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    Clinical Trial Results:
    A phase Ib/II, open-label, multi-center study of INC280 in combination with PDR001 or PDR001 single agent in advanced hepatocellular carcinoma

    Summary
    EudraCT number
    		 2015-005417-76
    Trial protocol
    		 DE   IT  
    Global end of trial date
    24 Jun 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Aug 2023
    First version publication date
    11 Jun 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC280X2108
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02795429
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4056, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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
    24 Jun 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
    The primary objectives of the trial were: • Phase Ib part: To characterize the safety and tolerability of capmatinib in combination with spartalizumab and identify the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D). • Phase II part: To compare the efficacy of capmatinib in combination with spartalizumab vs. spartalizumab single agent.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 4
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hong Kong: 15
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Country: Number of subjects enrolled
    Taiwan: 6
    Worldwide total number of subjects
    89
    EEA total number of subjects
    49
    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)
    43
    From 65 to 84 years
    45
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 18 investigative sites in 8 countries.

    Pre-assignment
    Screening details
    		 The screening period began once patients had signed the study informed consent. Screening evaluations were performed within 21 days prior to the first dose of study medication. After screening, the treatment period started on Cycle 1 Day 1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W
    Arm description
    		 Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab 300 mg was administered via intravenous (i.v.) infusion once every 3 weeks (Q3W)

    Investigational medicinal product name
    Capmatinib
    Investigational medicinal product code
    INC280
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capmatinib 200 mg was administered orally as a tablet twice daily (BID)

    Arm title
    		 Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W
    Arm description
    		 Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capmatinib
    Investigational medicinal product code
    INC280
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capmatinib 300 mg was administered orally as a tablet twice daily (BID)

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab 300 mg was administered via intravenous (i.v.) infusion once every 3 weeks (Q3W)

    Arm title
    		 Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Arm description
    		 Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab 300 mg was administered via intravenous (i.v.) infusion once every 3 weeks (Q3W)

    Investigational medicinal product name
    Capmatinib
    Investigational medicinal product code
    INC280
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capmatinib 400 mg was administered orally as a tablet twice daily (BID)

    Arm title
    		 Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Arm description
    		 Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capmatinib
    Investigational medicinal product code
    INC280
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capmatinib 400 mg was administered orally as a tablet twice daily (BID)

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab 300 mg was administered via intravenous (i.v.) infusion once every 3 weeks (Q3W)

    Arm title
    		 Phase II: Spartalizumab 300 mg Q3W
    Arm description
    		 Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab 300 mg was administered via intravenous (i.v.) infusion once every 3 weeks (Q3W)

    Number of subjects in period 1
    		Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Started
    6
    10
    11
    32
    30
    Completed
    0
    0
    0
    0
    0
    Not completed
    6
    10
    11
    32
    30
         Physician decision
    -
    -
    2
    1
    5
         Death
    1
    -
    1
    2
    1
         Adverse event
    1
    2
    1
    2
    1
         Progressive disease
    3
    7
    6
    26
    20
         Subject/guardian decision
    1
    1
    1
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W
    Reporting group description
    		 Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib

    Reporting group title
    Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W
    Reporting group description
    		 Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib

    Reporting group title
    Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Reporting group description
    		 Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib

    Reporting group title
    Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Reporting group description
    		 Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II

    Reporting group title
    Phase II: Spartalizumab 300 mg Q3W
    Reporting group description
    		 Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II

    Reporting group values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W Total
    Number of subjects
    		 6 10 11 32 30 89
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 2 6 5 15 15 43
        From 65-84 years
    		 4 4 6 16 15 45
        85 years and over
    		 0 0 0 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.5 ( 7.42 ) 63.2 ( 10.24 ) 64.6 ( 8.99 ) 64.8 ( 10.02 ) 63.4 ( 9.97 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 0 2 2 3 5 12
        Male
    		 6 8 9 29 25 77
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 3 3 4 12 12 34
        White
    		 3 7 6 10 10 36
        Unknown
    		 0 0 1 10 8 19

    End points

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    End points reporting groups
    Reporting group title
    Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W
    Reporting group description
    		 Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib

    Reporting group title
    Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W
    Reporting group description
    		 Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib

    Reporting group title
    Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Reporting group description
    		 Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib

    Reporting group title
    Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Reporting group description
    		 Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II

    Reporting group title
    Phase II: Spartalizumab 300 mg Q3W
    Reporting group description
    		 Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II

    Primary: Phase Ib: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the on-treatment period

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    End point title
    		 Phase Ib: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the on-treatment period [1] [2]
    End point description
    Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE.
    End point type
    Primary
    End point timeframe
    From first dose of study medication up to 30 days after last dose, with a maximum duration of 3.3 years
    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 analysis were planned for this primary endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    Units: participants
        AEs
    6
    10
    10
        Treatment-related AEs
    5
    7
    10
        AEs with grade ≥ 3
    6
    7
    7
        Treatment-related AEs with grade ≥ 3
    4
    4
    6
        SAEs
    1
    1
    6
        Treatment-related SAEs
    0
    0
    5
        Fatal SAEs
    1
    0
    1
        Treatment-related fatal SAEs
    0
    0
    1
        AEs leading to discontinuation
    3
    4
    4
        Treatment-related AEs leading to discontinuation
    2
    1
    4
        AEs leading to dose adjustment/interruption
    3
    6
    7
        AEs requiring additional therapy
    6
    9
    10
        AE due to infusion reaction
    0
    0
    1
    No statistical analyses for this end point

    Primary: Phase Ib: Number of participants with dose reductions and dose interruptions of capmatinib and spartalizumab

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    End point title
    		 Phase Ib: Number of participants with dose reductions and dose interruptions of capmatinib and spartalizumab [3] [4]
    End point description
    Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab. No dose modifications (i.e. dose reduction) were allowed for spartalizumab.
    End point type
    Primary
    End point timeframe
    From first dose of study medication up to last dose, with a maximum duration of 3.2 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were planned for this primary endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    Units: participants
        Capmatinib dose reduction
    2
    4
    8
        Capmatinib dose interruption
    4
    6
    8
        Spartalizumab dose reduction
    0
    0
    0
        Spartalizumab dose interruption
    4
    4
    7
    No statistical analyses for this end point

    Primary: Phase Ib: Number of participants with Dose-Limiting Toxicities (DLTs) during the first 2 cycles of treatment

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    End point title
    		 Phase Ib: Number of participants with Dose-Limiting Toxicities (DLTs) during the first 2 cycles of treatment [5] [6]
    End point description
    A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first 2 cycles of treatment with capmatinib in combination with spartalizumab during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 21 days.
    End point type
    Primary
    End point timeframe
    42 days
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were planned for this primary endpoint.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    8
    9
    Units: participants
    0
    0
    1
    No statistical analyses for this end point

    Primary: Phase Ib: Dose intensity of capmatinib

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    End point title
    		 Phase Ib: Dose intensity of capmatinib [7] [8]
    End point description
    Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
    End point type
    Primary
    End point timeframe
    From first dose of study medication up to last dose, with a maximum duration of 3.2 years
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were planned for this primary endpoint.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    Units: mg/day
        median (full range (min-max))
    391.2 (294 to 400)
    580.0 (390 to 600)
    755.6 (371 to 800)
    No statistical analyses for this end point

    Primary: Phase Ib: Dose intensity of spartalizumab

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    End point title
    		 Phase Ib: Dose intensity of spartalizumab [9] [10]
    End point description
    Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
    End point type
    Primary
    End point timeframe
    From first dose of study medication up to last dose, with a maximum duration of 3.2 years
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were planned for this primary endpoint.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    Units: mg/3W
        median (full range (min-max))
    293.18 (235.7 to 300.0)
    300.00 (225.0 to 300.0)
    300.00 (272.7 to 300.0)
    No statistical analyses for this end point

    Primary: Phase II: Overall Response Rate (ORR) per RECIST v1.1

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    End point title
    		 Phase II: Overall Response Rate (ORR) per RECIST v1.1 [11]
    End point description
    Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Primary
    End point timeframe
    From start of treatment until end of treatment, assessed up to 2.2 years
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase II arms.
    End point values
    		 Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    32
    30
    Units: percentage of participants
        number (confidence interval 95%)
    9.4 (2.0 to 25.0)
    10.0 (2.1 to 26.5)
    Statistical analysis title
    		 combination vs. single agent
    Statistical analysis description
    Posterior probability of Odds ratio [ORR(spartalizumab+capmatinib) to ORR(spartalizumab)] was >=1
    Comparison groups
    Phase II: Spartalizumab 300 mg Q3W v Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    Method
    		 Bayesian Logistic Regression Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.561
    Confidence interval
         level
    		 0%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 999
    Notes
    [12] - Due to EudraCT system limitations, three data fields in this record (% Confidence Interval, Number of sides and corresponding Limits) cannot be empty. Therefore, data entered in these three fields (0%CI, 1-sided, upper limit ‘999’) are not an accurate representation of the results but entered to resolve a validation error.

    Secondary: Phase Ib and Phase II: Best Overall Response (BOR) per RECIST v1.1

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    End point title
    		 Phase Ib and Phase II: Best Overall Response (BOR) per RECIST v1.1
    End point description
    BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per RECIST v1.1. For RECIST v1.1, R=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; PD= At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression). The number of participants in each response category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: participants
        Complete Response (CR)
    0
    0
    0
    0
    0
        Partial Response (PR)
    2
    0
    2
    3
    3
        Stable Disease (SD)
    1
    7
    2
    12
    9
        Progressive Disease (PD)
    3
    2
    7
    13
    15
        Unknown
    0
    1
    0
    4
    3
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Best Overall Response (BOR) per irRC

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    End point title
    		 Phase Ib and Phase II: Best Overall Response (BOR) per irRC
    End point description
    BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per Immune-related Response Criteria (irRC). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters; irPD= At least a 20% increase in the sum of diameters of all measured target lesions including new measurable lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm; irSD= Neither sufficient shrinkage to qualify for irPR or irCR nor an increase in lesions which would qualify for irPD).
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: participants
        Immune-related Complete Response (irCR)
    0
    0
    0
    0
    0
        Immune-related Partial Response (irPR)
    2
    0
    3
    4
    3
        Immune-related Stable Disease (irSD)
    1
    7
    3
    15
    9
        Immune-related Progressive Disease (irPD)
    3
    2
    5
    10
    14
        Unknown
    0
    1
    0
    3
    4
    No statistical analyses for this end point

    Secondary: Phase Ib: Overall Response Rate (ORR) per RECIST v1.1

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    End point title
    		 Phase Ib: Overall Response Rate (ORR) per RECIST v1.1 [13]
    End point description
    Tumor response was based on local investigator assessment as per RECIST v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of treatment, assessed up to 3.2 years
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (4.3 to 77.7)
    0 (0.0 to 30.8)
    18.2 (2.3 to 51.8)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Overall Response Rate (ORR) per irRC

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    End point title
    		 Phase Ib and Phase II: Overall Response Rate (ORR) per irRC
    End point description
    Tumor response was based on local investigator assessment as per irRC. ORR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR) or immune related Partial Response (irPR). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (4.3 to 77.7)
    0 (0.0 to 30.8)
    27.3 (6.0 to 61.0)
    12.5 (3.5 to 29.0)
    10.0 (2.1 to 26.5)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Duration of Response (DOR) per RECIST v1.1

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    End point title
    		 Phase Ib and Phase II: Duration of Response (DOR) per RECIST v1.1
    End point description
    DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment of overall lesion response according to RECIST v1.1. DOR is defined as the time from the date of first documented response (confirmed CR or confirmed PR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any. According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    2
    0 [14]
    2
    3
    3
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    ( to )
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    Notes
    [14] - No patients with CR or PR
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Duration of Response (DOR) per irRC

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    End point title
    		 Phase Ib and Phase II: Duration of Response (DOR) per irRC
    End point description
    DOR only applies to patients for whom best overall response is immune-related complete response (irCR) or immune-related partial response (irPR) based on local investigator assessment of overall lesion response according to irRC. DOR is defined as the time from the date of first documented response (confirmed irCR or confirmed irPR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any. According to the SAP, summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving confirmed irCR or irPR in each treatment group. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’
    End point type
    Secondary
    End point timeframe
    From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    2
    0 [15]
    3
    4
    3
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    ( to )
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    Notes
    [15] - No patients with CR or PR
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Time to Response (TTR) per RECIST v1.1

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    End point title
    		 Phase Ib and Phase II: Time to Response (TTR) per RECIST v1.1
    End point description
    TTR is defined as the time from the date of start of treatment to the date of first documented response (CR or PR, which must be confirmed subsequently) for patients who achieved a confirmed CR or PR. Tumor response was based on local investigator assessment per RECIST v1.1. Patients who did not achieve a confirmed CR or PR were censored at the maximum follow-up time for patients who had a PFS event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise. According to the SAP, summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving confirmed CR or PR in each treatment group. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Time to Response (TTR) per irRC

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    End point title
    		 Phase Ib and Phase II: Time to Response (TTR) per irRC
    End point description
    TTR is defined as the time from the date of start of treatment to the date of first documented response (irCR or irPR, which must be confirmed subsequently) for patients who achieved confirmed irCR or irPR. Tumor response was based on local investigator assessment per irRC. Patients who did not achieve confirmed irCR or irPR were censored at the maximum follow-up time for patients who had a PFS event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise. According to the SAP, summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving confirmed irCR or irPR in each treatment group. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating not available). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’
    End point type
    Secondary
    End point timeframe
    From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Progression-Free Survival (PFS) per RECIST v1.1

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    End point title
    		 Phase Ib and Phase II: Progression-Free Survival (PFS) per RECIST v1.1
    End point description
    PFS is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1. PFS was estimated using the Kaplan-Meier Method. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: months
        median (confidence interval 95%)
    3.42 (1.18 to 999)
    4.44 (1.25 to 999)
    1.35 (1.22 to 13.73)
    2.79 (2.60 to 3.88)
    2.79 (1.45 to 4.07)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Progression-Free Survival (PFS) per irRC

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    End point title
    		 Phase Ib and Phase II: Progression-Free Survival (PFS) per irRC
    End point description
    PFS is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC. PFS was estimated using the Kaplan-Meier Method. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: months
        median (confidence interval 95%)
    3.42 (1.18 to 999)
    4.44 (1.68 to 999)
    5.55 (1.25 to 999)
    3.06 (2.63 to 4.17)
    2.79 (1.61 to 5.75)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Time to Progression (TTP) per RECIST v1.1

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    End point title
    		 Phase Ib and Phase II: Time to Progression (TTP) per RECIST v1.1
    End point description
    TTP is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1. TTP was estimated using the Kaplan-Meier Method. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: months
        median (confidence interval 95%)
    3.42 (1.18 to 999)
    4.44 (1.25 to 999)
    1.35 (1.22 to 999)
    2.79 (2.60 to 3.88)
    2.79 (1.45 to 4.07)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Time to Progression (TTP) per irRC

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    End point title
    		 Phase Ib and Phase II: Time to Progression (TTP) per irRC
    End point description
    TTP is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: months
        median (confidence interval 95%)
    3.42 (1.18 to 999)
    4.44 (1.68 to 999)
    5.55 (1.25 to 999)
    3.06 (2.63 to 4.17)
    2.79 (1.61 to 5.75)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Overall Survival (OS)

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    End point title
    		 Phase Ib and Phase II: Overall Survival (OS)
    End point description
    OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient was not known to have died, OS time was censored at the date of last contact. OS was estimated using the Kaplan-Meier Method. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    From start of treatment until death due to any cause, assessed up to 3.6 years in Phase Ib and up to 2.9 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: months
        median (confidence interval 95%)
    14.98 (2.37 to 999)
    12.11 (1.68 to 19.45)
    16.53 (2.83 to 999)
    14.88 (9.00 to 19.48)
    9.78 (3.65 to 22.31)
    No statistical analyses for this end point

    Secondary: Phase II: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the on-treatment period

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    End point title
    		 Phase II: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the on-treatment period [16]
    End point description
    Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE.
    End point type
    Secondary
    End point timeframe
    From first dose of study medication up to 30 days after last dose, with a maximum duration of 2.3 years
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase II arms.
    End point values
    		 Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    32
    30
    Units: participants
        AEs
    32
    30
        Treatment-related AEs
    30
    18
        AEs with grade ≥ 3
    25
    15
        Treatment-related AEs with grade ≥ 3
    18
    3
        SAEs
    14
    10
        Treatment-related SAEs
    7
    1
        Fatal SAEs
    1
    1
        AEs leading to discontinuation
    10
    1
        Treatment-related AEs leading to discontinuation
    7
    0
        AEs leading to dose adjustment/interruption
    22
    11
        AEs requiring additional therapy
    30
    29
        AE due to infusion reaction
    1
    0
    No statistical analyses for this end point

    Secondary: Phase II: Number of participants with dose reductions and dose interruptions of capmatinib and spartalizumab

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    End point title
    		 Phase II: Number of participants with dose reductions and dose interruptions of capmatinib and spartalizumab [17]
    End point description
    Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab. No dose modifications (i.e. dose reduction) were allowed for spartalizumab. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    From first dose of study medication up to last dose, with a maximum duration of 2.2 years
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase II arms.
    End point values
    		 Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    32
    30
    Units: participants
        Capmatinib dose reduction
    18
    999
        Capmatinib dose interruption
    22
    999
        Spartalizumab dose reduction
    0
    0
        Spartalizumab dose interruption
    12
    13
    No statistical analyses for this end point

    Secondary: Phase II: Dose intensity of capmatinib

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    End point title
    		 Phase II: Dose intensity of capmatinib [18]
    End point description
    Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
    End point type
    Secondary
    End point timeframe
    From first dose of study medication up to last dose, with a maximum duration of 2.2 years
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase II arms.
    End point values
    		 Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    32
    0 [19]
    Units: mg/day
        median (full range (min-max))
    696.4 (167 to 800)
    ( to )
    Notes
    [19] - Patients did not receive capmatinib
    No statistical analyses for this end point

    Secondary: Phase Ib: Maximum observed plasma concentration (Cmax) of capmatinib

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    End point title
    		 Phase Ib: Maximum observed plasma concentration (Cmax) of capmatinib [20]
    End point description
    Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    4
    5
    7
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1680 ( 64.0 )
    3110 ( 61.2 )
    4980 ( 23.0 )
    No statistical analyses for this end point

    Secondary: Phase II: Dose intensity of spartalizumab

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    End point title
    		 Phase II: Dose intensity of spartalizumab [21]
    End point description
    Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
    End point type
    Secondary
    End point timeframe
    From first dose of study medication up to last dose, with a maximum duration of 2.2 years
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase II arms.
    End point values
    		 Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    32
    30
    Units: mg/3W
        median (full range (min-max))
    300.00 (200.0 to 300.0)
    300.00 (166.7 to 300.0)
    No statistical analyses for this end point

    Secondary: Phase Ib: Time to reach maximum plasma concentration (Tmax) of capmatinib

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    End point title
    		 Phase Ib: Time to reach maximum plasma concentration (Tmax) of capmatinib [22]
    End point description
    Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    4
    5
    7
    Units: hours
        median (full range (min-max))
    0.959 (0.567 to 1.00)
    1.00 (1.00 to 2.05)
    1.00 (1.00 to 4.22)
    No statistical analyses for this end point

    Secondary: Phase Ib: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of capmatinib

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    End point title
    		 Phase Ib: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of capmatinib [23]
    End point description
    Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase 1b arms.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
    Number of subjects analysed
    4
    5
    7
    Units: hours*ng/mL
        geometric mean (geometric coefficient of variation)
    5740 ( 51.6 )
    8570 ( 60.7 )
    16000 ( 30.6 )
    No statistical analyses for this end point

    Secondary: Phase II: Pre-dose plasma concentration of capmatinib

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    End point title
    		 Phase II: Pre-dose plasma concentration of capmatinib [24]
    End point description
    Capmatinib plasma concentration was assessed in samples taken at pre-dose. Pre-dose samples were collected before the next dose administration.
    End point type
    Secondary
    End point timeframe
    Pre-dose of capmatinib on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1. The duration of one cycle was 21 days.
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to Phase II arms.
    End point values
    		 Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    32
    0 [25]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 2 Day 1 (n=16,0)
    607 ( 99.4 )
    ( )
        Cycle 3 Day 1 (n=16,0)
    345 ( 110 )
    ( )
        Cycle 4 Day 1 (n=16,0)
    410 ( 132 )
    ( )
        Cycle 5 Day 1 (n=10,0)
    363 ( 68.6 )
    ( )
        Cycle 6 Day 1 (n=11,0)
    275 ( 102 )
    ( )
    Notes
    [25] - Patients did not receive capmatinib
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Maximum observed serum concentration (Cmax) of spartalizumab

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    End point title
    		 Phase Ib and Phase II: Maximum observed serum concentration (Cmax) of spartalizumab
    End point description
    Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
    End point type
    Secondary
    End point timeframe
    pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=6,9,11,32,30)
    75.7 ( 22.6 )
    77.2 ( 20.9 )
    84.7 ( 23.3 )
    81.7 ( 30.1 )
    72.8 ( 30.9 )
        Cycle 3 (n=5,8,7,27,21)
    105 ( 35.8 )
    101 ( 22.3 )
    128 ( 20.9 )
    115 ( 30.2 )
    101 ( 42.2 )
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Time to reach maximum serum concentration (Tmax) of spartalizumab

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    End point title
    		 Phase Ib and Phase II: Time to reach maximum serum concentration (Tmax) of spartalizumab
    End point description
    Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
    End point type
    Secondary
    End point timeframe
    pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: hours
    median (full range (min-max))
        Cycle 1 (n=6,9,11,32,30)
    1.51 (1.42 to 1.77)
    1.50 (0.583 to 1.67)
    1.50 (1.18 to 1.73)
    1.64 (0.917 to 581)
    1.59 (0.633 to 22.9)
        Cycle 3 (n=5,8,7,27,21)
    1.53 (1.50 to 1.60)
    1.47 (1.42 to 22.6)
    1.52 (1.45 to 1.92)
    1.75 (0.00 to 24.2)
    1.58 (1.33 to 22.3)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of spartalizumab

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    End point title
    		 Phase Ib and Phase II: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of spartalizumab
    End point description
    Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
    End point type
    Secondary
    End point timeframe
    pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6
    10
    11
    32
    30
    Units: day*µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=6,9,11,32,30)
    739 ( 24.7 )
    726 ( 20.9 )
    813 ( 19.4 )
    805 ( 33.4 )
    693 ( 35.3 )
        Cycle 3 (n=5,8,7,27,21)
    1280 ( 39.2 )
    1220 ( 25.5 )
    1630 ( 23.2 )
    1330 ( 41.6 )
    883 ( 79.1 )
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Percent marker area for CD8 expression in tumor samples

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    End point title
    		 Phase Ib and Phase II: Percent marker area for CD8 expression in tumor samples
    End point description
    The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples.
    End point type
    Secondary
    End point timeframe
    Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    4
    9
    8
    22
    23
    Units: CD8 percent marker area
    median (full range (min-max))
        Baseline (n=4,7,7,19,19)
    0.6 (0 to 1)
    0.9 (0 to 37)
    0.4 (0 to 3)
    0.5 (0 to 5)
    0.3 (0 to 27)
        Post-baseline (n=1,8,3,10,12)
    3.0 (3 to 3)
    2.6 (0 to 14)
    1.0 (0 to 1)
    1.3 (0 to 7)
    0.9 (0 to 21)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: PD-L1 percent positive tumor

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    End point title
    		 Phase Ib and Phase II: PD-L1 percent positive tumor
    End point description
    The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples.
    End point type
    Secondary
    End point timeframe
    Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    4
    10
    8
    26
    24
    Units: PD-L1 positivity percentage
    median (full range (min-max))
        Baseline (n=4,8,7,21,22)
    0.0 (0 to 5)
    0.0 (0 to 90)
    0.0 (0 to 2)
    0.0 (0 to 7)
    0.0 (0 to 3)
        Post-baseline (n=2,8,3,10,10)
    12.5 (0 to 25)
    0.0 (0 to 100)
    0.0 (0 to 5)
    0.0 (0 to 3)
    0.0 (0 to 5)
    No statistical analyses for this end point

    Post-hoc: Phase Ib and Phase II: All-Collected Deaths

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    End point title
    		 Phase Ib and Phase II: All-Collected Deaths
    End point description
    On-treatment and post-treatment safety follow-up deaths were collected from first dose of study medication to 150 days after the last dose of study medication, for a maximum duration of 3.6 years in Phase Ib and 2.6 years in Phase II. Post-treatment survival follow-up deaths were collected from day 151 after last dose of study medication to end of study, up to 3.6 years in Phase Ib and 2.9 years in Phase II. All deaths refer to the sum of on-treatment and post-treatment safety follow-up deaths plus post-treatment survival follow-up deaths.
    End point type
    Post-hoc
    End point timeframe
    On-treatment and post-treatment safety follow-up deaths: up to 3.6 years in Phase Ib and 2.6 years in Phase II. Post treatment survival follow-up deaths: up to 3.6 years in Phase Ib and 2.9 years in Phase II
    End point values
    		 Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Phase II: Spartalizumab 300 mg Q3W
    Number of subjects analysed
    6 [26]
    10 [27]
    11 [28]
    32 [29]
    30 [30]
    Units: participants
        On-treatment and post-treatment safety FU deaths
    3
    3
    4
    8
    13
        Post-treatment survival FU deaths
    3
    5
    4
    15
    10
        All deaths
    6
    8
    8
    23
    23
    Notes
    [26] - n= 6 (on-treatment and safety FU), 3 (survival), 6 (all)
    [27] - n= 10 (on-treatment and safety FU), 7 (survival), 10 (all)
    [28] - n= 11 (on-treatment and safety FU), 7 (survival), 11 (all)
    [29] - n= 32 (on-treatment and safety FU), 24 (survival), 32 (all)
    [30] - n= 30 (on-treatment and safety FU), 17 (survival), 30 (all)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 3.6 years in Phase Ib and 2.6 years in Phase II. AEs were collected from first dose to 150 days after last dose (on-treatment and post-treatment safety FU).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator. Deaths in the survival FU are not considered AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Ib: Capmatinib 200mg BID + Spartalizumab 300mg Q3W-Safety FU
    Reporting group description
    		 AEs during on-treatment period and post-treatment safety follow-up (FU) (up to 150 days post-treatment)

    Reporting group title
    II: Spartalizumab 300mg Q3W-Safety FU
    Reporting group description
    		 AEs during on-treatment period and post-treatment safety follow-up (FU) (up to 150 days post-treatment)

    Reporting group title
    II: Capmatinib 400mg BID + Spartalizumab 300mg Q3W-Safety FU
    Reporting group description
    		 AEs during on-treatment period and post-treatment safety follow-up (up to 150 days post-treatment)

    Reporting group title
    Ib: Capmatinib 300mg BID + Spartalizumab 300mg Q3W-Safety FU
    Reporting group description
    		 AEs during on-treatment period and post-treatment safety follow-up (up to 150 days post-treatment)

    Reporting group title
    Ib: Capmatinib 400mg BID + Spartalizumab 300mg Q3W-Safety FU
    Reporting group description
    		 AEs during on-treatment period and post-treatment safety follow-up (up to 150 days post-treatment)

    Serious adverse events
    		 Ib: Capmatinib 200mg BID + Spartalizumab 300mg Q3W-Safety FU II: Spartalizumab 300mg Q3W-Safety FU II: Capmatinib 400mg BID + Spartalizumab 300mg Q3W-Safety FU Ib: Capmatinib 300mg BID + Spartalizumab 300mg Q3W-Safety FU Ib: Capmatinib 400mg BID + Spartalizumab 300mg Q3W-Safety FU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    12 / 30 (40.00%)
    14 / 32 (43.75%)
    1 / 10 (10.00%)
    6 / 11 (54.55%)
         number of deaths (all causes)
    3
    13
    8
    3
    4
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 30 (6.67%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 30 (6.67%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood corticotrophin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural fever
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    5 / 32 (15.63%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash pruritic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ib: Capmatinib 200mg BID + Spartalizumab 300mg Q3W-Safety FU II: Spartalizumab 300mg Q3W-Safety FU II: Capmatinib 400mg BID + Spartalizumab 300mg Q3W-Safety FU Ib: Capmatinib 300mg BID + Spartalizumab 300mg Q3W-Safety FU Ib: Capmatinib 400mg BID + Spartalizumab 300mg Q3W-Safety FU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    30 / 30 (100.00%)
    32 / 32 (100.00%)
    10 / 10 (100.00%)
    10 / 11 (90.91%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Haematoma
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Hypotension
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    2
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    5 / 32 (15.63%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    8
    0
    2
    Asthenia
         subjects affected / exposed
    2 / 6 (33.33%)
    10 / 30 (33.33%)
    14 / 32 (43.75%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    11
    30
    0
    2
    Fatigue
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 30 (6.67%)
    4 / 32 (12.50%)
    3 / 10 (30.00%)
    4 / 11 (36.36%)
         occurrences all number
    2
    3
    4
    3
    4
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Nodule
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    2 / 10 (20.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    2
    1
    Oedema peripheral
         subjects affected / exposed
    4 / 6 (66.67%)
    6 / 30 (20.00%)
    15 / 32 (46.88%)
    6 / 10 (60.00%)
    6 / 11 (54.55%)
         occurrences all number
    7
    7
    26
    12
    7
    Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 30 (6.67%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 6 (50.00%)
    5 / 30 (16.67%)
    14 / 32 (43.75%)
    0 / 10 (0.00%)
    4 / 11 (36.36%)
         occurrences all number
    4
    6
    28
    0
    8
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    6
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 30 (6.67%)
    5 / 32 (15.63%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    8
    7
    1
    2
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    4 / 32 (12.50%)
    1 / 10 (10.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    2
    5
    1
    4
    Dyspnoea exertional
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    0
    0
    0
    3
    Pulmonary embolism
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    2 / 10 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    1
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 30 (13.33%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    4
    5
    0
    2
    Irritability
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 6 (50.00%)
    6 / 30 (20.00%)
    4 / 32 (12.50%)
    2 / 10 (20.00%)
    5 / 11 (45.45%)
         occurrences all number
    3
    7
    5
    3
    6
    Amylase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    4 / 32 (12.50%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    4
    0
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 6 (50.00%)
    10 / 30 (33.33%)
    7 / 32 (21.88%)
    2 / 10 (20.00%)
    3 / 11 (27.27%)
         occurrences all number
    3
    11
    9
    4
    3
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    6
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 30 (13.33%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    6
    3
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 30 (13.33%)
    8 / 32 (25.00%)
    2 / 10 (20.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    5
    9
    3
    2
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 30 (0.00%)
    5 / 32 (15.63%)
    2 / 10 (20.00%)
    3 / 11 (27.27%)
         occurrences all number
    4
    0
    8
    3
    8
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    6 / 32 (18.75%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    7
    0
    12
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    2
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    2
    1
    2
    Weight increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Weight decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    3
    0
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 30 (10.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Angina unstable
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    3
    0
    2
    Cerebral ischaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    0
    3
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 30 (10.00%)
    5 / 32 (15.63%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    7
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Serotonin syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 30 (10.00%)
    4 / 32 (12.50%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    5
    4
    5
    0
    Neutropenia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    4
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Diplopia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    5 / 30 (16.67%)
    7 / 32 (21.88%)
    1 / 10 (10.00%)
    3 / 11 (27.27%)
         occurrences all number
    1
    5
    9
    1
    5
    Abdominal distension
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 30 (10.00%)
    4 / 32 (12.50%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    3
    5
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 30 (10.00%)
    5 / 32 (15.63%)
    2 / 10 (20.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    3
    6
    3
    2
    Anal fissure
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Abdominal tenderness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Aptyalism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Ascites
         subjects affected / exposed
    1 / 6 (16.67%)
    5 / 30 (16.67%)
    7 / 32 (21.88%)
    2 / 10 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    5
    9
    2
    0
    Chapped lips
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 30 (10.00%)
    4 / 32 (12.50%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    4
    5
    0
    1
    Dry mouth
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    6 / 30 (20.00%)
    10 / 32 (31.25%)
    3 / 10 (30.00%)
    3 / 11 (27.27%)
         occurrences all number
    2
    10
    25
    4
    15
    Dyspepsia
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 30 (13.33%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    5
    3
    0
    2
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    0
    3
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 30 (6.67%)
    15 / 32 (46.88%)
    2 / 10 (20.00%)
    5 / 11 (45.45%)
         occurrences all number
    3
    2
    26
    3
    9
    Plicated tongue
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 30 (6.67%)
    2 / 32 (6.25%)
    4 / 10 (40.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    2
    2
    4
    0
    Vomiting
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 30 (3.33%)
    9 / 32 (28.13%)
    1 / 10 (10.00%)
    3 / 11 (27.27%)
         occurrences all number
    3
    1
    17
    1
    4
    Toothache
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Liver injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Blister
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Dry skin
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Lichen planus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Pruritus
         subjects affected / exposed
    3 / 6 (50.00%)
    8 / 30 (26.67%)
    4 / 32 (12.50%)
    2 / 10 (20.00%)
    4 / 11 (36.36%)
         occurrences all number
    4
    9
    7
    3
    5
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 30 (13.33%)
    4 / 32 (12.50%)
    3 / 10 (30.00%)
    3 / 11 (27.27%)
         occurrences all number
    2
    6
    5
    3
    4
    Psoriasis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 30 (6.67%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    0
    2
    Rash pruritic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    Skin ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    1
    Stasis dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Lichenoid keratosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    0
    1
    Adrenal insufficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 30 (10.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    3
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 30 (10.00%)
    5 / 32 (15.63%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    10
    6
    0
    2
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 30 (10.00%)
    3 / 32 (9.38%)
    3 / 10 (30.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    4
    3
    3
    0
    Bone pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    0
    1
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    2 / 10 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    3 / 32 (9.38%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    4
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 30 (6.67%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    0
    1
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    1
    0
    2
    Folliculitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    2
    Oral fungal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    1
    1
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    0
    0
    3
    Paronychia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 30 (10.00%)
    15 / 32 (46.88%)
    2 / 10 (20.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    4
    18
    3
    3
    Hypercalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 30 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    2
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 30 (13.33%)
    9 / 32 (28.13%)
    3 / 10 (30.00%)
    3 / 11 (27.27%)
         occurrences all number
    2
    4
    12
    5
    3
    Hypocalcaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 30 (6.67%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    4
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 30 (3.33%)
    4 / 32 (12.50%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    6
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 30 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    2
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 30 (3.33%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    2
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jun 2016
    Based on Health Authority requests, the following changes were implemented: • Subjects who refused sorafenib treatment were excluded from the subject population to be enrolled in this study. To be eligible, subjects should have received prior systemic sorafenib treatment for HCC with documented progression during or after discontinuation of sorafenib treatment, or were intolerant to sorafenib (that led to sorafenib discontinuation). • A mandatory HIV test was introduced at screening. Considering the limited clinical experience with PD-1 inhibitors in HIV positive subjects, to reduce the potential risk of virus reactivation, HIV testing was mandated and HIV positive subjects were excluded from the study. • Thrombocytopenia CTCAE grade 3 with clinically significant bleeding was listed as DLT, as well as nausea/vomiting grade 4 (regardless of anti-emetic treatment) and diarrhea grade 4 (regardless of anti-diarrheal treatment). • Enrollment of subjects potentially eligible for any loco regional liver treatment (e.g. hepatic resection, hepatic arterial embolization, radiofrequency ablation) was not allowed. • History of organ transplant was added as an additional exclusion criterion. Limited data were reported for the efficacy and toxicity, such as organ rejection, of immune checkpoints including PD-1 inhibitors in subjects with organ transplant, therefore considering the risk, subjects with a history of organ transplant were excluded from the study.
    07 Nov 2017
    The main purpose for this amendment was threefold. The first was to reduce the focus on the cMET high population; the second was to expand the eligible clinical population to include subjects with HCV, and subjects with mild ascites; and the third to introduce additional biomarker collections based on emerging PD data.
    27 Mar 2018
    The main purpose of this amendment was to update the exclusion criteria, the list of prohibited medications, the list of medications used with caution and the criteria for dose modifications based on the available capmatinib clinical data as per capmatinib Investigator’s Brochure edition 8 with primary focus on pneumonitis/ILD events that were reported with capmatinib.
    14 Sep 2018
    The primary purpose of this amendment was to incorporate health authority-requested language requiring study treatment discontinuation in the event of Stevens-Johnson syndrome/ Toxic epidermal necrolysis (SJS/TEN). After the occurrence of a case of SJS in a study with spartalizumab in combination with another investigational agent, the dose modification guidelines for protocols using spartalizumab were updated to mandate permanent discontinuation of study treatment for subjects who experienced SJS or Lyell syndrome/TEN. This change was already implemented as part of an urgent safety measure released on 15-Jun-2018. This protocol amendment was now formalizing these changes in the dose modification section and corresponding table describing the criteria for dose reduction/interruption and re-initiation of treatment for adverse drug reactions. In addition, based on a health authority request, subjects with indolent malignancies that have never required therapy were no longer considered eligible for this study. Exclusion criterion ‘Malignant disease, other than that being treated in this study. Exceptions to this exclusion included the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type’ was updated accordingly.
    14 Feb 2020
    The primary purpose of this amendment was to incorporate dose modification and management guidelines for myocarditis, as well as the option for subjects to be transferred to another study or an alternative treatment option to continue study treatment at the time of end of this study. After the occurrence of a case of myocarditis, the dose modification guidelines for protocols using capmatinib in combination with spartalizumab were updated to mandate permanent discontinuation of study treatment in case of myocarditis grade ≥ 2 or other cardiac event grade ≥ 3. In addition, recommended clinical management guidelines in case of such an event were provided. This protocol amendment revised the definition of end of study to include the option for subjects still on study treatment and who, in the opinion of the Investigator, were still deriving clinical benefit at the time of end of study, to transfer to another study or to an alternative treatment option to continue providing study treatment to these subjects.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
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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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