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    Clinical Trial Results:
    An Open-Label Study of Regorafenib in Combination with Pembrolizumab in Patients with Advanced or Metastatic Hepatocellular Carcinoma (HCC) after PD-1/PD-L1 Immune Checkpoint Inhibitors

    Summary
    EudraCT number
    		 2020-003555-16
    Trial protocol
    		 FR   DE   IT   ES  
    Global end of trial date
    23 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2025
    First version publication date
    10 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY73-4506/21469
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04696055
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.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
    23 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the objective anti-tumor activity of regorafenib in combination with pembrolizumab as a second line treatment for advanced HCC
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects (or their legally authorized representative according to local legislation). Participating subjects (or their legally authorized representative according to local legislation) signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Feb 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 9 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 63
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Worldwide total number of subjects
    136
    EEA total number of subjects
    84
    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)
    57
    From 65 to 84 years
    78
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 03 February 2021 (first subject first visit) and 23 April 2024 (last subject last visit) at multi-centers in 9 countries.

    Pre-assignment
    Screening details
    		 A total of 136 participants were screened, of whom 41 were screening failures. A total of 95 participants were assigned to treatment.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab]
    Arm description
    		 Cohort 1 with subjects after one systemic line of therapy consisting of atezolizumab plus bevacizumab treatment combination only. Pembrolizumab 400 mg was administered as an intravenous (IV) infusion every 6 weeks. Regorafenib was given orally at a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    BAY 73-4506
    Other name
    Stivarga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off), oral. If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg, IV infusion, every 6 weeks

    Arm title
    		 Regorafenib + Pembro [1L: Any other IO containing treatment]
    Arm description
    		 Cohort 2 with subjects after one systemic line of therapy consisting of any PD-1/PD-L1 immune oncology (IO) containing first line treatment (excluding atezolizumab with or without bevacizumab) in monotherapy or combination regimens. Pembrolizumab 400 mg was administered as an IV infusion every 6 weeks. Regorafenib was given orally at a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg, IV infusion, every 6 weeks

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    BAY 73-4506
    Other name
    Stivarga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off), oral. If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle.

    Number of subjects in period 1 [1]
    		Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab] Regorafenib + Pembro [1L: Any other IO containing treatment]
    Started
    68
    27
    Completed
    0
    0
    Not completed
    68
    27
         Physician decision
    3
    -
         Subject Decision
    1
    2
         Adverse Event
    10
    2
         Progressive Disease - Radiological Progression
    42
    20
         Death
    4
    -
         Unspecified
    7
    2
         Progressive Disease - Clinical Progression
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 136 subjects were screened, of whom 41 were screening failures. Only 95 subjects were assigned to treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab]
    Reporting group description
    		 Cohort 1 with subjects after one systemic line of therapy consisting of atezolizumab plus bevacizumab treatment combination only. Pembrolizumab 400 mg was administered as an intravenous (IV) infusion every 6 weeks. Regorafenib was given orally at a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib.

    Reporting group title
    Regorafenib + Pembro [1L: Any other IO containing treatment]
    Reporting group description
    		 Cohort 2 with subjects after one systemic line of therapy consisting of any PD-1/PD-L1 immune oncology (IO) containing first line treatment (excluding atezolizumab with or without bevacizumab) in monotherapy or combination regimens. Pembrolizumab 400 mg was administered as an IV infusion every 6 weeks. Regorafenib was given orally at a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib.

    Reporting group values
    		 Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab] Regorafenib + Pembro [1L: Any other IO containing treatment] Total
    Number of subjects
    		 68 27 95
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.7 ( 13.1 ) 70.9 ( 7.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 15 7 22
        Male
    		 53 20 73
    Race
    Units: Subjects
        Asian
    		 19 3 22
        Black or African American
    		 2 0 2
        White
    		 37 20 57
        Multiple
    		 1 0 1
        Not reported
    		 9 4 13
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 7 3 10
        Not Hispanic or Latino
    		 50 17 67
        Not reported
    		 11 7 18

    End points

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    End points reporting groups
    Reporting group title
    Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab]
    Reporting group description
    		 Cohort 1 with subjects after one systemic line of therapy consisting of atezolizumab plus bevacizumab treatment combination only. Pembrolizumab 400 mg was administered as an intravenous (IV) infusion every 6 weeks. Regorafenib was given orally at a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib.

    Reporting group title
    Regorafenib + Pembro [1L: Any other IO containing treatment]
    Reporting group description
    		 Cohort 2 with subjects after one systemic line of therapy consisting of any PD-1/PD-L1 immune oncology (IO) containing first line treatment (excluding atezolizumab with or without bevacizumab) in monotherapy or combination regimens. Pembrolizumab 400 mg was administered as an IV infusion every 6 weeks. Regorafenib was given orally at a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who took at least 1 dose of study intervention were included in the efficacy and safety evaluation

    Primary: Overall response rate (ORR) per RECIST 1.1 by central assessment

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    End point title
    		 Overall response rate (ORR) per RECIST 1.1 by central assessment [1]
    End point description
    Overall response rate (ORR) is defined as the percentage of subjects with best overall response of confirmed complete response (CR) or partial response (PR). ORR per RECIST 1.1 by independent central assessment is reported). RECIST 1.1: response evaluation criteria in solid tumors version 1.1
    End point type
    Primary
    End point timeframe
    Up to 15 months. Data up to 38 months are now available and are also reported for full transparency.
    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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed.
    End point values
    		 Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab] Regorafenib + Pembro [1L: Any other IO containing treatment]
    Number of subjects analysed
    68 [2]
    27 [3]
    Units: Percentage
    number (confidence interval 95%)
        Up to 15 months (primary outcome)
    5.9 (1.6 to 14.4)
    11.1 (2.4 to 29.2)
        Up to 38 months (as of study completion)
    7.4 (2.4 to 16.3)
    14.8 (4.2 to 33.7)
    Notes
    [2] - FAS
    [3] - FAS
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) per RECIST 1.1 by investigator assessment

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    End point title
    		 Overall response rate (ORR) per RECIST 1.1 by investigator assessment
    End point description
    Overall response rate (ORR) is defined as the percentage of subjects with best overall response of confirmed complete response (CR) or partial response (PR). ORR by RECIST 1.1 investigator review is reported. RECIST 1.1: response evaluation criteria in solid tumors version 1.1
    End point type
    Secondary
    End point timeframe
    Up to 38 months
    End point values
    		 Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab] Regorafenib + Pembro [1L: Any other IO containing treatment]
    Number of subjects analysed
    68 [4]
    27 [5]
    Units: Percentage
        number (confidence interval 95%)
    7.4 (2.4 to 16.3)
    18.5 (6.3 to 38.1)
    Notes
    [4] - FAS
    [5] - FAS
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) per RECIST 1.1 by central assessment and investigator assessment

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    End point title
    		 Duration of response (DOR) per RECIST 1.1 by central assessment and investigator assessment
    End point description
    Duration of response (DOR) for partial response (PR) and complete response (CR) was defined as the time from the first documented objective response of PR or CR, whichever noted earlier, to disease progression or death (if death occurs before progression was documented). DOR was defined for confirmed responders only, i.e., subjects with a CR or PR. RECIST 1.1: response evaluation criteria in solid tumors version 1.1
    End point type
    Secondary
    End point timeframe
    Up to 38 months
    End point values
    		 Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab] Regorafenib + Pembro [1L: Any other IO containing treatment]
    Number of subjects analysed
    5 [6]
    5 [7]
    Units: day
    median (full range (min-max))
        Central assessment
    210 (158 to 937)
    195 (83 to 280)
        Investigator assessment
    431 (82 to 893)
    364 (117 to 839)
    Notes
    [6] - Confirmed responders in FAS
    [7] - Confirmed responders in FAS. 4 / 5 subjects analyzed by central/investigator assessment respectively
    No statistical analyses for this end point

    Secondary: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    		 Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
    End point description
    An AE was considered as treatment-emergent (TEAE) if arising or worsening after start of first study intervention administration until 30 days after administration of any study intervention. In addition, any AEs qualifying as a serious adverse event (SAE) were collected for 90 days after the last dose of pembrolizumab, unless a new anti-cancer therapy had been initiated.
    End point type
    Secondary
    End point timeframe
    Up to 38 months
    End point values
    		 Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab] Regorafenib + Pembro [1L: Any other IO containing treatment]
    Number of subjects analysed
    68 [8]
    27 [9]
    Units: subject
        Any TEAE
    68
    27
        Any SAE
    37
    11
    Notes
    [8] - FAS
    [9] - FAS
    No statistical analyses for this end point

    Secondary: Number of subjects with safety-relevant changes in clinical parameters

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    End point title
    		 Number of subjects with safety-relevant changes in clinical parameters
    End point description
    Number of subjects with clinically relevant trends observed in laboratory data, ECG data, or ECOG performance status is reported.
    End point type
    Secondary
    End point timeframe
    Up to 38 months
    End point values
    		 Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab] Regorafenib + Pembro [1L: Any other IO containing treatment]
    Number of subjects analysed
    68 [10]
    27 [11]
    Units: subject
    0
    0
    Notes
    [10] - FAS
    [11] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of subjects with dose modification

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    End point title
    		 Percentage of subjects with dose modification
    End point description
    Dose modification included dose interruption, dose reduction, dose discontinuation.
    End point type
    Secondary
    End point timeframe
    Up to 38 months
    End point values
    		 Regorafenib + Pembro [1L: Atezolizumab + Bevacizumab] Regorafenib + Pembro [1L: Any other IO containing treatment]
    Number of subjects analysed
    68 [12]
    27 [13]
    Units: Percentage
    number (not applicable)
        Regorafenib - drug interruptions or delays
    63.2
    70.4
        Regorafenib - dose reductions
    41.2
    63.0
        Regorafenib - drug withdrawal
    16.2
    25.9
        Pembrolizumab - dose interruptions or delays
    14.7
    25.9
        Pembrolizumab - drug withdrawal
    4.4
    11.1
    Notes
    [12] - FAS
    [13] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After start of first study intervention administration until 30 days after administration of any study intervention. Serious adverse events were collected for 90 days after the last dose of pembrolizumab unless a new anti-cancer therapy had been initiated
    Adverse event reporting additional description
    Adverse event reporting for the the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Regorafenib+Pembrolizumab [Any other IO containing treatment]
    Reporting group description
    		 Cohort 2 with participants after one systemic line of therapy consisting of any PD-1/PD-L1 immune oncology (IO) containing first line treatment (excluding atezolizumab with or without bevacizumab) in monotherapy or combination regimens. Pembrolizumab 400 mg was administered as an intravenous (IV) infusion every 6 weeks (Q6W). Regorafenib was given orally (p.o.) at a starting dose of 90 mg once daily (QD) for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib.

    Reporting group title
    Regorafenib+Pembrolizumab [1L: Atezolizumab + Bevacizumab]
    Reporting group description
    		 Cohort 1 with participants after one systemic line of therapy consisting of atezolizumab plus bevacizumab treatment combination only. Pembrolizumab 400 mg was administered as an intravenous (IV) infusion every 6 weeks (Q6W). Regorafenib was given orally (p.o.) at a starting dose of 90 mg once daily (QD) for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib.

    Serious adverse events
    		 Regorafenib+Pembrolizumab [Any other IO containing treatment] Regorafenib+Pembrolizumab [1L: Atezolizumab + Bevacizumab]
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 27 (40.74%)
    37 / 68 (54.41%)
         number of deaths (all causes)
    20
    53
         number of deaths resulting from adverse events
    0
    5
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Capillary leak syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site haematoma
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningorrhagia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 68 (4.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Biliary sepsis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperlipasaemia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Regorafenib+Pembrolizumab [Any other IO containing treatment] Regorafenib+Pembrolizumab [1L: Atezolizumab + Bevacizumab]
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 27 (100.00%)
    63 / 68 (92.65%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 27 (33.33%)
    15 / 68 (22.06%)
         occurrences all number
    20
    23
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    18 / 27 (66.67%)
    23 / 68 (33.82%)
         occurrences all number
    54
    52
    Fatigue
         subjects affected / exposed
    4 / 27 (14.81%)
    14 / 68 (20.59%)
         occurrences all number
    6
    21
    Mucosal inflammation
         subjects affected / exposed
    4 / 27 (14.81%)
    9 / 68 (13.24%)
         occurrences all number
    6
    9
    Oedema peripheral
         subjects affected / exposed
    1 / 27 (3.70%)
    8 / 68 (11.76%)
         occurrences all number
    1
    9
    Pyrexia
         subjects affected / exposed
    5 / 27 (18.52%)
    13 / 68 (19.12%)
         occurrences all number
    9
    16
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 68 (7.35%)
         occurrences all number
    1
    6
    Dyspnoea exertional
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 68 (0.00%)
         occurrences all number
    3
    0
    Dyspnoea
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 68 (5.88%)
         occurrences all number
    3
    4
    Dysphonia
         subjects affected / exposed
    5 / 27 (18.52%)
    13 / 68 (19.12%)
         occurrences all number
    7
    16
    Cough
         subjects affected / exposed
    3 / 27 (11.11%)
    6 / 68 (8.82%)
         occurrences all number
    4
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 27 (14.81%)
    6 / 68 (8.82%)
         occurrences all number
    4
    7
    Investigations
    Weight decreased
         subjects affected / exposed
    4 / 27 (14.81%)
    7 / 68 (10.29%)
         occurrences all number
    8
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 27 (11.11%)
    4 / 68 (5.88%)
         occurrences all number
    8
    4
    Lipase increased
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 68 (4.41%)
         occurrences all number
    2
    7
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 68 (2.94%)
         occurrences all number
    3
    2
    Blood bilirubin increased
         subjects affected / exposed
    6 / 27 (22.22%)
    9 / 68 (13.24%)
         occurrences all number
    23
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 27 (11.11%)
    9 / 68 (13.24%)
         occurrences all number
    7
    16
    Transaminases increased
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 68 (5.88%)
         occurrences all number
    1
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 68 (5.88%)
         occurrences all number
    0
    8
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 68 (1.47%)
         occurrences all number
    2
    1
    Headache
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 68 (7.35%)
         occurrences all number
    2
    6
    Dizziness
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 68 (2.94%)
         occurrences all number
    3
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 27 (7.41%)
    11 / 68 (16.18%)
         occurrences all number
    12
    22
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 27 (14.81%)
    4 / 68 (5.88%)
         occurrences all number
    6
    6
    Abdominal pain
         subjects affected / exposed
    5 / 27 (18.52%)
    15 / 68 (22.06%)
         occurrences all number
    9
    17
    Stomatitis
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 68 (7.35%)
         occurrences all number
    3
    9
    Vomiting
         subjects affected / exposed
    3 / 27 (11.11%)
    9 / 68 (13.24%)
         occurrences all number
    4
    10
    Nausea
         subjects affected / exposed
    5 / 27 (18.52%)
    13 / 68 (19.12%)
         occurrences all number
    8
    15
    Constipation
         subjects affected / exposed
    5 / 27 (18.52%)
    14 / 68 (20.59%)
         occurrences all number
    6
    17
    Diarrhoea
         subjects affected / exposed
    13 / 27 (48.15%)
    23 / 68 (33.82%)
         occurrences all number
    34
    37
    Dry mouth
         subjects affected / exposed
    3 / 27 (11.11%)
    6 / 68 (8.82%)
         occurrences all number
    3
    6
    Dyspepsia
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 68 (4.41%)
         occurrences all number
    3
    3
    Ascites
         subjects affected / exposed
    3 / 27 (11.11%)
    5 / 68 (7.35%)
         occurrences all number
    3
    9
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 68 (5.88%)
         occurrences all number
    0
    7
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 68 (7.35%)
         occurrences all number
    1
    5
    Eczema
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 68 (0.00%)
         occurrences all number
    2
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    14 / 27 (51.85%)
    27 / 68 (39.71%)
         occurrences all number
    24
    64
    Pruritus
         subjects affected / exposed
    5 / 27 (18.52%)
    7 / 68 (10.29%)
         occurrences all number
    6
    9
    Rash
         subjects affected / exposed
    6 / 27 (22.22%)
    10 / 68 (14.71%)
         occurrences all number
    12
    16
    Alopecia
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 68 (4.41%)
         occurrences all number
    4
    4
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 68 (7.35%)
         occurrences all number
    0
    5
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    2 / 27 (7.41%)
    8 / 68 (11.76%)
         occurrences all number
    3
    8
    Muscle spasms
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 68 (4.41%)
         occurrences all number
    2
    4
    Arthralgia
         subjects affected / exposed
    10 / 27 (37.04%)
    13 / 68 (19.12%)
         occurrences all number
    20
    14
    Back pain
         subjects affected / exposed
    2 / 27 (7.41%)
    7 / 68 (10.29%)
         occurrences all number
    3
    12
    Infections and infestations
    COVID-19
         subjects affected / exposed
    6 / 27 (22.22%)
    3 / 68 (4.41%)
         occurrences all number
    7
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 27 (48.15%)
    21 / 68 (30.88%)
         occurrences all number
    22
    32
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 27 (3.70%)
    6 / 68 (8.82%)
         occurrences all number
    2
    19
    Hyponatraemia
         subjects affected / exposed
    1 / 27 (3.70%)
    7 / 68 (10.29%)
         occurrences all number
    1
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2021
    Key modifications were: • Duration of contraception use was clarified to align with wording of Investigator’s Brochure (IB). • Exclusion criteria and dose modification sections adapted to align with wording from regorafenib Summary of Product Characteristics (SmPC). • Guidance for regorafenib non-hematologic toxicities and liver toxicities added. • Guidance for Grade 3 immune-related adverse events (irAEs) added. • HCV serotyping added if genotyping was not available for hepatitis C virus (HCV) infection.

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

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

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