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    Clinical Trial Results:
    A Phase 2, Open-label, Multicenter Study to Evaluate the Safety and Clinical Activity of Durvalumab in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (R-CHOP) or with Lenalidomide plus R-CHOP (R2-CHOP) in Subjects With Previously Untreated, High-Risk Diffuse Large B-Cell Lymphoma

    Summary
    EudraCT number
    		 2015-005173-20
    Trial protocol
    		 AT   DK   EE   SK   PL  
    Global end of trial date
    24 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 May 2023
    First version publication date
    10 May 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MEDI4736-DLBCL-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    09 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to explore the clinical activity of durvalumab (MEDI4736) in combination with R-CHOP or R2-CHOP followed by durvalumab consolidation therapy in previously untreated subjects diagnosed with high-risk DLBCL.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Austria: 15
    Worldwide total number of subjects
    46
    EEA total number of subjects
    23
    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)
    24
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 46 participants were enrolled and treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DUR + R-CHOP
    Arm description
    		 Participants receive Induction Therapy (21-day cycles): Durvalumab 1125 mg intravenously (IV) on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5). Participants then receive Consolidation Therapy (28-day cycles): Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1 of induction therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 1.4 mg/m2 BSA (recommended capping at 2 mg absolute dose) on Day 1 of each 21-day cycle for 6-8 cycles as part of the R-CHOP treatment regimen.

    Investigational medicinal product name
    Prednisone / Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Oral solution
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    a 100 mg

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 50 mg/m2 BSA on Day 1 of each 21-day cycle for 6 to 8 cycles as part of the R-CHOP treatment regimen.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 375 mg/m2 BSA on Day 1 of each 21-day cycle for 6 to 8 cycles as part of the R-CHOP treatment regimen.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 750 mg/m2 BSA on Day 1 of each 21-day cycle for 6 to 8 cycles as part of the R-CHOP treatment regimen.

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1125 and 1500 mg administered intravenously (IV)

    Arm title
    		 DUR + R2-CHOP
    Arm description
    		 Participants receive Induction Therapy (21-day cycles): Cycle 1 - induction therapy of durvalumab in combination with R-CHOP (as described in DUR + R-CHOP arm). Starting at cycle 2 - Durvalumab 1125 mg IV on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R2-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5; daily oral lenalidomide 15 mg from Day 1 to 14) from the cycle following COO determination until end of induction therapy (Cycle 6 or Cycle 8) or starting Cycle 1 if ABC subtype is identified prior to C1D1. Participants then receive Consolidation Therapy (28-day cycles): Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1 of induction therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1125 and 1500 mg administered intravenously (IV)

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 375 mg/m2 BSA on Day 1 of each 21-day cycle for 6 to 8 cycles as part of the R-CHOP treatment regimen.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 750 mg/m2 BSA on Day 1 of each 21-day cycle for 6 to 8 cycles as part of the R-CHOP treatment regimen.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 50 mg/m2 BSA on Day 1 of each 21-day cycle for 6 to 8 cycles as part of the R-CHOP treatment regimen.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at 1.4 mg/m2 BSA (recommended capping at 2 mg absolute dose) on Day 1 of each 21-day cycle for 6-8 cycles as part of the R-CHOP treatment regimen.

    Investigational medicinal product name
    Prednisone / Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Oral use
    Dosage and administration details
    a 100 mg

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Oral solution
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    15 mg

    Number of subjects in period 1
    		DUR + R-CHOP DUR + R2-CHOP
    Started
    43
    3
    Completed Induction Treatment
    31
    3
    Completed Consolidation Treatment
    14
    2
    Completed
    14
    2
    Not completed
    29
    1
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    6
    -
         Adverse event, non-fatal
    9
    -
         Other reasons
    4
    -
         Progressive disease
    9
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DUR + R-CHOP
    Reporting group description
    		 Participants receive Induction Therapy (21-day cycles): Durvalumab 1125 mg intravenously (IV) on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5). Participants then receive Consolidation Therapy (28-day cycles): Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1 of induction therapy.

    Reporting group title
    DUR + R2-CHOP
    Reporting group description
    		 Participants receive Induction Therapy (21-day cycles): Cycle 1 - induction therapy of durvalumab in combination with R-CHOP (as described in DUR + R-CHOP arm). Starting at cycle 2 - Durvalumab 1125 mg IV on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R2-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5; daily oral lenalidomide 15 mg from Day 1 to 14) from the cycle following COO determination until end of induction therapy (Cycle 6 or Cycle 8) or starting Cycle 1 if ABC subtype is identified prior to C1D1. Participants then receive Consolidation Therapy (28-day cycles): Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1 of induction therapy.

    Reporting group values
    		 DUR + R-CHOP DUR + R2-CHOP Total
    Number of subjects
    		 43 3 46
    Age Categorical
    Units: participants
        <65 years
    		 23 1 24
        >=65 years
    		 20 2 22
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.1 ( 12.77 ) 67.7 ( 8.62 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 17 1 18
        Male
    		 26 2 28
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 43 3 46
        Unknown or Not Reported
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Black or African American
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 42 3 45
        Not Colected or Reported
    		 0 0 0
        Other
    		 1 0 1
    Eastern Cooperative Oncology Group
    ECOG performance status is used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. - 0 = Fully Active (most favorable status); - 1 = Restricted activity but ambulatory; - 2 = Ambulatory but unable to carry out work activities; - 3 = Limited Self-Care; - 4 = Completely Disabled, No self-care (least favorable status)
    Units: Subjects
        0 = Fully Active
    		 16 2 18
        1 = Restricted activity but ambulatory
    		 19 0 19
        2 = Ambulatory but unable to work
    		 8 1 9
        3 = Limited Self-Care
    		 0 0 0
        4 = Completely Disabled, No self-care
    		 0 0 0
    Ann Arbor Stage at Diagnosis
    The criteria for Clinical Stage (Ann Arbor staging) are as below: - I: involvement of a single nodal region. - II: involvement of 2 or more lymph node regions on the same side of the diaphragm. - III: involvement of lymph node regions on both sides of the diaphragm. - IV: disseminated involvement of 1 or more extra-lymphatic sites with or without associated lymph node involvement.
    Units: Subjects
        Stage I
    		 0 0 0
        Stage II
    		 0 0 0
        Stage III
    		 9 2 11
        Stage IV
    		 34 1 35
    Presence of Bulky Disease (Baseline)
    Bulky disease refers to the size of the tumor.
    Units: Subjects
        Yes = tumor diameter >= 7.0 cm
    		 21 2 23
        No = tumor diameter < 7.0 cm
    		 22 1 23
    International Prognostic Index (IPSS) Score
    The IPI assesses risk of central nervous system disease according to the following scale: - 0-1: Low risk - 2: Low-Intermediate risk - 3: High-Intermediate risk - 4-5: High risk
    Units: Subjects
        0-1: Low risk
    		 0 0 0
        2: Low-Intermediate risk
    		 9 0 9
        3: High-Intermediate risk
    		 21 0 21
        4-5: High risk
    		 9 2 11
        Missing
    		 4 1 5
    Subject analysis sets

    Subject analysis set title
    High Group for CD8 Density
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their CD8 density evaluation was above threshold,defined as the median of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods. Participants with values above threshold were predicted to be responders.

    Subject analysis set title
    Low Group for CD8 Density
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their CD8 density evaluation was below threshold,defined as the median of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods. Participants with values below threshold were predicted to be non-responders.

    Subject analysis set title
    High Group for PDL1 % of total cells
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their PDL1 % of total cell evaluation was above threshold,defined as the median of 13.8% found in commercial DLBCL samples using matched analytical methods. Participants with values above threshold were predicted to be responders.

    Subject analysis set title
    Low Group for PDL1 % of total cells
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their PDL1 % of total cell evaluation was below threshold,defined as the median of 13.8% found in commercial DLBCL samples using matched analytical methods. Participants with values below threshold were predicted to be non-responders.

    Subject analysis set title
    High Group for PDL1 % of tumor cells
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their PD-1 % of tumor cell evaluation was above threshold,defined as the median of 6.2% found in commercial DLBCL samples using matched analytical methods. Participants with values above threshold were predicted to be responders.

    Subject analysis set title
    Low Group for PDL1 % of tumor cells
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their PDL1 % of tumor cell evaluation was below threshold,defined as the median of 6.2% found in commercial DLBCL samples using matched analytical methods. Participants with values below threshold were predicted to be non-responders.

    Subject analysis set title
    High Group for RNA IFN Gamma Score
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had RNA IFN Gamma Score calculated based on a biopsy sample collected before treatment on this protocol. The result of their RNA IFN Gamma Score was above threshold,defined as the median of 3.28 found in commercial DLBCL samples using matched analytical methods. Participants with values above threshold were predicted to be responders.

    Subject analysis set title
    Low Group for RNA IFN Gamma Score
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had RNA IFN Gamma Score calculated based on a biopsy sample collected before treatment on this protocol. The result of their RNA IFN Gamma Score was below threshold,defined as the median of 3.28 found in commercial DLBCL samples using matched analytical methods. Participants with values below threshold were predicted to be non-responders.

    Subject analysis sets values
    		 High Group for CD8 Density Low Group for CD8 Density High Group for PDL1 % of total cells Low Group for PDL1 % of total cells High Group for PDL1 % of tumor cells Low Group for PDL1 % of tumor cells High Group for RNA IFN Gamma Score Low Group for RNA IFN Gamma Score
    Number of subjects
    15
    11
    20
    5
    11
    9
    7
    20
    Age Categorical
    Units: participants
        <65 years
        >=65 years
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    67 ( )
    64 ( )
    75 ( )
    20 ( )
    64 ( )
    56 ( )
    43 ( )
    60 ( )
    Sex: Female, Male
    Units: participants
        Female
        Male
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Black or African American
        Native Hawaiian or Other Pacific Islander
        White
        Not Colected or Reported
        Other
    Eastern Cooperative Oncology Group
    ECOG performance status is used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. - 0 = Fully Active (most favorable status); - 1 = Restricted activity but ambulatory; - 2 = Ambulatory but unable to carry out work activities; - 3 = Limited Self-Care; - 4 = Completely Disabled, No self-care (least favorable status)
    Units: Subjects
        0 = Fully Active
        1 = Restricted activity but ambulatory
        2 = Ambulatory but unable to work
        3 = Limited Self-Care
        4 = Completely Disabled, No self-care
    Ann Arbor Stage at Diagnosis
    The criteria for Clinical Stage (Ann Arbor staging) are as below: - I: involvement of a single nodal region. - II: involvement of 2 or more lymph node regions on the same side of the diaphragm. - III: involvement of lymph node regions on both sides of the diaphragm. - IV: disseminated involvement of 1 or more extra-lymphatic sites with or without associated lymph node involvement.
    Units: Subjects
        Stage I
        Stage II
        Stage III
        Stage IV
    Presence of Bulky Disease (Baseline)
    Bulky disease refers to the size of the tumor.
    Units: Subjects
        Yes = tumor diameter >= 7.0 cm
        No = tumor diameter < 7.0 cm
    International Prognostic Index (IPSS) Score
    The IPI assesses risk of central nervous system disease according to the following scale: - 0-1: Low risk - 2: Low-Intermediate risk - 3: High-Intermediate risk - 4-5: High risk
    Units: Subjects
        0-1: Low risk
        2: Low-Intermediate risk
        3: High-Intermediate risk
        4-5: High risk
        Missing

    End points

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    End points reporting groups
    Reporting group title
    DUR + R-CHOP
    Reporting group description
    		 Participants receive Induction Therapy (21-day cycles): Durvalumab 1125 mg intravenously (IV) on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5). Participants then receive Consolidation Therapy (28-day cycles): Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1 of induction therapy.

    Reporting group title
    DUR + R2-CHOP
    Reporting group description
    		 Participants receive Induction Therapy (21-day cycles): Cycle 1 - induction therapy of durvalumab in combination with R-CHOP (as described in DUR + R-CHOP arm). Starting at cycle 2 - Durvalumab 1125 mg IV on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R2-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5; daily oral lenalidomide 15 mg from Day 1 to 14) from the cycle following COO determination until end of induction therapy (Cycle 6 or Cycle 8) or starting Cycle 1 if ABC subtype is identified prior to C1D1. Participants then receive Consolidation Therapy (28-day cycles): Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1 of induction therapy.

    Subject analysis set title
    High Group for CD8 Density
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their CD8 density evaluation was above threshold,defined as the median of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods. Participants with values above threshold were predicted to be responders.

    Subject analysis set title
    Low Group for CD8 Density
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their CD8 density evaluation was below threshold,defined as the median of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods. Participants with values below threshold were predicted to be non-responders.

    Subject analysis set title
    High Group for PDL1 % of total cells
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their PDL1 % of total cell evaluation was above threshold,defined as the median of 13.8% found in commercial DLBCL samples using matched analytical methods. Participants with values above threshold were predicted to be responders.

    Subject analysis set title
    Low Group for PDL1 % of total cells
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their PDL1 % of total cell evaluation was below threshold,defined as the median of 13.8% found in commercial DLBCL samples using matched analytical methods. Participants with values below threshold were predicted to be non-responders.

    Subject analysis set title
    High Group for PDL1 % of tumor cells
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their PD-1 % of tumor cell evaluation was above threshold,defined as the median of 6.2% found in commercial DLBCL samples using matched analytical methods. Participants with values above threshold were predicted to be responders.

    Subject analysis set title
    Low Group for PDL1 % of tumor cells
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had IHC analysis performed on a biopsy sample collected before treatment on this protocol. The result of their PDL1 % of tumor cell evaluation was below threshold,defined as the median of 6.2% found in commercial DLBCL samples using matched analytical methods. Participants with values below threshold were predicted to be non-responders.

    Subject analysis set title
    High Group for RNA IFN Gamma Score
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had RNA IFN Gamma Score calculated based on a biopsy sample collected before treatment on this protocol. The result of their RNA IFN Gamma Score was above threshold,defined as the median of 3.28 found in commercial DLBCL samples using matched analytical methods. Participants with values above threshold were predicted to be responders.

    Subject analysis set title
    Low Group for RNA IFN Gamma Score
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants had RNA IFN Gamma Score calculated based on a biopsy sample collected before treatment on this protocol. The result of their RNA IFN Gamma Score was below threshold,defined as the median of 3.28 found in commercial DLBCL samples using matched analytical methods. Participants with values below threshold were predicted to be non-responders.

    Primary: Percentage of Participants Who Achieved a Complete Response (CR) at the End of Induction Therapy

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    End point title
    		 Percentage of Participants Who Achieved a Complete Response (CR) at the End of Induction Therapy [1]
    End point description
    The primary efficacy analysis evaluated the complete response rate (CRR) at the end of the induction therapy in the efficacy evaluable population in a comparative manner against historical control. The response to treatment was assessed according to the 2014 International Working Group (IWG) Response Criteria for Non-Hodgkin’s Lymphoma (NHL) (Cheson, 2014). CR was defined as a complete metabolic response and radiographic evidence showing target nodes/nodal masses regressed to ≤ 1.5 cm in longest diameter, no new lesions, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. Clopper-Pearson two-sided 95% confidence interval is reported. Null hypothesis for the primary endpoint was rejected if the lower limit of the confidence interval for the complete response rate at the completion of the induction therapy in the efficacy evaluable population is above 55%.
    End point type
    Primary
    End point timeframe
    From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 – maximum duration of Induction Period).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint.
    End point values
    		 DUR + R-CHOP DUR + R2-CHOP
    Number of subjects analysed
    37
    3
    Units: percentage of participants
        number (confidence interval 95%)
    54.1 (36.9 to 70.5)
    66.7 (9.4 to 99.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) CD8 T-Cell Density

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    End point title
    		 Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) CD8 T-Cell Density
    End point description
    Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome.
    End point type
    Secondary
    End point timeframe
    Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 – maximum duration of Induction Period).
    End point values
    		 High Group for CD8 Density Low Group for CD8 Density
    Number of subjects analysed
    15
    11
    Units: percentage of participants
    67
    64
    Statistical analysis title
    		 CD8 T-cell density
    Comparison groups
    High Group for CD8 Density v Low Group for CD8 Density
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 > 0.99 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - Significance defined as 0.05.
    Statistical analysis title
    		 CD8 T-cell density
    Statistical analysis description
    The Area Under the Receiver Operator Characteristic Curve (AUC-ROC) is the estimated parameter. Responders were compared to non-responders by ranking them according to their CD8 density.
    Comparison groups
    High Group for CD8 Density v Low Group for CD8 Density
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.872 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - Significance defined as 0.05.

    Secondary: Percentage of Participants Who Responded During Induction and Continued into Consolidation Therapy (Database cutoff date: 02-Aug-2018)

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    End point title
    		 Percentage of Participants Who Responded During Induction and Continued into Consolidation Therapy (Database cutoff date: 02-Aug-2018)
    End point description
    The percentage of participants who achieved a partial response (PR) or complete response (CR) at the end of Induction and continued into consolidation period in the efficacy evaluable population in a comparative manner against historical control. The response to treatment was assessed according to the 2014 International Working Group (IWG) Response Criteria for Non-Hodgkin’s Lymphoma (NHL) (Cheson, 2014). CR was defined in outcome #1. PR was defined as a partial metabolic response and radiographic evidence showing ≥ 50% decrease in sum of perpendicular diameters (SPD) of up to 6 target measurable nodes and extranodal sites, no new lesions, spleen must have regressed > 50% in length beyond normal, and residual bone marrow involvement improved from baseline. Clopper-Pearson two-sided 95% confidence interval is reported. Null hypothesis was rejected if the lower limit of the confidence interval for the rate of subjects who continue consolidation therapy out of all subjects.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to completion of at least one cycle in the Consolidation Period (Day 1 up to Week 52)
    End point values
    		 DUR + R-CHOP DUR + R2-CHOP
    Number of subjects analysed
    37
    3
    Units: percentage of participants
        number (confidence interval 95%)
    67.6 (50.2 to 82.0)
    66.7 (9.4 to 99.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand – 1 (PDL1) Total Percentage

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    End point title
    		 Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand – 1 (PDL1) Total Percentage
    End point description
    Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome.
    End point type
    Secondary
    End point timeframe
    Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 – maximum duration of Induction Period).
    End point values
    		 High Group for PDL1 % of total cells Low Group for PDL1 % of total cells
    Number of subjects analysed
    20
    5
    Units: percentage of participants
    75
    20
    Statistical analysis title
    		 PDL1 (Total Percentage)
    Statistical analysis description
    The Area Under the Receiver Operator Characteristic Curve (AUC-ROC) is the estimated parameter. Responders were compared to non-responders by ranking them according to their PDL1 % of total cells.
    Comparison groups
    High Group for PDL1 % of total cells v Low Group for PDL1 % of total cells
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.523 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Significance defined as 0.05.
    Statistical analysis title
    		 PDL1 (Total Percentage)
    Comparison groups
    High Group for PDL1 % of total cells v Low Group for PDL1 % of total cells
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0403 [5]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [5] - Significance defined as 0.05.

    Secondary: Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand – 1 (PDL1) Percentage of Tumor Cells

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    End point title
    		 Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand – 1 (PDL1) Percentage of Tumor Cells
    End point description
    Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome.
    End point type
    Secondary
    End point timeframe
    Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 – maximum duration of Induction Period).
    End point values
    		 High Group for PDL1 % of tumor cells Low Group for PDL1 % of tumor cells
    Number of subjects analysed
    11
    9
    Units: percentage of participants
    64
    56
    Statistical analysis title
    		 PDL1 (Percentage of tumor cells)
    Statistical analysis description
    The Area Under the Receiver Operator Characteristic Curve (AUC-ROC) is the estimated parameter. Responders were compared to non-responders by ranking them according to their PDL1 % of tumor cells.
    Comparison groups
    High Group for PDL1 % of tumor cells v Low Group for PDL1 % of tumor cells
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.557 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - Significance defined as 0.05.
    Statistical analysis title
    		 PDL1 (Percentage of tumor cells)
    Comparison groups
    High Group for PDL1 % of tumor cells v Low Group for PDL1 % of tumor cells
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 > 0.99 [7]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [7] - Significance defined as 0.05.

    Secondary: Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for the Interferon Gamma Score (IFNG-Score) from Ribonucleic Acid (RNA)-Sequencing Data

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    End point title
    		 Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for the Interferon Gamma Score (IFNG-Score) from Ribonucleic Acid (RNA)-Sequencing Data
    End point description
    Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome.
    End point type
    Secondary
    End point timeframe
    Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 – maximum duration of Induction Period).
    End point values
    		 High Group for RNA IFN Gamma Score Low Group for RNA IFN Gamma Score
    Number of subjects analysed
    7
    20
    Units: percentage of participants
    43
    60
    Statistical analysis title
    		 RNA Sequencing
    Statistical analysis description
    The Area Under the Receiver Operator Characteristic Curve (AUC-ROC) is the estimated parameter. Responders were compared to non-responders by ranking them according to their IFNG-Score.
    Comparison groups
    High Group for RNA IFN Gamma Score v Low Group for RNA IFN Gamma Score
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.399 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - Significance defined as 0.05.
    Statistical analysis title
    		 RNA Sequencing
    Comparison groups
    High Group for RNA IFN Gamma Score v Low Group for RNA IFN Gamma Score
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.662 [9]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [9] - Significance defined as 0.05.

    Secondary: Participants with Treatment Emergent Adverse Events (TEAE)

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    End point title
    		 Participants with Treatment Emergent Adverse Events (TEAE)
    End point description
    An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during a study. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild (no limitation in activity or intervention); - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required); - Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); - Grade 4 = Life-threatening; - Grade 5 = Death. Relation to IP is determined by the investigator. 99999= N/A
    End point type
    Secondary
    End point timeframe
    From the date of the first dose of study drug to within 90 days after the last dose of durvalumab or 28 days after the last dose of any investigational product (IP) whichever is greater. (Up to approximately 72 weeks)
    End point values
    		 DUR + R-CHOP DUR + R2-CHOP
    Number of subjects analysed
    43
    3
    Units: participants
        >= 1 Treatment-emergent adverse event (TEAE)
    43
    3
        >=1 TEAE related to durvalumab
    33
    3
        >=1 TEAE related to R-CHOP
    40
    3
        >=1 TEAE related to lenalidomide
    99999
    3
        >=1 TEAE related to durvalumab or any other IP
    41
    3
        >=1 TEAE severity grade 3-4
    37
    3
        >=1 TEAE severity grade 3-4 related to durvalumab
    18
    1
        >=1 TEAE severity grade 3-4 related to R-CHOP
    27
    3
        >=1 TEAE severity grade 3-4 related to lenalidomid
    99999
    2
        >=1 TEAE severity grade 3-4 related to any IP
    31
    3
        >=1 TEAE severity grade 5
    3
    0
        >=1 TEAE severity grade 5 related to any IP
    0
    0
        >=1 serious TEAE
    23
    1
        >=1 serious TEAE related to durvalumab
    10
    1
        >=1 serious TEAE related to R-CHOP
    10
    1
        >=1 serious TEAE related to lenalidomide
    99999
    1
        >=1 serious TEAE related to any IP
    14
    1
        >=1 leading to discontinuation of durvalumab
    13
    0
        >=1 leading to discontinuation of R-CHOP
    4
    0
        >=1 leading to discontinuation of lenalidomide
    99999
    0
        >=1 leading to discontinuation of any IP
    13
    0
        >=1 leading to interruption of durvalumab
    15
    2
        >=1 leading to interruption of R-CHOP
    12
    1
        >=1 leading to interruption of lenalidomide
    99999
    2
        >=1 leading to interruption of any IP
    18
    3
        >=1 leading to infusion interruption of durvalumab
    2
    0
        >=1 leading to dose reduction of vincristine
    4
    1
        >=1 leading to dose reduction of lenalidomide
    99999
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Assessed from first dose to 90 days after the last dose of durvalumab or 28 days after other IP and up to 5 years after C1D1 of the last lenalidomide dose. All-Cause Mortality was assessed in participants from first dose to study completion.
    Adverse event reporting additional description
    Participants treated with lenalidomide during any stage of the study will be continued to be followed for Second Primary Malignancies (SPM) for up to 5 years after enrollment (C1D1) of the last Participant to receive lenalidomide as part of their study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    DUR + R-CHOP
    Reporting group description
    		 Participants receive Induction Therapy (21-day cycles): Durvalumab 1125 mg intravenously (IV) on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5). Participants then receive Consolidation Therapy (28-day cycles): Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1 of induction therapy.

    Reporting group title
    DUR + R2-CHOP
    Reporting group description
    		 Participants receive Induction Therapy (21-day cycles): Cycle 1 - induction therapy of durvalumab in combination with R-CHOP (as described in DUR + R-CHOP arm). Starting at cycle 2 - Durvalumab 1125 mg IV on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R2-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5; daily oral lenalidomide 15 mg from Day 1 to 14) from the cycle following COO determination until end of induction therapy (Cycle 6 or Cycle 8) or starting Cycle 1 if ABC subtype is identified prior to C1D1. Participants then receive Consolidation Therapy (28-day cycles): Durvalumab 1500 mg IV on Day 1 of each 28-day cycle for up to a total of 12 months from C1D1 of induction therapy.

    Serious adverse events
    		 DUR + R-CHOP DUR + R2-CHOP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 43 (53.49%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    5
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Diffuse large B-cell lymphoma recurrent
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 43 (13.95%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral diarrhoea
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DUR + R-CHOP DUR + R2-CHOP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 43 (100.00%)
    3 / 3 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Histiocytic necrotising lymphadenitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Hot flush
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Fatigue
         subjects affected / exposed
    26 / 43 (60.47%)
    2 / 3 (66.67%)
         occurrences all number
    29
    3
    Mucosal inflammation
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Oedema peripheral
         subjects affected / exposed
    6 / 43 (13.95%)
    1 / 3 (33.33%)
         occurrences all number
    6
    1
    Pyrexia
         subjects affected / exposed
    9 / 43 (20.93%)
    0 / 3 (0.00%)
         occurrences all number
    9
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 43 (20.93%)
    0 / 3 (0.00%)
         occurrences all number
    13
    0
    Dyspnoea
         subjects affected / exposed
    10 / 43 (23.26%)
    0 / 3 (0.00%)
         occurrences all number
    10
    0
    Oropharyngeal pain
         subjects affected / exposed
    6 / 43 (13.95%)
    0 / 3 (0.00%)
         occurrences all number
    6
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Insomnia
         subjects affected / exposed
    11 / 43 (25.58%)
    0 / 3 (0.00%)
         occurrences all number
    18
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Weight decreased
         subjects affected / exposed
    7 / 43 (16.28%)
    0 / 3 (0.00%)
         occurrences all number
    7
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Infusion related reaction
         subjects affected / exposed
    5 / 43 (11.63%)
    1 / 3 (33.33%)
         occurrences all number
    6
    1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    9 / 43 (20.93%)
    1 / 3 (33.33%)
         occurrences all number
    10
    1
    Dysgeusia
         subjects affected / exposed
    6 / 43 (13.95%)
    0 / 3 (0.00%)
         occurrences all number
    8
    0
    Headache
         subjects affected / exposed
    11 / 43 (25.58%)
    0 / 3 (0.00%)
         occurrences all number
    11
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    23 / 43 (53.49%)
    2 / 3 (66.67%)
         occurrences all number
    24
    2
    Restless legs syndrome
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    Sensory disturbance
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Taste disorder
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 43 (16.28%)
    1 / 3 (33.33%)
         occurrences all number
    8
    3
    Neutropenia
         subjects affected / exposed
    21 / 43 (48.84%)
    3 / 3 (100.00%)
         occurrences all number
    39
    5
    Thrombocytopenia
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 3 (33.33%)
         occurrences all number
    4
    2
    Leukopenia
         subjects affected / exposed
    7 / 43 (16.28%)
    1 / 3 (33.33%)
         occurrences all number
    10
    1
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Abdominal pain upper
         subjects affected / exposed
    5 / 43 (11.63%)
    0 / 3 (0.00%)
         occurrences all number
    7
    0
    Constipation
         subjects affected / exposed
    9 / 43 (20.93%)
    2 / 3 (66.67%)
         occurrences all number
    9
    2
    Diarrhoea
         subjects affected / exposed
    13 / 43 (30.23%)
    1 / 3 (33.33%)
         occurrences all number
    18
    1
    Dry mouth
         subjects affected / exposed
    8 / 43 (18.60%)
    0 / 3 (0.00%)
         occurrences all number
    9
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    18 / 43 (41.86%)
    2 / 3 (66.67%)
         occurrences all number
    24
    2
    Stomatitis
         subjects affected / exposed
    8 / 43 (18.60%)
    2 / 3 (66.67%)
         occurrences all number
    12
    2
    Vomiting
         subjects affected / exposed
    10 / 43 (23.26%)
    0 / 3 (0.00%)
         occurrences all number
    17
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Erythema
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    Generalised erythema
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    5 / 43 (11.63%)
    0 / 3 (0.00%)
         occurrences all number
    6
    0
    Rash
         subjects affected / exposed
    8 / 43 (18.60%)
    1 / 3 (33.33%)
         occurrences all number
    11
    1
    Alopecia
         subjects affected / exposed
    10 / 43 (23.26%)
    0 / 3 (0.00%)
         occurrences all number
    10
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Back pain
         subjects affected / exposed
    7 / 43 (16.28%)
    0 / 3 (0.00%)
         occurrences all number
    8
    0
    Muscle spasms
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 3 (33.33%)
         occurrences all number
    4
    1
    Myalgia
         subjects affected / exposed
    7 / 43 (16.28%)
    0 / 3 (0.00%)
         occurrences all number
    8
    0
    Pain in extremity
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Spinal pain
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    5 / 43 (11.63%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Influenza
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Lung infection
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    7
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Oral herpes
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    Pneumonia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 43 (27.91%)
    0 / 3 (0.00%)
         occurrences all number
    13
    0
    Hypokalaemia
         subjects affected / exposed
    8 / 43 (18.60%)
    1 / 3 (33.33%)
         occurrences all number
    8
    1
    Hypomagnesaemia
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2019
    Discontinuation of Follow-up Period, assessments and data collection. Second Primary Malignancies (SPMs) data collection.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    After the US FDA Partial Clinical Hold, enrollment of new subjects into Arm B was discontinued.
    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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