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    Clinical Trial Results:
    A Phase III, Open-Label, Multicenter, Three-Arm, Randomized Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy vs. Regorafenib in Patients With Previously Treated Unresectable Locally Advanced or Metastatic Colorectal Adenocarcinoma.

    Summary
    EudraCT number
    		 2016-000202-11
    Trial protocol
    		 GB   BE   DE   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    24 Mar 2019
    First version publication date
    24 Mar 2019
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GO30182
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02788279
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    09 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Mar 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of cobimetinib plus atezolizumab compared to regorafenib on the basis of overall survival (OS). Atezolizumab monotherapy will also be evaluated compared to regorafenib on the basis of OS.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jul 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
    Australia: 26
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Italy: 59
    Country: Number of subjects enrolled
    Korea, Republic of: 32
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    United States: 108
    Worldwide total number of subjects
    363
    EEA total number of subjects
    160
    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)
    255
    From 65 to 84 years
    107
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 490 participants were screened of whom only 363 participants were randomized.

    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
    		 Regorafenib
    Arm description
    		 Participants will receive regorafenib 160 mg orally on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    Other name
    Stivarga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 160 mg orally once daily on Days 1 to 21 in a 28-day cycle.

    Arm title
    		 Cobimetinib + Atezolizumab
    Arm description
    		 Participants will receive cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sterile concentrate
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 840 mg IV on Day 1 and Day 15 in a 28-day cycle.

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 60 mg (three tablets of 20 mg each) orally once daily for Days 1 to 21 in a 28-day cycle.

    Arm title
    		 Atezolizumab
    Arm description
    		 Participants will receive atezolizumab monotherapy 1200 milligrams (mg) intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sterile concentrate
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received a single dose of 1200 mg IV on Day 1 in a 21-day cycle.

    Number of subjects in period 1
    		Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Started
    90
    183
    90
    Received treatment (Safety Population)
    80
    179
    90
    Modified ITT population
    57
    125
    61
    Completed
    0
    0
    0
    Not completed
    90
    183
    90
         Adverse event, serious fatal
    57
    125
    65
         Still on study
    24
    43
    18
         Consent withdrawn by subject
    9
    12
    5
         Lost to follow-up
    -
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Regorafenib
    Reporting group description
    		 Participants will receive regorafenib 160 mg orally on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Reporting group title
    Cobimetinib + Atezolizumab
    Reporting group description
    		 Participants will receive cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Reporting group title
    Atezolizumab
    Reporting group description
    		 Participants will receive atezolizumab monotherapy 1200 milligrams (mg) intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Reporting group values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab Total
    Number of subjects
    		 90 183 90 363
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 62 125 68 255
        From 65-84 years
    		 28 57 22 107
        85 years and over
    		 0 1 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.4 ± 10.3 58.0 ± 11.9 56.7 ± 11.1 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 39 76 31 146
        Male
    		 51 107 59 217
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 12 18 11 41
        Native Hawaiian or Other Pacific Islander
    		 0 1 1 2
        Black or African American
    		 0 8 2 10
        White
    		 71 152 73 296
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 7 4 3 14
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 9 11 5 25
        Not Hispanic or Latino
    		 77 166 82 325
        Unknown or Not Reported
    		 4 6 3 13

    End points

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    End points reporting groups
    Reporting group title
    Regorafenib
    Reporting group description
    		 Participants will receive regorafenib 160 mg orally on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Reporting group title
    Cobimetinib + Atezolizumab
    Reporting group description
    		 Participants will receive cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Reporting group title
    Atezolizumab
    Reporting group description
    		 Participants will receive atezolizumab monotherapy 1200 milligrams (mg) intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival is defined as the time (in months) between the date of randomization and the date of death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.
    End point type
    Primary
    End point timeframe
    From randomization up to death due to any cause (up to approximately 20 months or data cutoff of 09-Mar-2018)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    90
    183
    90
    Units: months
        median (confidence interval 95%)
    8.51 (6.41 to 10.71)
    8.87 (7.00 to 10.61)
    7.10 (6.05 to 10.05)
    Statistical analysis title
    		 Cobimetinib + Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Cobimetinib + Atezolizumab
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9871
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.38
    Statistical analysis title
    		 Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Atezolizumab
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.336
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.71
    Statistical analysis title
    		 Cobimetinib + Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Cobimetinib + Atezolizumab
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9686
    Method
    		 Unstratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.38
    Statistical analysis title
    		 Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Atezolizumab
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3553
    Method
    		 Unstratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.69

    Secondary: Progression-Free Survival (PFS) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    		 Progression-Free Survival (PFS) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
    End point description
    PFS was defined as the time from randomization to disease progression as determined by the investigator with the use of RECIST v1.1 or death due to any cause, whichever occurred earlier. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.
    End point type
    Secondary
    End point timeframe
    From randomization up to disease progression or death due to any cause (up to approximately 20 months or data cutoff of 09-Mar-2018)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    90
    183
    90
    Units: months
        median (confidence interval 95%)
    2.00 (1.87 to 3.61)
    1.91 (1.87 to 1.97)
    1.94 (1.91 to 2.10)
    Statistical analysis title
    		 Cobimetinib + Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Cobimetinib + Atezolizumab
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1208
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.65
    Statistical analysis title
    		 Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Atezolizumab
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0509
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.94
    Statistical analysis title
    		 Cobimetinib + Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Cobimetinib + Atezolizumab
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1726
    Method
    		 Unstratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.6
    Statistical analysis title
    		 Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Atezolizumab
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0467
    Method
    		 Unstratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.91

    Secondary: Percentage of Participants with Investigator-Assessed Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.1

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    End point title
    		 Percentage of Participants with Investigator-Assessed Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.1
    End point description
    PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). Objective response and its 95% CI were calculated using the Clopper-Pearson method.
    End point type
    Secondary
    End point timeframe
    From randomization up to death due to any cause (up to approximately 20 months or data cutoff of 09-Mar-2018)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    90
    183
    90
    Units: percentage of participants
        number (confidence interval 95%)
    2.2 (0.27 to 7.80)
    2.7 (0.89 to 6.26)
    2.2 (0.27 to 7.80)
    Statistical analysis title
    		 Cobimetinib + Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Cobimetinib + Atezolizumab
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Stratified Cochrane-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.92
         upper limit
    		 4.94
    Statistical analysis title
    		 Atezolizumab vs. Regorafenib
    Comparison groups
    Regorafenib v Atezolizumab
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Stratified Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.89
         upper limit
    		 4.89

    Secondary: Duration of Response (DOR) According to RECIST Version 1.1

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    End point title
    		 Duration of Response (DOR) According to RECIST Version 1.1
    End point description
    DOR is defined as the period measured from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented. Disease progression was determined on the basis of investigator assessment with use of RECIST v1.1. Median DOR was estimated using the Kaplan-Meier method, and the 95% CI was calculated using the method of Brookmeyer and Crowley.
    End point type
    Secondary
    End point timeframe
    From first occurrence of CR or PR up to disease progression or death due to any cause (up to approximately 20 months or data cutoff of 09-Mar-2018)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    2
    5
    2
    Units: months
        median (confidence interval 95%)
    4.50 (3.61 to 5.39)
    1.97 (1.77 to 3.81)
    2.81 (1.84 to 3.78)
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Physical Functioning Sub-scale Score

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Physical Functioning Sub-scale Score
    End point description
    The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
    End point type
    Secondary
    End point timeframe
    From randomization up to data cutoff of 09-Mar-2018 (up to approximately 20 months)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    0 [1]
    0 [2]
    0 [3]
    Units: units of a scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [1] - The results will be provided at the time of final results disclosure in December 2019.
    [2] - The results will be provided at the time of final results disclosure in December 2019.
    [3] - The results will be provided at the time of final results disclosure in December 2019.
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Global Quality of Life Sub-scale Score at the End of the Study

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Global Quality of Life Sub-scale Score at the End of the Study
    End point description
    The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, end of the study (up to approximately 3 years)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    0 [4]
    0 [5]
    0 [6]
    Units: units of a scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [4] - The results will be provided at the time of final results disclosure in December 2019.
    [5] - The results will be provided at the time of final results disclosure in December 2019.
    [6] - The results will be provided at the time of final results disclosure in December 2019.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events (AEs)

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    End point title
    		 Percentage of Participants with Adverse Events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately data cutoff of 09-Mar-2018 (approximately 20 months)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    80
    179
    90
    Units: percentage of participants
        number (not applicable)
    97.5
    99.4
    92.2
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Cobimetinib

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    End point title
    		 Plasma Concentration of Cobimetinib
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (0 hours) and 3 to 6 hours after dose on Day 15 of Cycles 1 and 4 (1 cycle = 28 days)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [7] - The results will be provided at the time of final results disclosure in December 2019.
    [8] - The results will be provided at the time of final results disclosure in December 2019.
    [9] - The results will be provided at the time of final results disclosure in December 2019.
    No statistical analyses for this end point

    Secondary: Serum Concentration of Atezolizumab

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    End point title
    		 Serum Concentration of Atezolizumab
    End point description
    Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4; 30 minutes post-infusion on Day 1 of Cycles 1 and 4; pre-infusion (0 hours) on Day 1 of Cycle 8 and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 3 years) (1 cycle = 28 days)
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 hours) on Day 1 of Cycle 1 up to approximately 3 years. Detailed time frame is explained in the outcome measure description field.
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    0 [10]
    0 [11]
    0 [12]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [10] - The results will be provided at the time of final results disclosure in December 2019.
    [11] - The results will be provided at the time of final results disclosure in December 2019.
    [12] - The results will be provided at the time of final results disclosure in December 2019.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

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    End point title
    		 Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Atezolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4, 8, and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 3 years) (1 cycle = 28 days)
    End point values
    		 Regorafenib Cobimetinib + Atezolizumab Atezolizumab
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    Units: percentage of participants
        number (not applicable)
    Notes
    [13] - The results will be provided at the time of final results disclosure in December 2019.
    [14] - The results will be provided at the time of final results disclosure in December 2019.
    [15] - The results will be provided at the time of final results disclosure in December 2019.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to clinical cut-off of 09-Mar-2018 (approximately 20 months).
    Adverse event reporting additional description
    The safety analysis set (SAF) included all enrolled participants, who received at least one dose of any study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Atezolizumab
    Reporting group description
    		 Participants will receive atezolizumab monotherapy 1200 milligrams (mg) intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Reporting group title
    Regorafenib
    Reporting group description
    		 Participants will receive regorafenib 160 mg orally on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Reporting group title
    Cobimetinib + Atezolizumab
    Reporting group description
    		 Participants will receive cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant’s or physician decision to withdraw, or pregnancy, whichever occurs first.

    Serious adverse events
    		 Atezolizumab Regorafenib Cobimetinib + Atezolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 90 (16.67%)
    18 / 80 (22.50%)
    71 / 179 (39.66%)
         number of deaths (all causes)
    65
    54
    123
         number of deaths resulting from adverse events
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    PELVIC VENOUS THROMBOSIS
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 80 (2.50%)
    12 / 179 (6.70%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    12 / 15
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    12 / 15
    ASTHENIA
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    CHILLS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    DEATH
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    INFLAMMATION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
    PLEURAL EFFUSION
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    PNEUMONITIS
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    HYPOXIA
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    DELIRIUM
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Investigations
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    INFLUENZA A VIRUS TEST POSITIVE
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    3 / 179 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    HIP FRACTURE
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    STOMA SITE HAEMORRHAGE
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    SYNCOPE
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    ATAXIA
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    COGNITIVE DISORDER
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    DIZZINESS
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    ENCEPHALOPATHY
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    GUILLAIN−BARRE SYNDROME
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    METABOLIC ENCEPHALOPATHY
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    NONINFECTIVE ENCEPHALITIS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    5 / 179 (2.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    2 / 5
    Eye disorders
    MACULOPATHY
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 80 (3.75%)
    6 / 179 (3.35%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    6 / 6
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 80 (2.50%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    COLITIS
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    INTESTINAL PERFORATION
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 80 (2.50%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    VOMITING
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    ANAL HAEMORRHAGE
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    COLONIC FISTULA
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    ILEUS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    PANCREATITIS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    SUBILEUS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    VOLVULUS OF SMALL BOWEL
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Hepatobiliary disorders
    AUTOIMMUNE HEPATITIS
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    BILE DUCT OBSTRUCTION
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    CHOLANGITIS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    NEPHRITIS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    STERILE PYURIA
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Endocrine disorders
    ADRENAL INSUFFICIENCY
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    MUSCULAR WEAKNESS
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    BACK PAIN
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Infections and infestations
    SEPSIS
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 80 (2.50%)
    4 / 179 (2.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    4 / 4
    PNEUMONIA
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    PULMONARY SEPSIS
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    ABDOMINAL HERNIA INFECTION
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    BACTERIAL SEPSIS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    INFECTION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    LUNG INFECTION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    ORAL CANDIDIASIS
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    PNEUMONIA PNEUMOCOCCAL
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    RHINOVIRUS INFECTION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 80 (1.25%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    DECREASED APPETITE
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 80 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atezolizumab Regorafenib Cobimetinib + Atezolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 90 (88.89%)
    78 / 80 (97.50%)
    172 / 179 (96.09%)
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    7 / 90 (7.78%)
    17 / 80 (21.25%)
    8 / 179 (4.47%)
         occurrences all number
    7
    18
    9
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    6 / 90 (6.67%)
    7 / 80 (8.75%)
    16 / 179 (8.94%)
         occurrences all number
    8
    8
    26
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 80 (2.50%)
    22 / 179 (12.29%)
         occurrences all number
    0
    3
    38
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    8 / 90 (8.89%)
    1 / 80 (1.25%)
    13 / 179 (7.26%)
         occurrences all number
    11
    1
    13
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    5 / 90 (5.56%)
    5 / 80 (6.25%)
    10 / 179 (5.59%)
         occurrences all number
    5
    6
    17
    LIPASE INCREASED
         subjects affected / exposed
    1 / 90 (1.11%)
    6 / 80 (7.50%)
    9 / 179 (5.03%)
         occurrences all number
    2
    7
    10
    BLOOD THYROID STIMULATING HORMONE INCREASED
         subjects affected / exposed
    3 / 90 (3.33%)
    4 / 80 (5.00%)
    3 / 179 (1.68%)
         occurrences all number
    3
    4
    5
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    2 / 90 (2.22%)
    4 / 80 (5.00%)
    3 / 179 (1.68%)
         occurrences all number
    2
    7
    3
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 90 (0.00%)
    5 / 80 (6.25%)
    3 / 179 (1.68%)
         occurrences all number
    0
    6
    3
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    4 / 90 (4.44%)
    25 / 80 (31.25%)
    9 / 179 (5.03%)
         occurrences all number
    6
    31
    10
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    11 / 90 (12.22%)
    10 / 80 (12.50%)
    15 / 179 (8.38%)
         occurrences all number
    11
    12
    19
    DIZZINESS
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 80 (3.75%)
    9 / 179 (5.03%)
         occurrences all number
    0
    3
    11
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    23 / 90 (25.56%)
    37 / 80 (46.25%)
    63 / 179 (35.20%)
         occurrences all number
    27
    45
    73
    PYREXIA
         subjects affected / exposed
    12 / 90 (13.33%)
    19 / 80 (23.75%)
    52 / 179 (29.05%)
         occurrences all number
    13
    23
    66
    ASTHENIA
         subjects affected / exposed
    12 / 90 (13.33%)
    16 / 80 (20.00%)
    37 / 179 (20.67%)
         occurrences all number
    19
    21
    53
    OEDEMA PERIPHERAL
         subjects affected / exposed
    8 / 90 (8.89%)
    3 / 80 (3.75%)
    27 / 179 (15.08%)
         occurrences all number
    9
    3
    32
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    4 / 90 (4.44%)
    6 / 80 (7.50%)
    16 / 179 (8.94%)
         occurrences all number
    6
    8
    19
    CHILLS
         subjects affected / exposed
    4 / 90 (4.44%)
    4 / 80 (5.00%)
    13 / 179 (7.26%)
         occurrences all number
    5
    4
    14
    FACE OEDEMA
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 80 (0.00%)
    10 / 179 (5.59%)
         occurrences all number
    0
    0
    12
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    5 / 90 (5.56%)
    8 / 80 (10.00%)
    23 / 179 (12.85%)
         occurrences all number
    5
    9
    24
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 80 (2.50%)
    10 / 179 (5.59%)
         occurrences all number
    0
    2
    10
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    17 / 90 (18.89%)
    30 / 80 (37.50%)
    113 / 179 (63.13%)
         occurrences all number
    23
    58
    195
    NAUSEA
         subjects affected / exposed
    19 / 90 (21.11%)
    11 / 80 (13.75%)
    66 / 179 (36.87%)
         occurrences all number
    23
    12
    92
    VOMITING
         subjects affected / exposed
    13 / 90 (14.44%)
    7 / 80 (8.75%)
    51 / 179 (28.49%)
         occurrences all number
    15
    8
    77
    ABDOMINAL PAIN
         subjects affected / exposed
    13 / 90 (14.44%)
    22 / 80 (27.50%)
    27 / 179 (15.08%)
         occurrences all number
    19
    29
    31
    CONSTIPATION
         subjects affected / exposed
    11 / 90 (12.22%)
    17 / 80 (21.25%)
    32 / 179 (17.88%)
         occurrences all number
    12
    19
    39
    STOMATITIS
         subjects affected / exposed
    0 / 90 (0.00%)
    13 / 80 (16.25%)
    18 / 179 (10.06%)
         occurrences all number
    0
    21
    18
    DRY MOUTH
         subjects affected / exposed
    2 / 90 (2.22%)
    4 / 80 (5.00%)
    9 / 179 (5.03%)
         occurrences all number
    2
    4
    9
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    7 / 90 (7.78%)
    2 / 80 (2.50%)
    3 / 179 (1.68%)
         occurrences all number
    8
    2
    3
    DYSPEPSIA
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 80 (0.00%)
    10 / 179 (5.59%)
         occurrences all number
    2
    0
    10
    PROCTALGIA
         subjects affected / exposed
    0 / 90 (0.00%)
    4 / 80 (5.00%)
    2 / 179 (1.12%)
         occurrences all number
    0
    4
    2
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    12 / 90 (13.33%)
    13 / 80 (16.25%)
    32 / 179 (17.88%)
         occurrences all number
    12
    13
    34
    COUGH
         subjects affected / exposed
    12 / 90 (13.33%)
    7 / 80 (8.75%)
    29 / 179 (16.20%)
         occurrences all number
    12
    9
    30
    DYSPHONIA
         subjects affected / exposed
    1 / 90 (1.11%)
    19 / 80 (23.75%)
    0 / 179 (0.00%)
         occurrences all number
    1
    27
    0
    EPISTAXIS
         subjects affected / exposed
    0 / 90 (0.00%)
    7 / 80 (8.75%)
    9 / 179 (5.03%)
         occurrences all number
    0
    7
    9
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    2 / 90 (2.22%)
    4 / 80 (5.00%)
    7 / 179 (3.91%)
         occurrences all number
    2
    5
    8
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    8 / 90 (8.89%)
    19 / 80 (23.75%)
    82 / 179 (45.81%)
         occurrences all number
    8
    21
    116
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 80 (2.50%)
    46 / 179 (25.70%)
         occurrences all number
    3
    2
    57
    PALMAR−PLANTAR
         subjects affected / exposed
    1 / 90 (1.11%)
    42 / 80 (52.50%)
    3 / 179 (1.68%)
         occurrences all number
    1
    69
    3
    ERYTHRODYSAESTHESIA SYNDROME PRURITUS
         subjects affected / exposed
    3 / 90 (3.33%)
    2 / 80 (2.50%)
    22 / 179 (12.29%)
         occurrences all number
    3
    2
    25
    DRY SKIN
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 80 (1.25%)
    14 / 179 (7.82%)
         occurrences all number
    3
    1
    14
    RASH MACULO−PAPULAR
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 80 (3.75%)
    11 / 179 (6.15%)
         occurrences all number
    1
    3
    12
    ERYTHEMA
         subjects affected / exposed
    0 / 90 (0.00%)
    5 / 80 (6.25%)
    1 / 179 (0.56%)
         occurrences all number
    0
    5
    1
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    6 / 90 (6.67%)
    3 / 80 (3.75%)
    9 / 179 (5.03%)
         occurrences all number
    6
    3
    9
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    13 / 90 (14.44%)
    8 / 80 (10.00%)
    15 / 179 (8.38%)
         occurrences all number
    15
    10
    19
    ARTHRALGIA
         subjects affected / exposed
    8 / 90 (8.89%)
    5 / 80 (6.25%)
    13 / 179 (7.26%)
         occurrences all number
    8
    6
    13
    PAIN IN EXTREMITY
         subjects affected / exposed
    6 / 90 (6.67%)
    6 / 80 (7.50%)
    12 / 179 (6.70%)
         occurrences all number
    6
    7
    15
    MYALGIA
         subjects affected / exposed
    3 / 90 (3.33%)
    7 / 80 (8.75%)
    9 / 179 (5.03%)
         occurrences all number
    3
    10
    12
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    2 / 90 (2.22%)
    4 / 80 (5.00%)
    4 / 179 (2.23%)
         occurrences all number
    2
    4
    4
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 90 (0.00%)
    4 / 80 (5.00%)
    3 / 179 (1.68%)
         occurrences all number
    0
    4
    3
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 90 (2.22%)
    4 / 80 (5.00%)
    7 / 179 (3.91%)
         occurrences all number
    2
    8
    9
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    6 / 90 (6.67%)
    2 / 80 (2.50%)
    4 / 179 (2.23%)
         occurrences all number
    6
    2
    6
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    21 / 90 (23.33%)
    33 / 80 (41.25%)
    48 / 179 (26.82%)
         occurrences all number
    27
    39
    54
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    3 / 90 (3.33%)
    7 / 80 (8.75%)
    10 / 179 (5.59%)
         occurrences all number
    3
    7
    10
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 80 (3.75%)
    12 / 179 (6.70%)
         occurrences all number
    1
    4
    15
    HYPOCALCAEMIA
         subjects affected / exposed
    2 / 90 (2.22%)
    5 / 80 (6.25%)
    7 / 179 (3.91%)
         occurrences all number
    2
    5
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2016
    Key changes to the protocol included: clarification on regorafenib classification as IMP/NIMP, to update data on atezolizumab and cobimetinib, and to expand the window for baseline tumor assessments.
    04 May 2016
    Key change to the protocol was to perform thyroid function test laboratory monitoring at Day 1 of every cycle rather than Cycle 1 Day 1 and every fourth cycle.
    21 Oct 2016
    Key changes to the protocol included: an update to the safety information for identified risks of cobimetinib and an update to the safety language for atezolizumab.
    28 Nov 2017
    Key changes to the protocol included: update to the hierarchical testing procedures for OS, PFS and ORR, removal of reference to Foundation Medicine, update to adverse events management and updates to the Medical Manager contact information and web address for Global Policy on Sharing of Clinical Trials Data.

    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.
    The results represent the data up to primary completion date (09 Mar 2018).
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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