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    Clinical Trial Results:
    The GOING Study: Regorafenib followed by nivolumab in patients with Hepatocellular Carcinoma progressing under sorafenib or after discontinuation of atezolizumab plus bevacizumab

    Summary
    EudraCT number
    		 2019-003108-10
    Trial protocol
    		 ES  
    Global end of trial date
    09 Jul 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2025
    First version publication date
    25 Jul 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GOING
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04170556
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    FRCB-IDIBAPS (Fundació de Recerca Clínic Barcelona - Institut d’Investigacions Biomèdiques August Pi i Sunyer)
    Sponsor organisation address
    C/Roselló149-153, Barcelona, Spain, 08036
    Public contact
    Dr. Maria Reig, BCLC group. Liver Unit. ICMDM. CIBEREHD. IDIBAPS - Hospital Clinic Barcelona., Fundació Clínic per a la Recerca Biomèdica (FCRB), +34 93 227 98 03, mreig1@clinic.cat
    Scientific contact
    Dr. Maria Reig, BCLC group. Liver Unit. ICMDM. CIBEREHD. IDIBAPS - Hospital Clinic Barcelona., Fundació Clínic per a la Recerca Biomèdica (FCRB), +34 93 227 98 03, mreig1@clinic.cat
    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
    27 Apr 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jul 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of regorafenib in combination with Nivolumab.
    Protection of trial subjects
    All patients including in Safety set signed informed consent and meet the selection criteria. To ensure patient safety, the following procedures were performed at all study visits during treatment: Physical examination, ECOG performance status, ECG, Vital signs, Assessment of AEs/SAEs, Concomitant medications, Serum chemistry, Hematology, Coagulation and Urinalysis. Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Jan 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 67
    Worldwide total number of subjects
    67
    EEA total number of subjects
    67
    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)
    32
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The screened patients were 85 and 16 of them were screening failure. Two additional patients who signed the informed consent form did not start study treatment. Finally 67 patients received study treatment, 53 in cohort A (previous sorafenib) and 14 in cohort B (previous atezolizumab+bevacizumab).

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 67
    Number of subjects completed
    		 67

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

    Arms
    Arm title
    		 Experimental
    Arm description
    		 Regorafenib + Nivolumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Regorafenib was initiated at full dose (160 mg/day; 3 weeks on and 1 week off) in monotherapy for the first 8 weeks and the dose was modified upon development of adverse events according to the manufacturer’s recommendations. After week 8, regorafenib was continued in combination with nivolumab, until symptomatic tumor progression, unacceptable adverse events, patient decision or death. Further regorafenib dose modifications were allowed in the combination phase, according to the development of adverse events.

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab started in combination with regorafenib after 8 weeks of regorafenib monotherapy. Nivolumab (30-minutes IV infusion every 2 weeks) was administered in the first 5 enrolled patients at the dose of 3 mg/kg to define the tolerance and, if no severe adverse event was reported, the following 5 patients received 3 mg/Kg. If no severe adverse event was reported, the following patients received 240 mg/infusion. Treatment continued until symptomatic tumor progression, unacceptable adverse events, patient decision or death. The dose of nivolumab was not modified during the treatment of each patient.

    Number of subjects in period 1
    		Experimental
    Started
    67
    Completed
    67

    Baseline characteristics

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

    Reporting group values
    		 Overall Total
    Number of subjects
    		 67 67
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 32 32
        From 65-84 years
    		 35 35
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.4 ( 8.19 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 59 59
    Etnicity
    Units: Subjects
        Asian
    		 1 1
        Latin or Hispanic
    		 2 2
        White
    		 64 64
    Tumor burden
    Units: Subjects
        Extrahepatic spread
    		 22 22
        Multinodular
    		 23 23
        Portal invasion
    		 14 14
        Single ≤ 2 cm
    		 1 1
        Single or up to 3 nodules ≤ 3 cm
    		 7 7
    Cirrhosis
    Units: Subjects
        No
    		 28 28
        Yes
    		 39 39
    Vascular invasion
    Units: Subjects
        No
    		 41 41
        Yes
    		 26 26
    ECOG
    Units: Subjects
        ECOG 0
    		 60 60
        ECOG 1
    		 7 7
    HIV infection
    Units: Subjects
        No
    		 66 66
        Yes
    		 1 1
    First line treatment
    Units: Subjects
        Sorafenib
    		 53 53
        Atezolizumab plus bevacizumab
    		 14 14
    Worst type of progression to first line treatment
    Units: Subjects
        Extrahepatic Growth
    		 18 18
        Intrahepatic Growth
    		 25 25
        New Extrahepatic Lesion
    		 12 12
        New Intrahepatic Lesion
    		 12 12
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 74.9 ( 14.2 ) -
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 25.9 ( 4.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 Regorafenib + Nivolumab

    Primary: Adverse event

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    End point title
    		 Adverse event [1]
    End point description
    Patients with at least one adverse event
    End point type
    Primary
    End point timeframe
    At each study visit until end of treatment.
    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: Single arm study. No statistical analyses for this end point.
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: Patients
        Yes
    67
        No
    0
    No statistical analyses for this end point

    Primary: Treatment-related adverse event

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    End point title
    		 Treatment-related adverse event [2]
    End point description
    Patients with at least one treatment-realted adverse event
    End point type
    Primary
    End point timeframe
    At each study visit until end of treatment.
    Notes
    [2] - 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: Single arm study. No statistical analyses for this end point.
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: Patients
        Yes
    64
        No
    3
    No statistical analyses for this end point

    Primary: Adverse event with death

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    End point title
    		 Adverse event with death [3]
    End point description
    Patients with at least one adverse event leading to death
    End point type
    Primary
    End point timeframe
    At each study visit until end of treatment.
    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: Single arm study. No statistical analyses for this end point.
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: Patients
        Yes
    6
        No
    61
    No statistical analyses for this end point

    Primary: Serious adverse event

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    End point title
    		 Serious adverse event [4]
    End point description
    Patients with at least one serious adverse event
    End point type
    Primary
    End point timeframe
    At each study visit until end of treatment.
    Notes
    [4] - 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: Single arm study. No statistical analyses for this end point.
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: Patients
        Yes
    38
        No
    29
    No statistical analyses for this end point

    Primary: Treatment-related serious adverse event

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    End point title
    		 Treatment-related serious adverse event [5]
    End point description
    Patients with at least one treatment-related serious adverse event
    End point type
    Primary
    End point timeframe
    At each study visit until end of treatment.
    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: Single arm study. No statistical analyses for this end point.
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: Patients
        Yes
    14
        No
    53
    No statistical analyses for this end point

    Primary: Adverse event leading to discontinuation

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    End point title
    		 Adverse event leading to discontinuation [6]
    End point description
    Patients with at least one adverse event leading to discontinuation of regorafenib and/or nivolumab
    End point type
    Primary
    End point timeframe
    At each study visit until end of treatment.
    Notes
    [6] - 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: Single arm study. No statistical analyses for this end point.
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: Patients
        Yes
    28
        No
    39
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Patients with partial or complete response at any time, i.e. the best response from inclusion along all follow-up.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: Percentage
        number (confidence interval 95%)
    16.4 (8.5 to 27.5)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    The time from the inclusion date to death from any cause
    End point type
    Secondary
    End point timeframe
    From start of treatment to death or last follow up
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: month
        median (confidence interval 95%)
    20 (11 to 37)
    No statistical analyses for this end point

    Secondary: Time to progression

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    End point title
    		 Time to progression
    End point description
    The time from the inclusion date to progression
    End point type
    Secondary
    End point timeframe
    Every 8 weeks
    End point values
    		 Experimental
    Number of subjects analysed
    67
    Units: month
        median (confidence interval 95%)
    4 (2 to 6)
    No statistical analyses for this end point

    Secondary: Progresion pattern

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    End point title
    		 Progresion pattern
    End point description
    o Intrahepatic growth: increased size of intrahepatic target lesions or progression of intrahepatic "non-target" lesions at baseline. o New intrahepatic lesion: emergence of new intrahepatic lesions o Extrahepatic growth: increased size of extrahepatic target lesions, progression of extrahepatic "non-target" lesions at baseline or progression of the existing vascular invasion. o New extrahepatic lesion: emergence of new extrahepatic lesions Only for the 45 patients with available radiological progression.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks
    End point values
    		 Experimental
    Number of subjects analysed
    48 [7]
    Units: Patients
        New extrahepatic lesion
    14
        Extrahepatic growth
    6
        New intrahepatic lesion
    13
        Intrahepatic growth
    15
    Notes
    [7] - Only for patients with available radiological progression.
    No statistical analyses for this end point

    Secondary: Post-progression survival

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    End point title
    		 Post-progression survival
    End point description
    For those patients who progressed, the time from the progression date to death from any cause
    End point type
    Secondary
    End point timeframe
    From progression disease to death or last follow up
    End point values
    		 Experimental
    Number of subjects analysed
    55
    Units: month
        median (confidence interval 95%)
    12 (5 to 19)
    No statistical analyses for this end point

    Secondary: New extrahepatic spread

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    End point title
    		 New extrahepatic spread
    End point description
    Rate of patients who develop new extra-hepatic spread. Only for patients with available radiological progression.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks
    End point values
    		 Experimental
    Number of subjects analysed
    48
    Units: percent
    number (confidence interval 95%)
        Yes
    29.2 (17.0 to 44.1)
        No
    70.8 (55.9 to 83.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Every study visit until end of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 -

    Serious adverse events
    		 Experimental
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 67 (56.72%)
         number of deaths (all causes)
    42
         number of deaths resulting from adverse events
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Lung neoplasm
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Pyrexia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Disease progression
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Conduction disorder
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    1 / 1
    Diarrhoea
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune-mediated myositis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 67 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    32 / 67 (47.76%)
         occurrences all number
    69
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    35 / 67 (52.24%)
         occurrences all number
    86
    Chest pain
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    6
    Discomfort
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    6
    Fatigue
         subjects affected / exposed
    10 / 67 (14.93%)
         occurrences all number
    19
    Influenza like illness
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    6
    Mucosal inflammation
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    16
    Oedema
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    7
    Oedema peripheral
         subjects affected / exposed
    13 / 67 (19.40%)
         occurrences all number
    19
    Pyrexia
         subjects affected / exposed
    14 / 67 (20.90%)
         occurrences all number
    28
    Decreased appetite
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Aphonia
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Cough
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    10
    Dysphonia
         subjects affected / exposed
    10 / 67 (14.93%)
         occurrences all number
    12
    Dyspnoea
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    9
    Rhinorrhoea
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Oropharyngeal pain
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 67 (28.36%)
         occurrences all number
    37
    Amylase increased
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    21 / 67 (31.34%)
         occurrences all number
    48
    Blood bilirubin increased
         subjects affected / exposed
    10 / 67 (14.93%)
         occurrences all number
    21
    Blood creatinine increased
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    8
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    7
    Gamma-glutamyl transferase increased
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    6
    Lipase increased
         subjects affected / exposed
    11 / 67 (16.42%)
         occurrences all number
    24
    Weight decreased
         subjects affected / exposed
    10 / 67 (14.93%)
         occurrences all number
    12
    Blood alkaline phospatase increased
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    7
    Headache
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    7
    Paraesthesia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 67 (23.88%)
         occurrences all number
    28
    Eosinophilia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    6
    Lymphopenia
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    12
    Thrombocytopenia
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    9
    Leukocytosis
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Abdominal pain
         subjects affected / exposed
    21 / 67 (31.34%)
         occurrences all number
    26
    Abdominal pain upper
         subjects affected / exposed
    10 / 67 (14.93%)
         occurrences all number
    16
    Ascites
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    16
    Constipation
         subjects affected / exposed
    11 / 67 (16.42%)
         occurrences all number
    15
    Diarrhoea
         subjects affected / exposed
    32 / 67 (47.76%)
         occurrences all number
    70
    Dyspepsia
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    7
    Nausea
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    14
    Vomiting
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    30
    Hepatobiliary disorders
    Hyperbilirrubinaemia
         subjects affected / exposed
    14 / 67 (20.90%)
         occurrences all number
    33
    Hypertransaminaemia
         subjects affected / exposed
    9 / 67 (13.43%)
         occurrences all number
    21
    Immune-mediated hepatitis
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Hyperkeratosis
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    5
    Palmar-plantar erythrdysaesthesia syndrome
         subjects affected / exposed
    28 / 67 (41.79%)
         occurrences all number
    65
    Pruritus
         subjects affected / exposed
    9 / 67 (13.43%)
         occurrences all number
    11
    Rash
         subjects affected / exposed
    9 / 67 (13.43%)
         occurrences all number
    11
    Skin lesion
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    6
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    9 / 67 (13.43%)
         occurrences all number
    22
    Endocrine disorders
    Hypothyriodism
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 67 (20.90%)
         occurrences all number
    24
    Back pain
         subjects affected / exposed
    12 / 67 (17.91%)
         occurrences all number
    17
    Muscle spasm
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    11
    Myalgia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    5
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    8
    Respiratory tract infection
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    6
    COVID-19
         subjects affected / exposed
    9 / 67 (13.43%)
         occurrences all number
    11
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Hyperkalaemia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Hypomagnesaemia
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Hyponatraemia
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    14
    Decreased appetite
         subjects affected / exposed
    22 / 67 (32.84%)
         occurrences all number
    39

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2020
    To add a new objective: “Serum and Tissue marker characterization”. To add an exclusion criteria: “Concomitant anticoagulation…are permitted” To add the quality of life: HCC18, QCQ-30, ISS Pruritus and Microbiota questionnaries.
    15 Apr 2021
    To include an additional cohort (B) of patients treated with first line of Atezolizumab plus bevacizumab
    03 Mar 2022
    To extend the trial recruitment period for 9 months till 31st of December 2022 Other changes includes change of the study finalization definition, some changes on inclusion and exclusion criteria. Also, admin changes were included.
    10 Aug 2023
    To shorten the follow-up period of Cohort A and B from 18 to 10 months. The study end date was updated and admin changes were included.

    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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