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    Clinical Trial Results:
    A Phase 2, Randomized, Open-Label Study of Nivolumab Combined with Ipilimumab Versus Standard of Care in Subjects with Previously Untreated and Advanced (unresectable or metastatic) non-clear Cell Renal Cell Carcinoma

    Summary
    EudraCT number
    		 2016-000706-12
    Trial protocol
    		 DE   AT   NL   CZ   BE   ES   GB   FR   IT  
    Global end of trial date
    23 Nov 2023

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SUNNIFORECAST
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03075423
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Goethe University Frankfurt
    Sponsor organisation address
    Theodor-Stern-Kai 7, Frankfurt/Main, Germany, 60590
    Public contact
    Dr. Nicola Gökbuget, Goethe University Frankfurt, 0049 6963016366, goekbuget@em.uni-frankfurt.de
    Scientific contact
    Dr. Nicola Gökbuget, Goethe University Frankfurt, 0049 6963016366, goekbuget@em.uni-frankfurt.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
    29 May 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the of OS rate at 12 months of Nivolumab combined with Ipilimumab to Standard of Care in patients with previously untreated and advanced non-clear cell RCC.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice (GCP), as defined by the International Conference on Harmonisation (ICH) and in accordance with European Union Directive 2001/20/EC. The protocol and any amendments and the subject informed consent document received approval/favorable opinion from all involved national Compentent Authorities and/or from Institutional Review Boards/Independent Ethics Committees (IRB/IEC), as appropriate. All potential serious breaches of the study protocol had to be reported to the sponsor immediately. A serious breach was defined as a breach of the conditions and principles of GCP in connection with the study or the protocol, which was likely to affect, to a significant degree, the safety or physical or mental integrity of the participants of the study or the scientific value of the study. Informed consent had to be obtained before the performance of any protocol related procedures that were not part of normal patient care. Investigators had to ensure that subjects were clearly and fully informed about the purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer to participate.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Nov 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
    Netherlands: 44
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    France: 101
    Country: Number of subjects enrolled
    Germany: 86
    Worldwide total number of subjects
    316
    EEA total number of subjects
    294
    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)
    176
    From 65 to 84 years
    139
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In total, 372 patients were screened, of which 316 were enrolled, and 56 were screening failures.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivo/Ipi
    Arm description
    		 Four cycles of run-in treatment with combined nivolumab and ipilimumab was followed by nivolumab monotherapy maintenance treatment.
    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 administered during four cycles of run-in treatment every three weeeks in combination with ipilimumab. During the run-in phase, nivolumab was dosed at 3 mg/kg body weight. After run-in, nivolumab was administered at a fixed dose of 240 mg every two weeks, or at 480 mg every four weeks. Treatment was to continue until disease progression (under certain conditions, treatment beyond progression was allowed), unacceptable toxicity, withdrawal of consent, or death.

    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 administered during four cycles of run-in treatment every three weeeks in combination with nivolumab. Ipilimumab was dosed at 1 mg/kg body weight. Treatment was to continue until disease progression (under certain conditions, treatment beyond progression was allowed), unacceptable toxicity, withdrawal of consent, or death.

    Arm title
    		 Standard-of-care (SOC)
    Arm description
    		 At the beginnig of the study, sunitinib was the only SOC comparator to be used as per protocol. The protocol was then amended to allow for all authorized treatment regimens, to be allocated to patients as per standard-of-care and by discretion of the investigator. Of the 143 patients treated in the SOC arm, 112 (78.3%) received sunitinib, 10 (7.0%) cabozantinib, 1 (0.7%) pazopanib, 1 (0.7%) lenvatinib 15 (10.5%) axitinib in combination with a checkpoint inhibitor, 2 (1.4%) cabozantinib combined with nivolumab, and one patient each (0.7%, respectively) received cisplatin with gemcitabine, and MVAC (methotrexate, vinblastine, doxorubicin and cisplatin).
    Arm type
    		 standard-of-care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Nivo/Ipi Standard-of-care (SOC)
    Started
    157
    152
    Completed
    156
    143
    Not completed
    1
    9
         Consent withdrawn by subject
    -
    5
         Patient's wish
    -
    2
         Other
    1
    1
         Study ended by sponsor
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 316 enrolled patients, 7 were not randomized. The full analysis set for this study, therefore, contains the 309 randomized participants, and baseline characteristics are reported for this set.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivo/Ipi
    Reporting group description
    		 Four cycles of run-in treatment with combined nivolumab and ipilimumab was followed by nivolumab monotherapy maintenance treatment.

    Reporting group title
    Standard-of-care (SOC)
    Reporting group description
    		 At the beginnig of the study, sunitinib was the only SOC comparator to be used as per protocol. The protocol was then amended to allow for all authorized treatment regimens, to be allocated to patients as per standard-of-care and by discretion of the investigator. Of the 143 patients treated in the SOC arm, 112 (78.3%) received sunitinib, 10 (7.0%) cabozantinib, 1 (0.7%) pazopanib, 1 (0.7%) lenvatinib 15 (10.5%) axitinib in combination with a checkpoint inhibitor, 2 (1.4%) cabozantinib combined with nivolumab, and one patient each (0.7%, respectively) received cisplatin with gemcitabine, and MVAC (methotrexate, vinblastine, doxorubicin and cisplatin).

    Reporting group values
    		 Nivo/Ipi Standard-of-care (SOC) Total
    Number of subjects
    		 157 152 309
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 61.4 (18.8 to 81.8) 64.0 (19.4 to 86.2) -
    Gender categorical
    Units: Subjects
        Female
    		 45 45 90
        Male
    		 112 107 219
    Histology
    Histology as registered in the eCRF for stratified randomization. Per default, results from central pathology assessments were to be used. However, if central pathology results were pending at the time of randomization, local pathology results were used instead.
    Units: Subjects
        Papillary
    		 99 91 190
        Non-papillary
    		 58 60 118
        Missing
    		 0 1 1
    IMDC Score
    Prognosis according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score
    Units: Subjects
        Favourable
    		 39 35 74
        Intermediate
    		 79 81 160
        Poor
    		 39 36 75

    End points

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    End points reporting groups
    Reporting group title
    Nivo/Ipi
    Reporting group description
    		 Four cycles of run-in treatment with combined nivolumab and ipilimumab was followed by nivolumab monotherapy maintenance treatment.

    Reporting group title
    Standard-of-care (SOC)
    Reporting group description
    		 At the beginnig of the study, sunitinib was the only SOC comparator to be used as per protocol. The protocol was then amended to allow for all authorized treatment regimens, to be allocated to patients as per standard-of-care and by discretion of the investigator. Of the 143 patients treated in the SOC arm, 112 (78.3%) received sunitinib, 10 (7.0%) cabozantinib, 1 (0.7%) pazopanib, 1 (0.7%) lenvatinib 15 (10.5%) axitinib in combination with a checkpoint inhibitor, 2 (1.4%) cabozantinib combined with nivolumab, and one patient each (0.7%, respectively) received cisplatin with gemcitabine, and MVAC (methotrexate, vinblastine, doxorubicin and cisplatin).

    Primary: OS rate after 12 months

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    End point title
    		 OS rate after 12 months
    End point description
    End point type
    Primary
    End point timeframe
    Overall survival was defined as the time from randomization to the date of death from any cause. OS rate at 12 months was defined as the proportion of patients alive at the milestone of 12 months after randomization.
    End point values
    		 Nivo/Ipi Standard-of-care (SOC)
    Number of subjects analysed
    157
    152
    Units: Percentage
        number (confidence interval 95%)
    78.25 (70.93 to 83.94)
    68.33 (59.98 to 75.30)
    Statistical analysis title
    		 Superiority of OS12 rate
    Statistical analysis description
    The statstical hypothesis test was a standard z test for comparison of 2 survival rates using Greenwood's formula.
    Comparison groups
    Nivo/Ipi v Standard-of-care (SOC)
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0263
    Method
    		 see 'Analysis description'
    Confidence interval

    Secondary: OS rates after 6 and 18 months

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    End point title
    		 OS rates after 6 and 18 months
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival was defined as the time from randomization to the date of death from any cause. OS milestone rates were defined as the proportion of patients alive at the milestone of 6 and 18 months after randomization.
    End point values
    		 Nivo/Ipi Standard-of-care (SOC)
    Number of subjects analysed
    157
    152
    Units: Percentage
    number (confidence interval 95%)
        OS rate at 6 months
    91.08 (85.40 to 94.62)
    85.41 (78.50 to 90.23)
        OS rate at 18 monhts
    66.69 (58.71 to 73.49)
    60.22 (51.61 to 67.78)
    No statistical analyses for this end point

    Secondary: Median OS

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    End point title
    		 Median OS
    End point description
    For subjects that were alive, their survival time was to be censored at the date of last contact (“last known alive date”). Overall survival was to be censored for subjects at the date of randomization if they were randomized but had no follow-up.
    End point type
    Secondary
    End point timeframe
    Overall survival was defined as the time from randomization to the date of death from any cause.
    End point values
    		 Nivo/Ipi Standard-of-care (SOC)
    Number of subjects analysed
    157
    152
    Units: Months
        median (confidence interval 95%)
    33.22 (23.37 to 40.76)
    25.22 (18.81 to 33.02)
    No statistical analyses for this end point

    Secondary: PFS rates after 6, 12, and 18 months

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    End point title
    		 PFS rates after 6, 12, and 18 months
    End point description
    The following censoring rules were to be applied for the primary definition of PFS: • Subjects who did not progress were to be censored on the date of their last evaluable tumor assessment. • Subjects who did not have any on-study tumor assessments and did not die were to be censored on their date of randomization. • Subjects who received subsequent systemic anti-cancer therapy prior to documented progression were to be censored at the date of the last tumor assessment prior to the initiation of the new therapy.
    End point type
    Secondary
    End point timeframe
    PFS was specified as the time between the date of randomization and the first date of documented progression, based on assessment by Independent Radiology Review Committee (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first.
    End point values
    		 Nivo/Ipi Standard-of-care (SOC)
    Number of subjects analysed
    157
    152
    Units: Percentage
    number (confidence interval 95%)
        6-month PFS rate
    45.25 (37.12 to 53.02)
    46.60 (37.86 to 53.02)
        12-month PFS rate
    28.81 (21.39 to 36.64)
    30.37 (22.50 to 38.60)
        18-month PFS rate
    23.44 (16.50 to 31.10)
    20.55 (13.81 to 28.23)
    No statistical analyses for this end point

    Secondary: Median PFS

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    End point title
    		 Median PFS
    End point description
    The following censoring rules were to be applied for the primary definition of PFS: • Subjects who did not progress were to be censored on the date of their last evaluable tumor assessment. • Subjects who did not have any on-study tumor assessments and did not die were to be censored on their date of randomization. • Subjects who received subsequent systemic anti-cancer therapy prior to documented progression were to be censored at the date of the last tumor assessment prior to the initiation of the new therapy.
    End point type
    Secondary
    End point timeframe
    PFS was specified as the time between the date of randomization and the first date of documented progression, based on IRRC assessment (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first.
    End point values
    		 Nivo/Ipi Standard-of-care (SOC)
    Number of subjects analysed
    157
    152
    Units: Months
        median (confidence interval 95%)
    5.36 (3.17 to 7.80)
    5.65 (5.39 to 8.30)
    No statistical analyses for this end point

    Secondary: Radiologic response

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    End point title
    		 Radiologic response
    End point description
    For patients without a documented end of treatment date, the date of last infusion (experimental arm) respective the last date of the last cycles (SOC arm) was used to determine the end of treatment. All tumor assessments until 35 days after the end of treatment were included in the analysis of best overall response.
    End point type
    Secondary
    End point timeframe
    Radiologic response was assessed by the clinicians using the RECIST 1.1 criteria for tumor response at baseline and the every 12 weeks as long as the patient was under study treatment.
    End point values
    		 Nivo/Ipi Standard-of-care (SOC)
    Number of subjects analysed
    125
    124
    Units: Patients
        Complete Response
    10
    2
        Partial Response
    31
    22
        Stable Disease
    41
    77
        Progressive Disease
    43
    23
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    The objective response rate was defined as the proportion of randomized subjects who achieve a best response of complete remission (CR) or partial remission (PR) using the RECIST1.1 criteria.
    End point type
    Secondary
    End point timeframe
    Radiologic response was assessed by the clinicians using the RECIST criteria for tumor response at baseline and the every 12 weeks as long as the patient was under study treatment.
    End point values
    		 Nivo/Ipi Standard-of-care (SOC)
    Number of subjects analysed
    125
    124
    Units: Patients
        Patients with objective response
    41
    24
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from start of study drug treatment until 30 days after discontinuation of dosing. Adverse events occurring before administration of study drug were considered and documented as baseline signs and symptoms.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Experimental (Nivo-Ipi)
    Reporting group description
    		 -

    Reporting group title
    Standard-of-care
    Reporting group description
    		 -

    Serious adverse events
    		 Experimental (Nivo-Ipi) Standard-of-care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    75 / 156 (48.08%)
    55 / 152 (36.18%)
         number of deaths (all causes)
    93
    90
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms - other
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    1 / 156 (0.64%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures - other
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Unintended pregnancy
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 156 (1.28%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    4 / 156 (2.56%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu like symptoms
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and asc - other
         subjects affected / exposed
    2 / 156 (1.28%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 156 (1.28%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmue disorder
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnea
         subjects affected / exposed
    3 / 156 (1.92%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Epistaxis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngopharyngeal dysesthesia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 156 (1.92%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders - other
         subjects affected / exposed
    2 / 156 (1.28%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CPK increased
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations - other
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell decreased
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders - other
         subjects affected / exposed
    3 / 156 (1.92%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Heart failure
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dysarthria
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders - other
         subjects affected / exposed
    1 / 156 (0.64%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Neuralgia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischemic attacks
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders - other
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye disorders - other
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 156 (3.85%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ascites
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colitis
         subjects affected / exposed
    5 / 156 (3.21%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 156 (1.92%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    3 / 156 (1.92%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophagitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders - other
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders - other
         subjects affected / exposed
    4 / 156 (2.56%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Portal vein throbosis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Bullous dermatitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders - other
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 156 (0.00%)
    6 / 152 (3.95%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis noninfective
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematuria
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal hemorrhage
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    3 / 156 (1.92%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders - other
         subjects affected / exposed
    3 / 156 (1.92%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders - other
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Biliary tract infection
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - other
         subjects affected / exposed
    3 / 156 (1.92%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 156 (2.56%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcemia
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalemia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders - other
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental (Nivo-Ipi) Standard-of-care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    152 / 156 (97.44%)
    140 / 152 (92.11%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    26 / 156 (16.67%)
    20 / 152 (13.16%)
         occurrences all number
    29
    24
    Creatinine increased
         subjects affected / exposed
    8 / 156 (5.13%)
    12 / 152 (7.89%)
         occurrences all number
    9
    13
    Lipase increased
         subjects affected / exposed
    8 / 156 (5.13%)
    9 / 152 (5.92%)
         occurrences all number
    9
    11
    Neutrophil count decreased
         subjects affected / exposed
    2 / 156 (1.28%)
    16 / 152 (10.53%)
         occurrences all number
    2
    24
    Platelet count decreased
         subjects affected / exposed
    3 / 156 (1.92%)
    24 / 152 (15.79%)
         occurrences all number
    12
    29
    Serum amylase increased
         subjects affected / exposed
    9 / 156 (5.77%)
    4 / 152 (2.63%)
         occurrences all number
    9
    6
    Weight loss
         subjects affected / exposed
    12 / 156 (7.69%)
    15 / 152 (9.87%)
         occurrences all number
    12
    15
    White blood cell decreased
         subjects affected / exposed
    0 / 156 (0.00%)
    7 / 152 (4.61%)
         occurrences all number
    0
    10
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 156 (6.41%)
    57 / 152 (37.50%)
         occurrences all number
    12
    68
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 156 (8.33%)
    13 / 152 (8.55%)
         occurrences all number
    17
    13
    Insomnia
         subjects affected / exposed
    9 / 156 (5.77%)
    10 / 152 (6.58%)
         occurrences all number
    9
    10
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    24 / 156 (15.38%)
    28 / 152 (18.42%)
         occurrences all number
    30
    35
    General disorders and administration site conditions
    Edema face
         subjects affected / exposed
    0 / 156 (0.00%)
    11 / 152 (7.24%)
         occurrences all number
    0
    13
    Edema limbs
         subjects affected / exposed
    12 / 156 (7.69%)
    7 / 152 (4.61%)
         occurrences all number
    15
    10
    Fatigue
         subjects affected / exposed
    69 / 156 (44.23%)
    91 / 152 (59.87%)
         occurrences all number
    91
    117
    Pain
         subjects affected / exposed
    16 / 156 (10.26%)
    20 / 152 (13.16%)
         occurrences all number
    21
    22
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 156 (8.97%)
    20 / 152 (13.16%)
         occurrences all number
    16
    22
    Constipation
         subjects affected / exposed
    31 / 156 (19.87%)
    26 / 152 (17.11%)
         occurrences all number
    38
    29
    Diarrhea
         subjects affected / exposed
    43 / 156 (27.56%)
    71 / 152 (46.71%)
         occurrences all number
    63
    123
    Dry mouth
         subjects affected / exposed
    11 / 156 (7.05%)
    7 / 152 (4.61%)
         occurrences all number
    11
    9
    Dysgeusia
         subjects affected / exposed
    6 / 156 (3.85%)
    41 / 152 (26.97%)
         occurrences all number
    7
    44
    Gastroesophageal reflux disease
         subjects affected / exposed
    5 / 156 (3.21%)
    25 / 152 (16.45%)
         occurrences all number
    5
    28
    Mucositis oral
         subjects affected / exposed
    7 / 156 (4.49%)
    55 / 152 (36.18%)
         occurrences all number
    8
    68
    Nausea
         subjects affected / exposed
    32 / 156 (20.51%)
    46 / 152 (30.26%)
         occurrences all number
    41
    70
    Vomiting
         subjects affected / exposed
    16 / 156 (10.26%)
    24 / 152 (15.79%)
         occurrences all number
    19
    24
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 156 (14.10%)
    21 / 152 (13.82%)
         occurrences all number
    23
    22
    Dyspnea
         subjects affected / exposed
    17 / 156 (10.90%)
    18 / 152 (11.84%)
         occurrences all number
    19
    22
    Epistaxis
         subjects affected / exposed
    1 / 156 (0.64%)
    15 / 152 (9.87%)
         occurrences all number
    1
    19
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    13 / 156 (8.33%)
    10 / 152 (6.58%)
         occurrences all number
    14
    11
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 156 (1.92%)
    40 / 152 (26.32%)
         occurrences all number
    3
    58
    Pruritus
         subjects affected / exposed
    45 / 156 (28.85%)
    4 / 152 (2.63%)
         occurrences all number
    51
    4
    Rash maculo-papular
         subjects affected / exposed
    23 / 156 (14.74%)
    8 / 152 (5.26%)
         occurrences all number
    25
    8
    Skin hypopigmentation
         subjects affected / exposed
    0 / 156 (0.00%)
    8 / 152 (5.26%)
         occurrences all number
    0
    8
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    7 / 156 (4.49%)
    9 / 152 (5.92%)
         occurrences all number
    8
    10
    Urinary tract infection
         subjects affected / exposed
    5 / 156 (3.21%)
    7 / 152 (4.61%)
         occurrences all number
    5
    8
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    25 / 156 (16.03%)
    3 / 152 (1.97%)
         occurrences all number
    27
    3
    Hypothyroidism
         subjects affected / exposed
    21 / 156 (13.46%)
    34 / 152 (22.37%)
         occurrences all number
    21
    34
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    19 / 156 (12.18%)
    16 / 152 (10.53%)
         occurrences all number
    20
    17
    Myalgia
         subjects affected / exposed
    11 / 156 (7.05%)
    8 / 152 (5.26%)
         occurrences all number
    13
    12
    Pain in extremity
         subjects affected / exposed
    6 / 156 (3.85%)
    8 / 152 (5.26%)
         occurrences all number
    6
    8
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    22 / 156 (14.10%)
    33 / 152 (21.71%)
         occurrences all number
    23
    34

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Nov 2017
    Protocol version 3.0 introduced a substantial change in the allowed treatment regimens in the comparator arm. In the initial protocol, the only drug to be used in the comparator arm was sunitinib. This was amended to allow all authorized standard-of-care agents. The reason behind this extension of comparator options was to adapt the study to the clinical reality, especially in European countries other than Germany, and to thus facilitate recruitment and the participation of study sites from different countries. However, the use of immune checkpoint inhibitors was precluded by the exclusion criteria.
    02 Jun 2020
    Protocol version 4.0 removed the restriction of using regimens containing immune checkpoint inhibitors in the SOC arm. Moreover, for the experimental arm, the option of using fixed doses of nivolumab at 480 mg 4-weekly during maintenance therapy was introduced. Moreover, instructions for toxicity management were updated, and corrections, edits for consistency and clarifications were introduced.
    20 Jul 2020
    With protocol version 4.1 the time point for the interim analysis was amended. Initially, interim analysis was to take place after 2/3 of the planned patient number had been accrued. This was changed to conducting the interim analysis after inclusion of 50% of the planned patient number. The amendment also included the correction of minor errors and updates to study results in the introduction.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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