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    Clinical Trial Results:
    A Phase Ib/II Study Evaluating the Safety and Efficacy of Obinutuzumab in Combination with Atezolizumab Plus Polatuzumab Vedotin in Patients with Relapsed or Refractory Follicular Lymphoma and Rituximab in Combination with Atezolizumab Plus Polatuzumab Vedotin in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

    Summary
    EudraCT number
    		 2015-004845-25
    Trial protocol
    		 DE   PL  
    Global end of trial date
    07 Oct 2019

    Results information
    Results version number
    		 v4(current)
    This version publication date
    16 Dec 2020
    First version publication date
    21 Sep 2019
    Other versions
    		 v1 , v2 , v3
    Version creation reason
    • Correction of full data set
    Based on comments from the NIH, arm descriptions have been updated. Also, certain end point descriptions have been updated with time frame information.

    Trial information

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    Trial identification
    Sponsor protocol code
    BO29561
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02729896
    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, globa.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To Evaluate the Safety and Efficacy of Obinutuzumab in Combination with Atezolizumab plus Polatuzumab Vedotin in Patients with Relapsed or Refractory Follicular Lymphoma and Rituximab in Combination with Atezolizumab plus Polatuzumab Vedotin in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Nov 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
    Germany: 11
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    36
    EEA total number of subjects
    25
    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)
    20
    From 65 to 84 years
    15
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 56 patients were screened and 36 patients enrolled and dosed in the study.

    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
    		 Dose-Escalation FL Cohort 1.4 mg
    Arm description
    		 During the induction treatment Cycle 1 (21-day cycles): participants received obinutuzumab on Days 1, 8, and 15 and pola on Day 1; Cycles 2-6: participants received 1000 milligram (mg) of obinutuzumab on Day 1, 1200 mg of atezo on Day 1, and 1.4 mg/kilogram (kg) of pola on Day 1. The 1.4 mg/kg dose was cleared by an Internal Monitoring Committee (IMC) review and escalated to 1.8 mg/kg. This was followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg

    Investigational medicinal product name
    Polatuzumab Vedotin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg

    Arm title
    		 Dose-Escalation and Expansion FL Cohort 1.8 mg
    Arm description
    		 During the induction treatment Cycle 1 (21-day cycles): participants received obinutuzumab on Days 1, 8, and 15 and pola on Day 1; Cycles 2-6: participants received 1000 mg of obinutuzumab on Day 1, 1200 mg of atezo on Day 1, and pola was escalated to 1.8 mg/kg (on Day 1); once cleared by the IMC it was declared as the recommended phase 2 dose (RP2D). This was followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants. Due to unexpected toxicity, recruitment was stopped, and atezolizumab discontinued in all treated patients. This combination will not be further developed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg

    Investigational medicinal product name
    Polatuzumab Vedotin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.8 mg

    Arm title
    		 Safety Run-in and Expansion DLBCL Cohort
    Arm description
    		 For DLBCL, during the induction treatment Cycles 1-6 (21-day cycles): participants received a 375 mg/m^2 IV of rituximab on Day 1 and on Day 1 of every other month during consolidation. Participants also received a 1.8 mg/kg IV of Pola on Day 1. Cycles 2-6: participants received 1200 mg of Atezo on Day 1. Due to unexpected toxicity, recruitment was stopped, and atezolizumab discontinued in all treated patients. This combination will not be further developed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg

    Investigational medicinal product name
    Polatuzumab Vedotin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg or 1.8 mg

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m˄2

    Number of subjects in period 1
    		Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Started
    3
    10
    23
    Completed
    1
    1
    1
    Not completed
    2
    9
    22
         Physician decision
    1
    2
    3
         Withdrawal By Subject
    1
    -
    3
         Death
    -
    2
    13
         Progressive Disease
    -
    1
    -
         Not Specified
    -
    2
    -
         Lost to follow-up
    -
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose-Escalation FL Cohort 1.4 mg
    Reporting group description
    		 During the induction treatment Cycle 1 (21-day cycles): participants received obinutuzumab on Days 1, 8, and 15 and pola on Day 1; Cycles 2-6: participants received 1000 milligram (mg) of obinutuzumab on Day 1, 1200 mg of atezo on Day 1, and 1.4 mg/kilogram (kg) of pola on Day 1. The 1.4 mg/kg dose was cleared by an Internal Monitoring Committee (IMC) review and escalated to 1.8 mg/kg. This was followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants.

    Reporting group title
    Dose-Escalation and Expansion FL Cohort 1.8 mg
    Reporting group description
    		 During the induction treatment Cycle 1 (21-day cycles): participants received obinutuzumab on Days 1, 8, and 15 and pola on Day 1; Cycles 2-6: participants received 1000 mg of obinutuzumab on Day 1, 1200 mg of atezo on Day 1, and pola was escalated to 1.8 mg/kg (on Day 1); once cleared by the IMC it was declared as the recommended phase 2 dose (RP2D). This was followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants. Due to unexpected toxicity, recruitment was stopped, and atezolizumab discontinued in all treated patients. This combination will not be further developed.

    Reporting group title
    Safety Run-in and Expansion DLBCL Cohort
    Reporting group description
    		 For DLBCL, during the induction treatment Cycles 1-6 (21-day cycles): participants received a 375 mg/m^2 IV of rituximab on Day 1 and on Day 1 of every other month during consolidation. Participants also received a 1.8 mg/kg IV of Pola on Day 1. Cycles 2-6: participants received 1200 mg of Atezo on Day 1. Due to unexpected toxicity, recruitment was stopped, and atezolizumab discontinued in all treated patients. This combination will not be further developed.

    Reporting group values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort Total
    Number of subjects
    		 3 10 23 36
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 2 6 12 20
        >=65 years
    		 1 4 11 16
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 52.3 ( 13.6 ) 57.7 ( 11.7 ) 64.3 ( 15.3 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 0 4 9 13
        Male
    		 3 6 14 23
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 0 1 3 4
        Not Hispanic or Latino
    		 3 9 18 30
        Unknown
    		 0 0 2 2
    Race/Ethnicity, Customized
    Units: Subjects
        Other
    		 0 1 2 3
        White
    		 3 9 21 33

    End points

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    End points reporting groups
    Reporting group title
    Dose-Escalation FL Cohort 1.4 mg
    Reporting group description
    		 During the induction treatment Cycle 1 (21-day cycles): participants received obinutuzumab on Days 1, 8, and 15 and pola on Day 1; Cycles 2-6: participants received 1000 milligram (mg) of obinutuzumab on Day 1, 1200 mg of atezo on Day 1, and 1.4 mg/kilogram (kg) of pola on Day 1. The 1.4 mg/kg dose was cleared by an Internal Monitoring Committee (IMC) review and escalated to 1.8 mg/kg. This was followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants.

    Reporting group title
    Dose-Escalation and Expansion FL Cohort 1.8 mg
    Reporting group description
    		 During the induction treatment Cycle 1 (21-day cycles): participants received obinutuzumab on Days 1, 8, and 15 and pola on Day 1; Cycles 2-6: participants received 1000 mg of obinutuzumab on Day 1, 1200 mg of atezo on Day 1, and pola was escalated to 1.8 mg/kg (on Day 1); once cleared by the IMC it was declared as the recommended phase 2 dose (RP2D). This was followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants. Due to unexpected toxicity, recruitment was stopped, and atezolizumab discontinued in all treated patients. This combination will not be further developed.

    Reporting group title
    Safety Run-in and Expansion DLBCL Cohort
    Reporting group description
    		 For DLBCL, during the induction treatment Cycles 1-6 (21-day cycles): participants received a 375 mg/m^2 IV of rituximab on Day 1 and on Day 1 of every other month during consolidation. Participants also received a 1.8 mg/kg IV of Pola on Day 1. Cycles 2-6: participants received 1200 mg of Atezo on Day 1. Due to unexpected toxicity, recruitment was stopped, and atezolizumab discontinued in all treated patients. This combination will not be further developed.

    Primary: Percentage of Participants with CR at EOI, as Determined by the investigator on the Basis of Positron Emission Tomography and Computed Tomography (PET-CT) Scan

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    End point title
    		 Percentage of Participants with CR at EOI, as Determined by the investigator on the Basis of Positron Emission Tomography and Computed Tomography (PET-CT) Scan [1]
    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% confidence interval (CI) for percentage of responders was calculated using Clopper-Pearson method. All 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
    Within 6 to 8 weeks after Day 1 of Cycle 6 (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: This endpoint is only reporting the percentage of participants
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    7
    16
    Units: Percentage of participants
        number (not applicable)
    33.33
    14.30
    12.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with CR at EOI, as Determined by Investigator on the Basis of CT Scans Alone

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    End point title
    		 Percentage of Participants with CR at EOI, as Determined by Investigator on the Basis of CT Scans Alone
    End point description
    Tumor response assessment was performed by investigator according to modified Lugano classification using computed tomography (CT) scan. OR: a response of CR or PR. CR: Target nodes/nodal masses regressed to <= 1.5 cm in LDi; no extralymphatic sites of disease; organ enlargement regressed to normal; no new lesions; normal/IHC-negative bone marrow morphology. All CT evaluable 1L FL and 1L DLBCL patients with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 6 months)
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    7
    16
    Units: Percentage of participants
        number (not applicable)
    0.00
    57.14
    12.50
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Objective Response (CR + PR) at EOI, as Determined by the Investigator on the Basis of PET-CT Scans

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    End point title
    		 Percentage of Participants with Objective Response (CR + PR) at EOI, as Determined by the Investigator on the Basis of PET-CT Scans
    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 PET evaluable 1L FL and 1L DLBCL patients with at least one dose of atezolizumab were included in efficacy population
    End point type
    Secondary
    End point timeframe
    Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 6 months)
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    7
    16
    Units: Percentage of participants
        number (not applicable)
    33.33
    57.14
    25.00
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Objective Response (CR + PR) at EOI, as Determined by the Investigator on the Basis of CT Scans Alone

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    End point title
    		 Percentage of Participants with Objective Response (CR + PR) at EOI, as Determined by the Investigator on the Basis of CT Scans Alone
    End point description
    Tumor response assessment was performed by investigator according to modified Lugano classification using CT scan. OR: a response of CR or PR. CR: Target nodes/nodal masses regressed to <= 1.5 cm in LDi; no extralymphatic sites of disease; organ enlargement regressed to normal; no new lesions; normal/IHC-negative bone marrow morphology. PR with >= 50 percet decrease in SPD of up to six target measurable nodes and extranodal sites, a 5 mm x 5 mm default value when lesions were too small, 0 x0 mm value when lesions were no longer visible, actual measurements were used for nodes greater than 5 mm x 5 mm for lymph nodes & extralymphatic sites; absent/normal, regression for non-measured lesion; spleen enlargement regression by > 50 percent; no new lesions; reduced residual uptake in bone marrow compared to baseline. All CT evaluable 1L FL and 1L DLBCL patients with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 6 months)
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    7
    16
    Units: Percentage of participants
        number (not applicable)
    33.33
    57.14
    25.00
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Best Response of CR or PR during the Study, as Determined by the Investigator on the Basis of CT Scans Alone

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    End point title
    		 Percentage of Participants with Best Response of CR or PR during the Study, as Determined by the Investigator on the Basis of CT Scans Alone
    End point description
    Tumor response assessment was performed by investigator according to modified Lugano classification using CT scan. OR: a response of CR or PR. CR: Target nodes/nodal masses regressed to <= 1.5 cm in LDi; no extralymphatic sites of disease; organ enlargement regressed to normal; no new lesions; normal/IHC-negative bone marrow morphology. PR with >= 50 percet decrease in SPD of up to six target measurable nodes and extranodal sites, a 5 mm x 5 mm default value when lesions were too small, 0 x0 mm value when lesions were no longer visible, actual measurements were used for nodes greater than 5 mm x 5 mm for lymph nodes & extralymphatic sites; absent/normal, regression for non-measured lesion; spleen enlargement regression by > 50 percent; no new lesions; reduced residual uptake in bone marrow compared to baseline. All CT evaluable 1L FL and 1L DLBCL patients with at least one dose of atezolizumab were included in efficacy population.
    End point type
    Secondary
    End point timeframe
    Baseline up to 35 months
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    7
    16
    Units: Percentage of participants
    number (not applicable)
        Complete response
    33.3
    14.3
    12.5
        Partial response
    0
    42.9
    12.5
        Stable disease
    33.3
    14.3
    6.3
        Progressive disease
    33.3
    14.3
    31.3
        Not available
    0
    14.3
    37.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events and Serious Adverse Events

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    End point title
    		 Percentage of Participants with Adverse Events and Serious Adverse Events
    End point description
    An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the treatment. An adverse event was therefore any unfavourable 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. Grading was completed according to the CTCAE, version 4.0 for severity and tumor flare reactions were graded according to NCI CTCAE v3.0.
    End point type
    Secondary
    End point timeframe
    Baseline up to 35 months
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    10
    21
    Units: Participants
        number (not applicable)
    100.00
    100.00
    81.00
    No statistical analyses for this end point

    Secondary: Serum Obinutuzumab Concentration

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    End point title
    		 Serum Obinutuzumab Concentration [2]
    End point description
    pre-dose (0 hr), 30 min after EOI on Day 1 Cycle 1; pre-dose (within 5 hr), 30 min after EOI on Day 1 of Cycles 2, 4, 6; maintenance phase: pre-dose (within 5 hr) on Day 1 of Months 1, 7, 13, 19; anytime during treatment discontinuation visit, 120 days after the last dose, and 1 year after the last dose up to 35 months (1 cycle=21 days; infusion rate: starts with 50 mg/hr and decreases every 30 min to maximum of 400 mg/hr). 99999 represents the upper limit of confidence interval was not estimable due to the low number of subjects within events.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr) up to 35 months
    Notes
    [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: Only arms treated with Obinutuzumab were included in this endpoint
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg
    Number of subjects analysed
    3
    10
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Induction cycle 1 Day 1 Pre-dose (N=3, 10)
    99999 ( 99999 )
    99999 ( 99999 )
        Induction cycle 1 Day 1 Post-dose (N=3, 10)
    308 ( 41.6 )
    295 ( 171 )
        Induction cycle 2 Day 1 Pre-dose (N=3, 10)
    351 ( 81.3 )
    403 ( 143 )
        Induction cycle 2 Day 1 Post-dose (N=3, 10)
    616 ( 115 )
    672 ( 130 )
        Induction cycle 4 Day 1 Pre-dose (N=3, 10)
    433 ( 322 )
    311 ( 177 )
        Induction cycle 4 Day 1 Post-dose (N=3, 18)
    583 ( 189 )
    619 ( 160 )
        Induction cycle 6 Day 1 Pre-dose (N=3, 9)
    288 ( 123 )
    308 ( 194 )
        Induction cycle 6 Day 1 Post-dose (N=3, 8)
    514 ( 121 )
    605 ( 161 )
        Maintenance Month 1 Day 1 Pre-dose (N=1, 6)
    221 ( 99999 )
    171 ( 131 )
        Maintenance Month 7 Pre-dose (N=2, 6)
    90.4 ( 58.8 )
    83.8 ( 59.6 )
        Maintenance Month 13 Pre-dose (N=2, 2)
    78.8 ( 42.8 )
    158 ( 1.41 )
        Drug completion or early discontinuation (N=0, 1)
    0 ( 0 )
    37.2 ( 99999 )
        PK and Immunogenicity follow up (N=2, 3)
    110 ( 120 )
    15.4 ( 3.20 )
    No statistical analyses for this end point

    Secondary: Serum Rituximab Concentration

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    End point title
    		 Serum Rituximab Concentration [3]
    End point description
    pre-dose (0 hr), 30 min after EOI on Day 1 Cycle 1; pre-dose (within 5 hr) on Day 1 of Cycles 2, 4; pre-dose (within 5 hr), 30 min after EOI on Day 1 of Cycle 6; anytime during treatment discontinuation visit, 120 days after the last dose, and 1 year after the last dose up to 35 months (1 cycle=21 days; infusion rate: starts with 50 mg/hr and increases every 30 min to maximum of 400 mg/hr)
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr) up to 35 months
    Notes
    [3] - 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: Only arms treated with Rituximab were included in this endpoint
    End point values
    		 Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    21
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Induction Cycle 1 Day 1 Pre-dose (N=9)
    30.4 ( 28.8 )
        Induction Cycle 1 Day 1 Post-dose (N=19)
    197 ( 56.9 )
        Induction Cycle 2 Day 1 Pre-dose (N=17)
    43.5 ( 28.7 )
        Induction Cycle 4 Day 1 Pre-dose (N=10)
    84.8 ( 35.7 )
        Induction Cycle 6 Day 1 Pre-dose (N=13)
    101 ( 45.5 )
        Induction Cycle 6 Day 1 Post-dose (N=12)
    239 ( 42.8 )
    No statistical analyses for this end point

    Secondary: Serum Atezo Concentration

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    End point title
    		 Serum Atezo Concentration
    End point description
    pre-dose (within 5 hr), 30 min after EOI on Day 1 of Cycles 2, 3, 4; pre-dose (within 5 hr) on Day 1 of Cycle 6; maintenance phase: pre-dose (within 5 hr) on Day 1 of Month 1; 30 min after EOI on Day 2 of Month 1; pre-dose (within 5 hr) on Day 1 of Month 4, 7, 13, 19; anytime during treatment discontinuation visit, 120 days after the last dose, and 1-2 years after the last dose up to 35 months (1 cycle=21 days; infusion rate: starts with 60 min and decreases to 30 min). 99999 represents the upper limit of confidence interval was not estimable due to the low number of subjects within events.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr) up to 35 months
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    10
    21
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Induction Cycle 2 Day 1 Pre-dose (N=3, 10, 18)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Induction Cycle 2 Day 1 Post-dose (N=3, 10, 18)
    332 ( 56.7 )
    365 ( 80.7 )
    355 ( 78.8 )
        Induction Cycle 3 Day 1 Pre-dose (N=3, 9, 14)
    86.9 ( 28.8 )
    78.7 ( 18.4 )
    79.7 ( 30.6 )
        Induction Cycle 4 Day 1 Pre-dose (N=3, 7, 9)
    139 ( 33.1 )
    125 ( 47.3 )
    139 ( 56.4 )
        Induction Cycle 4 Day 1 Post-dose (N=3, 6, 8)
    462 ( 82.0 )
    450 ( 136 )
    489 ( 131 )
        Induction Cycle 6 Day 1 Pre-dose (N=3, 6, 8)
    194 ( 67.7 )
    181 ( 112 )
    180 ( 90.6 )
        Maintenance Month 1 Day 1 Pre-dose (N=2, 4, 0)
    100 ( 66.0 )
    70.7 ( 55.5 )
    0 ( 0 )
        Maintenance Month 1 Day 2 Post-dose (N=3, 4, 0)
    577 ( 144 )
    473 ( 177 )
    0 ( 0 )
        Maintenance Month 4 Pre-dose (N=3, 3, 0)
    240 ( 101 )
    140 ( 141 )
    0 ( 0 )
        Maintenance Month 7 Pre-dose (N=2, 2, 0)
    226 ( 134 )
    221 ( 90.5 )
    0 ( 0 )
        Maintenance Month 13 Pre-dose (N=2, 0, 0)
    106 ( 83.0 )
    0 ( 0 )
    0 ( 0 )
        Drug completion or early discontinuation (N=0,1,2)
    0 ( 0 )
    127 ( 99999 )
    93.0 ( 14.2 )
        Consolidation Month 1 Day 1 Pre-dose (N=0, 0, 4)
    0 ( 0 )
    0 ( 0 )
    132 ( 43.3 )
        Consolidation Month 1 Day 2 Post-dose (N=0, 0, 3)
    0 ( 0 )
    0 ( 0 )
    503 ( 214 )
        PK and Immunogenicity followup 120D (N=2, 3, 2)
    61.4 ( 60.3 )
    16.8 ( 26.8 )
    19.9 ( 0.778 )
        PK and Immunogenicity followup 1 Year (N=0, 2, 0)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Serum Pola Concentration

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    End point title
    		 Serum Pola Concentration
    End point description
    pre-dose (0 hr) on Day 1 Cycle 1; pre-dose (within 5 hr) on Day 1 of Cycles 2, 4; maintenance phase: pre-dose (within 5 hr) on Day 1 of Months 1; anytime during treatment discontinuation visit, 120 days after the last dose, and 1 year after the last dose up to 35 months (1 cycle=21 days; infusion rate: starts with 90 min and decreases to 30 min). 99999 represents the upper limit of confidence interval was not estimable due to the low number of subjects within events.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr) up to 35 months
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    10
    21
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Pre Day 120 Follow-up (N=0, 1, 1)
    0 ( 0 )
    0.136 ( 99999 )
    2.91 ( 99999 )
        Induction Cycle 1 Day 1 Pre-dose (N=0, 1, 1)
    0 ( 0 )
    0.847 ( 99999 )
    35.9 ( 99999 )
        Induction Cycle 2 Day 1 Pre-dose (N=3, 8, 17)
    2.54 ( 0.918 )
    2.62 ( 1.22 )
    3.37 ( 3.60 )
        Induction Cycle 4 Day 1 Pre-dose (N=3, 9, 12)
    4.73 ( 2.10 )
    4.27 ( 1.63 )
    4.92 ( 2.65 )
        Maintenance Month 1 Day 1 Pre-dose (N=2, 3, 0)
    1.30 ( 0.696 )
    1.63 ( 1.75 )
    0 ( 0 )
        Drug completion or early discontinuation (N=0,0,2)
    0 ( 0 )
    0 ( 0 )
    0.716 ( 0.200 )
    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 [4]
    End point description
    Pre-dose (0 hr) on Day 1 of Cycle 1, 6, anytime during treatment discontinuation visit, 120 days after the last dose, and 1 year after the last dose up to 35 months (1 cycle=21 days; infusion rate: starts with 50 mg/hr and increased every 30 min to maximum of 400 mg/hr)
    End point type
    Secondary
    End point timeframe
    Baseline up to 35 months
    Notes
    [4] - 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: Only arms treated with Obinutuzumab were included in this endpoint
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg
    Number of subjects analysed
    3
    10
    Units: Percentage of participants
    0
    0
    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 [5]
    End point description
    Pre-dose (0 hr) on Day 1 of Cycle 1, 2, 4, 6, anytime during treatment discontinuation visit, 120 days after the last dose, and 1 year after the last dose up to 35 months (1 cycle=21 days; infusion rate: starts with 50 mg/hr and increased every 30 min to maximum of 400 mg/hr)
    End point type
    Secondary
    End point timeframe
    Baseline to 35 months
    Notes
    [5] - 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: Only arms treated with Rituximab were included in this endpoint
    End point values
    		 Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    21
    Units: Percentage of participants
    number (not applicable)
        Baseline, positive (N=18)
    5.6
        Baseline, negative (N=18)
    94.4
        Induction Cycle 2 Day 1, positive (N=18)
    5.6
        Induction Cycle 2 Day 1, negative (N=18)
    94.4
        Induction Cycle 4 Day 1 (N=12)
    100
        Induction Cycle 6 Day 1 (N=13)
    100
        Study drug completion (N=1)
    100
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Atezo
    End point description
    Pre-dose (0 hr) on Day 1 of Cycle 2, 3, 4, 6, Month 1, 4, 7, 13 and 19, anytime during treatment discontinuation visit, 120 days after the last dose, and 1 year after the last dose up to 35 months (1 cycle=21 days; infusion rate: starts with 60 min and decreases to 30 min)
    End point type
    Secondary
    End point timeframe
    Baseline to 35 months
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    10
    21
    Units: Percentage of participants
    number (not applicable)
        Induction, Cycle 2 Day 1, positive (N=3, 10, 1)
    0
    0
    5.3
        Induction, Cycle 2 Day 1, negative (N=3, 10, 18)
    0
    0
    94.7
        Induction, Cycle 3 Day 1, positive (N=3, 10, 1)
    0
    0
    7.1
        Induction, Cycle 3 Day 1, negative (N=3, 10, 13)
    0
    0
    92.9
        Induction, Cycle 4 Day 1, negative (N=3, 10, 9)
    0
    0
    100.0
        Induction, Cycle 6 Day 1, negative (N=3, 10, 7)
    0
    0
    100.0
        Consolidation Month 1 Day 1, negative (N=3, 10, 4)
    0
    0
    100.0
        Study drug completion, negative (N=3, 10, 2)
    0
    0
    100.0
        PK Immuno. Follow up (120D), negative (N=3, 10, 2)
    0
    0
    100.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with ATAs to Pola

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    End point title
    		 Percentage of Participants with ATAs to Pola
    End point description
    Pre-dose (0 hr) on Day 1 of Cycle 1, 2, 4, anytime during treatment discontinuation visit, 120 days after the last dose, and 1 year after the last dose up to 35 months (1 cycle=21 days; infusion rate: starts with 90 min and decreases to 30 min)
    End point type
    Secondary
    End point timeframe
    Baseline to 35 months
    End point values
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Number of subjects analysed
    3
    10
    21
    Units: Percentage of participants
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization up to 35 months
    Adverse event reporting additional description
    All adverse events that occurred on or after the first dose of study treatment are summarized by mapped term, appropriate thesaurus levels, and National Cancer Institute Common Terminology Criteria (NCI CTCAE) v4.0 grade. All-Cause Mortality is reported for the ITT population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Dose-Escalation FL Cohort 1.4 mg
    Reporting group description
    		 During the induction treatment Cycle 1 (21-day cycles): participants received obinutuzumab on Days 1, 8, and 15 and pola on Day 1; Cycles 2-6: participants received 1000 milligram (mg) of obinutuzumab on Day 1, 1200 mg of atezo on Day 1, and 1.4 mg/kilogram (kg) of pola on Day 1. The 1.4 mg/kg dose was cleared by an Internal Monitoring Committee (IMC) review and escalated to 1.8 mg/kg. This was followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants.

    Reporting group title
    Dose-Escalation and Expansion FL Cohort 1.8 mg
    Reporting group description
    		 During the induction treatment Cycle 1 (21-day cycles): participants received obinutuzumab on Days 1, 8, and 15 and pola on Day 1; Cycles 2-6: participants received 1000 mg of obinutuzumab on Day 1, 1200 mg of atezo on Day 1, and pola was escalated to 1.8 mg/kg (on Day 1); once cleared by the IMC it was declared as the recommended phase 2 dose (RP2D). This was followed by obinutuzumab on Day 1 of every other month starting with Month 1 for 24 months, during maintenance treatment for FL participants. Due to unexpected toxicity, recruitment was stopped, and atezolizumab discontinued in all treated patients. This combination will not be further developed.

    Reporting group title
    Safety Run-in and Expansion DLBCL Cohort
    Reporting group description
    		 For DLBCL, during the induction treatment Cycles 1-6 (21-day cycles): participants received a 375 mg/m^2 IV of rituximab on Day 1 and on Day 1 of every other month during consolidation. Participants also received a 1.8 mg/kg IV of Pola on Day 1. Cycles 2-6: participants received 1200 mg of Atezo on Day 1. Due to unexpected toxicity, recruitment was stopped, and atezolizumab discontinued in all treated patients. This combination will not be further developed.

    Serious adverse events
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 10 (40.00%)
    2 / 23 (8.70%)
         number of deaths (all causes)
    0
    2
    13
         number of deaths resulting from adverse events
    Investigations
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed [1]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    GUILLAIN-BARRE SYNDROME
         subjects affected / exposed [2]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (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
    LETHARGY
         subjects affected / exposed [3]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed [4]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (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 [5]
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed [6]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    PYREXIA
         subjects affected / exposed [7]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed [8]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed [9]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PLEURAL EFFUSION
         subjects affected / exposed [10]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    PNEUMONITIS
         subjects affected / exposed [11]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS
         subjects affected / exposed [12]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYTHEMA
         subjects affected / exposed [13]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    BRONCHOPULMONARY ASPERGILLOSIS
         subjects affected / exposed [14]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    ERYSIPELAS
         subjects affected / exposed [15]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (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
    SEPSIS
         subjects affected / exposed [16]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose-Escalation FL Cohort 1.4 mg Dose-Escalation and Expansion FL Cohort 1.8 mg Safety Run-in and Expansion DLBCL Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    10 / 10 (100.00%)
    15 / 23 (65.22%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed [17]
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed [18]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    THROMBOSIS
         subjects affected / exposed [19]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed [20]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    FACE OEDEMA
         subjects affected / exposed [21]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    FATIGUE
         subjects affected / exposed [22]
    2 / 3 (66.67%)
    3 / 10 (30.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    3
    1
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed [23]
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    INFUSION SITE EXTRAVASATION
         subjects affected / exposed [24]
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    OEDEMA
         subjects affected / exposed [25]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed [26]
    0 / 3 (0.00%)
    3 / 10 (30.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    3
    5
    PERIPHERAL SWELLING
         subjects affected / exposed [27]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    3
    1
    PYREXIA
         subjects affected / exposed [28]
    0 / 3 (0.00%)
    4 / 10 (40.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed [29]
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    3
    DYSPNOEA
         subjects affected / exposed [30]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    DYSPNOEA EXERTIONAL
         subjects affected / exposed [31]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    HICCUPS
         subjects affected / exposed [32]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    LARYNGEAL OEDEMA
         subjects affected / exposed [33]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    PULMONARY EMBOLISM
         subjects affected / exposed [34]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    PULMONARY THROMBOSIS
         subjects affected / exposed [35]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed [36]
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    INSOMNIA
         subjects affected / exposed [37]
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    ANXIETY
         subjects affected / exposed [38]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed [39]
    1 / 3 (33.33%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    BLOOD CREATININE INCREASED
         subjects affected / exposed [40]
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed [41]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed [42]
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    5
    0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed [43]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    LIPASE INCREASED
         subjects affected / exposed [44]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed [45]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    PROCALCITONIN INCREASED
         subjects affected / exposed [46]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    THYROXINE DECREASED
         subjects affected / exposed [47]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    TRI-IODOTHYRONINE DECREASED
         subjects affected / exposed [48]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    WEIGHT DECREASED
         subjects affected / exposed [49]
    0 / 3 (0.00%)
    4 / 10 (40.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    4
    0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed [50]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed [51]
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Cardiac disorders
    SINUS TACHYCARDIA
         subjects affected / exposed [52]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed [53]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    2
    FACIAL PARALYSIS
         subjects affected / exposed [54]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    HEADACHE
         subjects affected / exposed [55]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    HYPOAESTHESIA
         subjects affected / exposed [56]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    NEUROPATHY PERIPHERAL
         subjects affected / exposed [57]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    PARAESTHESIA
         subjects affected / exposed [58]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    POLYNEUROPATHY
         subjects affected / exposed [59]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed [60]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    2
    ANAEMIA FOLATE DEFICIENCY
         subjects affected / exposed [61]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    LEUKOPENIA
         subjects affected / exposed [62]
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    5
    1
    NEUTROPENIA
         subjects affected / exposed [63]
    1 / 3 (33.33%)
    4 / 10 (40.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    7
    4
    THROMBOCYTOPENIA
         subjects affected / exposed [64]
    0 / 3 (0.00%)
    4 / 10 (40.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    5
    0
    Eye disorders
    DRY EYE
         subjects affected / exposed [65]
    0 / 3 (0.00%)
    2 / 10 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    GLAUCOMA
         subjects affected / exposed [66]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    SCLERITIS
         subjects affected / exposed [67]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    CATARACT NUCLEAR
         subjects affected / exposed [68]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    VITREOUS DEGENERATION
         subjects affected / exposed [69]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed [70]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    CONSTIPATION
         subjects affected / exposed [71]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    DIARRHOEA
         subjects affected / exposed [72]
    0 / 3 (0.00%)
    3 / 10 (30.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    0
    DRY MOUTH
         subjects affected / exposed [73]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    DYSPEPSIA
         subjects affected / exposed [74]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed [75]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    STOMATITIS
         subjects affected / exposed [76]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    VOMITING
         subjects affected / exposed [77]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    NIGHT SWEATS
         subjects affected / exposed [78]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    RASH
         subjects affected / exposed [79]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    4
    0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed [80]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    3
    Endocrine disorders
    AUTOIMMUNE THYROIDITIS
         subjects affected / exposed [81]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    HYPOTHYROIDISM
         subjects affected / exposed [82]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed [83]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    BACK PAIN
         subjects affected / exposed [84]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    BONE PAIN
         subjects affected / exposed [85]
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed [86]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    SACROILIITIS
         subjects affected / exposed [87]
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    TENDONITIS
         subjects affected / exposed [88]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    BACTERAEMIA
         subjects affected / exposed [89]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    BACTERIAL INFECTION
         subjects affected / exposed [90]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    BRONCHOPULMONARY ASPERGILLOSIS
         subjects affected / exposed [91]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    CONJUNCTIVITIS
         subjects affected / exposed [92]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed [93]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    LARYNGITIS
         subjects affected / exposed [94]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    NASOPHARYNGITIS
         subjects affected / exposed [95]
    1 / 3 (33.33%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    2
    0
    ORAL FUNGAL INFECTION
         subjects affected / exposed [96]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    PELVIC ABSCESS
         subjects affected / exposed [97]
    1 / 3 (33.33%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    PNEUMONIA
         subjects affected / exposed [98]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    RHINITIS
         subjects affected / exposed [99]
    1 / 3 (33.33%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    1
    0
    SINUSITIS
         subjects affected / exposed [100]
    2 / 3 (66.67%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed [101]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    2
    3
    URINARY TRACT INFECTION
         subjects affected / exposed [102]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    VIRAL INFECTION
         subjects affected / exposed [103]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed [104]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    ACUTE SINUSITIS
         subjects affected / exposed [105]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    CONJUNCTIVITIS VIRAL
         subjects affected / exposed [106]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed [107]
    0 / 3 (0.00%)
    3 / 10 (30.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    3
    1
    FLUID RETENTION
         subjects affected / exposed [108]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    HYPERGLYCAEMIA
         subjects affected / exposed [109]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    HYPOALBUMINAEMIA
         subjects affected / exposed [110]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    HYPOKALAEMIA
         subjects affected / exposed [111]
    0 / 3 (0.00%)
    3 / 10 (30.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    3
    1
    Notes
    [17] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [18] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [19] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [20] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [21] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [22] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [23] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [24] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [25] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [26] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [27] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [28] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [29] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [30] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [31] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [32] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [33] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [34] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [35] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [36] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [37] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [38] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [39] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [40] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [41] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [42] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [43] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [44] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [45] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [46] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [47] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [48] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [49] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [50] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [51] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [52] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [53] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [54] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [55] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [56] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [57] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [58] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [59] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [60] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [61] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [62] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [63] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [64] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [65] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [66] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [67] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [68] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [69] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [70] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [71] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [72] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [73] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [74] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [75] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [76] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [77] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [78] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [79] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [80] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [81] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [82] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [83] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [84] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [85] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [86] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [87] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [88] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [89] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [90] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [91] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [92] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [93] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [94] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [95] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [96] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [97] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [98] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [99] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [100] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [101] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [102] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [103] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [104] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [105] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [106] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [107] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [108] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [109] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [110] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).
    [111] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: In the DLBCL Safety Run in phase 23 subjects enrolled in study. However two patients did not receive any study treatment and therefore were not included in the Safety Evaluable population (n=21).

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jan 2016
    Version 2: The protocol has been revised to update the DLT window and to clarify inclusion/exclusion and stopping criteria. Additional minor changes have been made to improve clarity and consistency.
    28 Jun 2016
    Version 3: The inclusion criterion on contraception requirements for women of childbearing potential has been revised to include the duration of contraception for atezolizumab and polatuzumab vedotin. Enrollment rules into the dose escalation phase have been updated, for patients’ safety considerations. A sequential enrollment instead of a parallel enrollment will be used for each of the two dosing groups,
    17 Nov 2016
    Version 4: “Immune-mediated” was revised to “immune-related” when referring to adverse events. Cut-off date for Atezolizumab was changed to 15 December 2016. The title has been revised. Study treatment has been modified to include Rituximab (RO0452294) in combination with atezolizumab plus polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma.
    04 May 2017
    Version 5: The protocol has been modified to prohibit use of the term "sudden death" on the Adverse Event eCRF, unless it is combined with the presumed cause of death. Language has been added to clarify that the Sponsor will review all protocol deviations, and clarification has been added that prospective requests to deviate from the protocol are not allowed.
    21 Dec 2017
    Version 6: Clinical Data) has been updated with the most recent efficacy and safety results from Study GO29383. Aligned the protocol with the current atezolizumab Investigator’s Brochure, Version 10. A few exclusion criteria updated.
    01 May 2018
    Version 7: The study design and treatment schedule has been revised to reflect discontinuation of atezolizumab in patients still receiving study treatment. In addition, the post-induction (rituximab + atezolizumab consolidation) treatment phase has been removed from the treatment schedule (rituximab + atezolizumab + polatuzumab vedotin [R+Atezo+Pola] treatment group) of patients with RR DLBCL.
    07 Nov 2018
    Version 8: Lists of risks for atezolizumab-associated adverse events were revised to include nephritis. Regular Internal Monitoring Committee assessments stopped taking place as no new safety signals identified. Language was changed allowing patients still under treatment to enter the extension study. Medical Moniter information was updated. Survival follow-up period for assessment of new anti-lymphoma treatment re-added. PK sampling one year after last dose for polatuzumab vedotin was removed.

    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.
    A safety signal was observed during the study in two patients in the R/R FL cohort. As a result, enrollment was permanently discontinued and atezolizumab was discontinued for all patients still receiving study treatment.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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