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    Clinical Trial Results:
    An Open-label Phase 2 Multi-cohort Trial of Nivolumab in Advanced or Metastatic Malignancies (CheckMate 627: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 627)

    Summary
    EudraCT number
    		 2016-000461-23
    Trial protocol
    		 DE  
    Global end of trial date
    24 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2022
    First version publication date
    22 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-627
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    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 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the investigator-assessed ORR of nivolumab monotherapy in advanced or metastatic malignancies
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Feb 2016
    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: 65
    Country: Number of subjects enrolled
    United States: 174
    Worldwide total number of subjects
    239
    EEA total number of subjects
    65
    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)
    152
    From 65 to 84 years
    84
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 239 participants were treated.

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

    Arms
    Arm title
    		 Advanced Malignancies Cohort
    Arm description
    		 Treatment period 1: Nivolumab 240 mg Q2W for 8 doses. Treatment period 2: Nivolumab 480 mg Q4W
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-936558
    Investigational medicinal product code
    Other name
    Nivolumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg Q2W for 8 doses

    Number of subjects in period 1
    		Advanced Malignancies Cohort
    Started
    239
    Completed
    110
    Not completed
    129
         Adverse event, serious fatal
    2
         No longer meet study criteria
    1
         Disease progression
    90
         Participant withdrew consent
    3
         Participant request to discontinue
    9
         Adverse event unrelated to study drug
    12
         Other reasons
    6
         Study Drug Toxicity
    6
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Advanced Malignancies Cohort
    Arm description
    		 Treatment period 1: Nivolumab 240 mg Q2W for 8 doses. Treatment period 2: Nivolumab 480 mg Q4W
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-936558
    Investigational medicinal product code
    Other name
    Nivolumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg Q4W up to 24 months of total treatment (Treatment Period 1 + Treatment Period 2)

    Number of subjects in period 2 [1]
    		Advanced Malignancies Cohort
    Started
    103
    Completed
    19
    Not completed
    84
         Disease progression
    69
         Participant withdrew consent
    3
         Maximum clinical benefit
    1
         Participant request to discontinue
    2
         Adverse event unrelated to study drug
    1
         Other reasons
    3
         Study Drug Toxicity
    5
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all the participants who completed Treatment Period 1 continued in Treatment Period 2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Advanced Malignancies Cohort
    Reporting group description
    		 Treatment period 1: Nivolumab 240 mg Q2W for 8 doses. Treatment period 2: Nivolumab 480 mg Q4W

    Reporting group values
    		 Advanced Malignancies Cohort Total
    Number of subjects
    		 239 239
    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)
    		 152 152
        From 65-84 years
    		 84 84
        85 years and over
    		 3 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.2 ( 13.79 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 148 148
        Male
    		 91 91
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 9 9
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 20 20
        White
    		 203 203
        More than one race
    		 0 0
        Unknown or Not Reported
    		 7 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 11 11
        Not Hispanic or Latino
    		 158 158
        Unknown or Not Reported
    		 70 70

    End points

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    End points reporting groups
    Reporting group title
    Advanced Malignancies Cohort
    Reporting group description
    		 Treatment period 1: Nivolumab 240 mg Q2W for 8 doses. Treatment period 2: Nivolumab 480 mg Q4W
    Reporting group title
    Advanced Malignancies Cohort
    Reporting group description
    		 Treatment period 1: Nivolumab 240 mg Q2W for 8 doses. Treatment period 2: Nivolumab 480 mg Q4W

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1]
    End point description
    ORR is defined as the percentage of participants with a best overall response (BOR) of confirmed Complete Response (CR) or Partial Response (PR). Best overall response is defined as the best response designation, as determined by investigator, recorded in the specified timeframe, according to the RECIST 1.1 criteria.
    End point type
    Primary
    End point timeframe
    From first dose to the date of objectively documented progression (per tumor-specific response criteria) or the date of subsequent therapy, whichever occurs first (up to approximately 24 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed for this endpoint
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Percent of Participants
        number (confidence interval 95%)
    7.9 (4.9 to 12.1)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR is defined as the time from first confirmed response (Complete Response, CR or Partial Response, PR) to the date of the first documented tumor progression (as determined by investigator) or death due to any cause, whichever occurs first. Median DOR computed using Kaplan-Meier method
    End point type
    Secondary
    End point timeframe
    From the time of first confirmed response to the date of the first documented progression (up to approximately 22 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    19
    Units: Months
        median (full range (min-max))
    21.78 (2.8 to 22.3)
    No statistical analyses for this end point

    Secondary: Time to Objective Response (TTR)

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    End point title
    		 Time to Objective Response (TTR)
    End point description
    TTR is defined as the time from first dosing date to the date of the first confirmed response (Complete Response, CR or Partial Response, PR), as assessed by investigator.
    End point type
    Secondary
    End point timeframe
    From the first dosing date to the date of the first confirmed response (up to approximately 10 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    19
    Units: Months
        arithmetic mean (standard deviation)
    3.54 ( 2.337 )
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    CBR is defined as the percentage of participants with a best overall response of confirmed Complete Response (CR) or Partial Response (PR) or Stable Disease (SD).
    End point type
    Secondary
    End point timeframe
    From the first dosing date to the date of the last dose (approximately 24 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Percent of participants
        number (confidence interval 95%)
    49.8 (43.3 to 56.3)
    No statistical analyses for this end point

    Secondary: Overall Survival Rate at 1 Year

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    End point title
    		 Overall Survival Rate at 1 Year
    End point description
    Overall Survival (OS) is defined as the time from the first dosing date to the date of death. A participant who has not died will be censored at last known date alive. OS rate at 1 year is measured as the percent of participants still alive at 1 year after first dosing, measured from Kaplan-Meier curve of OS.
    End point type
    Secondary
    End point timeframe
    From the first dosing date to 1 year later
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Percent of participants
        number (confidence interval 95%)
    56.1 (49.1 to 62.5)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Died

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    End point title
    		 Number of Participants Who Died
    End point description
    Number of participants who died for any cause
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days following last dose (up approximately 27 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Participants
    72
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Adverse Events (AEs)

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    End point title
    		 Number of Participants Experiencing Adverse Events (AEs)
    End point description
    Number of participants who experienced any grade, any cause AEs
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days following the last dose (up to approximately 25 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Participants
    234
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants Experiencing Serious Adverse Events (SAEs)
    End point description
    Number of participants who experienced any grade, any cause SAEs
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days following the last dose (up to approximately 27 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Participants
    148
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation

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    End point title
    		 Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation
    End point description
    Number of participants who experienced AEs leading to discontinuation of study therapy
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days following the last dose (up to approximately 25 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Participants
    41
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Immune-mediated Adverse Events (IMAEs)

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    End point title
    		 Number of Participants Experiencing Immune-mediated Adverse Events (IMAEs)
    End point description
    Number of participants who experienced IMAEs. IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity.
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days following the last dose (up to approximately 27 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Participants
    8
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Select Adverse Events

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    End point title
    		 Number of Participants Experiencing Select Adverse Events
    End point description
    Number of participants who experienced Select Adverse Events. Select Adverse Events categories include: gastrointestinal, hepatic, pulmonary, renal, skin, hypersensitivity/infusion reaction.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days following the last dose (up to approximately 25 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Participants
        Gastrointestinal Select AEs
    57
        Hepatic Select AEs
    33
        Pulmonary Select AEs
    6
        Renal Select AEs
    22
        Skin Select AEs
    59
        Hypersensitivity/Infusion Reaction
    7
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Adverse Events (AEs) Leading to Dose Delay or Dose Reduction

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    End point title
    		 Number of Participants Experiencing Adverse Events (AEs) Leading to Dose Delay or Dose Reduction
    End point description
    Number of participants who experienced AEs leading to dose delay or dose reduction. A dose will be considered as delayed if the delay is exceeding 3 days after the intended dose date (i.e., greater than or equal to 4 days from scheduled dosing date)
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days following the last dose (up to approximately 25 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    239
    Units: Participants
    61
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Laboratory Abnormalities in Specific Liver Tests

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    End point title
    		 Number of Participants Experiencing Laboratory Abnormalities in Specific Liver Tests
    End point description
    Number of participants who experienced the laboratory abnormalities in specific liver tests described in the individual categories. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days following the last dose (up to approximately 25 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    231
    Units: Participants
        ALT OR AST > 3XULN
    11
        ALT OR AST > 5XULN
    8
        ALT OR AST > 10XULN
    3
        ALT OR AST > 20XULN
    1
        TOTAL BILIRUBIN > 2XULN
    5
        ALT/AST > 3XULN + BILIR > 2XULN 1 DAY
    3
        ALT/AST > 3XULN + BILIR > 2XULN 30 DAYS
    3
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Laboratory Abnormalities in Specific Thyroid Tests

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    End point title
    		 Number of Participants Experiencing Laboratory Abnormalities in Specific Thyroid Tests
    End point description
    Number of participants who experienced the laboratory abnormalities in specific thyroid tests described in the individual categories. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days following the last dose (up to approximately 27 months)
    End point values
    		 Advanced Malignancies Cohort
    Number of subjects analysed
    238
    Units: Participants
        TSH > ULN
    62
        TSH > ULN WITH TSH <= ULN AT BASELINE
    42
        TSH > ULN WITH AT LEAST 1 FT3/FT4 TEST VALUE < LLN
    12
        TSH > ULN WITH ALL FT3/FT4 TEST VALUE >= LLN
    0
        TSH > ULN WITH FT3/FT4 MISSING
    2
        TSH < LLN
    38
        TSH < LLN WITH TSH >= LLN AT BASELINE
    25
        TSH < LLN WITH AT LEAST 1 FT3/FT4 TEST VALUE > ULN
    8
        TSH < LLN WITH ALL FT3/FT4 TEST VALUES <= ULN
    1
        TSH < LLN WITH FT3/FT4 TEST MISSING
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was assessed from first dose to study completion date (approximately 64 months). SAEs and Other AEs were assessed from first dose to 100 days following administration of the last dose (approximately 27 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Advanced Malignancies Cohort
    Reporting group description
    		 Treatment period 1: Nivolumab 240 mg Q2W for 8 doses. Treatment period 2: Nivolumab 480 mg Q4W

    Serious adverse events
    		 Advanced Malignancies Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    148 / 239 (61.92%)
         number of deaths (all causes)
    156
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Infected neoplasm
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenoid cystic carcinoma
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm of cornea
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    58 / 239 (24.27%)
         occurrences causally related to treatment / all
    0 / 59
         deaths causally related to treatment / all
    0 / 52
    Mesothelioma
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Tumour haemorrhage
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    4 / 239 (1.67%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Penis carcinoma metastatic
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous stenosis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    4 / 239 (1.67%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyrexia
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vulvovaginal pain
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    3 / 239 (1.26%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 239 (1.67%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngeal haemorrhage
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 239 (2.09%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural fever
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuritis cranial
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial mass
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 239 (1.26%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Eye swelling
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye pain
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 239 (3.77%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 239 (2.09%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    4 / 239 (1.67%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal oedema
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    6 / 239 (2.51%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    Proctalgia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 239 (1.67%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 239 (1.67%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 239 (1.26%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 239 (1.67%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Chronic kidney disease
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Urinary tract obstruction
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 239 (1.26%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Arthralgia
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 239 (1.26%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fungaemia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    7 / 239 (2.93%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Perinephric abscess
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal abscess
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 239 (3.35%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 3
    Septic shock
         subjects affected / exposed
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 239 (1.26%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 239 (2.09%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Advanced Malignancies Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    216 / 239 (90.38%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    17 / 239 (7.11%)
         occurrences all number
    17
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    14 / 239 (5.86%)
         occurrences all number
    16
    Fatigue
         subjects affected / exposed
    90 / 239 (37.66%)
         occurrences all number
    102
    Oedema peripheral
         subjects affected / exposed
    24 / 239 (10.04%)
         occurrences all number
    25
    Pyrexia
         subjects affected / exposed
    24 / 239 (10.04%)
         occurrences all number
    29
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    43 / 239 (17.99%)
         occurrences all number
    53
    Dyspnoea
         subjects affected / exposed
    44 / 239 (18.41%)
         occurrences all number
    51
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    18 / 239 (7.53%)
         occurrences all number
    18
    Anxiety
         subjects affected / exposed
    13 / 239 (5.44%)
         occurrences all number
    13
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    12 / 239 (5.02%)
         occurrences all number
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 239 (7.53%)
         occurrences all number
    19
    Alanine aminotransferase increased
         subjects affected / exposed
    16 / 239 (6.69%)
         occurrences all number
    19
    Blood creatinine increased
         subjects affected / exposed
    15 / 239 (6.28%)
         occurrences all number
    15
    Weight decreased
         subjects affected / exposed
    22 / 239 (9.21%)
         occurrences all number
    23
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 239 (7.95%)
         occurrences all number
    21
    Dizziness
         subjects affected / exposed
    15 / 239 (6.28%)
         occurrences all number
    15
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    41 / 239 (17.15%)
         occurrences all number
    42
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    33 / 239 (13.81%)
         occurrences all number
    35
    Abdominal pain upper
         subjects affected / exposed
    12 / 239 (5.02%)
         occurrences all number
    12
    Vomiting
         subjects affected / exposed
    32 / 239 (13.39%)
         occurrences all number
    39
    Nausea
         subjects affected / exposed
    53 / 239 (22.18%)
         occurrences all number
    65
    Diarrhoea
         subjects affected / exposed
    52 / 239 (21.76%)
         occurrences all number
    66
    Constipation
         subjects affected / exposed
    50 / 239 (20.92%)
         occurrences all number
    50
    Dry mouth
         subjects affected / exposed
    14 / 239 (5.86%)
         occurrences all number
    14
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    26 / 239 (10.88%)
         occurrences all number
    29
    Rash
         subjects affected / exposed
    20 / 239 (8.37%)
         occurrences all number
    21
    Dry skin
         subjects affected / exposed
    12 / 239 (5.02%)
         occurrences all number
    12
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    21 / 239 (8.79%)
         occurrences all number
    22
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    15 / 239 (6.28%)
         occurrences all number
    16
    Arthralgia
         subjects affected / exposed
    34 / 239 (14.23%)
         occurrences all number
    38
    Back pain
         subjects affected / exposed
    27 / 239 (11.30%)
         occurrences all number
    30
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    22 / 239 (9.21%)
         occurrences all number
    26
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 239 (7.11%)
         occurrences all number
    21
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    18 / 239 (7.53%)
         occurrences all number
    24
    Dehydration
         subjects affected / exposed
    23 / 239 (9.62%)
         occurrences all number
    28
    Decreased appetite
         subjects affected / exposed
    37 / 239 (15.48%)
         occurrences all number
    39
    Hyponatraemia
         subjects affected / exposed
    15 / 239 (6.28%)
         occurrences all number
    17
    Hypophosphataemia
         subjects affected / exposed
    12 / 239 (5.02%)
         occurrences all number
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jan 2018
    - Changes to primary endpoint - Statistical section updates - Adverse events updates
    31 May 2018
    Statistical section updates

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

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

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