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    Clinical Trial Results:
    A Phase Ib/II Study Evaluating the Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab plus Lenalidomide in Patients with Relapsed or Refractory Follicular Lymphoma.

    Summary
    EudraCT number
    2015-002467-42
    Trial protocol
    FR  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Oct 2019
    First version publication date
    31 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BO29562
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02631577
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124., Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    23 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Oct 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the safety, efficacy, pharmacokinetics (PK), and immunogenicity of induction treatment consisting of atezolizumab (Atezo) in combination with obinutuzumab (G) plus lenalidomide (Len; Atezo-G-Len) in subjects with relapsed or refractory follicular lymphoma (r/r FL), followed by maintenance treatment with Atezo-G-Len in subjects who achieved a complete response (CR), a partial response (PR), or stable disease at end of induction (EOI).
    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
    31 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    France: 24
    Worldwide total number of subjects
    38
    EEA total number of subjects
    24
    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)
    25
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All subjects received daily low-dose aspirin (81-100 mg) during lenalidomide treatment and until 28 days after the last dose of lenalidomide. Subjects who are unable to tolerate aspirin, who have a history of thromboembolism (TE), and who are at high risk of TE, received warfarin or low-molecular-weight heparin (LMWH).

    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
    Atezolizumab-G-lena 15mg
    Arm description
    Subjects were administered obinutuzumab, atezolizumab, and 15 mg of lenalidomide
    Arm type
    Experimental

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Gazyvaro
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered obinutzumab by IV infusion at an absolute (flat) dose of 1000 mg on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during induction treatment, and on Day 1 of every other month (i.e., every 2 months) during maintenance treatment.

    Investigational medicinal product name
    Lenalidomid
    Investigational medicinal product code
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered lenalidomide orally once daily on Days 1-21 of Cycles 1-6 (28-day cycles) during induction treatment and on Days 1-21 of each month during maintenance treatment. During the dose-escalation phase, lenalidomide was administered at a dose of 15 or 20 mg during induction treatment and at 10 mg during maintenance treatment. During the expansion phase, lenalidomide was administered at the recommended phase 2 dose (RP2D) during induction treatment and at 10 mg during maintenance treatment.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered at a flat dose of atezolizumab consisting of one of the following: a) 840 mg every 2 weeks (Q2W) (840 mg on Days 1 and 15 of Cycles 26, given in 28-day cycles as induction treatment) and b) 1680 mg every 4 weeks (Q4W) (840 mg on Days 1 and 2 of each month, given as maintenance treatment).

    Arm title
    Atezolizumab-G-lena 20mg
    Arm description
    Subjects were administered obinutuzumab, atezolizumab, and 20 mg of lenalidomide.
    Arm type
    Experimental

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Gazyvaro
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered obinutzumab by IV infusion at an absolute (flat) dose of 1000 mg on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during induction treatment, and on Day 1 of every other month (i.e., every 2 months) during maintenance treatment.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered at a flat dose of atezolizumab consisting of one of the following: a) 840 mg Q2W (840 mg on Days 1 and 15 of Cycles 26, given in 28-day cycles as induction treatment) and b) 1680 mg Q4W (840 mg on Days 1 and 2 of each month, given as maintenance treatment).

    Investigational medicinal product name
    Lenalidomid
    Investigational medicinal product code
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered lenalidomide orally once daily on Days 1-21 of Cycles 1-6 (28-day cycles) during induction treatment and on Days 1-21 of each month during maintenance treatment. During the dose-escalation phase, lenalidomide was administered at a dose of 15 or 20 mg during induction treatment and at 10 mg during maintenance treatment. During the expansion phase, lenalidomide was administered at the recommended phase 2 dose (RP2D) during induction treatment and at 10 mg during maintenance treatment.

    Number of subjects in period 1
    Atezolizumab-G-lena 15mg Atezolizumab-G-lena 20mg
    Started
    4
    34
    Completed
    3
    30
    Not completed
    1
    4
         Adverse event, serious fatal
    1
    3
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezolizumab-G-lena 15mg
    Reporting group description
    Subjects were administered obinutuzumab, atezolizumab, and 15 mg of lenalidomide

    Reporting group title
    Atezolizumab-G-lena 20mg
    Reporting group description
    Subjects were administered obinutuzumab, atezolizumab, and 20 mg of lenalidomide.

    Reporting group values
    Atezolizumab-G-lena 15mg Atezolizumab-G-lena 20mg Total
    Number of subjects
    4 34 38
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    3 22 25
        From 65-84 years
    1 12 13
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    56.5 ± 9.1 60.4 ± 9.7 -
    Sex: Female, Male
    Units: Subjects
        Female
    1 18 19
        Male
    3 16 19
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    1 0 1
        Not Hispanic or Latino
    3 13 16
        Not Stated
    0 21 21
    Race/Ethnicity, Customized
    Units: Subjects
        Unknown
    0 20 20
        White
    4 14 18

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab-G-lena 15mg
    Reporting group description
    Subjects were administered obinutuzumab, atezolizumab, and 15 mg of lenalidomide

    Reporting group title
    Atezolizumab-G-lena 20mg
    Reporting group description
    Subjects were administered obinutuzumab, atezolizumab, and 20 mg of lenalidomide.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population included all subjects enrolled in the study.

    Subject analysis set title
    Safety Evaluable Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Evaluable Population that included subjects who received at least one dose of any study treatment.

    Subject analysis set title
    Efficacy Evaluable Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The Efficacy Evaluable population that included subjects who received at least one dose of each component of the combination. Only subjects who received lenalidomide induction at the RP2D were included in this population.

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

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    End point title
    Percentage of Subjects Achieving Complete Response (CR) at End of Induction (EOI), as Determined by the Independent Review Committee (IRC) Using Modified Lugano 2014 Criteria [1]
    End point description
    Complete response (CR) was evaluated through use of PET-CT scans alone, using the Modified Lugano 2014 criteria. Response was determined by the IRC. The Efficacy Evaluable population included all subjects who received at least one dose of each of the three study drugs and who received lenalidomide induction at the 20 mg recommended Phase II dose (RP2D).
    End point type
    Primary
    End point timeframe
    6 months (up to clinical cut-off date (CCOD) of 23 October 2018)
    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: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    Efficacy Evaluable Population
    Number of subjects analysed
    32
    Units: Percentage
    number (confidence interval 90%)
        Positron emission-computed tomography (PET-CT)
    71.9 (56.06 to 84.47)
    No statistical analyses for this end point

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

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    End point title
    Percentage of Subjects Achieving CR at EOI, as Determined by the Investigator Using Modified Lugano 2014 Criteria
    End point description
    CR was evaluated through use of PET-CT scans, using the Modified Lugano 2014 criteria. Response was determined by the Investigator. The Efficacy Evaluable population included all subjects who received at least one dose of each of the three study drugs and who received lenalidomide induction at the 20 mg RP2D.
    End point type
    Secondary
    End point timeframe
    6 months (up to CCOD of 23 October 2018)
    End point values
    Efficacy Evaluable Population
    Number of subjects analysed
    32
    Units: Percentage
    number (confidence interval 90%)
        Based on PET-CT
    75 (59.39 to 86.91)
    No statistical analyses for this end point

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

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    End point title
    Percentage of Subjects Achieving CR at EOI, as Determined by the IRC and Investigator Using Lugano 2014 Criteria
    End point description
    CR was evaluated through use of CT scans, using the Lugano 2014 criteria. Response was determined by the IRC and by the Investigator. he Efficacy Evaluable population included all subjects who received at least one dose of each of the three study drugs and who received lenalidomide induction at the 20 mg RP2D.
    End point type
    Secondary
    End point timeframe
    6 months (up to CCOD of 23 October 2018)
    End point values
    Efficacy Evaluable Population
    Number of subjects analysed
    32
    Units: Percentage
    number (confidence interval 90%)
        Determined by the IRC with CT or MRI
    31.3 (18.04 to 47.21)
        Determined by Investigator with CT or MRI
    50 (34.41 to 65.59)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Objective Response (CR or PR) at EOI

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    End point title
    Percentage of Subjects With Objective Response (CR or PR) at EOI
    End point description
    Objective response was evaluated through use of PET-CT scans or CT scans alone, using the Lugano 2014 or modified Lugano 2014 criteria. Response was determined by the IRC and by the Investigator. he Efficacy Evaluable population included all subjects who received at least one dose of each of the three study drugs and who received lenalidomide induction at the 20 mg RP2D.
    End point type
    Secondary
    End point timeframe
    6 months (up to CCOD of 23 October 2018)
    End point values
    Efficacy Evaluable Population
    Number of subjects analysed
    32
    Units: Percentage
    number (confidence interval 90%)
        Determined by IRC, based on Lugano 2014 - PET
    81.3 (66.31 to 91.50)
        Determined by Inv., based on Lugano 2014 - PET
    84.4 (69.92 to 93.63)
        Determined by IRC, based on Lugano 2014 - CT
    81.3 (66.31 to 91.50)
        Determined by Inv., based on Lugano 2014 - CT
    87.5 (73.64 to 95.62)
        Determined by IRC, Modified Lugano 2014 – PET-CT
    78.1 (62.81 to 89.26)
        Determined by Inv, Modified Lugano 2014 – PET-CT
    84.4 (69.92 to 93.63)
    No statistical analyses for this end point

    Secondary: Number of subjects with dose-limiting toxicities (DLTs) during cycle 2 of study treatment

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    End point title
    Number of subjects with dose-limiting toxicities (DLTs) during cycle 2 of study treatment
    End point description
    Does limiting toxicity (DLT) is defined as any one of the following events occurring during Cycle 2 of treatment and assessed by the investigator as related to study treatment: - Adverse event of any grade that leads to a delay of more than 14 days at the start of the next treatment cycle; - Hematologic adverse events (neutropenia, thrombocytopenia); - Non-hematologic adverse event, except IRRs, diarrhea, nausea or vomiting. The Safety Evaluable Population included subjects who received at least one dose of any study treatment.
    End point type
    Secondary
    End point timeframe
    Day 1 - Day 28 of second cycle
    End point values
    Atezolizumab-G-lena 15mg Atezolizumab-G-lena 20mg
    Number of subjects analysed
    4
    34
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    6 months
    Adverse event reporting additional description
    The safety population included all subjects who received at least one treatment with study medication. The adverse event severity grading scale for the NCI CTCAE v4.0 was used.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Atezolizumab-G-lena 20mg
    Reporting group description
    Subjects were administered obinutuzumab, atezolizumab, and 20 mg of lenalidomide.

    Reporting group title
    Atezolizumab-G-lena 15mg
    Reporting group description
    Subjects were administered obinutuzumab, atezolizumab, and 15 mg of lenalidomide

    Serious adverse events
    Atezolizumab-G-lena 20mg Atezolizumab-G-lena 15mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 34 (29.41%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    3
    1
         number of deaths resulting from adverse events
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MENINGIOMA
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYELODYSPLASTIC SYNDROME
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR FLARE
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ADMINISTRATION SITE EXTRAVASATION
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    EAR INFECTION
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPIDIDYMITIS
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA PARAINFLUENZAE VIRAL
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Atezolizumab-G-lena 20mg Atezolizumab-G-lena 15mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 34 (100.00%)
    4 / 4 (100.00%)
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    HYPERTENSION
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    11 / 34 (32.35%)
    0 / 4 (0.00%)
         occurrences all number
    14
    0
    AXILLARY PAIN
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    2
    2
    FATIGUE
         subjects affected / exposed
    8 / 34 (23.53%)
    1 / 4 (25.00%)
         occurrences all number
    8
    1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    OEDEMA PERIPHERAL
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 4 (25.00%)
         occurrences all number
    7
    1
    PERIPHERAL SWELLING
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    XEROSIS
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    PYREXIA
         subjects affected / exposed
    5 / 34 (14.71%)
    3 / 4 (75.00%)
         occurrences all number
    6
    3
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 4 (25.00%)
         occurrences all number
    5
    1
    DEPRESSION
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    INFUSION RELATED REACTION
         subjects affected / exposed
    11 / 34 (32.35%)
    1 / 4 (25.00%)
         occurrences all number
    12
    2
    SKIN ABRASION
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    2
    2
    AMYLASE INCREASED
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    LIPASE INCREASED
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 4 (25.00%)
         occurrences all number
    4
    2
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    TACHYCARDIA
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    4 / 34 (11.76%)
    2 / 4 (50.00%)
         occurrences all number
    4
    4
    DYSPNOEA
         subjects affected / exposed
    5 / 34 (14.71%)
    1 / 4 (25.00%)
         occurrences all number
    5
    1
    EPISTAXIS
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    NASAL CONGESTION
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    PNEUMONITIS
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    RHINORRHOEA
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    PRODUCTIVE COUGH
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    SINUS CONGESTION
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    6 / 34 (17.65%)
    1 / 4 (25.00%)
         occurrences all number
    6
    1
    LEUKOPENIA
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    NEUTROPENIA
         subjects affected / exposed
    11 / 34 (32.35%)
    3 / 4 (75.00%)
         occurrences all number
    30
    4
    THROMBOCYTOPENIA
         subjects affected / exposed
    9 / 34 (26.47%)
    1 / 4 (25.00%)
         occurrences all number
    14
    1
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    PARAESTHESIA
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    POST HERPETIC NEURALGIA
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    TREMOR
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    LACRIMATION INCREASED
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    ABDOMINAL PAIN
         subjects affected / exposed
    6 / 34 (17.65%)
    1 / 4 (25.00%)
         occurrences all number
    7
    2
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    3
    CONSTIPATION
         subjects affected / exposed
    10 / 34 (29.41%)
    3 / 4 (75.00%)
         occurrences all number
    10
    5
    DIARRHOEA
         subjects affected / exposed
    13 / 34 (38.24%)
    3 / 4 (75.00%)
         occurrences all number
    29
    9
    DYSPEPSIA
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    DYSPHAGIA
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    NAUSEA
         subjects affected / exposed
    4 / 34 (11.76%)
    4 / 4 (100.00%)
         occurrences all number
    4
    4
    HAEMATOCHEZIA
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    STOMATITIS
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    VOMITING
         subjects affected / exposed
    1 / 34 (2.94%)
    4 / 4 (100.00%)
         occurrences all number
    2
    8
    Renal and urinary disorders
    HYDRONEPHROSIS
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    URINARY RETENTION
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    HEPATOCELLULAR INJURY
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    ERYTHEMA
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    NIGHT SWEATS
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    PRURITUS
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 4 (50.00%)
         occurrences all number
    4
    2
    RASH
         subjects affected / exposed
    5 / 34 (14.71%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    ARTHRALGIA
         subjects affected / exposed
    5 / 34 (14.71%)
    2 / 4 (50.00%)
         occurrences all number
    7
    2
    BONE PAIN
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    GROIN PAIN
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    FLANK PAIN
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    MUSCLE SPASMS
         subjects affected / exposed
    7 / 34 (20.59%)
    0 / 4 (0.00%)
         occurrences all number
    11
    0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    MYALGIA
         subjects affected / exposed
    5 / 34 (14.71%)
    0 / 4 (0.00%)
         occurrences all number
    8
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    7 / 34 (20.59%)
    1 / 4 (25.00%)
         occurrences all number
    9
    1
    HYPOTHYROIDISM
         subjects affected / exposed
    6 / 34 (17.65%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    FLUID OVERLOAD
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    3
    HYPOKALAEMIA
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    Infections and infestations
    BRONCHIOLITIS
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    BRONCHITIS
         subjects affected / exposed
    4 / 34 (11.76%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    CONJUNCTIVITIS
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    FUNGAL SKIN INFECTION
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    GASTROENTERITIS
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    HERPES ZOSTER
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    INFLUENZA
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    LUNG INFECTION
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    4 / 34 (11.76%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    RHINITIS
         subjects affected / exposed
    4 / 34 (11.76%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    PHARYNGITIS
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    SINUSITIS
         subjects affected / exposed
    2 / 34 (5.88%)
    4 / 4 (100.00%)
         occurrences all number
    6
    5
    TINEA INFECTION
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2016
    The protocol was amended in response to a health authority request. The exclusion criterion related to history of prior malignancy other than lymphoma was updated, second primary malignancies were included as events immediately reportable to the Sponsor, and the Schedule of Assessments was updated to include urinalysis and a complete physical examination on Cycle 1 Day 1.
    20 Sep 2016
    Obinutuzumab exposure data was updated to reflect the latest information from clinical studies. It was clarified that atezolizumab could be given on Day 15 of induction Cycles 2 to 6 regardless of cytopenia. Based on the latest atezolizumab Investigator’s Brochure (IB; version 9), the summary of clinical safety, summary of clinical activity, the use of live vaccines after discontinuation of atezolizumab, management guidelines for non-hematologic AEs, and the list of AESIs were updated. In addition, the classification of diabetes mellitus and pancreatitis changed from ‘important potential risks’ to ‘important identified risks’.
    05 May 2017
    The classification of second malignancies was changed from a selected AE to AESI to more closely monitor this AE. In addition, conditions for resuming study treatment in case of Grade >=3 laboratory abnormalities were clarified, and the list of AESIs for atezolizumab were updated to align with the latest Atezolizumab IB (version 9).
    04 Dec 2017
    On 3 July 2017, two clinical trials, KEYNOTE-183 and KEYNOTE-185, evaluating pembrolizumab (PD-1 inhibitor) in combination with an immunomodulatory agent (pomalidomide or lenalidomide) for the treatment of multiple myeloma were placed on clinical hold by the U.S. Food and Drug Administration (FDA). The clinical hold was issued because interim results demonstrated a worse overall survival in the investigational pembrolizumab arm compared to the control arm. Based on these emerging data, on 1 September 2017 the FDA also requested that other studies of PD-1/PDL-1 inhibitors and immunomodulatory agents, including study BO29562 should be placed on partial clinical hold. Although study BO29562 is conducted in a different hematologic malignancy (i.e., relapsed or refractory follicular lymphoma) and a similar safety signal has not been seen to date, the Sponsor revised the protocol to maximize patient safety. FDA removed the partial clinical hold as of 21 November 2017. Changes to the protocol, along with a rationale for each change: 1) Available Clinical Data was updated with the most recent efficacy and safety data. Stopping rules for excess toxicity and the roles of the IMC were updated, and the frequency of interim safety and efficacy analyses were amended to occur every 4 months; 2) Risks associated with obinutuzumab were updated to reflect recent updates to the obinutuzumab IB (version 12); 3) Risks associated with atezolizumab and management guidelines for atezolizumab-associated AEs were updated according to updates to the atezolizumab IB (version 10).
    07 Nov 2018
    Protocol was amended to include new safety information: 1) Lists of risks for atezolizumab and guidelines for managing patients who experience atezolizumab-associated adverse events were revised to include nephritis; 2) Considering no new safety signals have been identified with atezolizumab in combination with obinutuzumab plus lenalidomide, once all patients have completed/discontinued maintenance, regular Internal Monitoring Committee assessments would no longer take place and ad hoc meetings maybe called at the discretion of the Medical Monitor in case of newly identified safety signals; 3) Post-trial access language was changed allowing patients still under study treatment to enter an extension study in case of earlier closure of Study BO29562; 4) The Medical Monitor information was updated; 5) The Lenalidomide Summary of Product Characteristics has replaced local labels as the reference document for determining reporting requirements for single adverse events

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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