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    Clinical Trial Results:
    Dose Optimization Study of Idelalisib in Follicular Lymphoma

    Summary
    EudraCT number
    		 2015-000366-66
    Trial protocol
    		 GB   CZ   PL   ES   FR   IT  
    Global end of trial date
    27 Sep 2022

    Results information
    Results version number
    		 v1
    This version publication date
    16 Jul 2023
    First version publication date
    16 Jul 2023
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-313-1580
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02536300
    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
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@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
    27 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to establish a safe and effective dosing regimen of idelalisib in participants with relapsed or refractory follicular lymphoma (FL) who have no other therapeutic options.
    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
    14 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 15
    Worldwide total number of subjects
    96
    EEA total number of subjects
    74
    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)
    45
    From 65 to 84 years
    48
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Australia, Canada, Europe, Israel, and the United Kingdom.

    Pre-assignment
    Screening details
    		 145 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
    Blinding implementation details
    Double-blind: Prior to protocol amendment 5; Open-label: Participants enrolled as of protocol amendment 5

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Idelalisib 150 mg BID
    Arm description
    		 Participants received idelalisib 150 mg tablets, orally, twice daily (BID), continuously for up to maximum 33.5 months.
    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
    Administered 150 mg, BID, continuously.

    Arm title
    		 Idelalisib 100 mg BID
    Arm description
    		 Participants received idelalisib 100 mg tablets, orally, BID, continuously for up to maximum 63.6 months.
    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
    Administered 100 mg, BID, continuously.

    Arm title
    		 Idelalisib 150 mg BID INT
    Arm description
    		 Participants received idelalisib 150 mg tablets, orally, BID for 21 days and 7 days off-treatment (intermittent [INT] dosing schedule) in each 28-day cycle for up to maximum of 24.6 months.
    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
    Administered 150 mg, BID for 21 days and 7 days off-treatment (INT dosing schedule) in each 28-day cycle.

    Number of subjects in period 1
    		Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Started
    47
    27
    22
    Completed
    0
    0
    0
    Not completed
    47
    27
    22
         Consent withdrawn by subject
    4
    2
    -
         Protocol violation
    -
    1
    -
         Non-compliance With Study Drug
    1
    -
    -
         Death
    7
    -
    5
         Investigator's Discretion
    17
    11
    2
         Progressive Disease
    11
    7
    6
         Study Terminated by Sponsor
    6
    4
    7
         Non-study Specific Anti-cancer Therapy Initiation
    1
    2
    1
         Enrolled but Never Treated
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Idelalisib 150 mg BID
    Reporting group description
    		 Participants received idelalisib 150 mg tablets, orally, twice daily (BID), continuously for up to maximum 33.5 months.

    Reporting group title
    Idelalisib 100 mg BID
    Reporting group description
    		 Participants received idelalisib 100 mg tablets, orally, BID, continuously for up to maximum 63.6 months.

    Reporting group title
    Idelalisib 150 mg BID INT
    Reporting group description
    		 Participants received idelalisib 150 mg tablets, orally, BID for 21 days and 7 days off-treatment (intermittent [INT] dosing schedule) in each 28-day cycle for up to maximum of 24.6 months.

    Reporting group values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT Total
    Number of subjects
    		 47 27 22
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65 ( 13.0 ) 62 ( 13.6 ) 63 ( 11.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 23 13 9 45
        Male
    		 24 14 13 51
    Race
    Units: Subjects
        White
    		 42 25 19 86
        Asian
    		 1 0 0 1
        Black or African American
    		 0 0 1 1
        Unknown or Not Reported
    		 4 1 2 7
        Other or More Than One Race
    		 0 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 2 3
        Not Hispanic or Latino
    		 42 26 18 86
        Unknown or Not Reported
    		 4 1 2 7

    End points

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    End points reporting groups
    Reporting group title
    Idelalisib 150 mg BID
    Reporting group description
    		 Participants received idelalisib 150 mg tablets, orally, twice daily (BID), continuously for up to maximum 33.5 months.

    Reporting group title
    Idelalisib 100 mg BID
    Reporting group description
    		 Participants received idelalisib 100 mg tablets, orally, BID, continuously for up to maximum 63.6 months.

    Reporting group title
    Idelalisib 150 mg BID INT
    Reporting group description
    		 Participants received idelalisib 150 mg tablets, orally, BID for 21 days and 7 days off-treatment (intermittent [INT] dosing schedule) in each 28-day cycle for up to maximum of 24.6 months.

    Primary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR) [1]
    End point description
    ORR=percentage of participants who achieve a partial response (PR)/ complete response (CR).PR criteria: No evidence of new disease,a ≥50% decrease from baseline in sum of products of diameters (SPD) of index lesions,no increase in non-index disease, liver/spleen size and no new liver/spleen enlargement.Persistence of bone marrow involvement in participant who meets other CR criteria based on disappearance of all nodal,extra-nodal masses.CR criteria:No evidence of new disease,regression of all index nodal lesions to normal size (≤1.5 cm in longest dimension (LD) for large nodes and ≤1.0 cm in LD,≤1.0 cm in longest perpendicular dimension (LPD) for small nodes),regression to normal of all nodal non-index disease,disappearance of all detectable extra-nodal index,non-index disease,normal spleen, liver size,no new liver/spleen enlargement,morphologically -ve bone marrow. Intent-to-Treat (ITT) analysis set=all participants who were randomized regardless of whether they received any drug.
    End point type
    Primary
    End point timeframe
    Randomization up to end of treatment (maximum duration: 73.5 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: No statistical comparison was planned or performed.
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    47
    27
    22
    Units: percentage of participants
        number (confidence interval 95%)
    38.3 (24.5 to 53.6)
    44.4 (25.5 to 64.7)
    40.9 (20.7 to 63.6)
    No statistical analyses for this end point

    Primary: Number of Participants With Grade 4 or Higher Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants With Grade 4 or Higher Treatment-Emergent Adverse Events (TEAEs) [2]
    End point description
    TEAEs were defined as 1 or both of any AEs leading to premature discontinuation of study drug, or any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. TEAEs severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants were counted at the highest AE grade experienced. Safety analysis set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    First dose date up to 30 days after last dose of study drug (maximum 64.6 months)
    Notes
    [2] - 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: No statistical comparison was planned or performed.
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    47
    27
    21
    Units: participants
    15
    12
    8
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR: interval from first documentation of CR/PR to earlier of first documentation of disease progression (PD) by independent review committee (IRC)/death from any cause. PR and CR criteria: Please refer the description of endpoint#2 (ORR). PD: New node of >1.5 cm or >1.0 to ≤1.5 cm in LD, >1.0 cm in LPD, new/unequivocal reappearance of resolved extra-nodal lesion, new non-index disease, increase by 50% in SPD of index lesions, LD of individual node/extra-nodal mass. Participants in the ITT analysis set who achieved CR or PR were analysed. 9999=The upper limit of 95% confidence interval (CI) was not estimable as the values were not reached.
    End point type
    Secondary
    End point timeframe
    From first documentation of CR or PR until PD or death from any cause (maximum duration: 73.5 months)
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    18
    12
    9
    Units: months
        median (confidence interval 95%)
    27.1 (7.7 to 9999)
    18.0 (2.7 to 9999)
    5.7 (0.3 to 9999)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) by Week 24

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    End point title
    		 Overall Response Rate (ORR) by Week 24
    End point description
    ORR by Week 24 is defined as the percentage of participants who achieve a PR or CR by Week 24. PR criteria: No evidence of new disease, a 50% decrease from baseline in SPD of index lesions, no increase in non-index disease, no increase in liver/spleen size and no new liver/spleen enlargement. CR criteria: No evidence of new disease, regression of all index nodal lesions to normal size (≤1.5 cm in LD for large nodes and ≤1.0 cm in LD, ≤1.0 cm in LPD for small nodes), regression to normal of all nodal non-index disease, disappearance of all detectable extra-nodal index and non-index disease, normal spleen and liver size, no new liver/spleen enlargement, morphologically negative bone marrow. Participants in the ITT analysis set were analysed.
    End point type
    Secondary
    End point timeframe
    First dose date up to Week 24
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    47
    27
    22
    Units: percentage of participants
        number (confidence interval 95%)
    36.2 (22.7 to 51.5)
    33.3 (16.5 to 54.0)
    27.3 (10.7 to 50.2)
    No statistical analyses for this end point

    Secondary: Number of Participants With any TEAE, Grade 3 or Higher TEAEs, Serious TEAEs, Idelalisib-related TEAEs, TEAEs Leading to Interruption or Discontinuation of Idelalisib

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    End point title
    		 Number of Participants With any TEAE, Grade 3 or Higher TEAEs, Serious TEAEs, Idelalisib-related TEAEs, TEAEs Leading to Interruption or Discontinuation of Idelalisib
    End point description
    TEAEs were defined as 1 or both of any AEs leading to premature discontinuation of study drug, or any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. TEAEs severity was graded according to the NCI CTCAE version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants are counted at the highest AE grade experienced. Participants in the safety analysis set were analysed.
    End point type
    Secondary
    End point timeframe
    First dose date up to 30 days after last dose of study drug (maximum 64.6 months)
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    47
    27
    21
    Units: participants
        Any TEAE
    45
    26
    19
        Grade 3 or Higher TEAEs
    41
    25
    12
        Serious TEAEs
    31
    19
    11
        Idelalisib-related TEAEs
    38
    25
    11
        TEAEs Leading to Interruption of Idelalisib
    32
    18
    6
        TEAEs Leading to Discontinuation of Idelalisib
    28
    13
    4
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Treatment-Emergent Laboratory Abnormalities

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    End point title
    		 Number of Participants With Clinically Significant Treatment-Emergent Laboratory Abnormalities
    End point description
    Treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from baseline at any time postbaseline up to and including the date of last study drug dose plus 30 days. Laboratory abnormalities included hematology and serum chemistry parameters. Clinically significant laboratory abnormalities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for severity as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (life threatening). The number of participants with any post-baseline abnormal laboratory value in Grade 1-4 categories are reported. Participants in the safety analysis set with available data were analysed.
    End point type
    Secondary
    End point timeframe
    First dose date up to 30 days after last dose of study drug (maximum 64.6 months)
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    47
    27
    20
    Units: participants
        Hematology: Grade 1
    7
    5
    2
        Hematology: Grade 2
    12
    7
    5
        Hematology: Grade 3
    15
    11
    5
        Hematology: Grade 4
    6
    3
    2
        Serum Chemistry: Grade 1 N=47,27,19
    9
    5
    8
        Serum Chemistry: Grade 2 N=47,27,19
    17
    8
    4
        Serum Chemistry: Grade 3 N=47,27,19
    10
    11
    6
        Serum Chemistry: Grade 4 N=47,27,19
    7
    3
    1
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is defined as the interval (in months) from randomization to the earlier of the first documentation of PD by IRC or death from any cause. PD criteria: New node of >1.5 cm or >1.0 cm to ≤1.5 cm in LD, >1.0 cm in LPD, new/unequivocal reappearance of resolved extra-nodal lesion, new non-index disease, increase by 50% in SPD of index lesions, LD of individual node/extra-nodal mass. Participants in the ITT analysis set were analysed.
    End point type
    Secondary
    End point timeframe
    Randomization up to PD or death from any cause (maximum duration: 73.5 months)
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    47
    27
    22
    Units: months
        median (confidence interval 95%)
    9.8 (5.5 to 28.7)
    19.4 (13.9 to 23.3)
    8.3 (2.9 to 8.7)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the interval (in months) from randomization to death from any cause. Participants in the ITT analysis set were analysed. 9999=The upper limit of 95% CI was not estimable as the values were not reached. 99999=Median and upper limit of 95% CI were not estimable as the values were not reached.
    End point type
    Secondary
    End point timeframe
    Randomization up to death from any cause (maximum duration: 73.5 months)
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    47
    27
    22
    Units: months
        median (confidence interval 95%)
    28.7 (14.0 to 9999)
    99999 (23.3 to 99999)
    99999 (13.9 to 99999)
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentration of Idelalisib

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    End point title
    		 Trough Plasma Concentration of Idelalisib
    End point description
    Pharmacokinetic (PK) analysis set included participants who received at least 1 dose of study drug and had at least 1 sample with detectable drug concentration. Participants in the PK analysis set with available data were analysed. 9999=Mean and Standard Deviation (SD) were not available as the values were below the level of quantitation.
    End point type
    Secondary
    End point timeframe
    Predose on Day (D) 1, Weeks (Wk) 2, 4, 6, 8, 10, 12, 16, 20, 24, 32, and 48
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    44
    27
    21
    Units: nanograms per millilitre (ng/ml)
    arithmetic mean (standard deviation)
        D 1 N=43,27,21
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Wk 2 N=44,25,17
    683.68 ( 514.166 )
    382.94 ( 352.842 )
    636.35 ( 461.042 )
        Wk 4 N=38,23,18
    623.64 ( 466.557 )
    447.78 ( 356.971 )
    94.14 ( 231.647 )
        Wk 6 N=34,23,15
    581.20 ( 470.988 )
    361.90 ( 248.996 )
    596.80 ( 401.619 )
        Wk 8 N=32,21,14
    655.16 ( 498.873 )
    430.33 ( 477.877 )
    77.66 ( 274.313 )
        Wk 10 N=25,22,15
    616.05 ( 370.862 )
    356.12 ( 372.557 )
    387.40 ( 314.249 )
        Wk 12 N=27,21,16
    630.56 ( 664.066 )
    389.21 ( 466.104 )
    272.44 ( 626.451 )
        Wk 16 N=26,20,15
    729.23 ( 832.158 )
    730.29 ( 936.798 )
    111.67 ( 296.666 )
        Wk 20 N=22,19,14
    525.91 ( 411.330 )
    745.58 ( 841.105 )
    107.34 ( 269.434 )
        Wk 24 N=19,17,12
    460.74 ( 321.766 )
    728.76 ( 760.391 )
    9999 ( 9999 )
        Wk 32 N=16,11,11
    446.13 ( 450.821 )
    388.58 ( 351.293 )
    352.73 ( 875.923 )
        Wk 48 N=8,8,5
    706.13 ( 580.022 )
    552.13 ( 571.081 )
    165.00 ( 368.951 )
    No statistical analyses for this end point

    Secondary: Peak Plasma Concentration of Idelalisib

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    End point title
    		 Peak Plasma Concentration of Idelalisib
    End point description
    Participants in the PK analysis set with available data were analysed.
    End point type
    Secondary
    End point timeframe
    1.5 hours postdose on Day (D) 1, Weeks (Wk) 2, 4, 6, 8, 10, 12, 16, 20, 24, 32, and 48
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    43
    27
    20
    Units: ng/ml
    arithmetic mean (standard deviation)
        D 1
    2626.12 ( 1330.290 )
    1575.81 ( 803.317 )
    2221.35 ( 1621.291 )
        Wk 2 N=42,24,18
    2306.12 ( 810.433 )
    1520.29 ( 675.089 )
    2186.89 ( 1265.850 )
        Wk 4 N=39,23,17
    2353.95 ( 930.754 )
    1528.48 ( 759.936 )
    2608.12 ( 1009.937 )
        Wk 6 N=30,21,15
    2433.33 ( 1092.969 )
    1682.52 ( 939.455 )
    2341.33 ( 948.133 )
        Wk 8 N=29,20,14
    2207.59 ( 980.606 )
    1649.25 ( 940.683 )
    2786.43 ( 1591.408 )
        Wk 10 N=24,19,15
    2435.00 ( 1027.469 )
    1601.11 ( 804.605 )
    2380.00 ( 1118.679 )
        Wk 12 N=24,19,15
    2328.13 ( 1141.764 )
    1658.89 ( 837.159 )
    2316.20 ( 1391.815 )
        Wk 16 N=23,20,12
    2634.39 ( 1323.611 )
    1756.37 ( 826.784 )
    2372.50 ( 1335.420 )
        Wk 20 N=19,17,13
    2354.26 ( 1440.587 )
    1925.29 ( 776.516 )
    2177.69 ( 1417.505 )
        Wk 24 N=15,17,10
    2058.47 ( 905.071 )
    1914.65 ( 1151.998 )
    1906.30 ( 1099.458 )
        Wk 32 N=14,10,10
    2009.71 ( 1231.296 )
    2028.00 ( 593.236 )
    1825.00 ( 947.892 )
        Wk 48 N=8,9,5
    2655.13 ( 1348.957 )
    1448.33 ( 650.798 )
    1312.00 ( 850.894 )
    No statistical analyses for this end point

    Secondary: Time to Onset of Adverse Events of Interest (AEIs)

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    End point title
    		 Time to Onset of Adverse Events of Interest (AEIs)
    End point description
    Time to onset of AEIs is defined as the interval (in months) from the start of idelalisib treatment to the first documentation of start of AEI. AEIs included grade ≥ 3 diarrhea/colitis, rash, febrile neutropenia, infection, and any grade of: Pneumonitis, bowel perforation, progressive multifocal leukoencephalopathy (PML), Pneumocystis jirovecii pneumonia (PJP), cytomegalovirus (CMV) infection, and organizing pneumonia.
    End point type
    Secondary
    End point timeframe
    First dose date up to 30 days after last dose of study drug (maximum 64.6 months)
    End point values
    		 Idelalisib 150 mg BID Idelalisib 100 mg BID Idelalisib 150 mg BID INT
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    Units: months
        median (inter-quartile range (Q1-Q3))
    ( to )
    ( to )
    ( to )
    Notes
    [3] - AEIs data was not collected for analysis.
    [4] - AEIs data was not collected for analysis.
    [5] - AEIs data was not collected for analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-Cause Mortality: Enrollment up to last follow up visit (maximum 73.5 months); Adverse Events: First dose date up to 30 days after last dose of study drug (maximum 64.6 months)
    Adverse event reporting additional description
    All-Cause Mortality: All enrolled analysis set included all participants who received a study participant identification number after screening and was used for participant enrollment summary and data listings, unless otherwise specified. Adverse Events: Safety analysis set included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Idelalisib 150 mg BID
    Reporting group description
    		 Participants received idelalisib 150 mg tablets, orally, BID, continuously for up to maximum 33.5 months.

    Reporting group title
    Idelalisib 150 mg BID INT
    Reporting group description
    		 Participants received idelalisib 150 mg tablets, orally, BID for 21 days and 7 days off-treatment (INT dosing schedule) in each 28-day cycle for up to maximum of 24.6 months.

    Reporting group title
    Idelalisib 100 mg BID
    Reporting group description
    		 Participants received idelalisib 100 mg tablets, orally, BID, continuously for up to maximum 63.6 months.

    Serious adverse events
    		 Idelalisib 150 mg BID Idelalisib 150 mg BID INT Idelalisib 100 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 47 (65.96%)
    11 / 21 (52.38%)
    19 / 27 (70.37%)
         number of deaths (all causes)
    20
    6
    12
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Lung disorder
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (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
    Pneumonitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio ~ increased
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Klebsiella test positive
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         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
    Pelvic fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (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
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Febrile neutropenia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual field defect
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 47 (14.89%)
    0 / 21 (0.00%)
    6 / 27 (22.22%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Hepatotoxicity
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Rash maculo-papular
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    4 / 27 (14.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Hydronephrosis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (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
    Renal failure
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Renal impairment
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 21 (4.76%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Covid-19 pneumonia
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 21 (9.52%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Abdominal infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (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
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Aspergillus infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Bronchitis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronavirus pneumonia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Neutropenic sepsis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (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
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         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 bacterial
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Suspected COVID-19
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    0 / 27 (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
    Hyperglycaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Idelalisib 150 mg BID Idelalisib 150 mg BID INT Idelalisib 100 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 47 (93.62%)
    16 / 21 (76.19%)
    24 / 27 (88.89%)
    Investigations
    Weight decreased
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 21 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    4
    0
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 47 (19.15%)
    0 / 21 (0.00%)
    5 / 27 (18.52%)
         occurrences all number
    11
    0
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 47 (17.02%)
    0 / 21 (0.00%)
    6 / 27 (22.22%)
         occurrences all number
    10
    0
    9
    Transaminases increased
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 47 (10.64%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    5
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
         occurrences all number
    3
    1
    3
    Dizziness
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 21 (9.52%)
    1 / 27 (3.70%)
         occurrences all number
    0
    2
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    6 / 47 (12.77%)
    0 / 21 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    7
    0
    5
    Neutropenia
         subjects affected / exposed
    12 / 47 (25.53%)
    4 / 21 (19.05%)
    10 / 27 (37.04%)
         occurrences all number
    29
    9
    21
    Anaemia
         subjects affected / exposed
    10 / 47 (21.28%)
    2 / 21 (9.52%)
    3 / 27 (11.11%)
         occurrences all number
    12
    4
    4
    Febrile neutropenia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    11 / 47 (23.40%)
    3 / 21 (14.29%)
    6 / 27 (22.22%)
         occurrences all number
    13
    6
    6
    Asthenia
         subjects affected / exposed
    4 / 47 (8.51%)
    3 / 21 (14.29%)
    4 / 27 (14.81%)
         occurrences all number
    5
    4
    6
    Oedema peripheral
         subjects affected / exposed
    5 / 47 (10.64%)
    3 / 21 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    5
    4
    2
    Fatigue
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
         occurrences all number
    5
    2
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 47 (40.43%)
    6 / 21 (28.57%)
    12 / 27 (44.44%)
         occurrences all number
    35
    9
    39
    Abdominal pain
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
         occurrences all number
    5
    2
    2
    Colitis
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    0
    1
    Nausea
         subjects affected / exposed
    5 / 47 (10.64%)
    4 / 21 (19.05%)
    6 / 27 (22.22%)
         occurrences all number
    5
    5
    7
    Constipation
         subjects affected / exposed
    6 / 47 (12.77%)
    2 / 21 (9.52%)
    4 / 27 (14.81%)
         occurrences all number
    6
    2
    6
    Vomiting
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 21 (4.76%)
    5 / 27 (18.52%)
         occurrences all number
    4
    2
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 47 (17.02%)
    0 / 21 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    8
    0
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    11 / 47 (23.40%)
    6 / 21 (28.57%)
    4 / 27 (14.81%)
         occurrences all number
    19
    9
    8
    Hyperhidrosis
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    4
    0
    0
    Psoriasis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Rash papular
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Dermatitis allergic
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 21 (9.52%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 21 (4.76%)
    4 / 27 (14.81%)
         occurrences all number
    4
    1
    5
    Muscle spasms
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 21 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 21 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    4
    0
    5
    Influenza
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 21 (9.52%)
    4 / 27 (14.81%)
         occurrences all number
    3
    2
    8
    Bronchitis
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 21 (9.52%)
    1 / 27 (3.70%)
         occurrences all number
    3
    3
    1
    Oral candidiasis
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
         occurrences all number
    4
    2
    0
    Covid-19
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 21 (9.52%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
         occurrences all number
    3
    2
    2
    Decreased appetite
         subjects affected / exposed
    5 / 47 (10.64%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
         occurrences all number
    6
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Mar 2016
    • Updated the safety information and guidelines for toxicity management to be consistent across idelalisib study protocols, changes included mandated prophylaxis for Pneumocystis jirovecii pneumonia (PJP), Cytomegalovirus (CMV) surveillance, and increased monitoring: CMV testing frequency update (once in 4weeks); Toxicity Management updated to ‘Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific Adverse Events or Conditions’ • Target population was modified to align with the European Union (EU) licensed indication of idelalisib. Inclusion criteria modified to require that participants be refractory to and disease progression within 6 months from the last dose of at least two lines of prior therapy; Title and all protocol language modified to include only participants with follicular lymphoma; Removed stratification by FL/Small Lymphocytic Lymphoma (SLL) • Clarified and revised inclusion/exclusion criterion requirements: Modified inclusion criteria to align with Grade 3 neutropenia, thrombocytopenia, and anemia; Removed inclusion criteria due to French central ethics committee (CEC) request • Clarified the section Vital Signs to specify which vital signs will be collected and at which visits • Revised text to allow for the 30-Day Follow-up visit to be conducted via phone (instead of a clinic visit) • Updated language added to Appendix Pregnancy Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirements to align with the EU guidance for Zydelig contraception language in protocol amendments • Updated language added to Appendix Efficacy Assessments, Nodal Index Lesions to align with Cheson criteria
    07 Jun 2016
    • Removed screening viral titers • Clarified that around the timing of protocol requires unblinding during study participation
    08 Sep 2016
    Alignment with Urgent Safety Measures to define the recommended versus required actions related to dose modifications for adverse events related to idelalisib.
    25 Sep 2017
    Organizing pneumonia (OP) emerged as a potential safety signal during Gilead routine signal detection monitoring. This risk was included in the Investigator’s Brochure (IB). All idelalisib protocols with ongoing participants were amended to add OP as a potential risk.
    13 Mar 2019
    Amended to fulfill a new post marketing requirement (PMR) 2180-10, to verify the clinical benefit of Zydelig, including defined efficacy and safety endpoints and an alternative, non-continuous dosing regimen proposed by Food and Drug Administration (FDA), as follows: • Conduct a trial establishing a safe and effective dosing regimen of idelalisib in patients with relapsed or refractory FL who have no other therapeutic options and require treatment. Include a dosing-regimen arm of 28-day cycles with 21 days on-treatment and 7 days off-treatment • The primary efficacy endpoint should be ORR. There should be sufficient follow-up to provide a credible assessment of DOR. A dosing regimen of idelalisib was considered to be effective in relapsed/refractory FL if the ORR is greater than 50% with a DOR of at least 6 months • The primary safety endpoint should be incidence of grade 4 and 5 TEAE. A dosing regimen of idelalisib was considered safe in this patient population if the rate of grade 4 and 5 TEAE is less than 30% • In addition, enrollment to Arm B was closed. This decision was based on preliminary data suggesting that Arm B appears unlikely to meet the PMR objective of achieving an ORR ≥50%, and there was insufficient exposure to the 100mg twice daily dosing regimen to evaluate intermediate and long term safety
    18 Mar 2021
    • Unblinded the remaining blinded participants on the study for data analysis and the study design was made open label and all subsequent participants moved into Arm A and all participants enlisted into newly created Arm C were enrolled in an unblinded manner. However, there were participants remaining on the study who had been originally blinded across Arm A and Arm B • Included appendix Pandemic Risk Assessment and Mitigation Plan, which summarized potential risks associated with participants being unable to attend study visits due to an ongoing pandemic and mitigation plans • Exclusion criteria was updated to clarify that participants who received antiviral prophylaxis specifically for CMV should be excluded. • Include drug reactions with eosinophilia and systemic symptoms (DRESS) and progressive multifocal leukoencephalopathy (PML) as specific adverse events to align with the current version of the IB • Added a section outlining coronavirus disease 2019 (COVID-19) vaccination guidelines whilst a participant is on study drug

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    27 Sep 2022
    Gilead has made the decision to close the study due to enrollment challenges.
    -

    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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