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    Clinical Trial Results:
    A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Idelalisib in Combination with Obinutuzumab Compared to Chlorambucil in Combination with Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukemia

    Summary
    EudraCT number
    		 2013-004551-20
    Trial protocol
    		 GB   PT   HU   ES   BE   BG   HR   IT  
    Global end of trial date
    13 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Apr 2017
    First version publication date
    15 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-312-0118
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01980875
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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
    13 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effects of idelalisib with obinutuzumab versus the combination of chlorambucil and obinutuzumab on progression-free survival (PFS) in participants with previously untreated chronic lymphocytic leukemia (CLL).
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Apr 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
    Poland: 28
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Australia: 4
    Worldwide total number of subjects
    57
    EEA total number of subjects
    39
    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)
    12
    From 65 to 84 years
    40
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Australia, Europe, and North America. The first participant was screened on 05 May 2015. The last study visit occurred on 13 May 2016.

    Pre-assignment
    Screening details
    		 80 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Safety Run-In: Idelalisib +Obinutuzumab
    Arm description
    		 Participants received idelalisib for up to 96 weeks and obinutuzumab over 21 weeks. Following 4 weeks of treatment, safety data was reviewed by an independent data monitoring committee (DMC). If acceptable tolerability was observed, the randomized portion of the study would begin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idelalisib
    Investigational medicinal product code
    Other name
    Zydelig®, GS-1101, CAL-101
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg tablet administered orally twice daily

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Gazyvaro, Gazyva
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg for a total of 8 doses

    Arm title
    		 Randomized: Idelalisib +Obinutuzumab
    Arm description
    		 Participants received idelalisib for up to 96 weeks and obinutuzumab over 21 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idelalisib
    Investigational medicinal product code
    Other name
    Zydelig®, GS-1101, CAL-101
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg tablet administered orally twice daily

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Gazyvaro, Gazyva
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg for a total of 8 doses

    Arm title
    		 Randomized: Obinutuzumab +Chlorambucil
    Arm description
    		 Participants received obinutuzumab over 21 weeks and chlorambucil over 23 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Gazyvaro, Gazyva
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg for a total of 8 doses

    Investigational medicinal product name
    Chlorambucil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg tablets administered at a dose of 0.5 mg/kg every other week for a total of 12 doses

    Number of subjects in period 1
    		Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Started
    8
    25
    24
    Completed
    0
    0
    0
    Not completed
    8
    25
    24
         Withdrew Consent
    1
    1
    1
         Study Terminated by Sponsor
    7
    24
    22
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety Run-In: Idelalisib +Obinutuzumab
    Reporting group description
    		 Participants received idelalisib for up to 96 weeks and obinutuzumab over 21 weeks. Following 4 weeks of treatment, safety data was reviewed by an independent data monitoring committee (DMC). If acceptable tolerability was observed, the randomized portion of the study would begin.

    Reporting group title
    Randomized: Idelalisib +Obinutuzumab
    Reporting group description
    		 Participants received idelalisib for up to 96 weeks and obinutuzumab over 21 weeks

    Reporting group title
    Randomized: Obinutuzumab +Chlorambucil
    Reporting group description
    		 Participants received obinutuzumab over 21 weeks and chlorambucil over 23 weeks.

    Reporting group values
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil Total
    Number of subjects
    		 8 25 24 57
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.1 ( 8.1 ) 72.2 ( 8.23 ) 71.1 ( 6.84 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 8 9 20
        Male
    		 5 17 15 37
    Race
    Units: Subjects
        Black or African American
    		 1 0 0 1
        White
    		 7 22 21 50
        Other
    		 0 1 0 1
        Not Permitted
    		 0 2 3 5
    Rai Stage
    Rai staging is a way to categorize the disease progression of chronic lymphocytic leukemia (CLL) with higher stages reflecting increasing severity. Rai Stage 0: Lymphocytosis only, Rai Stage I: Lymphocytosis with lymphadenopathy, Rai Stage II: Lymphocytosis with hepatomegaly or splenomegaly, Rai Stage III: Lymphocytosis with anemia, Rai Stage IV: Lymphocytosis with thrombocytopenia.
    Units: Subjects
        Stage I-II
    		 3 11 9 23
        Stage III-IV
    		 5 14 15 34
    IgHV Mutation
    The mutation status of the unique immunoglobulin gene (IgHV) rearrangement in the monoclonal proliferation of B-cells in CLL can be used to predict aggressiveness of the disease. Participants with a mutated IgHV gene usually have a less aggressive and more indolent disease, with longer overall survival. Participants with an unmutated IgHV gene usually have a more aggressive disease and shorter overall survival.
    Units: Subjects
        Unmutated
    		 5 16 17 38
        Mutated
    		 3 9 7 19
    17p Deletion in CLL Cells
    Participants with CLL who have deletion of 17p, a portion of the chromosome that acts to suppress cancer growth and is a recognized negative prognostic risk factor.
    Units: Subjects
        Present
    		 0 3 3 6
        Absent
    		 8 22 21 51

    End points

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    End points reporting groups
    Reporting group title
    Safety Run-In: Idelalisib +Obinutuzumab
    Reporting group description
    		 Participants received idelalisib for up to 96 weeks and obinutuzumab over 21 weeks. Following 4 weeks of treatment, safety data was reviewed by an independent data monitoring committee (DMC). If acceptable tolerability was observed, the randomized portion of the study would begin.

    Reporting group title
    Randomized: Idelalisib +Obinutuzumab
    Reporting group description
    		 Participants received idelalisib for up to 96 weeks and obinutuzumab over 21 weeks

    Reporting group title
    Randomized: Obinutuzumab +Chlorambucil
    Reporting group description
    		 Participants received obinutuzumab over 21 weeks and chlorambucil over 23 weeks.

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival [1]
    End point description
    Progression-free survival (PFS) is defined as the interval from randomization to the first documentation of definitive disease progression or death from any cause. Definitive disease progression is CLL progression based on standard criteria, excluding lymphocytosis alone. PFS was to be assessed by an independent review committee (IRC). Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Primary
    End point timeframe
    Not applicable
    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: Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point values
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: Not applicable
    Notes
    [2] - Analysis was not performed due to early study termination.
    [3] - Analysis was not performed due to early study termination.
    [4] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Overall response rate (ORR) is defined as the proportion of participants who achieve a confirmed complete or partial response. ORR was to be assessed by an IRC. Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: Not applicable
    Notes
    [5] - Analysis was not performed due to early study termination.
    [6] - Analysis was not performed due to early study termination.
    [7] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Nodal Response Rate

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    End point title
    		 Nodal Response Rate
    End point description
    Nodal response rate is defined as the proportion of participants who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Nodal response rate was to be assessed by an IRC. Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Not applicable
    Notes
    [8] - Analysis was not performed due to early study termination.
    [9] - Analysis was not performed due to early study termination.
    [10] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Complete Response Rate

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    End point title
    		 Complete Response Rate
    End point description
    Complete response rate is defined as the proportion of participants who achieve a confirmed complete response. Complete response rate was to be assessed by an IRC. Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: Not applicable
    Notes
    [11] - Analysis was not performed due to early study termination.
    [12] - Analysis was not performed due to early study termination.
    [13] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival is defined as the interval from randomization to death from any cause. Due to the early termination of the study, efficacy data were not mature for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    Units: Not applicable
    Notes
    [14] - Analysis was not performed due to early study termination.
    [15] - Analysis was not performed due to early study termination.
    [16] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Minimal Residual Disease Negativity Rate at Week 36

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    End point title
    		 Minimal Residual Disease Negativity Rate at Week 36
    End point description
    Minimal residual disease (MRD) negativity rate is defined as the proportion of participants with MRD < 10^-4 assessed by flow cytometry in bone marrow at Week 36 after therapy initiation. For participants receiving the final dose of obinutuzumab after the original scheduled date, the MRD assessment was performed no less than 12 weeks after the last dose of obinutuzumab. MRD negativity rate was to be assessed by an IRC. Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    Units: Not applicable
    Notes
    [17] - Analysis was not performed due to early study termination.
    [18] - Analysis was not performed due to early study termination.
    [19] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to the last dose date plus 30 days (maximum: 12 months)
    Adverse event reporting additional description
    Safety Analysis Set: participants who received at least 1 dose of study drug, with treatment group designated according to actual treatment received. NOTE: Serious adverse events and deaths causally related to “treatment” refers to events deemed related to idelalisib treatment per investigator assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Safety Run-In: Idelalisib +Obinutuzumab
    Reporting group description
    		 Participants received idelalisib for 96 weeks and obinutuzumab over 21 weeks. Following 4 weeks of treatment, safety data was reviewed by an independent data monitoring committee (DMC). If acceptable tolerability was observed, the randomized portion of the study would begin.

    Reporting group title
    Randomized: Idelalisib +Obinutuzumab
    Reporting group description
    		 Participants received idelalisib for 96 weeks and obinutuzumab over 21 weeks

    Reporting group title
    Randomized: Obinutuzumab +Chlorambucil
    Reporting group description
    		 Participants received obinutuzumab over 21 weeks and chlorambucil over 23 weeks.

    Serious adverse events
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    12 / 24 (50.00%)
    8 / 23 (34.78%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Richter's syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Leukoencephalopathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Secondary immunodeficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Acute respiratory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Pneumonitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 24 (8.33%)
    0 / 23 (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
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Bronchitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Lung infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (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
    Metabolism and nutrition disorders
    Tumour lysis syndromerome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Run-In: Idelalisib +Obinutuzumab Randomized: Idelalisib +Obinutuzumab Randomized: Obinutuzumab +Chlorambucil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    19 / 24 (79.17%)
    17 / 23 (73.91%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    1
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         occurrences all number
    1
    2
    0
    Face oedema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 24 (12.50%)
    2 / 23 (8.70%)
         occurrences all number
    1
    3
    2
    Influenza like illness
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 24 (12.50%)
    1 / 23 (4.35%)
         occurrences all number
    1
    3
    1
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 24 (4.17%)
    4 / 23 (17.39%)
         occurrences all number
    1
    2
    4
    Reproductive system and breast disorders
    Penile pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    1
    0
    1
    Insomnia
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         occurrences all number
    3
    2
    0
    Restlessness
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 8 (87.50%)
    5 / 24 (20.83%)
    1 / 23 (4.35%)
         occurrences all number
    8
    6
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 8 (87.50%)
    5 / 24 (20.83%)
    1 / 23 (4.35%)
         occurrences all number
    7
    6
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         occurrences all number
    0
    2
    0
    Heart rate increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 24 (12.50%)
    14 / 23 (60.87%)
         occurrences all number
    2
    3
    14
    Muscle strain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Cerebellar syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    0
    Circadian rhythm sleep disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Dementia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         occurrences all number
    1
    2
    0
    Dizziness postural
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 24 (8.33%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2
    3
    Psychomotor skills impaired
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Tremor
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    6 / 24 (25.00%)
    2 / 23 (8.70%)
         occurrences all number
    2
    6
    2
    Neutropenia
         subjects affected / exposed
    4 / 8 (50.00%)
    6 / 24 (25.00%)
    9 / 23 (39.13%)
         occurrences all number
    8
    10
    11
    Thrombocytopenia
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
         occurrences all number
    3
    3
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Eye swelling
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 24 (4.17%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    1
    Autoimmune colitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
         occurrences all number
    2
    2
    1
    Diarrhoea
         subjects affected / exposed
    4 / 8 (50.00%)
    4 / 24 (16.67%)
    1 / 23 (4.35%)
         occurrences all number
    4
    4
    1
    Flatulence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    0
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 24 (8.33%)
    4 / 23 (17.39%)
         occurrences all number
    3
    2
    4
    Stomatitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Night sweats
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    0
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Rash macular
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    Urinary retention
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         occurrences all number
    1
    2
    0
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    1
    Neck pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    1
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 24 (8.33%)
    2 / 23 (8.70%)
         occurrences all number
    3
    2
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    2
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 24 (12.50%)
    0 / 23 (0.00%)
         occurrences all number
    0
    4
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         occurrences all number
    1
    2
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Tetany
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 24 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Nov 2014
    – Updated the study design and background therapy in order to better align with current clinical trial results in frontline CLL. These recent results suggest new standards of care for patients not suitable for intensive chemoimmunotherapy. The design has been amended to an open-label study comparing idelalisib + obinutuzumab vs chlorambucil + obinutuzumab. – Clarified and edited the procedures section as applicable to the new therapies used in this study and to align all procedures to the schedule of assessments in the appendix. – Allowed for approximately 130 additional subjects to be enrolled to support design and statistical assumption changes.
    06 Mar 2015
    – Updated contraception requirements and guidance for management of tumor lysis syndrome.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Mar 2016
    An increased rate of deaths and serious adverse events (SAEs) among participants with front-line CLL and early-line iNHL treated with idelalisib in combination with standard therapies was observed by the independent data monitoring committee (DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data and terminated those studies in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA). All front-line studies of idelalisib, including this study, were also terminated.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    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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