240 mg q2w monotherapy until disease progression or inacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    OPDIVO
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cohort 1: - Part A: nivolumab (monotherapy) 240 mg as a 30 minute IV-infusion, every 2 weeks - Part B: nivolumab (in combination with ipilimumab) dose = 3 mg/kg as a 30 minute IV-infusion, every 2 weeks Cohort 2a and 2b: - Part A: 4 doses of nivolumab (in combination with ipilimumab), dose = 1 mg/kg as a 30 minute IV-infusion, every 3 weeks - Part B: nivolumab (monotherapy) 240 mg as a 30 minute IV-infusion every 2 weeks For combination therapy with ipilimumab: Nivolumab should be administered as a 30 minute infusion, followed by Ipilimumab as a 90 minutes infusion (in between 30 min break)

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    YERVOY
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cohort 1: - Part A: no administration of ipilimumab - Part B: ipilimumab (in combination with nivolumab) dose = 1 mg/kg as a 90 minute IV-infusion, every 6 weeks Cohort 2a and 2b: -Part A: four doses of ipilimumab (in combination with nivolumab) dose = 3 mg/kg as a 90 minute IV-infusion, every 3 weeks -Part B: no administration of ipilimumab For combination therapy of nivolumab + ipilimumab: nivolumab should be administered as a 30 minute infusion, followed by ipilimumab as a 90 minute infusion (in between 30 min break)

    Number of subjects in period 1
    		Single arm
    Started
    90
    Completed
    90

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 90 90
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 47 47
        From 65-84 years
    		 42 42
        85 years and over
    		 1 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 63.0 (38 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 41 41
        Male
    		 49 49
    Subject analysis sets

    Subject analysis set title
    Response-evaluable population - cohort 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The response-evaluable population includes all patients who received at least one dose of study medication and who had at least one follow-up tumor assessment (except patients with a switch of tumor histology (all cohorts) and patients who received additional tumor treatment within the trial). The response-evaluable population was the primary population for the efficacy endpoints ORR, DCR, DR, TTR, PFS and OS. Subjects who continued treatment beyond initial investigator-assessed, RECIST 1.1-defined progression were considered to have investigator-assessed progressive disease at the time of the initial progression event.

    Subject analysis set title
    Response-evaluable population - cohort 2b
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The response-evaluable population includes all patients who received at least one dose of study medication and who had at least one follow-up tumor assessment (except patients with a switch of tumor histology (all cohorts)). The response-evaluable population was the primary population for the efficacy endpoints ORR, DCR, DR, TTR, PFS and OS. Subjects who continued treatment beyond initial investigator-assessed, RECIST 1.1-defined progression were considered to have investigator-assessed progressive disease at the time of the initial progression event.

    Subject analysis set title
    Response-evaluable population - cohort 2a
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The response-evaluable population includes all patients who received at least one dose of study medication and who had at least one follow-up tumor assessment (except patients with a switch of tumor histology (all cohorts) patients in cohort 2a treated analogously to cohort 1). The response-evaluable population was the primary population for the efficacy endpoints ORR, DCR, DR, TTR, PFS and OS. Subjects who continued treatment beyond initial investigator-assessed, RECIST 1.1-defined progression were considered to have investigator-assessed progressive disease at the time of the initial progression event. Subjects in cohort 2a, who were treated analogous to cohort 1 for safety reasons after two treatmentrelated deaths occurred, were only included in the response-evaluable population, if they received at least one dose of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg + follow-up assessment before switch.

    Subject analysis set title
    Safety analysis population - cohort 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis population includes all enrolled patients who received at least one dose of study medication. It is the primary population for evaluating patient characteristics, treatment compliance, toxicity and AEs.

    Subject analysis set title
    Safety analysis population - cohort 2b
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The safety analysis population includes all enrolled patients who received at least one dose of study medication. It is the primary population for evaluating patient characteristics, treatment compliance, toxicity and AEs.

    Subject analysis set title
    Safety analysis population - cohort 2a
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The safety analysis population includes all enrolled patients who received at least one dose of study medication. It is the primary population for evaluating patient characteristics, treatment compliance, toxicity and AEs.

    Subject analysis sets values
    		 Response-evaluable population - cohort 1 Response-evaluable population - cohort 2b Response-evaluable population - cohort 2a Safety analysis population - cohort 1 Safety analysis population - cohort 2b Safety analysis population - cohort 2a
    Number of subjects
    25
    45
    15
    27
    45
    18
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    12
    26
    7
    13
    26
    8
        From 65-84 years
    13
    19
    8
    13
    19
    10
        85 years and over
    0
    0
    0
    1
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    66.0 (42 to 79)
    62.0 (38 to 79)
    65.0 (46 to 80)
    66.0 (42 to 85)
    62.0 (38 to 79)
    65.5 (64 to 80)
    Gender categorical
    Units: Subjects
        Female
    12
    23
    5
    12
    23
    6
        Male
    13
    22
    10
    15
    22
    12

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 Cohort 1 (non-squamous NSCLC): Treatment Part A: nivolumab 240 mg IV q2w as monotherapy; at the time of disease progression another re-biopsy; then Treatment Part B: combination therapy (nivolumab in a dose of 3 mg/kg q2w together with ipilimumab 1 mg/kg IV q6w (with a 12 days gap between last dose of nivolumab and nivolumab + ipilimumab). In case of occurrence of intolerable toxicity attributed to the combination therapy, treatment was continued with nivolumab 240 mg q2w monotherapy only. Cohort 2a (SCLC all-comer) + 2b (SCLC TMB high): Treatment Part A: nivolumab 1 mg/kg q3w together with ipilimumab 3 mg/kg q3w for a total of four doses, in case of occurrence of an AE and if AE was attributed to combination therapy, it was possible to continue treatment with Part B without completion of the four combined doses. Treatment Part B: another optional rebiopsy, then nivolumab 240 mg q2w monotherapy until disease progression or inacceptable toxicity

    Subject analysis set title
    Response-evaluable population - cohort 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The response-evaluable population includes all patients who received at least one dose of study medication and who had at least one follow-up tumor assessment (except patients with a switch of tumor histology (all cohorts) and patients who received additional tumor treatment within the trial). The response-evaluable population was the primary population for the efficacy endpoints ORR, DCR, DR, TTR, PFS and OS. Subjects who continued treatment beyond initial investigator-assessed, RECIST 1.1-defined progression were considered to have investigator-assessed progressive disease at the time of the initial progression event.

    Subject analysis set title
    Response-evaluable population - cohort 2b
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The response-evaluable population includes all patients who received at least one dose of study medication and who had at least one follow-up tumor assessment (except patients with a switch of tumor histology (all cohorts)). The response-evaluable population was the primary population for the efficacy endpoints ORR, DCR, DR, TTR, PFS and OS. Subjects who continued treatment beyond initial investigator-assessed, RECIST 1.1-defined progression were considered to have investigator-assessed progressive disease at the time of the initial progression event.

    Subject analysis set title
    Response-evaluable population - cohort 2a
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The response-evaluable population includes all patients who received at least one dose of study medication and who had at least one follow-up tumor assessment (except patients with a switch of tumor histology (all cohorts) patients in cohort 2a treated analogously to cohort 1). The response-evaluable population was the primary population for the efficacy endpoints ORR, DCR, DR, TTR, PFS and OS. Subjects who continued treatment beyond initial investigator-assessed, RECIST 1.1-defined progression were considered to have investigator-assessed progressive disease at the time of the initial progression event. Subjects in cohort 2a, who were treated analogous to cohort 1 for safety reasons after two treatmentrelated deaths occurred, were only included in the response-evaluable population, if they received at least one dose of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg + follow-up assessment before switch.

    Subject analysis set title
    Safety analysis population - cohort 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis population includes all enrolled patients who received at least one dose of study medication. It is the primary population for evaluating patient characteristics, treatment compliance, toxicity and AEs.

    Subject analysis set title
    Safety analysis population - cohort 2b
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The safety analysis population includes all enrolled patients who received at least one dose of study medication. It is the primary population for evaluating patient characteristics, treatment compliance, toxicity and AEs.

    Subject analysis set title
    Safety analysis population - cohort 2a
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The safety analysis population includes all enrolled patients who received at least one dose of study medication. It is the primary population for evaluating patient characteristics, treatment compliance, toxicity and AEs.

    Primary: Overall response rate (ORR)

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    End point title
    		 Overall response rate (ORR)
    End point description
    ORR per RECIST 1.1 with 95% confidence interval was calculated based on all patients in the response-evaluable population. ORR was defined as proportion of subjects whose best confirmed objective response is a CR or PR as assessed by RECIS v1.1, relative to the evaluable population. Cohort 1: ORR according to investigator-assessed RECIST 1.1 criteria of the combination of nivolumab and ipilimumab after progression on nivolumab monotherapy in patients re-lapsed with non-squamous NSCLC. Cohort 2a: ORR according to investigator-assessed RECIST 1.1 criteria of the combination of nivolumab and ipilimumab in patients with relapsed SCLC and non-discriminated TMB. Cohort 2b: ORR according to investigator-assessed RECIST 1.1 criteria of the combination of nivolumab and ipilimumab in patients with relapsed SCLC and high TMB.
    End point type
    Primary
    End point timeframe
    05/04/2017 to 31/08/2022
    End point values
    		 Response-evaluable population - cohort 1 Response-evaluable population - cohort 2b Response-evaluable population - cohort 2a
    Number of subjects analysed
    12 [1]
    43 [2]
    15
    Units: patients
    1
    4
    4
    Notes
    [1] - Only 12 patients were treated in treatment part B. ORR of treatment part B is the primary endpoint
    [2] - 2 pts are not included in per protocol analysis due to add. tumor treatment or staging too early
    Statistical analysis title
    		 Cohort 1, Cohort 2a, Cohort 2b
    Comparison groups
    Response-evaluable population - cohort 2b v Response-evaluable population - cohort 1 v Response-evaluable population - cohort 2a
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0 [3]
    Method
    		 p not applicable
    Confidence interval
    Notes
    [3] - No comparison was performed between the 3 cohorts
    Statistical analysis title
    		 Cohort 1, Cohort 2a, Cohort 2b
    Comparison groups
    Response-evaluable population - cohort 2a v Response-evaluable population - cohort 1 v Response-evaluable population - cohort 2b
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0 [4]
    Method
    		 p not applicable
    Confidence interval
    Notes
    [4] - No comparison between the 3 cohorts was performed
    Statistical analysis title
    		 Cohort 1, Cohort 2a, Cohort 2b
    Comparison groups
    Response-evaluable population - cohort 2b v Response-evaluable population - cohort 2a v Response-evaluable population - cohort 1
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0 [5]
    Method
    		 p not applicable
    Confidence interval
    Notes
    [5] - No comparison was done between the 3 cohorts

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first intake of study drug (or if adverse events related to study procedures, after signature of informed consent), and for a minimum of 100 days following the last intake of study drug (or for serious adverse events until end of survival follow-up)
    Adverse event reporting additional description
    Frequent study visits with laboratory assessments.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 NSCLC

    Reporting group title
    Cohort 2a
    Reporting group description
    		 SCLC all-comer

    Reporting group title
    Cohort 2b
    Reporting group description
    		 SCLC TMB high

    Serious adverse events
    		 Cohort 1 Cohort 2a Cohort 2b
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 27 (92.59%)
    18 / 18 (100.00%)
    43 / 45 (95.56%)
         number of deaths (all causes)
    18
    16
    37
         number of deaths resulting from adverse events
    18
    16
    37
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    14 / 27 (51.85%)
    9 / 18 (50.00%)
    25 / 45 (55.56%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 10
    0 / 28
         deaths causally related to treatment / all
    0 / 14
    0 / 9
    0 / 27
    Metastases to meninges
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Cancer pain
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Small cell lung cancer
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pseudoprogression
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cancer surgery
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheterisation venous
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 18 (5.56%)
    5 / 45 (11.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 5
    Fatigue
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 18 (11.11%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Injection site inflammation
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Pain
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Pyrexia
         subjects affected / exposed
    4 / 27 (14.81%)
    1 / 18 (5.56%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Dyspnoea
         subjects affected / exposed
    4 / 27 (14.81%)
    2 / 18 (11.11%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Pleural effusion
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 18 (11.11%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Transaminases
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Transaminases increased
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Femoral neck fracture
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Femur fracture
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Atrial flutter
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Cardiogenic shock
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Sinus tachycardia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Ventricular fibrillation
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Diabetic hyperosmolar coma
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Disorientation
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Hemiparesis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Seizure
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sensory loss
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Somnolence
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Lymphadenitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Neutropenia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         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
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Autoimmune colitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune pancreatitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Diarrhoea
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 18 (5.56%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Gastric perforation
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Immune-mediated pancreatitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Nausea
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Jaundice
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Prerenal failure
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Pyelocaliectasis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 18 (11.11%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hyperthyroidism
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (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
    COVID-19
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Infection
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 18 (11.11%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 45 (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
    Diabetes mellitus
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 18 (16.67%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 Cohort 2a Cohort 2b
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 27 (92.59%)
    16 / 18 (88.89%)
    39 / 45 (86.67%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    6 / 45 (13.33%)
         occurrences all number
    1
    4
    15
    Amylase increased
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 18 (16.67%)
    6 / 45 (13.33%)
         occurrences all number
    3
    3
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 18 (16.67%)
    5 / 45 (11.11%)
         occurrences all number
    1
    5
    11
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    7 / 45 (15.56%)
         occurrences all number
    2
    1
    8
    Blood creatinine increased
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 18 (22.22%)
    3 / 45 (6.67%)
         occurrences all number
    1
    6
    3
    C-reactive protein increased
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 18 (11.11%)
    1 / 45 (2.22%)
         occurrences all number
    3
    2
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 18 (11.11%)
    6 / 45 (13.33%)
         occurrences all number
    13
    3
    14
    Lipase increased
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 18 (16.67%)
    9 / 45 (20.00%)
         occurrences all number
    4
    5
    16
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    9 / 45 (20.00%)
         occurrences all number
    0
    0
    18
    Platelet count decreased
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 18 (11.11%)
    4 / 45 (8.89%)
         occurrences all number
    2
    2
    5
    Weight decreased
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    2
    0
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 18 (11.11%)
    2 / 45 (4.44%)
         occurrences all number
    11
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 27 (25.93%)
    3 / 18 (16.67%)
    5 / 45 (11.11%)
         occurrences all number
    10
    4
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    5 / 45 (11.11%)
         occurrences all number
    1
    0
    5
    Chest pain
         subjects affected / exposed
    6 / 27 (22.22%)
    1 / 18 (5.56%)
    0 / 45 (0.00%)
         occurrences all number
    6
    1
    0
    Fatigue
         subjects affected / exposed
    6 / 27 (22.22%)
    9 / 18 (50.00%)
    17 / 45 (37.78%)
         occurrences all number
    8
    10
    18
    Oedema peripheral
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    5 / 45 (11.11%)
         occurrences all number
    1
    1
    6
    Pyrexia
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 18 (16.67%)
    0 / 45 (0.00%)
         occurrences all number
    4
    3
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    1
    0
    5
    Diarrhoea
         subjects affected / exposed
    5 / 27 (18.52%)
    8 / 18 (44.44%)
    15 / 45 (33.33%)
         occurrences all number
    7
    13
    21
    Nausea
         subjects affected / exposed
    9 / 27 (33.33%)
    5 / 18 (27.78%)
    9 / 45 (20.00%)
         occurrences all number
    10
    6
    9
    Vomiting
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    3 / 45 (6.67%)
         occurrences all number
    1
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 27 (33.33%)
    4 / 18 (22.22%)
    4 / 45 (8.89%)
         occurrences all number
    11
    4
    6
    Dyspnoea
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 18 (11.11%)
    3 / 45 (6.67%)
         occurrences all number
    3
    2
    5
    Pneumonitis
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 18 (16.67%)
    4 / 45 (8.89%)
         occurrences all number
    2
    4
    4
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 18 (5.56%)
    4 / 45 (8.89%)
         occurrences all number
    2
    1
    4
    Pruritus
         subjects affected / exposed
    3 / 27 (11.11%)
    4 / 18 (22.22%)
    13 / 45 (28.89%)
         occurrences all number
    4
    4
    18
    Rash
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 18 (16.67%)
    8 / 45 (17.78%)
         occurrences all number
    2
    3
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 18 (16.67%)
    3 / 45 (6.67%)
         occurrences all number
    0
    3
    3
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 18 (22.22%)
    4 / 45 (8.89%)
         occurrences all number
    2
    4
    4
    Hypothyroidism
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 18 (11.11%)
    1 / 45 (2.22%)
         occurrences all number
    2
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 18 (27.78%)
    3 / 45 (6.67%)
         occurrences all number
    2
    6
    6
    Back pain
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 18 (11.11%)
    4 / 45 (8.89%)
         occurrences all number
    5
    4
    4
    Infections and infestations
    Infection
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 18 (5.56%)
    3 / 45 (6.67%)
         occurrences all number
    6
    1
    4
    Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    3 / 45 (6.67%)
         occurrences all number
    1
    1
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 27 (11.11%)
    4 / 18 (22.22%)
    3 / 45 (6.67%)
         occurrences all number
    5
    4
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 27 (14.81%)
    0 / 18 (0.00%)
    7 / 45 (15.56%)
         occurrences all number
    5
    0
    8
    Hypokalaemia
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 18 (11.11%)
    5 / 45 (11.11%)
         occurrences all number
    1
    4
    5
    Hyponatraemia
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 18 (11.11%)
    10 / 45 (22.22%)
         occurrences all number
    3
    3
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2018
    Protocol Amendment 1 comprised replacement of deep rectal swabs by stool samples for microbiome analysis, as this sample modality was more feasibly for patients to perform and a higher return flow for samples was expected. Some clarifications of reporting period for SAEs related to study drug or to study-related procedures were included as well as specification of SAE reporting of SAEs related to disease progression. Other changes in amendment 1 concerned new safety data on nivolumab and ipilimumab.
    30 Oct 2018
    With Protocol Amendment 2, cohort 2 was modified to include SCLC patients with high tumor mutation burden only and TMB pre-screening was implemented for SCLC patients. This amendment was necessary as in December 2017, two treatment-related had occured. As new data were presented, which indicated that the combination therapy of nivolumab and ipilimumab in SCLC patients only had beneficial effects in patients with high tumor mutation burden, a risk-benefit consideration lead to stop of recruitment in cohort 2. The remaining SCLC patients in the trial were treated analogous to the NSCLC patients in cohort 1 for safety reasons.
    18 Dec 2019
    Protocol Amendment 4: The original cohort 2 was subdivided in cohort 2a for the terminated cohort of SCLC patients who were not TMB discriminated and in cohort 2b for patients with high tumor mutation burden. The renaming was performed in order to have a clear separation of the biologically different patient groups. Additionally, the initial mandatory rebiopsy before study treatment was changed to optional in cohort 2b. This decision was made after one procedure-related death had occurred for bronchoscopic tumor biopsy in a trial subject who had responded well to study drug treatment. Protocol amendment 3 was rejected by EC, but approved by CA. Rrecruitment for NSCLC patients (cohort 1) was closed. This decision had been made as a high dropout rate from treatment part A to part B was observed. Thus, due to lack of feasibility, enrolment to this cohort was terminated early. Subjects enrolled into this cohort prior to the amendment continued to receive treatment with study drugs per protocol. For the SCLC cohort, the amendment included expansion of the patient number to a total of 79 trial subjects (TMB high plus TMB non-discriminated SCLC patients).
    05 Jun 2020
    Protocol Amendment 5 comprised a modification of inclusion criteria for SCLC patients in cohort 2b. Given the fact, that some patients receive rechallenge treatment with a platinum-based therapy instead of topotecan, enrolment after 2nd line therapy was allowed independent of the drug used in 2.line (with exception to monotherapy with anti-PD-1/-PD-L1/-CTLA-4 antibodies) to allow a more realistic treatment setting. Additionally, the interval between radiation of brain metastases and start of study treatment was eliminated as data indicated that both can be performed simultaneously without increase of toxicity. This indicated that delay of study treatment would be potentially more harmful to the patient, given the rapid growth of this tumor entity.
    15 Oct 2021
    Protocol Amendment 6 was performed for adjustment of statistical plan for cohort 2b. The original plan was a one-stage A’Hern design with response proportions ��0 = 0.075 and ��1 = 0.2, �� = 0.1 and �� = 0.10. Here, 51 evaluable patients were required, the null hypothesis ��0: �� ≤ 0.075 would have been rejected if at least 7 responses in 51 patients were observed. By the same assumptions and expectation as described above, 59 (≈ 51/0.9) patients would be needed to be enrolled, thus 563 patients were expected to be screened in total to include 59 TMB high patients. As recruitment into the trial was slower than anticipated, the patient number was reduced within a modified statistic which still provided sufficient power for primary endpoint analysis. Additionally, some clarifications concerning the screening biopsy in cohort 2b were provided.
    19 Dec 2022
    With Protocol Amendment 7, timelines for conduct of the trial were modified and enrolment for cohort 2b was closed, as the cohort was fully recruited.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Dec 2017
    The cohort 2a (SCLC all-comer) was stopped for recruitment after eighteen patients had been enrolled as two treatment-related deaths had occurred. Cohort 2b was opened for SCLC patients with high tumor mutation burden in October 2018.
    30 Oct 2018
    25 Apr 2019
    The cohort 1 (NSCLC) had to be terminated early due to lack of feasibility as there was a high dropout rate (50%) from treatment part A to part B. This was partially due to either rapid disease progression which led to physicians’ decision of performing treatment outside the trial and partially due to immune-related adverse events in treatment part A that would not allow therapy-escalation by adding ipilimumab. Furthermore, during the course of the trial the anti-PD-1 antibody pembrolizumab was approved in 1st line treatment of NSCLC, either alone or in combination with chemotherapy. This approval altered the basic conditions for the conduct of the trial as only immunotherapy-naïve were allowed to be enrolled into this cohort.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Cohort 1: terminated early Cohort 2a: terminated early

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26762738
    http://www.ncbi.nlm.nih.gov/pubmed/15117980
    http://www.ncbi.nlm.nih.gov/pubmed/7738624
    http://www.ncbi.nlm.nih.gov/pubmed/10080612
    http://www.ncbi.nlm.nih.gov/pubmed/27718847
    http://www.ncbi.nlm.nih.gov/pubmed/29658856
    http://www.ncbi.nlm.nih.gov/pubmed/12091876
    http://www.ncbi.nlm.nih.gov/pubmed/22658128
    http://www.ncbi.nlm.nih.gov/pubmed/22658127
    http://www.ncbi.nlm.nih.gov/pubmed/22437870
    http://www.ncbi.nlm.nih.gov/pubmed/20525992
    http://www.ncbi.nlm.nih.gov/pubmed/23897981
    http://www.ncbi.nlm.nih.gov/pubmed/25891304
    http://www.ncbi.nlm.nih.gov/pubmed/26027431
    http://www.ncbi.nlm.nih.gov/pubmed/26412456
    http://www.ncbi.nlm.nih.gov/pubmed/27932067
    http://www.ncbi.nlm.nih.gov/pubmed/30785829
    http://www.ncbi.nlm.nih.gov/pubmed/34648948
    http://www.ncbi.nlm.nih.gov/pubmed/33476593
    http://www.ncbi.nlm.nih.gov/pubmed/35719867
    http://www.ncbi.nlm.nih.gov/pubmed/34264316
    http://www.ncbi.nlm.nih.gov/pubmed/36426287
    http://www.ncbi.nlm.nih.gov/pubmed/29731394
    http://www.ncbi.nlm.nih.gov/pubmed/34562610
    http://www.ncbi.nlm.nih.gov/pubmed/28813164
    http://www.ncbi.nlm.nih.gov/pubmed/34051329
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