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    Clinical Trial Results:
    A Phase 1b/2, Open-Label, Randomized Study of Daratumumab Administered in Combination with Atezolizumab Compared with Atezolizumab Alone in Subjects with Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    2016-002579-83
    Trial protocol
    ES   HU   FR   PL  
    Global end of trial date
    26 Sep 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Oct 2020
    First version publication date
    11 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CR108256
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03023423
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 US Highway Route 202 South, Raritan, United States, NJ 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    26 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the overall response rate (ORR) in subjects treated with daratumumab in combination with atezolizumab versus atezolizumab alone.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included adverse events, routine clinical laboratory tests (hematology, chemistry, urinalysis), vital signs (temperature, pulse/heart rate, and blood pressure), physical examination, infusion related reactions and electrocardiogram (ECG).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    99
    EEA total number of subjects
    80
    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)
    53
    From 65 to 84 years
    45
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 100 subjects were enrolled in the study (7 in phase 1b [safety run-in phase], and 93 in Phase 2 [randomized phase]). Among them, 99 subjects (7 in phase 1b [safety run-in phase], and 92 in phase 2 [randomized phase]) were randomized as 1 subject was randomized after the clinical cutoff date (17-May-2018).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Safety Run-in Phase: Daratumumab + Atezolizumab
    Arm description
    Subjects received daratumumab (Dara) 16 milligram per kilogram (mg/kg) intravenously (IV) weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab (Atezo) IV at a dose of 1200 milligram (mg) on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received daratumumab 16 mg/kg intravenously weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received atezolizumab (Atezo) IV at a dose of 12 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Arm title
    Randomized Phase: Atezolizumab
    Arm description
    Subjects received atezolizumab IV at a dose of 1200 milligram (mg) on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.
    Arm type
    Active comparator

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received atezolizumab IV at a dose of 1200 mg on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Arm title
    Randomized Phase: Daratumumab + Atezolizumab
    Arm description
    Subjects received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Number of subjects in period 1
    Safety Run-in Phase: Daratumumab + Atezolizumab Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Started
    7
    46
    46
    Treated
    7
    44
    44
    Crossover from Atezo to Dara + Atezo
    0 [1]
    8 [2]
    0 [3]
    Completed
    2
    32
    24
    Not completed
    5
    14
    22
         Death
    5
    12
    20
         Unspecified
    -
    2
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: No subjects crossed over from Atezo arm to Dara + Atezo arm.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only 8 subjects crossed over from Atezo arm to Dara + Atezo arm.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: No subjects crossed over from Atezo arm to Dara + Atezo arm.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety Run-in Phase: Daratumumab + Atezolizumab
    Reporting group description
    Subjects received daratumumab (Dara) 16 milligram per kilogram (mg/kg) intravenously (IV) weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab (Atezo) IV at a dose of 1200 milligram (mg) on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Reporting group title
    Randomized Phase: Atezolizumab
    Reporting group description
    Subjects received atezolizumab IV at a dose of 1200 milligram (mg) on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Reporting group title
    Randomized Phase: Daratumumab + Atezolizumab
    Reporting group description
    Subjects received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Reporting group values
    Safety Run-in Phase: Daratumumab + Atezolizumab Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab Total
    Number of subjects
    7 46 46 99
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    3 29 21 53
        From 65 to 84 years
    4 17 25 46
        85 years and over
    0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    61 ± 9.73 61.7 ± 10.05 63.2 ± 10.76 -
    Title for Gender
    Units: subjects
        Female
    3 18 8 29
        Male
    4 28 38 70
    Race/Ethnicity
    Units: Subjects
        Other
    0 11 6 17
        White Non-Hispanic
    7 35 40 82
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    0 0 0 0
        White
    7 35 41 83
        More than one race
    0 0 0 0
        Unknown or Not Reported
    0 11 5 16
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 1 0 1
        Not Hispanic or Latino
    7 36 40 83
        Unknown or Not Reported
    0 9 6 15
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG performance status was used to evaluate the effect of the disease status on the activities of daily living. ECOG performance status was determined by ECOG 5-point scale: 0=Fully active, 1=Ambulatory, carry out work of sedentary nature, 2=Ambulatory, capable of all self-care, 3=Capable of limited self-care, confined to bed or chair more than 50% of waking hours, 4=Completely disabled, no self-care, totally confined to bed or chair, 5=Dead.
    Units: Subjects
        ECOG Score 0
    3 19 12 34
        ECOG Score 1
    4 27 33 64
        ECOG Score 2
    0 0 1 1
    Time from initial diagnosis
    Time from initial diagnosis is defined as the time from the initial diagnosis of non-small cell lung cancer (NSCLC) to the first dosing date or randomization date (if first dosing date is missing).
    Units: Months
        arithmetic mean (standard deviation)
    10.3 ± 9.29 18.8 ± 20.89 17.6 ± 14.17 -

    End points

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    End points reporting groups
    Reporting group title
    Safety Run-in Phase: Daratumumab + Atezolizumab
    Reporting group description
    Subjects received daratumumab (Dara) 16 milligram per kilogram (mg/kg) intravenously (IV) weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab (Atezo) IV at a dose of 1200 milligram (mg) on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Reporting group title
    Randomized Phase: Atezolizumab
    Reporting group description
    Subjects received atezolizumab IV at a dose of 1200 milligram (mg) on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Reporting group title
    Randomized Phase: Daratumumab + Atezolizumab
    Reporting group description
    Subjects received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Subject analysis set title
    Safety Run-in: Atezolizumab + Daratumumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received daratumumab 16 milligram per kilogram (mg/kg) Intravenously (IV) weekly for first 3 cycles and every 3 weeks for all cycles thereafter along with atezolizumab IV at a dose of 1200 milligram (mg) on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter.

    Subject analysis set title
    Randomized Phase: Atezolizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received atezolizumab IV at a dose of 1200 milligram (mg) on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Subject analysis set title
    Randomized Phase: Daratumumab + Atezolizumab
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Subject analysis set title
    Randomized Phase: Atezo Crossed Over to Dara + Atezo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who crossed over from Atezolizumab arm (Randomized Phase) to Daratumumab + Atezolizumab arm (Randomized Phase) received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol defined treatment discontinuation criteria.

    Primary: Percentage of Subjects with Overall Response Rate (ORR)

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    End point title
    Percentage of Subjects with Overall Response Rate (ORR)
    End point description
    ORR was defined as the percentage of subjects with partial response (PR) or complete response (CR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Criteria for CR: Disappearance of all target lesions; all lymph nodes must be of non-pathological in size (less than [<]10 millimeter [mm] short axis; normalization of tumor marker level. Criteria for PR: greater than or equal to (>=)30 percent (%) decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Overall Response (OR) = CR + PR. The endpoint was planned to be reported for subjects based on their initial assignment to Randomized Phase: Atezolizumab’. Intent-to-treat (ITT) analysis set included all subjects who had entered the Randomized phase of the study.
    End point type
    Primary
    End point timeframe
    Up to 1.5 years
    End point values
    Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    46
    46
    Units: Percentage of Subjects
        number (confidence interval 95%)
    13.0 (4.9 to 26.3)
    4.3 (0.5 to 14.8)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Randomized Phase: Atezolizumab v Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.03
         upper limit
    1.92

    Secondary: Number of Subjects with Adverse Events

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    End point title
    Number of Subjects with Adverse Events
    End point description
    An adverse event (AE) is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Crossover subjects were counted twice (in ‘Randomized Phase: Atezo arm’ and in ‘Randomized Phase: Atezo Crossed Over to Dara + Atezo’) for safety analysis. For cross-over subjects, AEs after initiation of cross-over treatment were summarized separately in the crossover arm, however, AEs occurred before crossover treatment were included in ‘Randomized Phase: Atezolizumab arm’. Safety analysis set included all subjects who had received at least 1 administration of any study medication.
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    Safety Run-in: Atezolizumab + Daratumumab Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab Randomized Phase: Atezo Crossed Over to Dara + Atezo
    Number of subjects analysed
    7
    44
    44
    8
    Units: Subjects
    7
    42
    44
    8
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    Duration of Response (DoR)
    End point description
    DOR: Duration from date of initial documentation of disease response to date of first documented evidence of recurrence/PD/death, whichever occurred first. PD:Sum of diameters increased by >=20%, >=5 mm from nadir. Subjects with measurable disease: Unequivocal progression(non-target disease, overall level of substantial worsening that merits discontinuation of therapy). Subjects without measurable disease: Unequivocal progression (non-target disease, increase in tumor burden comparable to increase required for PD of measurable disease). Endpoint was planned to be reported for subjects based on their initial assignment to 'Randomized Phase:Atezolizumab’. ITT set: subjects who had entered Randomized phase of study. N(number of subjects analyzed): number of subjects who were evaluable for this endpoint. 99999: lower/upper limit of 95% CI were not estimable due: lesser number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    6
    2
    Units: Months
        median (confidence interval 95%)
    5.8 (2.2 to 5.8)
    2.9 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate

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    End point title
    Clinical Benefit Rate
    End point description
    Clinical benefit rate was defined as percentage of subjects who achieved disease control (CR, PR, or SD). RECIST 1.1 Criteria for CR: Disappearance of all target lesions; all lymph nodes of non-pathological in size (<10 millimeter [mm] short axis); normalization of tumor marker level. Criteria for PR: >=30 % decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Criteria for SD: <30% decrease in sum of diameters of all target lesions compared with baseline and <20% increase compared with nadir, in absence of new lesions or unequivocal progression of nontarget lesions. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. ITT analysis set included all subjects who had entered the Randomized phase of the study.
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    46
    46
    Units: Percentage of Subjects
        number (confidence interval 95%)
    43.5 (28.9 to 58.9)
    52.2 (36.9 to 67.1)
    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 was defined as the duration from the date of randomization until the first documented disease progression (PD) or death, whichever occurred first. PD: Sum of diameters increased by >=20% and >=5 millimeter (mm) from nadir (including baseline if it was smallest sum). Subjects with measurable disease: for "unequivocal progression" based on non-target disease, overall level of substantial worsening that merits discontinuation of therapy (if target disease was stable disease [SD]/PR). Subjects without measurable disease: for "unequivocal progression" of non-target disease, increase in overall tumor burden comparable to increase required for PD of measurable disease. Appearance of 1/ more new lesions or unequivocal progression of non-target lesion was also considered as PD. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. ITT analysis set included all subjects who had entered the Randomized phase of the study.
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    46
    46
    Units: Months
        median (confidence interval 95%)
    1.48 (1.38 to 2.76)
    1.68 (1.41 to 2.79)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival was defined as the duration from the date of randomization to the date of subject’s death due to any cause. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. ITT analysis set included all subjects who had entered the Randomized phase of the study. Here 99999, signifies that the upper limit of 95% Confidence Interval (CI) was not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    46
    46
    Units: Months
        median (confidence interval 95%)
    99999 (7.43 to 99999)
    7.13 (3.52 to 99999)
    No statistical analyses for this end point

    Secondary: Daratumumab Serum Concentration

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    End point title
    Daratumumab Serum Concentration
    End point description
    Daratumumab serum concentrations were reported. Each cycle was of 21-days. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. Pharmacokinetic (PK)-evaluable analysis set included all subjects who had received at least 1 dose of daratumumab or atezolizumab and had at least 1 postinfusion sample collected. Here ‘n’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint at a given time point. Here 99999, signifies that Standard Deviation could not be calculated for a single subject.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (C1D1):predose and postdose; C2D1 and C3D1:predose; C3D15: predose and postdose; C4D1: predose and postdose; C8D1: predose and postdose; C12D1: predose; end of treatment (37 days after last dose); and post last dose (up to 1.5 years)
    End point values
    Safety Run-in: Atezolizumab + Daratumumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    7
    43
    Units: Microgram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 Predose (n=7, 43)
    0.00 ± 0.000
    0.00 ± 0.000
        Cycle 1 Day 1 Postdose (n=6, 38)
    417.13 ± 141.626
    296.12 ± 85.660
        Cycle 2 Day 1 Predose (n=4, 35)
    393.95 ± 139.480
    278.42 ± 89.340
        Cycle 3 Day 1 Predose (n=3, 26)
    740.17 ± 99.515
    487.65 ± 124.935
        Cycle 3 Day 15 Predose (n=4, 24)
    843.22 ± 156.792
    552.79 ± 180.549
        Cycle 3 Day 15 Postdose (n=4, 23)
    1088.73 ± 282.349
    827.72 ± 266.085
        Cycle 4 Day 1 Predose (n=3, 22)
    899.90 ± 123.305
    574.81 ± 181.193
        Cycle 4 Day 1 Postdose (n=3, 21)
    1416.40 ± 353.415
    856.30 ± 244.698
        Cycle 8 Day 1 Predose (n=1, 8)
    254.87 ± 99999
    288.84 ± 177.187
        Cycle 8 Day 1 Postdose (n=1, 8)
    824.64 ± 99999
    617.21 ± 239.962
        Cycle 12 Day 1 Predose (n=0, 2)
    99999 ± 99999
    260.21 ± 17.163
        End of Treatment (n=3, 13)
    405.14 ± 242.189
    187.75 ± 110.531
        Post Last Dose (n=2, 5)
    41.84 ± 23.082
    112.63 ± 115.727
    No statistical analyses for this end point

    Secondary: Atezolizumab Serum Concentration

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    End point title
    Atezolizumab Serum Concentration
    End point description
    Atezolizumab serum concentrations were reported. Each cycle was of 21-days. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. PK-evaluable analysis set: all subjects who received at least 1 dose of daratumumab/atezolizumab and had at least 1 postinfusion sample collected. Here N (number of subjects analyzed): subjects evaluable for this endpoint, and n (number of subjects analyzed): subjects evaluable for this endpoint at given timepoint. Here 99999, signifies that the standard deviation could not be calculated for a single subject.
    End point type
    Secondary
    End point timeframe
    C1D1:predose and postdose; C1D2:predose and postdose; C2D1, C3D1:predose; C3D15:predose and postdose; C4D1:predose and postdose; C8D1:predose and postdose; C12D1:predose; end of treatment (37 days after last dose); and post last dose (up to 1.5 years)
    End point values
    Safety Run-in: Atezolizumab + Daratumumab Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    7
    39
    39
    Units: Microgram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 Predose (n=0,37,13)
    99999 ± 99999
    0.00 ± 0.000
    0.00 ± 0.000
        Cycle 1 Day 1 Postdose (n=0,37,3)
    99999 ± 99999
    396.51 ± 103.196
    440.00 ± 93.145
        Cycle 1 Day 2 Predose (n=7,0,24)
    0.00 ± 0.000
    99999 ± 99999
    0.00 ± 0.000
        Cycle 1 Day 2 Postdose (n=7,0,34)
    362.14 ± 43.434
    99999 ± 99999
    343.82 ± 135.476
        Cycle 2 Day 1 Predose (n=5,30,20)
    91.16 ± 15.305
    78.85 ± 30.575
    81.90 ± 20.021
        Cycle 3 Day 1 Predose (n=2,21,17)
    176.50 ± 33.234
    117.61 ± 33.227
    123.51 ± 31.882
        Cycle 4 Day 1 Predose (n=2,18,12)
    166.50 ± 37.477
    145.64 ± 37.323
    157.79 ± 37.819
        Cycle 4 Day 1 Postdose (n=4,17,18)
    612.25 ± 81.578
    539.24 ± 116.291
    482.33 ± 139.879
        Cycle 8 Day 1 Predose (n-0,6,0)
    99999 ± 99999
    158.23 ± 77.778
    99999 ± 99999
        Cycle 8 Day 1 Postdose (n-0,8,4)
    99999 ± 99999
    527.50 ± 213.492
    515.25 ± 214.177
        Cycle 12 Day 1 Predose (n=0,1,1)
    99999 ± 99999
    183.00 ± 99999
    248.00 ± 99999
        End of Treatment (n=3,11,12)
    136.43 ± 73.002
    129.55 ± 79.720
    141.62 ± 71.756
        Post Last Dose (n=1,2,2)
    33.10 ± 99999
    13.17 ± 8.386
    115.10 ± 146.937
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-Daratumumab Antibodies

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    End point title
    Number of Subjects with Anti-Daratumumab Antibodies
    End point description
    Number of subjects with antibodies to daratumumab (tested using a validated immunoassay method) were reported. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. The immunogenicity-evaluable analysis set included all subjects who received at least 1 dose of atezolizumab or daratumumab and had appropriate samples for detection of antibodies to atezolizumab or daratumumab. Here 'N' (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    7
    37
    Units: Subjects
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-Atezolizumab Antibodies

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    End point title
    Number of Subjects with Anti-Atezolizumab Antibodies
    End point description
    Number of subjects with antibodies to atezolizumab (tested using a validated immunoassay method) were reported. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. The immunogenicity-evaluable analysis set included all subjects who received at least 1 dose of atezolizumab or daratumumab and had appropriate samples for detection of antibodies to atezolizumab or daratumumab.
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    Safety Run-in: Atezolizumab + Daratumumab Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab
    Number of subjects analysed
    7
    39
    38
    Units: Subjects
    0
    6
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 1.5 years
    Adverse event reporting additional description
    Safety analysis set=subjects who received at least 1 administration of any study drug. Crossover subjects were counted twice (in ‘Randomized Phase:Atezo arm’ and ‘Randomized Phase: Atezo Crossed Over to Dara+Atezo’). AEs summarized separately in crossover arm and occurred before crossover treatment were included in ‘Randomized Phase: Atezolizumab’.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Safety Run-in Phase: Daratumumab + Atezolizumab
    Reporting group description
    Subjects received daratumumab (Dara) 16 milligram per kilogram (mg/kg) intravenously (IV) weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab (Atezo) IV at a dose of 1200 milligram (mg) on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Reporting group title
    Randomized Phase: Atezolizumab
    Reporting group description
    Subjects received atezolizumab IV at a dose of 1200 milligram (mg) on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Reporting group title
    Randomized Phase: Daratumumab + Atezolizumab
    Reporting group description
    Subjects received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Reporting group title
    Randomized Phase: Atezo Crossed Over to Dara + Atezo
    Reporting group description
    Subjects who crossed over from Atezolizumab arm (Randomized Phase) to Daratumumab + Atezolizumab arm (Randomized Phase) received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

    Serious adverse events
    Safety Run-in Phase: Daratumumab + Atezolizumab Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab Randomized Phase: Atezo Crossed Over to Dara + Atezo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 7 (57.14%)
    15 / 44 (34.09%)
    21 / 44 (47.73%)
    3 / 8 (37.50%)
         number of deaths (all causes)
    2
    9
    11
    3
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Femur Fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial Fistula
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial Obstruction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    6 / 44 (13.64%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 7
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 2
    Haemoptysis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Painful Respiration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Respiratory Failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal Cord Paralysis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 44 (6.82%)
    3 / 44 (6.82%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Safety Run-in Phase: Daratumumab + Atezolizumab Randomized Phase: Atezolizumab Randomized Phase: Daratumumab + Atezolizumab Randomized Phase: Atezo Crossed Over to Dara + Atezo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    41 / 44 (93.18%)
    41 / 44 (93.18%)
    8 / 8 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Hypertension
         subjects affected / exposed
    4 / 7 (57.14%)
    0 / 44 (0.00%)
    4 / 44 (9.09%)
    0 / 8 (0.00%)
         occurrences all number
    7
    0
    5
    0
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Venous Thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    4 / 44 (9.09%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    4
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 7 (42.86%)
    15 / 44 (34.09%)
    14 / 44 (31.82%)
    2 / 8 (25.00%)
         occurrences all number
    4
    21
    23
    2
    Chest Discomfort
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Chest Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 44 (6.82%)
    3 / 44 (6.82%)
    2 / 8 (25.00%)
         occurrences all number
    0
    3
    3
    2
    Chills
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    3 / 44 (6.82%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    3
    1
    Fatigue
         subjects affected / exposed
    3 / 7 (42.86%)
    7 / 44 (15.91%)
    9 / 44 (20.45%)
    2 / 8 (25.00%)
         occurrences all number
    3
    11
    11
    4
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypothermia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Localised Oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mucosal Inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    2
    1
    Oedema Peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 44 (11.36%)
    4 / 44 (9.09%)
    2 / 8 (25.00%)
         occurrences all number
    3
    5
    5
    2
    Secretion Discharge
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Temperature Intolerance
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Depression
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nervousness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sleep Disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Buttock Injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eastern Cooperative Oncology Group Performance Status Worsened
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Lipase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Oxygen Saturation Decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight Decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Weight Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Pericardial Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinus Bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinus Tachycardia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    2
    1
    Tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Ventricular Extrasystoles
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Bronchospasm
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    3 / 44 (6.82%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    10 / 44 (22.73%)
    16 / 44 (36.36%)
    3 / 8 (37.50%)
         occurrences all number
    1
    13
    19
    4
    Dry Throat
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    5 / 7 (71.43%)
    9 / 44 (20.45%)
    13 / 44 (29.55%)
    0 / 8 (0.00%)
         occurrences all number
    5
    10
    18
    0
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 44 (11.36%)
    5 / 44 (11.36%)
    0 / 8 (0.00%)
         occurrences all number
    0
    6
    5
    0
    Laryngeal Oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal Congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    2
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Pleural Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pleurisy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pleuritic Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pneumothorax
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Productive Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sneezing
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Throat Irritation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    4 / 44 (9.09%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Throat Tightness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper-Airway Cough Syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    6 / 44 (13.64%)
    7 / 44 (15.91%)
    1 / 8 (12.50%)
         occurrences all number
    1
    10
    11
    1
    Deficiency Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Lymphopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    2
    1
    Dysgeusia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Headache
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    3
    2
    0
    2
    Hypokinesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 44 (6.82%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Seizure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry Eye
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye Irritation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vision Blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Visual Acuity Reduced
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal Pain
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 44 (0.00%)
    6 / 44 (13.64%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    6
    0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Constipation
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 44 (11.36%)
    4 / 44 (9.09%)
    1 / 8 (12.50%)
         occurrences all number
    2
    6
    7
    3
    Diarrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 44 (9.09%)
    4 / 44 (9.09%)
    0 / 8 (0.00%)
         occurrences all number
    2
    5
    4
    0
    Dry Mouth
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Flatulence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 7 (42.86%)
    8 / 44 (18.18%)
    7 / 44 (15.91%)
    2 / 8 (25.00%)
         occurrences all number
    4
    9
    9
    2
    Odynophagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 44 (6.82%)
    6 / 44 (13.64%)
    1 / 8 (12.50%)
         occurrences all number
    1
    3
    7
    1
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bladder Spasm
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pollakiuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal Colic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal Failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal Vein Thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urinary Retention
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis Acneiform
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dry Skin
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Eczema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Hair Disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Night Sweats
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 44 (9.09%)
    0 / 44 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    5
    0
    2
    Rash
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 44 (4.55%)
    3 / 44 (6.82%)
    1 / 8 (12.50%)
         occurrences all number
    2
    2
    4
    1
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash Papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash Pruritic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin Lesion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    8 / 44 (18.18%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    2
    11
    1
    0
    Arthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Back Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 44 (6.82%)
    3 / 44 (6.82%)
    0 / 8 (0.00%)
         occurrences all number
    0
    5
    3
    0
    Groin Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle Contracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle Spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Muscular Weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 44 (4.55%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Musculoskeletal Discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 44 (11.36%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    1
    11
    1
    0
    Neck Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in Extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 44 (9.09%)
    4 / 44 (9.09%)
    0 / 8 (0.00%)
         occurrences all number
    1
    5
    5
    0
    Spinal Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 44 (6.82%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    2 / 7 (28.57%)
    7 / 44 (15.91%)
    11 / 44 (25.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    10
    16
    1
    Dehydration
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    3 / 44 (6.82%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Furuncle
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Oral Herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    5 / 44 (11.36%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    15
    1
    Rhinitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tooth Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2016
    The overall reason for the amendment was to update toxicity and adverse event (AE) management in response to Health Authority request, to remove the subject-reported outcomes assessments (PRO), and to add timepoints for biomarker sample collection.
    22 Mar 2017
    The overall reason for the amendment was to allow subjects in Arm A (atezolizumab monotherapy) to cross over to Arm B (atezolizumab + daratumumab combination therapy) after confirmed disease progression. Combination therapy of daratumumab and atezolizumab may provide clinical benefit in non-small cell lung cancer (NSCLC) subjects who had disease progression on atezolizumab monotherapy. The combination of daratumumab with atezolizumab may lead to an improvement in clinical responses in NSCLC by enhancing the anti-tumor T cell responses facilitated by checkpoint inhibition. Therefore, subjects in Arm A with confirmed disease progression based on RECIST 1.1 may cross over to Arm B, provided all crossover eligibility criteria are met.
    24 Aug 2017
    The overall reason for the amendment was to allow for the enrollment of subjects in certain programmed-death ligand 1 (PD-L1) sub-groups to collect sufficient data to confirm clinical benefit.
    26 Feb 2018
    The overall reason for the amendment was to expand the Screening period for the informed consent and for PD-L1 testing, and to specify the PD-L1 score inclusion criterion. During its review of the study data at the initial interim analysis (40 evaluable subjects), the DMC determined that the study had enrolled a sufficient number of subjects with a PD-L1 score of tumor cells (TC0) and recommended continued enrollment only in subjects in the TC1-3 subgroups. In addition, the safety management guidelines for atezolizumab have been updated based on the current Investigator’s Brochure.
    19 Apr 2018
    The overall reason for the amendment was to added a phase 1b Dara-SC cohort combined with a corticosteroid tapering regimen to the study protocol, to minimize the risk of IRRs and to improve the safety outcomes after daratumumab administration. An optional prescreening phase for archival testing to assess PD-L1 status was specified.
    14 Aug 2018
    The overall reason for the amendment was to initiated response to the third planned (Data monitoring committee) DMC review of safety data on 23 May 2018 (88 subjects) and added the DMC recommendation to stop further enrollment into the study, with discontinuation of daratumumab+atezolizumab treatment and specified that ongoing subjects could continue on atezolizumab monotherapy until the subject met one or more of the treatment discontinuation criteria.
    04 Oct 2018
    The overall reason for the amendment was to pursuant to the DMC recommendation to stop enrollment into the study, it was clarified that subjects who were deriving clinical benefit from atezolizumab monotherapy, but did not have access to commercial atezolizumab, could continue treatment according to the local regulatory approvals and standard of care guidelines. Data from efficacy and safety evaluations performed according to the local regulatory approvals and standard of care guidelines were no longer to be collected with the exception of serious adverse events that were to be reported and entered in the Sponsor safety repository.

    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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