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    Clinical Trial Results:
    A Phase IB/II Study Evaluating the Safety and Efficacy of Atezolizumab in Combination With Either Obinutuzumab Plus Bendamustine or Obinutuzumab Plus CHOP in Patients with Follicular Lymphoma or Rituximab Plus CHOP in Patients With Diffuse Large B-Cell Lymphoma

    Summary
    EudraCT number
    		 2015-001364-19
    Trial protocol
    		 IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    25 Apr 2019
    First version publication date
    25 Apr 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BO29563
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02596971
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    11 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Apr 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    A Study of Atezolizumab in Combination With Either Obinutuzumab Plus Bendamustine or Obinutuzumab Plus (+) Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Participants With Follicular Lymphoma (FL) or Rituximab + CHOP in Participants With Diffuse Large B-Cell Lymphoma (DLBCL)
    Protection of trial subjects
    Each subject, or the subject's representative, signed an informed consent form prior to screening.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2015
    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
    Australia: 14
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    United States: 61
    Worldwide total number of subjects
    91
    EEA total number of subjects
    16
    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)
    61
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 15 sites in 3 countries (Italy, Australia, and USA).

    Pre-assignment
    Screening details
    		 Out of the 117 subjects who were screened for this study, 91 subjects were enrolled to either FL treatment cohort (Atezo-G-Benda, Atezo-G-CHOP) or DLBCL cohort (Atezo-R-CHOP) and 26 subjects failed screening.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases)
    Arm description
    		 Safety run-in phase: Participants with previously untreated or relapsed or refractory FL received obinutuzumab (G) and bendamustine during Cycle 1 (28-day cycle) and atezolizumab, obinutuzumab, and bendamustine during Cycles 2-6, during induction treatment, followed by atezolizumab (once monthly) and obinutuzumab (every other month [q2m]) for 24 months, during maintenance treatment. Expansion phase: Participants with previously untreated FL received same treatment regimen as described for safety run-in phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    RO5541267; Tecentriq
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab 840 milligrams (mg) intravenously (IV) on Days 1 and 15 of Cycles 2-6, during induction treatment, followed by 840 mg IV on Days 1 and 2 of each month, starting with Month 1, during maintenance treatment.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine administered at a dose of 90 milligrams per square meter (mg/m^2) IV on Days 1 and 2 of Cycles 1-6, during induction treatment.

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    GA101, RO5072759
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Obinutuzumab administered at a dose of 1000 mg IV on Days 1, 8, and 15 of Cycle 1 and 1000 mg IV on Day 1 of Cycles 2-6, during induction treatment, followed by 1000 mg IV on Day 1 of every other month, starting with Month 1, during maintenance treatment.

    Arm title
    		 Atezo-G-CHOP Cohort (Safety Run-In Phase)
    Arm description
    		 Safety run-in phase: Participants with previously untreated or relapsed or refractory FL received obinutuzumab and CHOP during Cycle 1 (21-day cycle) and atezolizumab, obinutuzumab, and CHOP during Cycles 2-6, during induction treatment, followed by atezolizumab (once monthly) and obinutuzumab (q2m) for 24 months, during maintenance treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    RO5541267; Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab 1200 mg IV on Day 1 Cycles 2-6, during induction treatment, followed by 840 mg IV on Days 1 and 2 of each month, starting with Month 1.

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    GA101, RO5072759
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Obinutuzumab administered at a dose of 1000 mg IV on Days 1, 8, and 15 of Cycle 1 and 1000 mg IV on Day 1 of Cycles 2-6 during induction treatment, followed by 1000 mg IV on Day 1 of every other month, starting with Month 1 during maintenance treatment.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 750 milligrams per square metre (mg/m^2), administered intravenously (IV) on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin will be administered at a dose of 50 mg/m^2 IV on Day 1 of Cycle 1-6/8, during induction treatment.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be administered at a dose of 40 mg/m^2 orally on Days 1-5 of Cycle 1-6/8, during induction treatment. Prednisolone may be given if prednisone is unavailable. The 40 mg/m^2 dose of prednisone on Day 1 will be replaced by oral corticosteroids given as premedication on Day 1 of Cycle 1 (and subsequent cycles).

    Arm title
    		 Atezo-R-CHOP Cohort (Expansion Phase)
    Arm description
    		 Participants with previously untreated DLBCL received rituximab and CHOP during Cycle 1 (21-day cycle) and atezolizumab, rituximab, and CHOP during Cycles 2-8 (atezolizumab and rituximab for 8 cycles and CHOP for either 6 or 8 cycles, as determined by the investigator), during induction treatment, followed by atezolizumab from Cycles 9-25 during consolidation treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    RO5541267; Tecentriq
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab 1200 mg IV on Day 1 Cycles 2-8, during induction treatment, followed by 1200 mg IV on Day 1 of Cycles 9-25.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intraventricular use , Intravenous use
    Dosage and administration details
    Cyclophosphamide will be administered at a dose of 750 mg/m^2 IV on Day 1 of Cycle 1-6/8, during induction treatment.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be administered at a dose of 40 mg/m^2 orally on Days 1-5 of Cycle 1-6/8, during induction treatment. Prednisolone may be given if prednisone is unavailable. The 40 mg/m^2 dose of prednisone on Day 1 will be replaced by oral corticosteroids given as premedication on Day 1 of Cycle 1 (and subsequent cycles).

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin will be administered at a dose of 50 mg/m^2 IV on Day 1 of Cycle 1-6/8, during induction treatment.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants with previously untreated DLBCL will receive rituximab at a dose of 375 mg/m^2 IV on Day 1 of Cycle 1-8, during induction treatment.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine will be administered at a dose of 1.4 mg/m^2 (maximum 2 mg) IV on Day 1 of Cycle 1-6/8, during induction treatment.

    Number of subjects in period 1
    		Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-G-CHOP Cohort (Safety Run-In Phase) Atezo-R-CHOP Cohort (Expansion Phase)
    Started
    42
    7
    42
    Completed
    0
    0
    0
    Not completed
    42
    7
    42
         Adverse event, serious fatal
    2
    -
    -
         Physician decision
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    2
         Ongoing
    36
    6
    24
         In Follow-up
    4
    -
    15
         Disease Progression
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases)
    Reporting group description
    		 Safety run-in phase: Participants with previously untreated or relapsed or refractory FL received obinutuzumab (G) and bendamustine during Cycle 1 (28-day cycle) and atezolizumab, obinutuzumab, and bendamustine during Cycles 2-6, during induction treatment, followed by atezolizumab (once monthly) and obinutuzumab (every other month [q2m]) for 24 months, during maintenance treatment. Expansion phase: Participants with previously untreated FL received same treatment regimen as described for safety run-in phase.

    Reporting group title
    Atezo-G-CHOP Cohort (Safety Run-In Phase)
    Reporting group description
    		 Safety run-in phase: Participants with previously untreated or relapsed or refractory FL received obinutuzumab and CHOP during Cycle 1 (21-day cycle) and atezolizumab, obinutuzumab, and CHOP during Cycles 2-6, during induction treatment, followed by atezolizumab (once monthly) and obinutuzumab (q2m) for 24 months, during maintenance treatment.

    Reporting group title
    Atezo-R-CHOP Cohort (Expansion Phase)
    Reporting group description
    		 Participants with previously untreated DLBCL received rituximab and CHOP during Cycle 1 (21-day cycle) and atezolizumab, rituximab, and CHOP during Cycles 2-8 (atezolizumab and rituximab for 8 cycles and CHOP for either 6 or 8 cycles, as determined by the investigator), during induction treatment, followed by atezolizumab from Cycles 9-25 during consolidation treatment.

    Reporting group values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-G-CHOP Cohort (Safety Run-In Phase) Atezo-R-CHOP Cohort (Expansion Phase) Total
    Number of subjects
    		 42 7 42 91
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 35 6 20 61
        >=65 years
    		 7 1 22 30
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.6 ± 10.9 57.4 ± 5.4 59.2 ± 15.7 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 20 4 16 40
        Male
    		 22 3 26 51
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 0 2 5
        Not Hispanic or Latino
    		 36 7 37 80
        Unknown or Not Reported
    		 3 0 3 6
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 3 1 0 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 37 6 40 83
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 2 0 2 4

    End points

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    End points reporting groups
    Reporting group title
    Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases)
    Reporting group description
    		 Safety run-in phase: Participants with previously untreated or relapsed or refractory FL received obinutuzumab (G) and bendamustine during Cycle 1 (28-day cycle) and atezolizumab, obinutuzumab, and bendamustine during Cycles 2-6, during induction treatment, followed by atezolizumab (once monthly) and obinutuzumab (every other month [q2m]) for 24 months, during maintenance treatment. Expansion phase: Participants with previously untreated FL received same treatment regimen as described for safety run-in phase.

    Reporting group title
    Atezo-G-CHOP Cohort (Safety Run-In Phase)
    Reporting group description
    		 Safety run-in phase: Participants with previously untreated or relapsed or refractory FL received obinutuzumab and CHOP during Cycle 1 (21-day cycle) and atezolizumab, obinutuzumab, and CHOP during Cycles 2-6, during induction treatment, followed by atezolizumab (once monthly) and obinutuzumab (q2m) for 24 months, during maintenance treatment.

    Reporting group title
    Atezo-R-CHOP Cohort (Expansion Phase)
    Reporting group description
    		 Participants with previously untreated DLBCL received rituximab and CHOP during Cycle 1 (21-day cycle) and atezolizumab, rituximab, and CHOP during Cycles 2-8 (atezolizumab and rituximab for 8 cycles and CHOP for either 6 or 8 cycles, as determined by the investigator), during induction treatment, followed by atezolizumab from Cycles 9-25 during consolidation treatment.

    Primary: Percentage of Subjects With CR at EOI, as Determined by the Independent Review Committee (IRC) Using Modified Lugano 2014 Criteria

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    End point title
    		 Percentage of Subjects With CR at EOI, as Determined by the Independent Review Committee (IRC) Using Modified Lugano 2014 Criteria [1] [2]
    End point description
    Primary end point was PET CR at EOI by IRC according to modified Lugano classification using PET/CT scan. CR was defined as a score of 1 (no uptake above background), 2 (uptake less than or equal to [</=] mediastinum), or 3 (uptake less than [<] mediastinum but </=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow; and normal/immunohistochemistry (IHC)-negative bone marrow morphology. All positron emission tomography (PET) evaluable 1L FL and 1L DLBCL patients with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Primary
    End point timeframe
    Up to approximately 6 months
    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: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    40 [3]
    40 [4]
    Units: percentage of participants
        number (confidence interval 90%)
    75 (61.29 to 85.76)
    77.5 (64.02 to 87.73)
    Notes
    [3] - 2 subjects excluded from Atezo-G-Benda cohort due to diagnosis of r/r FL.
    [4] - 2 subjects excluded as they were excluded prior to Cycle 2 and were not treated with atezolizumab.
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Adverse Events

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    End point title
    		 Percentage of Subjects With Adverse Events [5]
    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.
    End point type
    Primary
    End point timeframe
    Baseline up to approximately 4 years
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is an adverse event endpoint and did not report statistics.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-G-CHOP Cohort (Safety Run-In Phase) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    42
    7
    42
    Units: percentage of subjects
    100
    100
    100
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With CR at EOI, as Determined by the Investigator Using Lugano 2014 Criteria

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    End point title
    		 Percentage of Subjects With CR at EOI, as Determined by the Investigator Using Lugano 2014 Criteria [6]
    End point description
    Tumor response assessment was performed by the investigator according to modified Lugano classification using PET/CT scan. CR was defined as a score of 1 (no uptake above background), 2 (uptake </=mediastinum), or 3 (uptake <mediastinum but </=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. 90% CI for percentage of responders was calculated using Clopper-Pearson method. All positron emission tomography (PET) evaluable 1L FL and 1L DLBCL subjects with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 6 months
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    40 [7]
    40 [8]
    Units: percentage of subjects
        number (confidence interval 90%)
    87.5 (75.50 to 94.94)
    77.5 (64.02 to 87.73)
    Notes
    [7] - 2 subjects excluded from Atezo-G-Benda cohort due to diagnosis of r/r FL.
    [8] - 2 subjects excluded as they were excluded prior to Cycle 2 and were not treated with atezolizumab.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With CR at EOI, as Determined by the IRC Using Modified Cheson 2007 Criteria

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    End point title
    		 Percentage of Subjects With CR at EOI, as Determined by the IRC Using Modified Cheson 2007 Criteria [9]
    End point description
    Complete response according to the modified Cheson 2007 criteria using PET/CT scan: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy, liver and spleen have returned to normal size (if enlarged at baseline), If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites; no increase in the size of the other nodes, liver, or spleen; with the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. All positron emission tomography (PET) evaluable 1L FL and 1L DLBCL subjects with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 6 months
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    40 [10]
    40 [11]
    Units: percentage of subjects
        number (confidence interval 90%)
    75.0 (61.29 to 85.76)
    77.5 (64.02 to 87.73)
    Notes
    [10] - 2 subjects excluded from Atezo-G-Benda cohort due to diagnosis of r/r FL.
    [11] - 2 subjects excluded as they were excluded prior to Cycle 2 and were not treated with atezolizumab.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With CR at EOI, as Determined by the Investigator Using Modified Cheson 2007 Criteria

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    End point title
    		 Percentage of Subjects With CR at EOI, as Determined by the Investigator Using Modified Cheson 2007 Criteria [12]
    End point description
    Complete response according to modified Cheson 2007 criteria using PET/CT scan: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy, liver and spleen have returned to normal size (if enlarged at baseline), If bone marrow was involved by lymphoma prior to treatment, infiltrate must have cleared on repeat bone marrow biopsy. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites; no increase in the size of other nodes, liver, or spleen; with exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. All positron emission tomography (PET) evaluable 1L FL and 1L DLBCL subjects with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 6 months
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    40 [13]
    40 [14]
    Units: percentage of subjects
        number (confidence interval 90%)
    80.0 (66.80 to 89.64)
    75.0 (61.29 to 85.76)
    Notes
    [13] - 2 subjects excluded from Atezo-G-Benda cohort due to diagnosis of r/r FL.
    [14] - 2 subjects excluded as they were excluded prior to Cycle 2 and were not treated with atezolizumab.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Objective Response (CR or PR) at EOI, as Determined by the IRC Using Modified Cheson 2007 Criteria

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    End point title
    		 Percentage of Subjects With Objective Response (CR or PR) at EOI, as Determined by the IRC Using Modified Cheson 2007 Criteria [15]
    End point description
    Objective response: having CR or PR as assessed according to the modified response criteria for iNHL (Modified Cheson et al, 2007). CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy, liver and spleen have returned to normal size (if enlarged at baseline), If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites; no increase in the size of the other nodes, liver, or spleen; with the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. All positron emission tomography (PET) evaluable 1L FL and 1L DLBCL subjects with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 6 months
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    40 [16]
    40 [17]
    Units: percentage of subjects
        number (confidence interval 90%)
    90.0 (78.56 to 96.51)
    90.0 (78.56 to 96.51)
    Notes
    [16] - 2 subjecnts excluded from Atezo-G-Benda cohort due to diagnosis of r/r FL.
    [17] - 2 subjects excluded as they were excluded prior to Cycle 2 and were not treated with atezolizumab.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Objective Response (CR or PR) at EOI, as Determined by the Investigator Using Modified Cheson 2007 Criteria

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    End point title
    		 Percentage of Subjects With Objective Response (CR or PR) at EOI, as Determined by the Investigator Using Modified Cheson 2007 Criteria [18]
    End point description
    Objective response: having CR or PR as assessed according to the modified response criteria for iNHL (Modified Cheson et al, 2007). CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy, liver and spleen have returned to normal size (if enlarged at baseline), If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites; no increase in the size of the other nodes, liver, or spleen; with the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. All positron emission tomography (PET) evaluable 1L FL and 1L DLBCL subjects with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 6 months
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    40 [19]
    40 [20]
    Units: percentage of subjects
        number (confidence interval 90%)
    95.0 (85.08 to 99.10)
    87.5 (75.50 to 94.94)
    Notes
    [19] - 2 subjects excluded from Atezo-G-Benda cohort due to diagnosis of r/r FL.
    [20] - 2 subjects excluded as they were excluded prior to Cycle 2 and were not treated with atezolizumab.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Objective Response (CR or PR) at EOI, as Determined by the IRC Using Lugano 2014 Criteria

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    End point title
    		 Percentage of Subjects With Objective Response (CR or PR) at EOI, as Determined by the IRC Using Lugano 2014 Criteria [21]
    End point description
    Tumor response assessment was performed by IRC according to modified Lugano classification using PET/CT scan. OR defined as a response of CR or PR. CR: a score of 1 (no uptake above background), 2 (uptake </=mediastinum), or 3 (uptake <mediastinum but </=liver) with/without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. PR: a score 4 (uptake moderately greater than [>] liver) or 5 (uptake markedly >liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites; no new lesions; and reduced residual uptake in bone marrow compared with baseline. All positron emission tomography (PET) evaluable 1L FL and 1L DLBCL subjects with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 6 months
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    40 [22]
    40 [23]
    Units: percentage of subjects
        number (confidence interval 90%)
    90.0 (78.56 to 96.51)
    87.5 (75.50 to 94.94)
    Notes
    [22] - 2 subjects excluded from Atezo-G-Benda cohort due to diagnosis of r/r FL.
    [23] - 2 subjects excluded as they were excluded prior to Cycle 2 and were not treated with atezolizumab.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Objective Response (CR or PR) at EOI, as Determined by the Investigator Using Lugano 2014 Criteria

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    End point title
    		 Percentage of Subjects With Objective Response (CR or PR) at EOI, as Determined by the Investigator Using Lugano 2014 Criteria [24]
    End point description
    Tumor response assessment was performed by investigator according to modified Lugano classification using PET/CT scan. OR: a response of CR or PR. CR: a score of 1 (no uptake above background), 2 (uptake </=mediastinum), or 3 (uptake <mediastinum but </=liver) with or without a residual mass on PET 5-PS, for lymph nodes & extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. PR with a score 4 (uptake moderately greater than [>] liver) or 5 (uptake markedly >liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites; no new lesions; and reduced residual uptake in bone marrow compared with baseline. All positron emission tomography (PET) evaluable 1L FL and 1L DLBCL subjects with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 6 months
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    40 [25]
    40 [26]
    Units: percentage of subjects
        number (confidence interval 90%)
    95.0 (85.08 to 99.10)
    87.5 (75.50 to 94.94)
    Notes
    [25] - 2 subjects excluded from Atezo-G-Benda cohort due to diagnosis of r/r FL.
    [26] - 2 subjects excluded as they were excluded prior to Cycle 2 and were not treated with atezolizumab.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Best Response of CR or PR During Study, as Determined by Investigator Using Modified Cheson 2007 Criteria

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    End point title
    		 Percentage of Subjects With Best Response of CR or PR During Study, as Determined by Investigator Using Modified Cheson 2007 Criteria [27]
    End point description
    This endpoint will be reported at end of the study, approximatey 17 Apr 2020
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 4 years (assessed at Baseline, 6 to 8 weeks after Day [D] 1 of Cycle [Cy] 6 or 8 (1Cy: 21 or 28 days), then every 2 months up to 24 months, at 35 days of last dose, and at every 3 months post-treatment follow-up [up 4 years])
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    0 [28]
    0 [29]
    Units: percentage of subjects
        number (confidence interval 90%)
    ( to )
    ( to )
    Notes
    [28] - This endpoint will be reported at study completion date.
    [29] - This endpoint will be reported at study completion date.
    No statistical analyses for this end point

    Secondary: Observed Serum Obinutuzumab Concentration

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    End point title
    		 Observed Serum Obinutuzumab Concentration [30]
    End point description
    Predose time point was "any time prior to dose" for Cycle 1 and "within 5 hour prior to dose" for other cycles (Cycles 2,5,6) and for Months 1 to 24 during maintenance phase. Infusion duration for administration of first infusion should begin at an initial rate of 50 milligrams per hour (mg/hour). If no reaction occurs, increase the infusion rate in 100 mg/hour increments every 30 minutes to a maximum of 400 mg/hour.
    End point type
    Secondary
    End point timeframe
    Induction: Predose, 0.5 hour (h) postinfusion on D1 of Cy1,2,5,6 (1Cy: 21/28 days); Maintenance: Predose, 0.5h postinfusion on Day 1 of Month 1,3,7,15,23; 120 days & 1 year of last dose or at treatment discontinuation (up to 4 years)
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic endpoint and did not report statistics.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-G-CHOP Cohort (Safety Run-In Phase)
    Number of subjects analysed
    42
    7
    Units: ug/mL
    median (full range (min-max))
        C1 Cmax after 1st infusion
    329 (21.7 to 513)
    399 (236 to 611)
        C1 Cmin after the last infusion on C1
    322 (168 to 486)
    315 (284 to 450)
        C6 - Cmax after last dosing of induction
    544 (387 to 883)
    659 (287 to 838)
        C6 - Cmin after last dosing of induction
    203 (137 to 471)
    245 (171 to 481)
    No statistical analyses for this end point

    Secondary: Observed Serum Atezolizumab Concentration

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    End point title
    		 Observed Serum Atezolizumab Concentration
    End point description
    Atezo-G-Benda: Induction:Predose on D1 of Cy5,6 & D1,15 of Cy2,3 (1Cy:21/28 days), Cy2D1:0.5h postinfusion; Maintenance:Predose on D1 of Month 1,2,4,7,15,23, Month 2 D1: 0.5h postinfusion; 120 days & 1 year of last dose or at treatment discontinuation (up to 4 years); Atezo-G-CHOP: Induction:Predose on D1 of Cy2,3,5,6 (1Cy:21 days), Cy2D1:0.5h postinfusion; Maintenance:Predose on D1 of Month 1,2,3,4,7,15,23, Month 2 D1: 0.5h postinfusion; 120 days & 1 year of last dose or at treatment discontinuation (up to 4 years). Predose time point was "within 5 hour prior to dose" for Cy2,3,5,6 during induction phase and for Months 1 to 24 during maintenance phase. infusion length: 30-60 minutes. 0 represents no data was collected at that cycle.
    End point type
    Secondary
    End point timeframe
    Atezo-R-CHOP: Predose on D1 of Cy2,3,5,8,9,10,11,12,16,20,25 (1Cy:21 days), 0.5h postinfusion of D1 of Cy2,9; at 120 days & 1 year of last dose or at treatment discontinuation (up to 4 years)
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-G-CHOP Cohort (Safety Run-In Phase) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    42
    7
    42
    Units: ug/mL
    median (full range (min-max))
        Cycle 2 - Cmax after 1st infusion
    275 (193 to 388)
    424 (340 to 670)
    332 (227 to 472)
        C2 - Cmin before 2nd infusion
    83 (59 to 128)
    94 (65 to 139)
    82.1 (55.7 to 122)
        C6 - Cmin aftter 6th infusion
    256 (93 to 369)
    195 (157 to 296)
    0 (0 to 0)
        C8 - Cmax after 7th infusion
    0 (0 to 0)
    0 (0 to 0)
    486.5 (363 to 793)
        C8 - Cmin before 8th infusion
    0 (0 to 0)
    0 (0 to 0)
    184 (104 to 359)
    No statistical analyses for this end point

    Secondary: Observed Serum Rituximab Concentration

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    End point title
    		 Observed Serum Rituximab Concentration [31]
    End point description
    Predose time point was "any time prior to dose" for Cycle 1 and "within 5 hour prior to dose" for other cycles (Cycles 2,5,8) during induction phase and for Months 1 to 24 during maintenance phase. Infusion duration for administration of first infusion should begin at an initial rate of 50 mg/hour. If no infusion-related or hypersensitivity reaction occurs, increase the infusion rate in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour. If no reaction occurs, increase the infusion rate in 100 mg/hour increments every 30 minutes to a maximum of 400 mg/hour.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5h postinfusion on D1 of Cy1,2,5,8 (1Cy: 21 days); at 120 days and 1 year after last rituximab dose or at treatment discontinuation (up to 4 years)
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic endpoint and did not report statistics.
    End point values
    		 Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    42
    Units: ug/mL
    median (full range (min-max))
        C1 - Cmax after dosing C1 (n=34)
    159 (0.5 to 292)
        C1 - Ctrough after dosing C1 (n=34)
    26.1 (0.5 to 41.3)
        C8 - Cmax after dosing C8 (n=27)
    229 (185 to 303)
        C8 - Ctrough after dosing C8 (n=26)
    105.5 (39.9 to 150)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Human Anti-Human Antibodies (HAHAs) to Obinutuzumab

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    End point title
    		 Percentage of Participants With Human Anti-Human Antibodies (HAHAs) to Obinutuzumab [32]
    End point description
    End point type
    Secondary
    End point timeframe
    Induction: Predose (any time prior to dose) on D1 of Cy1,5,6 (1Cy: 21/28 days); Maintenance: Predose (any time prior to dose) on D1 of Month 1; at 120 days and 1 year of last obinutuzumab dose or at treatment discontinuation (up to 4 years)
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases)
    Number of subjects analysed
    42
    Units: percentage of participants
    number (not applicable)
        Induction Cycle 1 Day 1
    2.4
        Induction Cycle 5 Day 1
    0
        Induction Cycle 6 Day 1
    0
        Maintenance Month 1 (n = 6 subjects)
    0
        Study Drug Completion or Early Discontinuation
    100
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Human Anti-Chimeric Antibodies (HACAs) to Rituximab

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    End point title
    		 Percentage of Participants With Human Anti-Chimeric Antibodies (HACAs) to Rituximab [33]
    End point description
    End point type
    Secondary
    End point timeframe
    Induction: Predose (any time prior to dose) on D1 of Cy2,3,5,8 (1Cy: 21 days); Maintenance: Predose (any time prior to dose) on D1 of Month 1; at 120 days and 1 year of last rituximab dose or at treatment discontinuation (up to 4 years)
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    42
    Units: percentage of participants
    number (not applicable)
        Baseline
    21.9
        Induction Cycle 1 Day 1
    20.0
        Induction Cycle 5 Day 1
    0
        Induction Cycle 8 Day 1
    0
        Study Drug Completion or Early Discontinuation
    0
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab [34]
    End point description
    Atezo-G-CHOP: Induction: Predose on D1 of Cy2,3,5,6 (1 Cy: 21 days); Maintenance: Predose on D1 of Month 1,2,4,7,15,23; at 120 days and 1 year of last atezolizumab dose or at treatment discontinuation (up to 4 years); Atezo-R-CHOP: Predose on D1 of Cy 2,3,5,8,16,25 (1 Cy: 21 days); at 120 days and 1 year of last atezolizumab dose or at treatment discontinuation (up to 4 years). Predose time point was "any time prior to dose" for Cycles 2,3,5,6,8 during induction phase, for Cycles 16,25 during consolidation treatment, and for Months 1 to 24 during maintenance phase. 9999 = value was not collected
    End point type
    Secondary
    End point timeframe
    Atezo-G-Benda: Induction: Predose on D1 of Cy2,3,5,6 (1Cy: 28 days), Cy3D15: Predose; Maintenance: Predose on D1 of Month 1,4,7,15,23; at 120 days and 1 year of last atezolizumab dose or at treatment discontinuation (up to 4 years)
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Atezo-G-Benda Cohort (Safety Run-In and Expansion Phases) Atezo-R-CHOP Cohort (Expansion Phase)
    Number of subjects analysed
    42
    42
    Units: percentage of participants
    number (not applicable)
        Induction Cycle 2 Day 1
    0
    2.6
        Induction Cycle 3 Day 1
    0
    0
        Induction Cycle 5 Day 1
    0
    0
        Induction Cycle 8 Day 1
    9999
    0
        Consolidation Cycle 16
    9999
    0
        Study Drug Completion or Early Discontinuation
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to approximately 4 years
    Adverse event reporting additional description
    The safety population is defined as all patients who received at least one dose of the study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Atezo-G-Benda (Safety Run-In and Expansion Phases)
    Reporting group description
    		 Safety run-in phase: Participants with previously untreated or relapsed or refractory FL received obinutuzumab (G) and bendamustine during Cycle 1 (28-day cycle) and atezolizumab, obinutuzumab, and bendamustine during Cycles 2-6, during induction treatment, followed by atezolizumab (once monthly) and obinutuzumab (every other month [q2m]) for 24 months, during maintenance treatment. Expansion phase: Participants with previously untreated FL received same treatment regimen as described for safety run-in phase.

    Reporting group title
    Atezo-G-CHOP (Safety Run-In Phase)
    Reporting group description
    		 Safety run-in phase: Participants with previously untreated or relapsed or refractory FL received obinutuzumab and CHOP during Cycle 1 (21-day cycle) and atezolizumab, obinutuzumab, and CHOP during Cycles 2-6, during induction treatment, followed by atezolizumab (once monthly) and obinutuzumab (q2m) for 24 months, during maintenance treatment.

    Reporting group title
    Atezo-R-CHOP (Expansion Phase)
    Reporting group description
    		 Participants with previously untreated DLBCL received rituximab and CHOP during Cycle 1 (21-day cycle) and atezolizumab, rituximab, and CHOP during Cycles 2-8 (atezolizumab and rituximab for 8 cycles and CHOP for either 6 or 8 cycles, as determined by the investigator), during induction treatment, followed by atezolizumab from Cycles 9-25 during consolidation treatment.

    Serious adverse events
    		 Atezo-G-Benda (Safety Run-In and Expansion Phases) Atezo-G-CHOP (Safety Run-In Phase) Atezo-R-CHOP (Expansion Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 42 (28.57%)
    2 / 7 (28.57%)
    16 / 42 (38.10%)
         number of deaths (all causes)
    2
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon Cancer
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion Related Reaction
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Arrest
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    5 / 42 (11.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obliterative Bronchiolitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal Inflammation
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection Staphylococcal
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr Virus Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atezo-G-Benda (Safety Run-In and Expansion Phases) Atezo-G-CHOP (Safety Run-In Phase) Atezo-R-CHOP (Expansion Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 42 (100.00%)
    7 / 7 (100.00%)
    42 / 42 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Neoplasm
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Peripheral Coldness
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    22 / 42 (52.38%)
    5 / 7 (71.43%)
    16 / 42 (38.10%)
         occurrences all number
    24
    6
    20
    Mucosal Inflammation
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 7 (28.57%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    6
    Feeling Cold
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza Like Illness
         subjects affected / exposed
    6 / 42 (14.29%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    6
    1
    0
    Oedema Peripheral
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    3
    1
    0
    Pain
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    3
    1
    0
    Peripheral Swelling
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    3
    2
    0
    Chest Discomfort
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 7 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    6
    0
    7
    Chest Pain
         subjects affected / exposed
    6 / 42 (14.29%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    6
    0
    3
    Asthenia
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    0
    Reproductive system and breast disorders
    Vaginal Discharge
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 42 (40.48%)
    3 / 7 (42.86%)
    10 / 42 (23.81%)
         occurrences all number
    19
    3
    15
    Rhinorrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 7 (28.57%)
    4 / 42 (9.52%)
         occurrences all number
    0
    2
    5
    Dyspnoea
         subjects affected / exposed
    6 / 42 (14.29%)
    1 / 7 (14.29%)
    3 / 42 (7.14%)
         occurrences all number
    6
    1
    5
    Oropharyngeal Pain
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 7 (14.29%)
    4 / 42 (9.52%)
         occurrences all number
    4
    1
    4
    Pharyngeal Disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Productive Cough
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis Allergic
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Hiccups
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    3
    Nasal Congestion
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 42 (14.29%)
    2 / 7 (28.57%)
    7 / 42 (16.67%)
         occurrences all number
    6
    2
    8
    Anxiety
         subjects affected / exposed
    6 / 42 (14.29%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    6
    0
    6
    Investigations
    Lipase Increased
         subjects affected / exposed
    5 / 42 (11.90%)
    2 / 7 (28.57%)
    5 / 42 (11.90%)
         occurrences all number
    5
    2
    7
    Weight Decreased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    3
    Injury, poisoning and procedural complications
    Infusion Related Reaction
         subjects affected / exposed
    28 / 42 (66.67%)
    2 / 7 (28.57%)
    16 / 42 (38.10%)
         occurrences all number
    43
    2
    16
    Fall
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Joint Dislocation
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Ligament Sprain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    2
    0
    Meniscus Injury
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    2
    0
    Post Procedural Haematuria
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 7 (28.57%)
    0 / 42 (0.00%)
         occurrences all number
    0
    2
    0
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 7 (28.57%)
    0 / 42 (0.00%)
         occurrences all number
    3
    2
    0
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 7 (28.57%)
    13 / 42 (30.95%)
         occurrences all number
    0
    3
    14
    Amnesia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Balance Disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    6 / 42 (14.29%)
    1 / 7 (14.29%)
    4 / 42 (9.52%)
         occurrences all number
    9
    1
    6
    Headache
         subjects affected / exposed
    16 / 42 (38.10%)
    1 / 7 (14.29%)
    6 / 42 (14.29%)
         occurrences all number
    18
    1
    9
    Dysgeusia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    9 / 42 (21.43%)
         occurrences all number
    0
    0
    9
    Paraesthesia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    3
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    11 / 42 (26.19%)
    3 / 7 (42.86%)
    22 / 42 (52.38%)
         occurrences all number
    13
    4
    30
    Lymph Node Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Anaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    5
    Thrombocytopenia
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    6
    0
    0
    Eye disorders
    Dry Eye
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 7 (28.57%)
    0 / 42 (0.00%)
         occurrences all number
    0
    2
    0
    Ocular Hyperaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Photophobia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    19 / 42 (45.24%)
    5 / 7 (71.43%)
    12 / 42 (28.57%)
         occurrences all number
    28
    8
    21
    Diarrhoea
         subjects affected / exposed
    15 / 42 (35.71%)
    3 / 7 (42.86%)
    13 / 42 (30.95%)
         occurrences all number
    24
    10
    19
    Abdominal Pain
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 7 (28.57%)
    3 / 42 (7.14%)
         occurrences all number
    6
    3
    3
    Constipation
         subjects affected / exposed
    18 / 42 (42.86%)
    2 / 7 (28.57%)
    18 / 42 (42.86%)
         occurrences all number
    23
    3
    24
    Vomiting
         subjects affected / exposed
    9 / 42 (21.43%)
    2 / 7 (28.57%)
    10 / 42 (23.81%)
         occurrences all number
    10
    3
    11
    Ascites
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Defaecation Urgency
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    6 / 42 (14.29%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    8
    1
    0
    Glossitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Haematochezia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal Discharge
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Dry Mouth
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 7 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    4
    Abdominal Pain Upper
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    5
    0
    3
    Abdominal Discomfort
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    10 / 42 (23.81%)
         occurrences all number
    0
    1
    10
    Dermatitis Acneiform
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Dry Skin
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Rash Vesicular
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    9 / 42 (21.43%)
    0 / 7 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    12
    0
    6
    Night Sweats
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    3
    0
    3
    Pruritus
         subjects affected / exposed
    9 / 42 (21.43%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    10
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Micturition Urgency
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    6 / 42 (14.29%)
    4 / 7 (57.14%)
    6 / 42 (14.29%)
         occurrences all number
    6
    6
    10
    Arthralgia
         subjects affected / exposed
    7 / 42 (16.67%)
    2 / 7 (28.57%)
    7 / 42 (16.67%)
         occurrences all number
    8
    3
    9
    Joint Effusion
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Joint Swelling
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle Spasms
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    4 / 42 (9.52%)
         occurrences all number
    0
    1
    4
    Musculoskeletal Pain
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    3
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    4 / 42 (9.52%)
         occurrences all number
    0
    1
    4
    Bone Pain
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 7 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    6
    0
    5
    Pain in Extremity
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    6
    0
    0
    Flank Pain
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    6
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 7 (28.57%)
    0 / 42 (0.00%)
         occurrences all number
    0
    2
    0
    Herpes Zoster
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Oral Candidiasis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    2
    0
    Sinusitis
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 7 (14.29%)
    4 / 42 (9.52%)
         occurrences all number
    3
    1
    4
    Urinary Tract Infection
         subjects affected / exposed
    6 / 42 (14.29%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    6
    0
    0
    Vulvovaginal Mycotic Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 42 (14.29%)
    0 / 7 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    7
    0
    3
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 7 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    4
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    5 / 42 (11.90%)
    2 / 7 (28.57%)
    0 / 42 (0.00%)
         occurrences all number
    5
    2
    0
    Dehydration
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Iron Deficiency
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 7 (14.29%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2015
    MPDL3280A was changed to atezolizumab throughout the protocol. The management of gastrointestinal, dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, potential pancreatic or ocular events, and other immune mediated adverse events was updated. Guidance on investigations for the differential diagnosis of Systemic immune activation (SIA) was added. An exclusion criterion was added: “Known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug induced pneumonitis or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) was allowed.” The exclusion criterion related to infections was clarified as follows: “Active bacterial, viral, fungal, or other infection or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1”. The use of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (denosumab) was updated. Clarifications were made on the use of vaccines. The exclusion criterion related to prior treatment in relapse or refractory FL subjects (enrolled in safety run-in) was clarified. The administration sequence of the monoclonal antibodies and bendamustine in the Atezo-G-Benda treatment group was clarified. The administration sequence of the monoclonal antibodies and bendamustine in the Atezo-G-Benda treatment group was clarified.
    07 Sep 2016
    Further enrollment into the atezolizumab in combination with obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment group at the end of the safety run-in phase is stopped. In the expansion phase, subjects with previously untreated diffuse large B-cell lymphoma (DLBCL) will receive atezolizumab in combination with rituximab plus CHOP. The rationale for this change is based on results from the Phase III BO21005/GOYA study showing that the addition of obinutuzumab to CHOP chemotherapy in subjects with previously untreated DLBCL did not improve the primary endpoint progression-free survival (PFS) compared with the standard regimen of rituximab plus CHOP chemotherapy. Obinutuzumab exposure data has been updated. Guidance for the administration of atezolizumab on Day 15 for the atezolizumab in combination with obinutuzumab plus bendamustine treatment group has been clarified. Atezolizumab can be given on Day 15 of Cycles 2−6 regardless of cytopenia. The rationale for this update to the guidance is based on the mechanism of action of atezolizumab in conjunction with the available clinical experience showing minimal cytopenic effect of atezolizumab as a single agent, with an incidence of neutropenia of < 0.1%. Pharmacokinetic (PK) sampling schedule has been updated to include the “after atezolizumab infusion” serum atezolizumab PK samples at certain timepoints as well as to clarify the sampling time windows.
    26 May 2017
    The classification of second malignancies was changed from a selected adverse event to adverse event of special interest to more closely monitor this adverse event. Conditions for resuming study treatment in case of Grade ≥ 3 laboratory abnormalities was clarified. The list of adverse events of special interest for atezolizumab was updated. Language was modified to clarify the induction treatment with atezolizumab and CHOP. "Influenza-like illness" was added as an adverse event of special interest immediately reportable to the Sponsor. The protocol was modified to prohibit use of the term "sudden death" on the Adverse Event eCRF, unless it was combined with the presumed cause of death (e.g., "sudden cardiac death").
    22 Dec 2017
    Rationale for Treatment Combination section has been updated with the most recent efficacy and safety results from Study GO29383. Risks Associated with Obinutuzumab) has been updated to reflect recent updates to the Obinutuzumab treatment: Hypersensitivity reactions with delayed onset (e.g., serum sickness) have been added to previous warns related to hypersensitivity with immediate onset. The following observation has been added to warnings related to infections: In FL studies, a high incidence of infections was observed in all phases of the studies, including follow-up, with the highest incidence seen in maintenance. Section 5.1.3 (Risks Associated with Atezolizumab) have been revised to remove detailed presentation of the risks associated with atezolizumab. Section 5.1.7 (Management of Specific Adverse Events) management guidelines for atezolizumab-associated adverse events have been updated.

    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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