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    Clinical Trial Results:
    An Open-Label, Multicohort, Phase II Study of Atezolizumab in Advanced Solid Tumors

    Summary
    EudraCT number
    2015-000269-30
    Trial protocol
    DE   NL   IE   AT   ES   FI   GB   DK   PL   FR   IT  
    Global end of trial date
    28 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Apr 2021
    First version publication date
    09 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO29518
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02458638
    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
    Final
    Date of interim/final analysis
    21 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy objective of this study was to evaluate non-progression rate (NPR) at 18 weeks in participants with advanced solid tumors treated with atezolizumab, defined as the percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1, or according to disease-specific criteria for prostate cancer and malignant pleural mesothelioma.
    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
    16 Jul 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Brazil: 17
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    Switzerland: 14
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Denmark: 27
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Ireland: 15
    Country: Number of subjects enrolled
    Italy: 92
    Country: Number of subjects enrolled
    Netherlands: 31
    Country: Number of subjects enrolled
    Norway: 21
    Country: Number of subjects enrolled
    Poland: 56
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Turkey: 20
    Country: Number of subjects enrolled
    United States: 49
    Worldwide total number of subjects
    474
    EEA total number of subjects
    328
    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)
    351
    From 65 to 84 years
    121
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at 47 sites in 18 countries: Austria, Brazil, Canada, Denmark, Finland, France, Germany, Ireland, Italy, Netherlands, Norway, Poland, Russian Federation, Spain, Switzerland, Turkey, United Kingdom and United States.

    Pre-assignment
    Screening details
    Participants with advanced solid tumors were eligible to enroll in the study.

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

    Arms
    Arm title
    Atezolizumab
    Arm description
    Atezolizumab 1200 milligrams (mg) was administered by intravenous (IV) infusion on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq MPDL3280A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab 1200 mg was administered by IV infusion on Day 1 of each 3-week cycle.

    Number of subjects in period 1
    Atezolizumab
    Started
    474
    Completed
    15
    Not completed
    459
         Physician decision
    1
         Other Reasons
    4
         Adverse event, serious fatal
    309
         End of Cohort/End of Study
    67
         Consent withdrawn by subject
    47
         Lost to follow-up
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezolizumab
    Reporting group description
    Atezolizumab 1200 milligrams (mg) was administered by intravenous (IV) infusion on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity.

    Reporting group values
    Atezolizumab Total
    Number of subjects
    474 474
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    351 351
        From 65-84 years
    121 121
        85 years and over
    2 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    53.7 ± 13.9 -
    Sex: Female, Male
    Units: participants
        Female
    233 233
        Male
    241 241

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab
    Reporting group description
    Atezolizumab 1200 milligrams (mg) was administered by intravenous (IV) infusion on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity.

    Primary: Non-progression Rate (NPR) at 18 Weeks

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    End point title
    Non-progression Rate (NPR) at 18 Weeks [1]
    End point description
    NPR: percentage of participants with complete response (CR), partial response (PR) or stable disease (SD) as assessed by the Investigator according to RECIST v1.1 or according to Malignant Pleural Mesothelioma Response Evaluation Criteria. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the diameters of all target and all new measurable lesions in the absence of CR. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: At least a 20% increase in the sum of diameters of all target and all new measurable lesions. For prostate cancer according to Prostate Response Evaluation Criteria. CR: PSA <5 ng/ml measured twice at least 3 weeks apart or PSA response: PSA < 50% of the PSA reference value after treatment was initiated. Efficacy analysis set: all eligible and evaluable (received study drug, had baseline tumor assessment and at least one tumor assessment post-baseline) participants.
    End point type
    Primary
    End point timeframe
    At Week 18
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this one arm study.
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: percentage of participants
    number (confidence interval 95%)
        Overall Population (n=433)
    26.8 (22.7 to 31.2)
        Cervical Cancer (n=27)
    44.4 (25.5 to 64.7)
        Nasopharyngeal Carcinoma (n=27)
    29.6 (13.8 to 50.2)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    40.0 (12.2 to 73.8)
        BRCA Mutated Ovarian Cancer (n=15)
    26.7 (7.8 to 55.1)
        BRCA Mutated Breast Cancer (n=12)
    0 (0 to 26.5)
        Liposarcoma (n=13)
    7.7 (0.2 to 36.0)
        Leiomyosarcoma (n=17)
    17.6 (3.8 to 43.4)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    20.0 (4.3 to 48.1)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    0 (0 to 28.5)
        Known Translocation-Related Sarcomas (n=26)
    23.1 (9.0 to 43.6)
        Radiation Induced Sarcoma (n=8)
    25.0 (3.2 to 65.1)
        Osteosarcoma (n=11)
    45.5 (16.7 to 76.6)
        Chondrosarcoma (n=12)
    16.7 (2.1 to 48.4)
        Pleural Mesothelioma (n=13)
    38.5 (13.9 to 68.4)
        Peritoneal Mesothelioma (n=14)
    42.9 (17.7 to 71.1)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    15.4 (1.9 to 45.4)
        Anaplastic Thyroid Cancer (TC) (n=15)
    6.7 (0.2 to 31.9)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    54.5 (23.4 to 83.3)
        Medullary/Follicular/Papillary TC (n=7)
    28.6 (3.7 to 71.0)
        Gastric/GE Junction Adenocarcinoma (n=14)
    21.4 (4.7 to 50.8)
        Malignant Germ Cell Tumors (n=14)
    7.1 (0.2 to 33.9)
        ER+/HER2- Hypermutated MBC (n=12)
    8.3 (0.2 to 38.5)
        Thymoma (n=13)
    76.9 (46.2 to 95.0)
        Thymic cancer (n=12)
    41.7 (15.2 to 72.3)
        Low/Intermediate Grade Carcinoid (n=12)
    58.3 (27.7 to 84.8)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    25.0 (5.5 to 57.2)
        Head and Neck Squamous Cell Carcinoma (n=6)
    33.3 (4.3 to 77.7)
        Penile Cancer (n=4)
    0 (0 to 60.2)
        Anal Cancer (n=11)
    18.2 (2.3 to 51.8)
        Known MSI High or MMR Deficient Tumors (n=10)
    40.0 (12.2 to 73.8)
    No statistical analyses for this end point

    Secondary: NPR at 24 Weeks

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    End point title
    NPR at 24 Weeks
    End point description
    NPR: percentage of participants with complete response (CR), partial response (PR) or stable disease (SD) as assessed by the Investigator according to RECIST v1.1 or according to Malignant Pleural Mesothelioma Response Evaluation Criteria. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the diameters of all target and all new measurable lesions in the absence of CR. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: At least a 20% increase in the sum of diameters of all target and all new measurable lesions. For prostate cancer according to Prostate Response Evaluation Criteria. CR: PSA <5 ng/ml measured twice at least 3 weeks apart or PSA response: PSA < 50% of the PSA reference value after treatment was initiated. Efficacy analysis set: all eligible and evaluable (received study drug, had baseline tumor assessment and at least one tumor assessment post-baseline) participants.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: percentage of participants
    number (confidence interval 95%)
        Overall Population (n=433)
    22.4 (18.6 to 26.6)
        Cervical Cancer (n=27)
    40.7 (22.4 to 61.2)
        Nasopharyngeal Carcinoma (n=27)
    22.2 (8.6 to 42.3)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    40.0 (12.2 to 73.8)
        BRCA Mutated Ovarian Cancer (n=15)
    20.0 (4.3 to 48.1)
        BRCA Mutated Breast Cancer (n=12)
    0 (0 to 26.5)
        Liposarcoma (n=13)
    7.7 (0.2 to 36.0)
        Leiomyosarcoma (n=17)
    11.8 (1.5 to 36.4)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    13.3 (1.7 to 40.5)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    0 (0 to 28.5)
        Known Translocation-Related Sarcomas (n=26)
    23.1 (9.0 to 43.6)
        Radiation Induced Sarcoma (n=8)
    25.0 (3.2 to 65.1)
        Osteosarcoma (n=11)
    45.5 (16.7 to 76.6)
        Chondrosarcoma (n=12)
    0 (0 to 26.5)
        Pleural Mesothelioma (n=13)
    23.1 (5.0 to 53.8)
        Peritoneal Mesothelioma (n=14)
    28.6 (8.4 to 58.1)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    7.7 (0.2 to 36.0)
        Anaplastic Thyroid Cancer (TC) (n=15)
    6.7 (0.2 to 31.9)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    54.5 (23.4 to 83.3)
        Medullary/Follicular/Papillary TC (n=7)
    28.6 (3.7 to 71.0)
        Gastric/GE Junction Adenocarcinoma (n=14)
    7.1 (0.2 to 33.9)
        Malignant Germ Cell Tumors (n=14)
    7.1 (0.2 to 33.9)
        ER+/HER2- Hypermutated MBC (n=12)
    8.3 (0.2 to 38.5)
        Thymoma (n=13)
    76.9 (46.2 to 95.0)
        Thymic cancer (n=12)
    33.3 (9.9 to 65.1)
        Low/Intermediate Grade Carcinoid (n=12)
    58.3 (27.7 to 84.8)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    16.7 (2.1 to 48.4)
        Head and Neck Squamous Cell Carcinoma (n=6)
    16.7 (0.4 to 64.1)
        Penile Cancer (n=4)
    0 (0 to 60.2)
        Anal Cancer (n=11)
    18.2 (2.3 to 51.8)
        Known MSI High or MMR Deficient Tumors (n=10)
    30.0 (6.7 to 65.2)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    Overall Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants with CR or PR as assessed by the investigator using RECIST v1.1 or Malignant Pleural Mesothelioma Response Evaluation Criteria. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the diameters of all target and all new measurable lesions, taking as reference the baseline sum of diameters, in the absence of CR. For prostate cancer according to Prostate Response Evaluation Criteria. CR: PSA <5 ng/ml measured twice at least 3 weeks apart or PSA response: PSA < 50% of the PSA reference value occurring at any time after treatment was initiated. Efficacy analysis set included all eligible and evaluable participants. A participant was considered evaluable if they received study drug, had a baseline tumor assessment and at least one tumor assessment post-baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: percentage of participants
    number (confidence interval 95%)
        Overall Population (n=433)
    7.4 (5.1 to 10.3)
        Cervical Cancer (n=27)
    14.8 (4.2 to 33.7)
        Nasopharyngeal Carcinoma (n=27)
    7.4 (0.9 to 24.3)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    0 (0 to 30.8)
        BRCA Mutated Ovarian Cancer (n=15)
    13.3 (1.7 to 40.5)
        BRCA Mutated Breast Cancer (n=12)
    0 (0 to 26.5)
        Liposarcoma (n=13)
    0 (0 to 24.7)
        Leiomyosarcoma (n=17)
    5.9 (0.1 to 28.7)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    0 (0 to 21.8)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    0 (0 to 28.5)
        Known Translocation-Related Sarcomas (n=26)
    7.7 (0.9 to 25.1)
        Radiation Induced Sarcoma (n=8)
    12.5 (0.3 to 52.7)
        Osteosarcoma (n=11)
    9.1 (0.2 to 41.3)
        Chondrosarcoma (n=12)
    0 (0 to 26.5)
        Pleural Mesothelioma (n=13)
    7.7 (0.2 to 36.0)
        Peritoneal Mesothelioma (n=14)
    14.3 (1.8 to 42.8)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    0 (0 to 24.7)
        Anaplastic Thyroid Cancer (TC) (n=15)
    0 (0 to 21.8)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    9.1 (0.2 to 41.3)
        Medullary/Follicular/Papillary TC (n=7)
    0 (0 to 41.0)
        Gastric/GE Junction Adenocarcinoma (n=14)
    7.1 (0.2 to 33.9)
        Malignant Germ Cell Tumors (n=14)
    0 (0 to 23.2)
        ER+/HER2- Hypermutated MBC (n=12)
    8.3 (0.2 to 38.5)
        Thymoma (n=13)
    38.5 (13.9 to 68.4)
        Thymic cancer (n=12)
    8.3 (0.2 to 38.5)
        Low/Intermediate Grade Carcinoid (n=12)
    0 (0 to 26.5)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    16.7 (2.1 to 48.4)
        Head and Neck Squamous Cell Carcinoma (n=6)
    16.7 (0.4 to 64.1)
        Penile Cancer (n=4)
    0 (0 to 60.2)
        Anal Cancer (n=11)
    9.1 (0.2 to 41.3)
        Known MSI High or MMR Deficient Tumors (n=10)
    20.0 (2.5 to 55.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Best Overall Response (BOR)

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    End point title
    Percentage of Participants by Best Overall Response (BOR)
    End point description
    BOR was based on RECIST v1.1, Malignant Pleural Mesothelioma Response Evaluation Criteria or Prostate Response Evaluation Criteria. For an individual participant BOR was obtained as follows: 1) CR: overall tumor response assessment of CR at 2 consecutive visits at least 28 days apart. 2) PR: overall tumor response assessment of PR or CR at 2 consecutive visits at least 28 days apart without being a CR. 3) SD: overall tumor response assessment of SD, PR, or CR at one or more visits at least 42 days after start of study treatment, but was not a confirmed CR or PR. 4) PD: an overall tumor response assessment of PD at any visit, and did not meet the criteria for a BOR of CR, PR or SD. 5) Missing: an assessment of SD, PR or CR in the first 42 days after start of study treatment and no further tumor assessments thereafter. Efficacy analysis set: all eligible and evaluable (received study drug, had baseline tumor assessment and at least one tumor assessment post-baseline) participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: percentage of participants
    number (not applicable)
        Overall Population: CR (n=433)
    0.7
        Overall Population: PR (n=433)
    6.7
        Overall Population: SD (n=433)
    36.3
        Overall Population: PD (n=433)
    53.3
        Overall Population: Missing (n=433)
    3.0
        Cervical Cancer: CR (n=27)
    3.7
        Cervical Cancer: PR (n=27)
    11.1
        Cervical Cancer: SD (n=27)
    40.7
        Cervical Cancer: PD (n=27)
    40.7
        Cervical Cancer: Missing (n=27)
    3.7
        Nasopharyngeal Carcinoma: CR (n=27)
    0
        Nasopharyngeal Carcinoma: PR (n=27)
    7.4
        Nasopharyngeal Carcinoma: SD (n=27)
    44.4
        Nasopharyngeal Carcinoma: PD (n=27)
    48.1
        Nasopharyngeal Carcinoma: Missing (n=27)
    0
        MSI-H or MMR Deficient Colorectal Cancer CR (n=10)
    0
        MSI-H or MMR Deficient Colorectal Cancer PR (n=10)
    0
        MSI-H or MMR Deficient Colorectal Cancer SD (n=10)
    40.0
        MSI-H or MMR Deficient Colorectal Cancer PD (n=10)
    50.0
        MSI-H or MMR Deficient Colorectal Missing (n=10)
    10.0
        BRCA Mutated Ovarian Cancer: CR (n=15)
    0
        BRCA Mutated Ovarian Cancer: PR (n=15)
    13.3
        BRCA Mutated Ovarian Cancer: SD (n=15)
    33.3
        BRCA Mutated Ovarian Cancer: PD (n=15)
    46.7
        BRCA Mutated Ovarian Cancer: Missing (n=15)
    6.7
        BRCA Mutated Breast Cancer: CR (n=12)
    0
        BRCA Mutated Breast Cancer: PR (n=12)
    0
        BRCA Mutated Breast Cancer: SD (n=12)
    8.3
        BRCA Mutated Breast Cancer: PD (n=12)
    91.7
        BRCA Mutated Breast Cancer: Missing (n=12)
    0
        Liposarcoma: CR (n=13)
    0
        Liposarcoma: PR (n=13)
    0
        Liposarcoma: SD (n=13)
    30.8
        Liposarcoma: PD (n=13)
    61.5
        Liposarcoma: Missing (n=13)
    7.7
        Leiomyosarcoma: CR (n=17)
    0
        Leiomyosarcoma: PR (n=17)
    5.9
        Leiomyosarcoma: SD (n=17)
    17.6
        Leiomyosarcoma: PD (n=17)
    64.7
        Leiomyosarcoma: Missing (n=17)
    11.8
        Gastrointestinal Stromal Tumor (GIST): CR (n=15)
    0
        Gastrointestinal Stromal Tumor (GIST): PR (n=15)
    0
        Gastrointestinal Stromal Tumor (GIST): SD (n=15)
    33.3
        Gastrointestinal Stromal Tumor (GIST): PD (n=15)
    66.7
        Gastrointestinal Stromal Tumor: Missing (n=15)
    0
        Undifferentiated Pleomorphic Sarcoma: CR (n=11)
    0
        Undifferentiated Pleomorphic Sarcoma: PR (n=11)
    0
        Undifferentiated Pleomorphic Sarcoma: SD (n=11)
    9.1
        Undifferentiated Pleomorphic Sarcoma: PD (n=11)
    90.9
        Undifferentiated Pleomorphic Sarc: Missing (n=11)
    0
        Known Translocation-Related Sarcomas: CR (n=26)
    0
        Known Translocation-Related Sarcomas: PR (n=26)
    7.7
        Known Translocation-Related Sarcomas: SD (n=26)
    34.6
        Known Translocation-Related Sarcomas: PD (n=26)
    53.8
        Known Translocation-Related Sarc. Missing (n=26)
    3.8
        Radiation Induced Sarcoma: CR (n=8)
    0
        Radiation Induced Sarcoma: PR (n=8)
    12.5
        Radiation Induced Sarcoma: SD (n=8)
    12.5
        Radiation Induced Sarcoma: PD (n=8)
    75.0
        Radiation Induced Sarcoma: Missing (n=8)
    0
        Osteosarcoma: CR (n=11)
    0
        Osteosarcoma: PR (n=11)
    9.1
        Osteosarcoma: SD (n=11)
    36.4
        Osteosarcoma: PD (n=11)
    54.5
        Osteosarcoma: Missing (n=11)
    0
        Chondrosarcoma: CR (n=12)
    0
        Chondrosarcoma: PR (n=12)
    0
        Chondrosarcoma: SD (n=12)
    41.7
        Chondrosarcoma: PD (n=12)
    58.3
        Chondrosarcoma: Missing (n=12)
    0
        Pleural Mesothelioma: CR (n=13)
    0
        Pleural Mesothelioma: PR (n=13)
    7.7
        Pleural Mesothelioma: SD (n=13)
    61.5
        Pleural Mesothelioma: PD (n=13)
    30.8
        Pleural Mesothelioma: Missing (n=13)
    0
        Peritoneal Mesothelioma: CR (n=14)
    0
        Peritoneal Mesothelioma: PR (n=14)
    14.3
        Peritoneal Mesothelioma: SD (n=14)
    42.9
        Peritoneal Mesothelioma: PD (n=14)
    42.9
        Peritoneal Mesothelioma: Missing (n=14)
    0
        Cholangiocarcinoma/Biliary Tract Cancer: CR (n=13)
    0
        Cholangiocarcinoma/Biliary Tract Cancer: PR (n=13)
    0
        Cholangiocarcinoma/Biliary Tract Cancer: SD (n=13)
    53.8
        Cholangiocarcinoma/Biliary Tract Cancer: PD (n=13)
    46.2
        Cholangiocarcinoma/Biliary Tract: Missing (n=13)
    0
        Anaplastic Thyroid Cancer (TC): CR (n=15)
    0
        Anaplastic Thyroid Cancer (TC): PR (n=15)
    0
        Anaplastic Thyroid Cancer (TC): SD (n=15)
    13.3
        Anaplastic Thyroid Cancer (TC): PD (n=15)
    73.3
        Anaplastic Thyroid Cancer (TC): Missing (n=15)
    13.3
        Follicular or Papillary TC: CR (n=11)
    0
        Follicular or Papillary TC: PR (n=11)
    9.1
        Follicular or Papillary Thyroid TC: SD (n=11)
    72.7
        Follicular or Papillary Thyroid TC: PD (n=11)
    18.2
        Follicular or Papillary Thyroid TC: Missing (n=11)
    0
        Medullary/Follicular/Papillary TC: CR (n=7)
    0
        Medullary/Follicular/Papillary TC: PR (n=7)
    0
        Medullary/Follicular/Papillary TC: SD (n=7)
    42.9
        Medullary/Follicular/Papillary TC: PD (n=7)
    42.9
        Medullary/Follicular/Papillary TC: Missing (n=7)
    14.3
        Gastric/GE Junction Adenocarcinoma: CR (n=14)
    0
        Gastric/GE Junction Adenocarcinoma: PR (n=14)
    7.1
        Gastric/GE Junction Adenocarcinoma: SD (n=14)
    21.4
        Gastric/GE Junction Adenocarcinoma: PD (n=14)
    57.1
        Gastric/GE Junction Adenocarcinoma: Missing (n=14)
    14.3
        Malignant Germ Cell Tumors: CR (n=14)
    0
        Malignant Germ Cell Tumors: PR (n=14)
    0
        Malignant Germ Cell Tumors: SD (n=14)
    35.7
        Malignant Germ Cell Tumors: PD (n=14)
    64.3
        Malignant Germ Cell Tumors: Missing (n=14)
    0
        ER+/HER2- Hypermutated MBC: CR (n=12)
    0
        ER+/HER2- Hypermutated MBC: PR (n=12)
    8.3
        ER+/HER2- Hypermutated MBC: SD (n=12)
    8.3
        ER+/HER2- Hypermutated MBC: PD (n=12)
    83.3
        ER+/HER2- Hypermutated MBC: Missing (n=12)
    0
        Thymoma: CR (n=13)
    0
        Thymoma: PR (n=13)
    38.5
        Thymoma: SD (n=13)
    46.2
        Thymoma: PD (n=13)
    7.7
        Thymoma: Missing (n=13)
    7.7
        Thymic cancer: CR (n=12)
    0
        Thymic cancer: PR (n=12)
    8.3
        Thymic cancer: SD (n=12)
    50.0
        Thymic cancer: PD (n=12)
    41.7
        Thymic cancer: Missing (n=12)
    0
        Low/Intermediate Grade Carcinoid: CR (n=12)
    0
        Low/Intermediate Grade Carcinoid: PR (n=12)
    0
        Low/Intermediate Grade Carcinoid: SD (n=12)
    100.0
        Low/Intermediate Grade Carcinoid: PD (n=12)
    0
        Low/Intermediate Grade Carcinoid: Missing (n=12)
    0
        Poorly Differentiated Grade: CR (n=12)
    0
        Poorly Differentiated Grade: PR (n=12)
    16.7
        Poorly Differentiated Grade: SD (n=12)
    16.7
        Poorly Differentiated Grade: PD (n=12)
    66.7
        Poorly Differentiated Grade: Missing (n=12)
    0
        Head and Neck Squamous Cell Carcinoma: CR (n=6)
    16.7
        Head and Neck Squamous Cell Carcinoma: PR (n=6)
    0
        Head and Neck Squamous Cell Carcinoma: SD (n=6)
    33.3
        Head and Neck Squamous Cell Carcinoma: PD (n=6)
    50.0
        Head and Neck Squamous Cell: Missing (n=6)
    0
        Penile Cancer: CR (n=4)
    0
        Penile Cancer: PR (n=4)
    0
        Penile Cancer: SD (n=4)
    50.0
        Penile Cancer: PD (n=4)
    50.0
        Penile Cancer: Missing (n=4)
    0
        Anal Cancer: CR (n=11)
    9.1
        Anal Cancer: PR (n=11)
    0
        Anal Cancer: SD (n=11)
    36.4
        Anal Cancer: PD (n=11)
    54.5
        Anal Cancer: Missing (n=11)
    0
        Known MSI High or MMR Deficient Tumors: CR (n=10)
    0
        Known MSI High or MMR Deficient Tumors: PR (n=10)
    20.0
        Known MSI High or MMR Deficient Tumors: SD (n=10)
    40.0
        Known MSI High or MMR Deficient Tumors: PD (n=10)
    40.0
        Known MSI High or MMR Deficient: Missing (n=10)
    0
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    Clinical Benefit Rate (CBR)
    End point description
    CBR was defined as the percentage of participants with CR, PR, or SD according to RECIST v1.1, Malignant Pleural Mesothelioma Response Evaluation Criteria or Prostate Response Evaluation Criteria lasting for >/=6 weeks. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the diameters of all target and all new measurable lesions in the absence of CR. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: At least a 20% increase in the sum of diameters of all target and all new measurable lesions. For prostate cancer: CR: PSA <5 ng/ml measured twice at least 3 weeks apart or PSA response: PSA < 50% of the PSA reference value occurring at any time after treatment was initiated. Efficacy analysis set: all eligible and evaluable (received study drug, had baseline tumor assessment and at least one tumor assessment post-baseline) participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: percentage of participants
    number (confidence interval 95%)
        Overall Population (n=433)
    43.6 (38.9 to 48.5)
        Cervical Cancer (n=27)
    55.6 (35.3 to 74.5)
        Nasopharyngeal Carcinoma (n=27)
    51.9 (31.9 to 71.3)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    40.0 (12.2 to 73.8)
        BRCA Mutated Ovarian Cancer (n=15)
    46.7 (21.3 to 73.4)
        BRCA Mutated Breast Cancer (n=12)
    8.3 (0.2 to 38.5)
        Liposarcoma (n=13)
    30.8 (9.1 to 61.4)
        Leiomyosarcoma (n=17)
    23.5 (6.8 to 49.9)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    33.3 (11.8 to 61.6)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    9.1 (0.2 to 41.3)
        Known Translocation-Related Sarcomas (n=26)
    42.3 (23.4 to 63.1)
        Radiation Induced Sarcoma (n=8)
    25.0 (3.2 to 65.1)
        Osteosarcoma (n=11)
    45.5 (16.7 to 76.6)
        Chondrosarcoma (n=12)
    41.7 (15.2 to 72.3)
        Pleural Mesothelioma (n=13)
    69.2 (38.6 to 90.9)
        Peritoneal Mesothelioma (n=14)
    57.1 (28.9 to 82.3)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    53.8 (25.1 to 80.8)
        Anaplastic Thyroid Cancer (TC) (n=15)
    13.3 (1.7 to 40.5)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    81.8 (48.2 to 97.7)
        Medullary/Follicular/Papillary TC (n=7)
    42.9 (9.9 to 81.6)
        Gastric/GE Junction Adenocarcinoma (n=14)
    28.6 (8.4 to 58.1)
        Malignant Germ Cell Tumors (n=14)
    35.7 (12.8 to 64.9)
        ER+/HER2- Hypermutated MBC (n=12)
    16.7 (2.1 to 48.4)
        Thymoma (n=13)
    84.6 (54.6 to 98.1)
        Thymic cancer (n=12)
    58.3 (27.7 to 84.8)
        Low/Intermediate Grade Carcinoid (n=12)
    100.0 (73.5 to 100.0)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    33.3 (9.9 to 65.1)
        Head and Neck Squamous Cell Carcinoma (n=6)
    50.0 (11.8 to 88.2)
        Penile Cancer (n=4)
    50.0 (6.8 to 93.2)
        Anal Cancer (n=11)
    45.5 (16.7 to 76.6)
        Known MSI High or MMR Deficient Tumors (n=10)
    60.0 (26.2 to 87.8)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response (DOR)

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    End point title
    Duration of Objective Response (DOR)
    End point description
    DOR, based on RECIST v1.1, was defined as the time from the first occurrence of a documented objective response (CR or PR) to the time of progression or death from any cause, whichever occurred first. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the diameters of all target and all new measurable lesions in the absence of CR. PD: At least a 20% increase in the sum of diameters of all target and all new measurable lesions. DOR was not analyzed if there were less than 4 participants available for the analysis. Efficacy analysis set included all eligible and evaluable participants. A participant was considered evaluable if they received study drug, had a baseline tumor assessment and at least one tumor assessment post-baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    0 [2]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [2] - Data not analyzed for less than 4 participants.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS, based on RECIST v1.1, was defined as the time from the first day of study treatment to the first occurrence of disease progression or death from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of all target and all new measurable lesions. Efficacy analysis set included all eligible and evaluable participants. A participant was considered evaluable if they received study drug, had a baseline tumor assessment and at least one tumor assessment post-baseline. 99999=Upper limit of CI was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: months
    median (confidence interval 95%)
        Cervical Cancer (n=27)
    4.14 (1.31 to 8.34)
        Nasopharyngeal Carcinoma (n=27)
    3.15 (1.35 to 4.60)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    1.51 (0.72 to 10.97)
        BRCA Mutated Ovarian Cancer (n=15)
    2.73 (1.45 to 4.01)
        BRCA Mutated Breast Cancer (n=12)
    1.38 (0.99 to 1.54)
        Liposarcoma (n=13)
    1.51 (1.25 to 4.70)
        Leiomyosarcoma (n=17)
    2.69 (1.28 to 3.12)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    1.41 (1.15 to 2.79)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    1.31 (1.25 to 1.35)
        Known Translocation-Related Sarcomas (n=26)
    2.73 (1.38 to 5.42)
        Radiation Induced Sarcoma (n=8)
    1.43 (1.25 to 14.39)
        Osteosarcoma (n=11)
    2.96 (1.28 to 16.69)
        Chondrosarcoma (n=12)
    1.87 (1.35 to 5.49)
        Pleural Mesothelioma (n=13)
    4.11 (1.25 to 5.49)
        Peritoneal Mesothelioma (n=14)
    4.78 (1.31 to 8.28)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    3.71 (1.31 to 4.27)
        Anaplastic Thyroid Cancer (TC) (n=15)
    1.41 (1.22 to 2.07)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    8.48 (1.31 to 15.41)
        Medullary/Follicular/Papillary TC (n=7)
    3.52 (1.25 to 12.39)
        Gastric/GE Junction Adenocarcinoma (n=14)
    1.68 (1.41 to 3.19)
        Malignant Germ Cell Tumors (n=14)
    2.73 (1.38 to 4.07)
        ER+/HER2- Hypermutated MBC (n=12)
    1.22 (1.08 to 1.48)
        Thymoma (n=13)
    11.76 (3.22 to 37.22)
        Thymic cancer (n=12)
    4.07 (1.38 to 13.96)
        Low/Intermediate Grade Carcinoid (n=12)
    8.54 (4.07 to 13.67)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    1.40 (1.08 to 9.72)
        Head and Neck Squamous Cell Carcinoma (n=6)
    2.76 (1.38 to 99999)
        Penile Cancer (n=4)
    2.07 (1.22 to 4.14)
        Anal Cancer (n=11)
    3.12 (1.31 to 4.11)
        Known MSI High or MMR Deficient Tumors (n=10)
    3.98 (1.18 to 16.92)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    Time to progression (TTP), based on RECIST v1.1, was defined as time from the first day of study treatment to the first occurrence of progressive disease or death due to disease progression, whichever occurred first. PD: At least a 20% increase in the sum of diameters of all target and all new measurable lesions. Efficacy analysis set included all eligible and evaluable participants. A participant was considered evaluable if they received study drug, had a baseline tumor assessment and at least one tumor assessment post-baseline. 99999=Upper limit of CI was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: months
    median (confidence interval 95%)
        Cervical Cancer (n=27)
    4.14 (1.31 to 8.34)
        Nasopharyngeal Carcinoma (n=27)
    3.45 (1.35 to 4.60)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    1.51 (0.72 to 10.97)
        BRCA Mutated Ovarian Cancer (n=15)
    2.73 (1.45 to 4.01)
        BRCA Mutated Breast Cancer (n=12)
    1.38 (0.99 to 1.54)
        Liposarcoma (n=13)
    1.51 (1.25 to 4.70)
        Leiomyosarcoma (n=17)
    2.69 (1.28 to 3.12)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    1.41 (1.15 to 2.79)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    1.31 (1.25 to 1.35)
        Known Translocation-Related Sarcomas (n=26)
    2.73 (1.38 to 3.55)
        Radiation Induced Sarcoma (n=8)
    1.43 (1.25 to 14.39)
        Osteosarcoma (n=11)
    2.96 (1.28 to 16.69)
        Chondrosarcoma (n=12)
    1.87 (1.35 to 5.49)
        Pleural Mesothelioma (n=13)
    4.11 (1.25 to 5.49)
        Peritoneal Mesothelioma (n=14)
    4.78 (1.31 to 8.28)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    3.71 (1.31 to 4.27)
        Anaplastic Thyroid Cancer (TC) (n=15)
    1.41 (1.22 to 2.07)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    8.48 (1.31 to 15.41)
        Medullary/Follicular/Papillary TC (n=7)
    5.52 (1.25 to 23.33)
        Gastric/GE Junction Adenocarcinoma (n=14)
    1.68 (1.41 to 3.19)
        Malignant Germ Cell Tumors (n=14)
    2.73 (1.38 to 4.07)
        ER+/HER2- Hypermutated MBC (n=12)
    1.22 (1.08 to 1.48)
        Thymoma (n=13)
    12.58 (3.22 to 37.22)
        Thymic cancer (n=12)
    2.76 (1.38 to 13.86)
        Low/Intermediate Grade Carcinoid (n=12)
    8.54 (4.07 to 10.94)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    1.40 (1.08 to 9.72)
        Head and Neck Squamous Cell Carcinoma (n=6)
    2.76 (1.38 to 99999)
        Penile Cancer (n=4)
    2.07 (1.22 to 4.14)
        Anal Cancer (n=11)
    3.12 (1.31 to 4.11)
        Known MSI High or MMR Deficient Tumors (n=10)
    3.98 (1.18 to 16.92)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from the first day of study treatment to death from any cause. Efficacy analysis set included all eligible and evaluable participants. A participant was considered evaluable if they received study drug, had a baseline tumor assessment and at least one tumor assessment post-baseline. 9999=Median OS was not reached; 00000=Lower limit of CI could not be determined as median OS was not reached; 99999=Upper limit of CI could not be determined due to low number of participants with events or median OS was not reached.
    End point type
    Secondary
    End point timeframe
    Baseline until death due to any cause (up to 4.5 years)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: months
    median (confidence interval 95%)
        Cervical Cancer (n=27)
    14.78 (10.55 to 26.51)
        Nasopharyngeal Carcinoma (n=27)
    17.97 (8.90 to 27.56)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    6.41 (0.99 to 22.90)
        BRCA Mutated Ovarian Cancer (n=15)
    24.02 (4.11 to 99999)
        BRCA Mutated Breast Cancer (n=12)
    5.09 (1.77 to 7.03)
        Liposarcoma (n=13)
    12.71 (4.37 to 24.44)
        Leiomyosarcoma (n=17)
    9.66 (3.12 to 13.67)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    7.39 (2.89 to 11.70)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    5.59 (3.52 to 9.26)
        Known Translocation-Related Sarcomas (n=26)
    17.74 (6.37 to 99999)
        Radiation Induced Sarcoma (n=8)
    8.33 (2.43 to 99999)
        Osteosarcoma (n=11)
    12.65 (2.50 to 99999)
        Chondrosarcoma (n=12)
    21.98 (4.76 to 99999)
        Pleural Mesothelioma (n=13)
    17.81 (9.10 to 99999)
        Peritoneal Mesothelioma (n=14)
    12.78 (4.21 to 99999)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    7.49 (3.25 to 11.20)
        Anaplastic Thyroid Cancer (TC) (n=15)
    4.62 (1.87 to 12.78)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    9999 (00000 to 99999)
        Medullary/Follicular/Papillary TC (n=7)
    18.92 (3.52 to 99999)
        Gastric/GE Junction Adenocarcinoma (n=14)
    8.57 (2.99 to 18.07)
        Malignant Germ Cell Tumors (n=14)
    8.15 (6.14 to 16.49)
        ER+/HER2- Hypermutated MBC (n=12)
    8.39 (2.69 to 20.27)
        Thymoma (n=13)
    9999 (00000 to 99999)
        Thymic cancer (n=12)
    9999 (00000 to 99999)
        Low/Intermediate Grade Carcinoid (n=12)
    27.20 (17.02 to 99999)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    16.16 (4.04 to 26.32)
        Head and Neck Squamous Cell Carcinoma (n=6)
    12.58 (2.40 to 99999)
        Penile Cancer (n=4)
    15.52 (5.49 to 99999)
        Anal Cancer (n=11)
    9999 (00000 to 99999)
        Known MSI High or MMR Deficient Tumors (n=10)
    18.66 (1.41 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events

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    End point title
    Number of Participants with Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Safety analysis set included all participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years
    End point values
    Atezolizumab
    Number of subjects analysed
    474
    Units: participants
    435
    No statistical analyses for this end point

    Secondary: Treatment Duration of Atezolizumab

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    End point title
    Treatment Duration of Atezolizumab
    End point description
    Safety analysis set included all participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 4.5 years
    End point values
    Atezolizumab
    Number of subjects analysed
    474
    Units: months
        median (full range (min-max))
    2.513 (0.03 to 52.47)
    No statistical analyses for this end point

    Secondary: Mean Number of Doses of Atezolizumab

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    End point title
    Mean Number of Doses of Atezolizumab
    End point description
    Safety analysis set included all participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 4.5 years
    End point values
    Atezolizumab
    Number of subjects analysed
    474
    Units: doses
        arithmetic mean (standard deviation)
    9.0 ± 11.28
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-drug Antibodies (ADAs) to Atezolizumab

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    End point title
    Percentage of Participants with Anti-drug Antibodies (ADAs) to Atezolizumab
    End point description
    Safety analysis set included all participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years
    End point values
    Atezolizumab
    Number of subjects analysed
    474
    Units: percentage of participants
    number (not applicable)
        Baseline ADAs
    1.9
        Treatment-emergent ADAs
    18.3
    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
    Safety analysis set included all participants who received at least one dose of study medication. 99999=not available as only one participant was analyzed.
    End point type
    Secondary
    End point timeframe
    Predose and postdose on Day 1 of Cycle 1, predose on Day 1 of Cycles 2, 3, 4, 8 (cycle length = 21 days), and every 8 cycles until treatment discontinuation; at follow up (approximately 120 days after last dose) up to approximately 4.5 years
    End point values
    Atezolizumab
    Number of subjects analysed
    474
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 01, Day 1 predose (n=452)
    45528.4 ± 84303.42
        Cycle 01, Day 1 postdose (n=454)
    422792.0 ± 225600.85
        Cycle 02, Day 1 predose (n=433)
    85674.3 ± 35394.34
        Cycle 03, Day 1 predose (n=342)
    131868.7 ± 60596.06
        Cycle 04, Day 1 predose (n=288)
    156555.7 ± 67478.76
        Cycle 08, Day 1 predose (n=156)
    201332.1 ± 96547.07
        Cycle 16, Day 1 predose (n=72)
    216038.7 ± 97136.92
        Cycle 24, Day 1 predose (n=32)
    224556.7 ± 104892.34
        Cycle 32, Day 1 predose (n=21)
    253873.7 ± 136820.70
        Cycle 40, Day 1 predose (n=12)
    284000.0 ± 110167.55
        Cycle 48, Day 1 predose (n=8)
    319500.0 ± 203543.61
        Cycle 56, Day 1 predose (n=1)
    203000.0 ± 99999
        Cycle 64, Day 1 predose (n=2)
    217000.0 ± 57982.76
        Follow Up (n=77)
    17565.6 ± 29505.18
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Best Overall Response Based on Modified RECIST v1.1 (mBOR)

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    End point title
    Percentage of Participants by Best Overall Response Based on Modified RECIST v1.1 (mBOR)
    End point description
    Modified RECIST: 1) New measurable lesions were added into the total tumor burden and followed; 2) Non-target lesions contributed only in the assessment of a CR; 3) Radiographic progression determined only on the basis of measurable disease; had to be confirmed by a consecutive assessment =/>4 weeks later. mBOR: 1) CR: assessment of CR at 2 consecutive visits at least 28 days apart. 2) PR: assessment of PR/CR at 2 consecutive visits at least 28 days apart without being CR. 3) SD: assessment of SD/PR/CR at one or more visits at least 42 days after start of study treatment, but not a confirmed CR or PR. 4) PD: assessment of PD at any visit, and not CR, PR or SD. 5) Missing: an assessment of SD, PR or CR in the first 42 days after start of study treatment and no further tumor assessments thereafter. Efficacy analysis set: all eligible and evaluable (received study drug, had baseline tumor assessment and at least one tumor assessment post-baseline) participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: percentage of participants
    number (not applicable)
        Overall Population: CR (n=433)
    0.7
        Overall Population: PR (n=433)
    7.2
        Overall Population: SD (n=433)
    43.9
        Overall Population: PD (n=433)
    38.3
        Overall Population: Missing (n=433)
    9.9
        Cervical Cancer: CR (n=27)
    3.7
        Cervical Cancer: PR (n=27)
    11.1
        Cervical Cancer: SD (n=27)
    44.4
        Cervical Cancer: PD (n=27)
    25.9
        Cervical Cancer: Missing (n=27)
    14.8
        Nasopharyngeal Carcinoma: CR (n=27)
    0
        Nasopharyngeal Carcinoma: PR (n=27)
    11.1
        Nasopharyngeal Carcinoma: SD (n=27)
    51.9
        Nasopharyngeal Carcinoma: PD (n=27)
    33.3
        Nasopharyngeal Carcinoma: Missing (n=27)
    3.7
        MSI-H or MMR Deficient Colorectal: CR (n=10)
    0
        MSI-H or MMR Deficient Colorectal: PR (n=10)
    0
        MSI-H or MMR Deficient Colorectal: SD (n=10)
    60.0
        MSI-H or MMR Deficient Colorectal: PD (n=10)
    30.0
        MSI-H or MMR Deficient Colorectal: Missing (n=10)
    10.0
        BRCA Mutated Ovarian Cancer: CR (n=15)
    0
        BRCA Mutated Ovarian Cancer: PR (n=15)
    13.3
        BRCA Mutated Ovarian Cancer: SD (n=15)
    40.0
        BRCA Mutated Ovarian Cancer: PD (n=15)
    33.3
        BRCA Mutated Ovarian Cancer: Missing (n=15)
    13.3
        BRCA Mutated Breast Cancer: CR (n=12)
    0
        BRCA Mutated Breast Cancer: PR (n=12)
    0
        BRCA Mutated Breast Cancer: SD (n=12)
    25.0
        BRCA Mutated Breast Cancer: PD (n=12)
    58.3
        BRCA Mutated Breast Cancer: Missing (n=12)
    16.7
        Liposarcoma: CR (n=13)
    0
        Liposarcoma: PR (n=13)
    0
        Liposarcoma: SD (n=13)
    38.5
        Liposarcoma: PD (n=13)
    53.8
        Liposarcoma: Missing (n=13)
    7.7
        Leiomyosarcoma: CR (n=17)
    0
        Leiomyosarcoma: PR (n=17)
    5.9
        Leiomyosarcoma: SD (n=17)
    23.5
        Leiomyosarcoma: PD (n=17)
    47.1
        Leiomyosarcoma: Missing (n=17)
    23.5
        Gastrointestinal Stromal Tumor (GIST): CR (n=15)
    0
        Gastrointestinal Stromal Tumor (GIST): PR (n=15)
    0
        Gastrointestinal Stromal Tumor (GIST): SD (n=15)
    40.0
        Gastrointestinal Stromal Tumor (GIST): PD (n=15)
    60.0
        Gastrointestinal Stromal Tumor: Missing (n=15)
    0
        Undifferentiated Pleomorphic Sarc: CR (n=11)
    0
        Undifferentiated Pleomorphic Sarc: PR (n=11)
    0
        Undifferentiated Pleomorphic Sarc: SD (n=11)
    9.1
        Undifferentiated Pleomorphic Sarc: PD (n=11)
    81.8
        Undifferentiated Pleomorphic Sarc: Missing (n=11)
    9.1
        Known Translocation-Related Sarcomas: CR (n=26)
    0
        Known Translocation-Related Sarcomas: PR (n=26)
    7.7
        Known Translocation-Related Sarcomas: SD (n=26)
    46.2
        Known Translocation-Related Sarcomas: PD (n=26)
    30.8
        Known Translocation-Related Sarc: Missing (n=26)
    15.4
        Radiation Induced Sarcoma: CR (n=8)
    0
        Radiation Induced Sarcoma: PR (n=8)
    12.5
        Radiation Induced Sarcoma: SD (n=8)
    37.5
        Radiation Induced Sarcoma: PD (n=8)
    37.5
        Radiation Induced Sarcoma: Missing (n=8)
    12.5
        Osteosarcoma: CR (n=11)
    0
        Osteosarcoma: PR (n=11)
    9.1
        Osteosarcoma: SD (n=11)
    36.4
        Osteosarcoma: PD (n=11)
    54.5
        Osteosarcoma: Missing (n=11)
    0
        Chondrosarcoma: CR (n=12)
    0
        Chondrosarcoma: PR (n=12)
    0
        Chondrosarcoma: SD (n=12)
    50.0
        Chondrosarcoma: PD (n=12)
    41.7
        Chondrosarcoma: Missing (n=12)
    8.3
        Pleural Mesothelioma: CR (n=13)
    0
        Pleural Mesothelioma: PR (n=13)
    7.7
        Pleural Mesothelioma: SD (n=13)
    61.5
        Pleural Mesothelioma: PD (n=13)
    23.1
        Pleural Mesothelioma: Missing (n=13)
    7.7
        Peritoneal Mesothelioma: CR (n=14)
    0
        Peritoneal Mesothelioma: PR (n=14)
    14.3
        Peritoneal Mesothelioma: SD (n=14)
    50.0
        Peritoneal Mesothelioma: PD (n=14)
    14.3
        Peritoneal Mesothelioma: Missing (n=14)
    21.4
        Cholangiocarcinoma/Biliary Tract Cancer: CR (n=13)
    0
        Cholangiocarcinoma/Biliary Tract Cancer: PR (n=13)
    0
        Cholangiocarcinoma/Biliary Tract Cancer: SD (n=13)
    69.2
        Cholangiocarcinoma/Biliary Tract Cancer: PD (n=13)
    15.4
        Cholangiocarcinoma/ Biliary Tract: Missing (n=13)
    15.4
        Anaplastic Thyroid Cancer (TC): CR (n=15)
    0
        Anaplastic Thyroid Cancer (TC): PR (n=15)
    0
        Anaplastic Thyroid Cancer (TC): SD (n=15)
    13.3
        Anaplastic Thyroid Cancer (TC): PD (n=15)
    73.3
        Anaplastic Thyroid Cancer (TC): Missing (n=15)
    13.3
        Follicular or Papillary TC: CR (n=11)
    0
        Follicular or Papillary TC: PR (n=11)
    9.1
        Follicular or Papillary TC: SD (n=11)
    72.7
        Follicular or Papillary TC: PD (n=11)
    9.1
        Follicular or Papillary Thyroid TC: Missing (n=11)
    9.1
        Medullary/Follicular/Papillary TC: CR (n=7)
    0
        Medullary/Follicular/Papillary TC: PR (n=7)
    0
        Medullary/Follicular/Papillary TC: SD (n=7)
    42.9
        Medullary/Follicular/Papillary TC: PD (n=7)
    42.9
        Medullary/Follicular/Papillary TC: Missing (n=7)
    14.3
        Gastric/GE Junction Adenocarcinoma: CR (n=14)
    0
        Gastric/GE Junction Adenocarcinoma: PR (n=14)
    7.1
        Gastric/GE Junction Adenocarcinoma: SD (n=14)
    35.7
        Gastric/GE Junction Adenocarcinoma: PD (n=14)
    35.7
        Gastric/GE Junction Adenocarcinoma: Missing (n=14)
    21.4
        Malignant Germ Cell Tumors: CR (n=14)
    0
        Malignant Germ Cell Tumors: PR (n=14)
    0
        Malignant Germ Cell Tumors: SD (n=14)
    50.0
        Malignant Germ Cell Tumors: PD (n=14)
    50.0
        Malignant Germ Cell Tumors: Missing (n=14)
    0
        ER+/HER2- Hypermutated MBC: CR (n=12)
    0
        ER+/HER2- Hypermutated MBC: PR (n=12)
    8.3
        ER+/HER2- Hypermutated MBC: SD (n=12)
    25.0
        ER+/HER2- Hypermutated MBC: PD (n=12)
    58.3
        ER+/HER2- Hypermutated MBC: Missing (n=12)
    8.3
        Thymoma: CR (n=13)
    0
        Thymoma: PR (n=13)
    38.5
        Thymoma: SD (n=13)
    46.2
        Thymoma: PD (n=13)
    7.7
        Thymoma: Missing (n=13)
    7.7
        Thymic cancer: CR (n=12)
    0
        Thymic cancer: PR (n=12)
    8.3
        Thymic cancer: SD (n=12)
    50.0
        Thymic cancer: PD (n=12)
    33.3
        Thymic cancer: Missing (n=12)
    8.3
        Low/Intermediate Grade Carcinoid: CR (n=12)
    0
        Low/Intermediate Grade Carcinoid: PR (n=12)
    0
        Low/Intermediate Grade Carcinoid: SD (n=12)
    100.0
        Low/Intermediate Grade Carcinoid: PD (n=12)
    0
        Low/Intermediate Grade Carcinoid: Missing (n=12)
    0
        Poorly Differentiated Grade: CR (n=12)
    0
        Poorly Differentiated Grade: PR (n=12)
    16.7
        Poorly Differentiated Grade: SD (n=12)
    16.7
        Poorly Differentiated Grade: PD (n=12)
    58.3
        Poorly Differentiated Grade: Missing (n=12)
    8.3
        Head and Neck Squamous Cell Carcinoma: CR (n=6)
    16.7
        Head and Neck Squamous Cell Carcinoma: PR (n=6)
    0
        Head and Neck Squamous Cell Carcinoma: SD (n=6)
    33.3
        Head and Neck Squamous Cell Carcinoma: PD (n=6)
    50.0
        Head and Neck Squamous Cell: Missing (n=6)
    0
        Penile Cancer: CR (n=4)
    0
        Penile Cancer: PR (n=4)
    0
        Penile Cancer: SD (n=4)
    50.0
        Penile Cancer: PD (n=4)
    50.0
        Penile Cancer: Missing (n=4)
    0
        Anal Cancer: CR (n=11)
    9.1
        Anal Cancer: PR (n=11)
    0
        Anal Cancer: SD (n=11)
    45.5
        Anal Cancer: PD (n=11)
    45.5
        Anal Cancer: Missing (n=11)
    0
        Known MSI High or MMR Deficient Tumors: CR (n=10)
    0
        Known MSI High or MMR Deficient Tumors: PR (n=10)
    20.0
        Known MSI High or MMR Deficient Tumors: SD (n=10)
    60.0
        Known MSI High or MMR Deficient Tumors: PD (n=10)
    20.0
        Known MSI High or MMR Deficient: Missing (n=10)
    0
    No statistical analyses for this end point

    Secondary: ORR Based on Modified RECIST v1.1

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    End point title
    ORR Based on Modified RECIST v1.1
    End point description
    Modified RECIST was based on the following: 1) New measurable lesions were added into the total tumor burden and followed; 2) Non-target lesions contributed only in the assessment of a CR; 3) Radiographic progression was determined only on the basis of measurable disease; had to be confirmed by a consecutive assessment =/>4 weeks from the date first documented. ORR was defined as the percentage of participants with CR or PR. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the diameters of all target and all new measurable lesions, taking as reference the baseline sum of diameters, in the absence of CR. Efficacy analysis set included all eligible and evaluable participants. A participant was considered evaluable if they received study drug, had a baseline tumor assessment and at least one tumor assessment post-baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: percentage of participants
    number (confidence interval 95%)
        Overall Population (n=433)
    7.9 (5.5 to 10.8)
        Cervical Cancer (n=27)
    14.8 (4.2 to 33.7)
        Nasopharyngeal Carcinoma (n=27)
    11.1 (2.4 to 29.2)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    0.0 (0.0 to 30.8)
        BRCA Mutated Ovarian Cancer (n=15)
    13.3 (1.7 to 40.5)
        BRCA Mutated Breast Cancer (n=12)
    0.0 (0.0 to 26.5)
        Liposarcoma (n=13)
    0.0 (0.0 to 24.7)
        Leiomyosarcoma (n=17)
    5.9 (0.1 to 28.7)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    0.0 (0.0 to 21.8)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    0.0 (0.0 to 28.5)
        Known Translocation-Related Sarcomas (n=26)
    7.7 (0.9 to 25.1)
        Radiation Induced Sarcoma (n=8)
    12.5 (0.3 to 52.7)
        Osteosarcoma (n=11)
    9.1 (0.2 to 41.3)
        Chondrosarcoma (n=12)
    0.0 (0.0 to 26.5)
        Pleural Mesothelioma (n=13)
    7.7 (0.2 to 36.0)
        Peritoneal Mesothelioma (n=14)
    14.3 (1.8 to 42.8)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    0.0 (0.0 to 24.7)
        Anaplastic Thyroid Cancer (TC) (n=15)
    0.0 (0.0 to 21.8)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    9.1 (0.2 to 41.3)
        Medullary/Follicular/Papillary TC (n=7)
    0.0 (0.0 to 41.0)
        Gastric/GE Junction Adenocarcinoma (n=14)
    7.1 (0.2 to 33.9)
        Malignant Germ Cell Tumors (n=14)
    0.0 (0.0 to 23.2)
        ER+/HER2- Hypermutated MBC (n=12)
    8.3 (0.2 to 38.5)
        Thymoma (n=13)
    38.5 (13.9 to 68.4)
        Thymic cancer (n=12)
    8.3 (0.2 to 38.5)
        Low/Intermediate Grade Carcinoid (n=12)
    0.0 (0.0 to 26.5)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    16.7 (2.1 to 48.4)
        Head and Neck Squamous Cell Carcinoma (n=6)
    16.7 (0.4 to 64.1)
        Penile Cancer (n=4)
    0.0 (0.0 to 60.2)
        Anal Cancer (n=11)
    9.1 (0.2 to 41.3)
        Known MSI High or MMR Deficient Tumors (n=10)
    20.0 (2.5 to 55.6)
    No statistical analyses for this end point

    Secondary: CBR Based on Modified RECIST v1.1

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    End point title
    CBR Based on Modified RECIST v1.1
    End point description
    Modified RECIST: 1) New measurable lesions were added into the total tumor burden and followed; 2) Non-target lesions contributed only in the assessment of a CR; 3) Radiographic progression was determined only on the basis of measurable disease; had to be confirmed by a consecutive assessment =/>4 weeks from the date first documented. CBR was defined as the percentage of participants with CR, PR, or SD lasting for >/=6 weeks. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the diameters of all target and all new measurable lesions in the absence of CR. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: At least a 20% increase in the sum of diameters of all target and all new measurable lesions. Efficacy analysis set: all eligible and evaluable (received study drug, had baseline tumor assessment and at least one tumor assessment post-baseline) participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to 4.5 years (assessed every 6 weeks for first 24 weeks and thereafter every 12 weeks up to loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first)
    End point values
    Atezolizumab
    Number of subjects analysed
    433
    Units: percentage of participants
    number (confidence interval 95%)
        Overall Population (n=433)
    51.7 (46.9 to 56.5)
        Cervical Cancer (n=27)
    59.3 (38.8 to 77.6)
        Nasopharyngeal Carcinoma (n=27)
    63.0 (42.4 to 80.6)
        MSI-H or MMR Deficient Colorectal Cancer (n=10)
    60.0 (26.2 to 87.8)
        BRCA Mutated Ovarian Cancer (n=15)
    53.3 (26.6 to 78.7)
        BRCA Mutated Breast Cancer (n=12)
    25.0 (5.5 to 57.2)
        Liposarcoma (n=13)
    38.5 (13.9 to 68.4)
        Leiomyosarcoma (n=17)
    29.4 (10.3 to 56.0)
        Gastrointestinal Stromal Tumor (GIST) (n=15)
    40.0 (16.3 to 67.7)
        Undifferentiated Pleomorphic Sarcoma (n=11)
    9.1 (0.2 to 41.3)
        Known Translocation-Related Sarcomas (n=26)
    53.8 (33.4 to 73.4)
        Radiation Induced Sarcoma (n=8)
    50.0 (15.7 to 84.3)
        Osteosarcoma (n=11)
    45.5 (16.7 to 76.6)
        Chondrosarcoma (n=12)
    50.0 (21.1 to 78.9)
        Pleural Mesothelioma (n=13)
    69.2 (38.6 to 90.9)
        Peritoneal Mesothelioma (n=14)
    64.3 (35.1 to 87.2)
        Cholangiocarcinoma/Biliary Tract Cancer (n=13)
    69.2 (38.6 to 90.9)
        Anaplastic Thyroid Cancer (TC) (n=15)
    13.3 (1.7 to 40.5)
        Follicular or Papillary Thyroid Cancer (TC) (n=11)
    81.8 (48.2 to 97.7)
        Medullary/Follicular/Papillary TC (n=7)
    42.9 (9.9 to 81.6)
        Gastric/GE Junction Adenocarcinoma (n=14)
    42.9 (17.7 to 71.1)
        Malignant Germ Cell Tumors (n=14)
    50.0 (23.0 to 77.0)
        ER+/HER2- Hypermutated MBC (n=12)
    33.3 (9.9 to 65.1)
        Thymoma (n=13)
    84.6 (54.6 to 98.1)
        Thymic cancer (n=12)
    58.3 (27.7 to 84.8)
        Low/Intermediate Grade Carcinoid (n=12)
    100.0 (73.5 to 100.0)
        Poorly Differentiated Grade (excl. SCLC) (n=12)
    33.3 (9.9 to 65.1)
        Head and Neck Squamous Cell Carcinoma (n=6)
    50.0 (11.8 to 88.2)
        Penile Cancer (n=4)
    50.0 (6.8 to 93.2)
        Anal Cancer (n=11)
    54.5 (23.4 to 83.3)
        Known MSI High or MMR Deficient Tumors (n=10)
    80.0 (44.4 to 97.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 4.5 years
    Adverse event reporting additional description
    Safety analysis set included all participants who received at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Atezolizumab
    Reporting group description
    Atezolizumab 1200 milligrams (mg) was administered by intravenous (IV) infusion on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity.

    Serious adverse events
    Atezolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    142 / 474 (29.96%)
         number of deaths (all causes)
    310
         number of deaths resulting from adverse events
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    EMBOLISM
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    NEPHROSTOMY TUBE REMOVAL
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    BASAL CELL CARCINOMA
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    CANCER PAIN
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    FATIGUE
         subjects affected / exposed
    3 / 474 (0.63%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    3 / 474 (0.63%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    MALAISE
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    PYREXIA
         subjects affected / exposed
    9 / 474 (1.90%)
         occurrences causally related to treatment / all
    5 / 9
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Reproductive system and breast disorders
    VAGINAL FISTULA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    FACIAL BONES FRACTURE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    OVERDOSE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    THORACIC VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    1 / 474 (0.21%)
         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 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    CARDIAC TAMPONADE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PALPITATIONS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE PULMONARY OEDEMA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    CHYLOTHORAX
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    8 / 474 (1.69%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    3 / 474 (0.63%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    PNEUMONITIS
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    PNEUMOTHORAX
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    PULMONARY EMBOLISM
         subjects affected / exposed
    3 / 474 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    TRACHEAL INFLAMMATION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    8 / 474 (1.69%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    APLASTIC ANAEMIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    AUTOIMMUNE HAEMOLYTIC ANAEMIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    GRANULOCYTOPENIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    LYMPH NODE HAEMORRHAGE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SPLENIC VEIN THROMBOSIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    THROMBOCYTOPENIA
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    CEREBELLAR ATAXIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    3 / 474 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    COGNITIVE DISORDER
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DIPLEGIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYDROCEPHALUS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    IMMUNE-MEDIATED ENCEPHALITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    MYASTHENIA GRAVIS
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    PARAESTHESIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SEIZURE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COLITIS
         subjects affected / exposed
    3 / 474 (0.63%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    ENTERITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    GASTRIC ULCER
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    ILEUS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    IMMUNE-MEDIATED ENTEROCOLITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    IMPAIRED GASTRIC EMPTYING
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    OESOPHAGEAL STENOSIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    STOMATITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    3 / 474 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYDRONEPHROSIS
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    AUTOIMMUNE HEPATITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HEPATIC STEATOSIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HEPATIC VEIN THROMBOSIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    HEPATITIS
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    BACK PAIN
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    BONE PAIN
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    MYOSITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    SACROILIITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    ADRENAL INSUFFICIENCY
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPOTHYROIDISM
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    TYPE 1 DIABETES MELLITUS
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    ABDOMINAL INFECTION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    BILIARY TRACT INFECTION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DIARRHOEA INFECTIOUS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    HEPATITIS E
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    INFECTION
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    KIDNEY INFECTION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MENINGITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PAROTITIS
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    9 / 474 (1.90%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA STAPHYLOCOCCAL
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SEPSIS
         subjects affected / exposed
    4 / 474 (0.84%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    SOFT TISSUE INFECTION
         subjects affected / exposed
    2 / 474 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    7 / 474 (1.48%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    1 / 474 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 474 (0.21%)
         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
    Atezolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    368 / 474 (77.64%)
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    25 / 474 (5.27%)
         occurrences all number
    27
    WEIGHT DECREASED
         subjects affected / exposed
    24 / 474 (5.06%)
         occurrences all number
    24
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    44 / 474 (9.28%)
         occurrences all number
    45
    DYSPNOEA
         subjects affected / exposed
    49 / 474 (10.34%)
         occurrences all number
    50
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    59 / 474 (12.45%)
         occurrences all number
    68
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    29 / 474 (6.12%)
         occurrences all number
    34
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    57 / 474 (12.03%)
         occurrences all number
    61
    FATIGUE
         subjects affected / exposed
    107 / 474 (22.57%)
         occurrences all number
    112
    OEDEMA PERIPHERAL
         subjects affected / exposed
    34 / 474 (7.17%)
         occurrences all number
    34
    PYREXIA
         subjects affected / exposed
    61 / 474 (12.87%)
         occurrences all number
    73
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    38 / 474 (8.02%)
         occurrences all number
    44
    CONSTIPATION
         subjects affected / exposed
    46 / 474 (9.70%)
         occurrences all number
    49
    DIARRHOEA
         subjects affected / exposed
    73 / 474 (15.40%)
         occurrences all number
    86
    NAUSEA
         subjects affected / exposed
    68 / 474 (14.35%)
         occurrences all number
    75
    VOMITING
         subjects affected / exposed
    56 / 474 (11.81%)
         occurrences all number
    61
    Skin and subcutaneous tissue disorders
    PRURITUS
         subjects affected / exposed
    34 / 474 (7.17%)
         occurrences all number
    46
    RASH
         subjects affected / exposed
    40 / 474 (8.44%)
         occurrences all number
    52
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    31 / 474 (6.54%)
         occurrences all number
    33
    MYALGIA
         subjects affected / exposed
    29 / 474 (6.12%)
         occurrences all number
    33
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    37 / 474 (7.81%)
         occurrences all number
    37
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    67 / 474 (14.14%)
         occurrences all number
    70
    HYPOKALAEMIA
         subjects affected / exposed
    24 / 474 (5.06%)
         occurrences all number
    25

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2015
    v2: The contraception requirements were clarified and the language in the protocol was aligned with the recommendations provided by the Clinical Trial Facilitation Group (Recommendations related to contraception and pregnancy testing in clinical trials). The inclusion criterion number 4 was clarified to include patients for whom alternative therapy (irrespective of being or not standard or curative) did not exist or was not considered appropriate by the investigator. Calculated creatinine clearance ≥30 mL/min was added to inclusion criterion number 8. The frequency of required thyroid function tests was increased to require regular testing during treatment. The prohibition against live, attenuated vaccines prior to and during treatment with MPDL3280A was extended to include a period of 90 days after discontinuation of MPDL3280A. The reporting for adverse events was extended to 90 days after last dose of study treatment or until initiation of a new anti-cancer therapy, whichever occured first. Since the investigated IMP was not yet approved for marketing, continued treatment beyond progression was only accepted for a period of two years in the individual patient. Should there be need for a further prolongation of the treatment period, additional approval should be applied for. The laboratory, biomarker and other biological samples were clarified. The Schedule of Assessments was revised to reflect the changes to the protocol. PK and ADA assessments were updated. Further clarity was provided around the evaluation of new lesions and lymph nodes according to modified RECIST. The IND number was included.
    29 Sep 2015
    v3: MPDL3280A was changed to the international nonproprietary name atezolizumab throughout the document. The inclusion criterion for histologically documented solid tumors was updated to mention "for which alternative therapy does not exist which is known to prolong survival. Advanced solid tumors for which existing alternative therapies are of no proven benefit are also eligible." Exclusion criteria were modified as follows: 1) Hematologic malignancies, NSCLC, triple-negative breast cancer, urothelial bladder cancer (urothelial [transitional cell] histology or mixed histologies with dominant transitional cell pattern), unresectable advanced or metastatic renal cell carcinoma with clear-cell histology and/or sarcomatoid carcinoma. 6) Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments. 9) Hormone-replacement therapy was added as an allowed approved anticancer therapy. Exclusion criteria of history of autoimmune disease (19) and active hepatitis B (24) were clarified. The exclusion criterion for known PD-L1 expression was removed. The protocol was amended to reflect the handling of Atezolizumab-Specific Adverse Events according to the new version of the investigators brochure of atezolizumab version 7. The protocol was amended to reflect an increase in sample size due to expansion of cohorts 4, 5, and 10. A clarification was added on patients with cancer of unknown primary site to be included in cohort 10. The schedule of assessment was clarified to what should be measured -14 days before day 1 cycle 1 and what could be done within 35 days before day 1 cycle 1.
    19 Aug 2016
    v4: Preliminary review of data from cohort 10 “Other solid tumors” that highlighted the difficulty of analyzing this cohort due to its high heterogeneity prompted a decision to close cohort 10 and replace it with 4 new cohorts and several new sub-cohorts in existing cohorts, to include tumors with a high medical need and a rationale for evaluation of atezolizumab. Inclusion and exclusion criteria were more clearly defined regarding histological types and subtypes accepted in each cohort as well as biomarkers mandated for accurate patient selection. New sub-cohorts were created as appropriate. Selection criteria for baseline general status became stricter. Sub-cohort definitions were clarified to make the patient population within individual sub-cohorts more homogeneous. The definition of evaluable patients was clarified. Guidance for contraception was revised and aligned with other protocols in the atezolizumab clinical development program.
    19 Jun 2017
    v5: Inclusion/exclusion criteria were clarified and adjusted based on questions raised by investigators during the conduct of the study. Rules for end of study and end of cohort were clarified. Statistical section was clarified after running the stages I and II analyses in the first cohorts to reach these stages. Safety data were updated in accordance with the most recent atezolizumab protocols and new safety information.
    01 Mar 2018
    v6: A new Appendix 8 was added to Version 6 to include the management of the adverse events as requested by the Spanish Agency of Medicines and Medical Devices (AEMPS). Related references were corrected in the protocol body.
    29 Oct 2018
    v7: Appendix 8 was updated to include the changes made to the TECENTRIQ® International Brochure versions 12 and 13.
    23 Oct 2019
    v8: Appendix 8: updated to include the changes in the Atezolizumab Investigator’s Brochure version 15 (IB v15), including the guidelines for management of immune-mediated myositis and for suspected hemophagocytic lymphohistiocytosis or macrophage activation syndrome, removed description and management guidelines for systemic immune activation, updated terminology changing "immune-related" to "immune-mediated" (and wherever applicable throughout the protocol). Clarified provisions for post-trial access to atezolizumab to allow for continued treatment of patients following last patient last visit (LPLV), and regarding data collection during transition to the extension study.

    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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