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    Clinical Trial Results:
    Phase 1b/Phase 3 Multicenter Study of Avelumab (MSB0010718C) in Combination Regimens That Include an Immune Agonist, Epigenetic Modulator, CD20 Antagonist and/or Conventional Chemotherapy in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

    Summary
    EudraCT number
    		 2016-002904-15
    Trial protocol
    		 BE   DE   SE   CZ   GB   ES   DK   FR  
    Global end of trial date
    02 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Dec 2020
    First version publication date
    05 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B9991011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02951156
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    06 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To asses safety, efficacy, and potentially select the most active treatment regimen among 3 treatment arms to advance to the Phase 3 component of the study.
    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 Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    29
    EEA total number of subjects
    7
    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)
    10
    From 65 to 84 years
    17
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study included subjects with relapsed or refractory DLBCL after completion of at least 2 and not more than 4 lines of rituximab-containing multi-agent chemotherapy (prior to this study), and/or in whom autologous stem cell transplant (ASCT) has failed, or who were not candidates for ASCT or who were not eligible for intensive chemotherapy.

    Pre-assignment
    Screening details
    		 A total of 41 subjects were screened and 29 subjects were randomised in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avelumab+Rituximab+Utomilumab
    Arm description
    		 Avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Rituximab 375 milligram per meter square (mg/m^2) IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the subject no longer received clinical benefit. The duration of each treatment cycle was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Avelumab 10 mg/kg IV infusion was administered on Day 2 and Day 16 of Cycles 1 and 2/Day 1 and Day 15 in Cycle 3 and all subsequent cycles.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles).

    Investigational medicinal product name
    Utomilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fixed dose of utomilumab 100 mg IV infusion on Day 2 of Cycles 1 and 2/Day 1 of Cycle 3 and all subsequent cycles.

    Arm title
    		 Avelumab+Azacitidine+Utomilumab
    Arm description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Azacitidine 40 mg/m^2 subcutaneous (SC) dose was administered on Days 1 to 5 of each treatment cycle until the subject no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the subject no longer received clinical benefit. The duration of each treatment cycle was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Avelumab 10 mg/kg IV infusion was administered on Day 2 and Day 16 of Cycles 1 and 2/Day 1 and Day 15 in Cycle 3 and all subsequent cycles.

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle.

    Investigational medicinal product name
    Utomilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fixed dose of utomilumab 100 mg IV infusion on Day 2 of Cycles 1 and 2/Day 1 of Cycle 3 and all subsequent cycles.

    Arm title
    		 Avelumab+Bendamustine+Rituximab
    Arm description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Avelumab 10 mg/kg IV infusion was administered on Day 2 and Day 16 of Cycles 1 and 2/Day 1 and Day 15 in Cycle 3 and all subsequent cycles.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles).

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine 90 mg/m^2 infusion was administered on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2/Day 1 and Day 2 in Cycle 3 and all subsequent cycles (maximum of 6 cycles).

    Number of subjects in period 1
    		Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Started
    9
    9
    11
    Completed
    0
    0
    1
    Not completed
    9
    9
    10
         Consent withdrawn by subject
    -
    -
    1
         Death
    3
    8
    5
         Study terminated by sponsor
    -
    -
    1
         Unspecified
    5
    1
    2
         Progressive disease
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avelumab+Rituximab+Utomilumab
    Reporting group description
    		 Avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Rituximab 375 milligram per meter square (mg/m^2) IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the subject no longer received clinical benefit. The duration of each treatment cycle was 28 days.

    Reporting group title
    Avelumab+Azacitidine+Utomilumab
    Reporting group description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Azacitidine 40 mg/m^2 subcutaneous (SC) dose was administered on Days 1 to 5 of each treatment cycle until the subject no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the subject no longer received clinical benefit. The duration of each treatment cycle was 28 days.

    Reporting group title
    Avelumab+Bendamustine+Rituximab
    Reporting group description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days.

    Reporting group values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab Total
    Number of subjects
    		 9 9 11 29
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 2 3 5 10
        >=65 years
    		 7 6 6 19
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.00 ( 5.79 ) 66.67 ( 13.11 ) 66.64 ( 15.16 ) -
    Sex: Female, Male
    Units:
        Female
    		 0 3 2 5
        Male
    		 9 6 9 24
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 8 8 11 27
        More than one race
    		 0 0 0 0
        Other
    		 1 1 0 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 1
        Not Hispanic or Latino
    		 7 8 11 26
        Unknown or Not Reported
    		 2 0 0 2

    End points

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    End points reporting groups
    Reporting group title
    Avelumab+Rituximab+Utomilumab
    Reporting group description
    		 Avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Rituximab 375 milligram per meter square (mg/m^2) IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the subject no longer received clinical benefit. The duration of each treatment cycle was 28 days.

    Reporting group title
    Avelumab+Azacitidine+Utomilumab
    Reporting group description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Azacitidine 40 mg/m^2 subcutaneous (SC) dose was administered on Days 1 to 5 of each treatment cycle until the subject no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the subject no longer received clinical benefit. The duration of each treatment cycle was 28 days.

    Reporting group title
    Avelumab+Bendamustine+Rituximab
    Reporting group description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days.

    Primary: Number of Subjects With Dose Limiting Toxicities (DLT)

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    End point title
    		 Number of Subjects With Dose Limiting Toxicities (DLT) [1]
    End point description
    AEs occurring in first 4 weeks of treatment,attributable to 1 of study drugs. Hematology:1)Grade (G) 4 neutropenia,2)G >=3 febrile neutropenia with single temperature of >38.3 degrees Celsius (C)/sustained temperature of >=38.0 degrees C for more than 1 hour with/without associated sepsis,3)G>=3 neutropenic infection,4) G 4 thrombocytopenia/G 3 thrombocytopenia with clinically significant bleeding,5)G 4 anemia 6)Any grade >=3 non-hematology toxicity except:transient G 3 flu like symptoms/fever controlled with standard medical management;transient G 3 fatigue,localized skin reactions/headache that resolves to Grade <=1;G 3 nausea,vomiting/diarrhea resolved to Grade <=1 in ˂72 hours after initiation of adequate medical management;Grade 3 skin toxicity resolved to G <=1 in ˂7 days;tumor flare;Single laboratory values that are out of normal range,that have noclinical correlate and resolve to Grade <=1 within 7 days with adequate medical management. DLT evaluable set analysed.
    End point type
    Primary
    End point timeframe
    Day 1 Cycle 1 up to 4 Weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was analyzed only in the reporting arms identified
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    7
    5
    10
    Units: Subjects
    1
    0
    0
    No statistical analyses for this end point

    Primary: Objective Response Rate (ORR) as Assessed by Investigator per Lugano Response Classification Criteria

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    End point title
    		 Objective Response Rate (ORR) as Assessed by Investigator per Lugano Response Classification Criteria [2]
    End point description
    Objective response rate (ORR) was defined as percentage of participants with complete response (CR) or partial response (PR), as assessed by investigator per lugano response classification criteria. CR was defined as a score of 1 (no uptake above background), 2 (uptake less than or equal to [<=] mediastinum), or 3 (uptake less than [<] mediastinum but <=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. PR was defined as >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in sum of products of diameters (SPD) of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. Full analysis set (FAS) population analysed.
    End point type
    Primary
    End point timeframe
    Randomization until date of PD, start of new anticancer therapy, discontinuation from study or death due to any cause, whichever occurred first (maximum up to 36 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: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    9
    9
    11
    Units: Percentage of subjects
        number (confidence interval 95%)
    11.1 (0.3 to 48.2)
    0 (0.0 to 33.6)
    27.3 (6.0 to 61.0)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Greater Than or Equal to (>=) Grade 3, As per National Cancer Institute Common Terminology Criteria For Adverse Events (NCI-CTCAE), Version 4.03

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Greater Than or Equal to (>=) Grade 3, As per National Cancer Institute Common Terminology Criteria For Adverse Events (NCI-CTCAE), Version 4.03
    End point description
    AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03,severity was graded as Grade(G)1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; G2:moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); G3: severe/medically significant but not immediately life-threatening, hospitalisation/prolongation of existing hospitalisation indicated, disabling, limiting self-care ADL; G4:life-threatening consequence, urgent intervention indicated; G5:death related to AE. TEAE was defined as events which occurred during on-treatment period beginning with first dose of study treatment through minimum (30 days + last dose of study treatment/start of new anti-cancer drug therapy). In this endpoint subject with any TEAE of G3 or above are reported. Safety analysis set (SAS) analysed.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    8
    9
    11
    Units: Subjects
    4
    7
    10
    No statistical analyses for this end point

    Secondary: Number of Subjects With Laboratory Abnormalities As per National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03

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    End point title
    		 Number of Subjects With Laboratory Abnormalities As per National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03
    End point description
    Laboratory parameters included hematological and biochemistry: Hematological parameters included: anemia, haemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cells decreased. Biochemistry parameters included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, cpk increased,creatinine increased, gamma glutamyl transferase(ggt)increased,hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia,hypertriglyceridemia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia,lipase increased, serum amylase increased. Abnormalities were graded by NCI CTCAE version 4.03 as G1=mild; G2=moderate; G3/G4=severe/life-threatening. SAS analysed. Here, n=subjects evaluable for specified rows.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    8
    9
    11
    Units: Subjects
        Anemia (n=8,8,10)
    6
    8
    10
        Hemoglobin increased (n=8,8,10)
    0
    0
    0
        Lymphocyte count decreased(n=7,8,10)
    4
    7
    9
        Lymphocyte count increased(n=7,8,10)
    0
    0
    0
        Neutrophil count decreased(n=8,8,10)
    2
    2
    9
        Platelet count decreased(n=8,8,10)
    4
    3
    8
        White blood cell decreased(n=7,8,10)
    1
    4
    8
        Alanine aminotransferase increased (n=7,8,10)
    2
    5
    2
        Alkaline phosphatase increased(n=7,8,10)
    3
    4
    6
        Aspartate aminotransferase increased(n=7,8,9)
    3
    6
    3
        Blood bilirubin increased(n=7,8,10)
    0
    3
    3
        Cholesterol high(n=7,7,10)
    2
    3
    3
        Cpk increased (n=7,7,10)
    2
    1
    2
        Creatinine increased(n=7,8,10)
    6
    6
    10
        GGT increased(n=7,7,10)
    3
    4
    6
        Hypercalcemia(n=7,8,10)
    0
    3
    2
        Hyperglycemia(n=7,8,10)
    3
    1
    2
        Hyperkalemia(n=8,8,10)
    0
    0
    2
        Hypermagnesemia(n=7,8,10)
    1
    1
    1
        Hypernatremia (n=7,8,10)
    0
    0
    1
        Hypertriglyceridemia (n=7,6,10)
    3
    3
    7
        Hypoalbuminemia (n=7,8,10)
    3
    4
    6
        Hypocalcemia (n=7,8,10)
    1
    0
    2
        Hypoglycemia (n=7,8,10)
    0
    0
    1
        Hypokalemia (n=8,8,10)
    1
    1
    4
        Hypomagnesemia (n=7,8,10)
    0
    0
    4
        Hyponatremia (n=7,8,10)
    0
    1
    3
        Hypophosphatemia (n=7,7,10)
    1
    0
    5
        Lipase increased (n=7,7,10)
    1
    2
    3
        Serum amylase increased (n=7,7,10)
    2
    1
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Electrocardiogram (ECG) Abnormalities

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    End point title
    		 Number of Subjects With Electrocardiogram (ECG) Abnormalities
    End point description
    ECG abnormalities included: 1) QT interval, QT interval corrected using Bazett's formula (QTcB) and QT interval corrected using Fridericia's formula (QTcF): increase from baseline greater than (>) 30 millisecond (ms) or 60 ms; absolute value >450 ms, >480 ms and >500 ms; 2) heart rate (HR): absolute value <=50 beats per minute (bpm) and decrease from baseline >=20 bpm; absolute value >=120 bpm and increase from baseline >=20 bpm; 3) PR interval: absolute value >=220 ms and increase from baseline >=20 ms; 4) QRS interval: absolute value >=120 ms. Safety analysis set population included all subjects who received at least 1 dose of study drug. Here, n=subjects evaluable for specified rows.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    8
    9
    11
    Units: Subjects
        QT: IFB:>30 ms (n=8,9,11)
    4
    4
    4
        QT: IFB: >60 ms (n=8,9,11)
    1
    3
    2
        QT: >450 ms (n=8,9,11)
    2
    2
    2
        QT: >480 ms (n= 8,9,11)
    0
    1
    1
        QT: >500 ms (n=8,9,11)
    0
    0
    0
        QTcB: IFB: >30 ms (n=7,9,10)
    1
    3
    4
        QTcB: IFB: >60 ms (n=7,9,10)
    1
    1
    0
        QTcB: >450 ms (n=7,9,11)
    4
    5
    9
        QTcB: >480 ms (n=7,9,11)
    2
    3
    4
        QTcB: >500 ms (n=7,9,11)
    1
    2
    1
        QTcF: IFB: >30 ms (n=7,9,10)
    1
    3
    3
        QTcF: IFB: >60 ms (n=7,9,10)
    0
    2
    0
        QTcF: >450 ms (n=7,9,11)
    4
    3
    6
        QTcF: >480 ms (n=7,9,11)
    0
    2
    0
        QTcF: >500 ms (n=7,9,11)
    0
    2
    0
        HR: <=50 bpm and DFB >=20bpm (n=7,9,10)
    0
    1
    0
        HR: >=120 bpm and IFB >=20bpm (n=7,9,10)
    0
    0
    1
        PR: >=220 ms and IFB >=20 ms (n=8,8,11)
    0
    0
    0
        QRS: >=120 ms (n=8,9,11)
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as Assessed by Investigator per Lugano Response Classification Criteria

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    End point title
    		 Duration of Response (DOR) as Assessed by Investigator per Lugano Response Classification Criteria
    End point description
    DOR in subjects with OR as time from first documentation of OR to time of PD/death due to any cause, whichever occurred first. CR: score of 1(no uptake above background),2(uptake <=mediastinum),or 3(uptake <mediastinum but <=liver)with/without residual mass on PET 5-PS,for lymph nodes extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow.PR:>=50% decrease in SPD of up to 6 of largest dominant lymph nodes, no increase in size of other nodes, liver, spleen volume,>=50% decrease in SPD of hepatic splenic nodules, absence of other organ involvement, no new sites of disease. PD: appearance of new lesion more than 1.5cm in any axis, at least 50% increase from nadir in SPD/longest diameter of previous lesion/node. Data censored on date of last adequate tumor assessment in subjects with no event, started new anti-cancer therapy/had 2/more missing assessments. Here, '99999'=due to no subject with PD/death, median and full range could not be estimated.
    End point type
    Secondary
    End point timeframe
    First response (CR or PR) to date of PD, start of new anti-cancer therapy, discontinuation from the study, censoring date or death due to any cause, whichever occurred first (maximum up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    1
    0 [3]
    3 [4]
    Units: Months
        median (full range (min-max))
    1.81 (1.81 to 1.81)
    ( to )
    99999 (99999 to 99999)
    Notes
    [3] - Due to zero number of subject who had events, median and full range were not estimable.
    [4] - All 3 subjects who achieved OR were not observed to have PD or death on study
    No statistical analyses for this end point

    Secondary: Time to Tumor Response (TTR) as Assessed by Investigator per Lugano Response Classification Criteria

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    End point title
    		 Time to Tumor Response (TTR) as Assessed by Investigator per Lugano Response Classification Criteria
    End point description
    TTR was defined for subjects who achieved objective response as time from randomization to first documentation of objective tumor response (CR or PR) that was subsequently confirmed. CR was defined as a score of 1 (no uptake above background), 2 (uptake <= mediastinum), or 3 (uptake <mediastinum but <=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow. PR was defined as >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. Here, “N”: subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    1
    0 [5]
    3
    Units: Months
        median (full range (min-max))
    1.8 (1.8 to 1.8)
    ( to )
    1.9 (1.7 to 2.6)
    Notes
    [5] - Due to zero number of subject who achieved OR, median and full range were not estimable.
    No statistical analyses for this end point

    Secondary: Disease Control Rate as Assessed by the Investigator per Lugano Response Classification Criteria

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    End point title
    		 Disease Control Rate as Assessed by the Investigator per Lugano Response Classification Criteria
    End point description
    Disease control rate was defined as percentage of subjects with disease control. Disease Control (DC) was defined as the best overall response of CR, PR, or stable disease (SD). CR: score of 1 (no uptake above background), 2 (uptake <= mediastinum), or 3 (uptake less than <mediastinum but <=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow. PR: >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. SD: <50% decrease in SDP of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease met. To qualify as a best overall response of SD, at least one SD assessment must be observed >=6 weeks after start date and before disease progression. FAS analysed.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the first documentation of PD, study discontinuation, start of new anti-cancer therapy or death due to any cause, whichever occurred first (maximum up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    9
    9
    11
    Units: Percentage of subjects
        number (confidence interval 95%)
    22.2 (2.8 to 60.0)
    0 (0 to 33.6)
    36.4 (10.9 to 69.2)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) as Assessed by the Investigator per Lugano Response Classification Criteria

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    End point title
    		 Progression-Free Survival (PFS) as Assessed by the Investigator per Lugano Response Classification Criteria
    End point description
    Investigator assessed PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. PFS data was censored on the date of the last adequate tumor assessment for subjects who had no an event (PD or death), for subjects who start a new anti-cancer therapy prior to an event or for subjects with an event after 2 or more missing or inadequate post-baseline tumor assessment. Subjects without an adequate baseline or post-baseline tumor assessment were censored on the date of randomization unless death occurred on or before the time of the second planned tumor assessment in which case the death was considered as an event. FAS analysed. Here, '99999' signifies that due to small number of subjects who had event, 95% CI was not estimable.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to progression of disease, study discontinuation, censoring date or death due to any cause, whichever occurred first (up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    9
    9
    11
    Units: Months
        median (confidence interval 95%)
    1.8 (0.6 to 3.5)
    1.5 (0.3 to 1.8)
    2.7 (1.3 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Subjects last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. Full analysis set population included all subjects who were randomised in the study. Here, '99999' signifies that due to small number of subjects who had event, 95% CI was not estimable.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to discontinuation from the study or death, whichever occurred first (maximum up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    9
    9
    11
    Units: Months
        median (confidence interval 95%)
    14.8 (0.9 to 99999)
    4.0 (0.3 to 11.3)
    5.2 (1.3 to 99999)
    No statistical analyses for this end point

    Secondary: Concentration Verses Time Summary of Avelumab

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    End point title
    		 Concentration Verses Time Summary of Avelumab
    End point description
    Avelumab pharmacokinetic concentration analysis set included all subjects who received at least 1 dose of study drug and who had at least 1 post-dose concentration measurement above the lower limit of quantitation for avelumab. Here, '9999' signifies data not available as none of the subjects were evaluable at specified time point, and '99999' signifies that due to single subject, standard deviation could not be calculated at specified time point. Here, “n”: subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    1 hour Post dose Day 2 Cycle 1, 144 hour Post dose Day 8 of Cycle 1, 0 hour Post dose Day 16 of Cycle 1, Day 1 of Cycle 4 and Cycle 6
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    8
    9
    11
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 2;(n=7,7,10)
    183.29 ( 83.809 )
    198.43 ( 29.387 )
    193.30 ( 29.702 )
        Cycle 1 Day 8; (n=8,8,10)
    75.14 ( 21.357 )
    68.44 ( 18.553 )
    65.33 ( 17.913 )
        Cycle 1 Day 16; (n=7,4,9)
    25.33 ( 13.197 )
    26.53 ( 9.237 )
    19.36 ( 7.810 )
        Cycle 4 Day 1;(n=2,1,4)
    25.00 ( 4.667 )
    62.00 ( 99999 )
    120.88 ( 165.187 )
        Cycle 6 Day 1; (n=0,1,4)
    9999 ( 9999 )
    7.57 ( 99999 )
    39.43 ( 18.327 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

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    End point title
    		 Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status
    End point description
    ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. Avelumab immunogenicity analysis set included subjects who had at least 1 ADA sample collected for avelumab.
    End point type
    Secondary
    End point timeframe
    Baseline: 2 hours pre-dose of first dose of avelumab, Post baseline: post first dose up to up to 30 Days after the end of treatment (maximum up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    8
    9
    11
    Units: Subjects
        Baseline: ADA ever-positive
    0
    0
    1
        Baseline: ADA never-positive
    8
    9
    10
        Post Baseline: ADA ever-positive
    0
    0
    0
        Post Baseline: ADA never-positive
    8
    9
    11
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Rituximab by Never and Ever Positive Status

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    End point title
    		 Number of Subjects With Anti-Drug Antibodies (ADA) Against Rituximab by Never and Ever Positive Status [6]
    End point description
    ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. Rituximab immunogenicity analysis set included subjects who had at least 1 ADA sample collected for rituximab.
    End point type
    Secondary
    End point timeframe
    From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analyzed only in the reporting arms identified
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    8
    11
    Units: Subjects
        ADA ever-positive
    0
    0
        ADA never-positive
    8
    11
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Utomilumab by Never and Ever Positive Status

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    End point title
    		 Number of Subjects With Anti-Drug Antibodies (ADA) Against Utomilumab by Never and Ever Positive Status [7]
    End point description
    ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. Utomilumab immunogenicity analysis set included subjects who had at least 1 ADA sample collected for utomilumab.
    End point type
    Secondary
    End point timeframe
    From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analyzed only in the reporting arms identified
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab
    Number of subjects analysed
    8
    9
    Units: Subjects
        ADA ever-positive
    1
    2
        ADA never-positive
    7
    7
    No statistical analyses for this end point

    Secondary: Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status

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    End point title
    		 Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status
    End point description
    nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point. Data for this endpoint was not collected since there was no subjects with post-baseline ADA ever positive sample for avelumab.
    End point type
    Secondary
    End point timeframe
    From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Subjects
    Notes
    [8] - There was no subjects with post-baseline ADA ever positive sample for avelumab.
    [9] - There was no subjects with post-baseline ADA ever positive sample for avelumab.
    [10] - There was no subjects with post-baseline ADA ever positive sample for avelumab.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Neutralizing Antibodies (nAb) Against Rituximab by Never and Ever Positive Status

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    End point title
    		 Number of Subjects With Neutralizing Antibodies (nAb) Against Rituximab by Never and Ever Positive Status [11]
    End point description
    nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point. Data for this this endpoint was not collected since there was no subjects with rituximab ADA ever positive sample.
    End point type
    Secondary
    End point timeframe
    From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analyzed only in the reporting arms identified
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Subjects
    Notes
    [12] - There was no subject with rituximab ADA ever positive sample.
    [13] - There was no subject with rituximab ADA ever positive sample.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Neutralizing Antibodies (nAb) Against Utomilumab by Never and Ever Positive Status

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    End point title
    		 Number of Subjects With Neutralizing Antibodies (nAb) Against Utomilumab by Never and Ever Positive Status [14]
    End point description
    nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point. Utomilumab immunogenicity analysis set included subjects from the safety analysis set who had at least one ADA/nAb sample collected for utomilumab. Here, N=subjects who were ADA positive and whose samples were further analysed for nAb.
    End point type
    Secondary
    End point timeframe
    From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analyzed only in the reporting arms identified
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab
    Number of subjects analysed
    1
    2
    Units: Subjects
        nAb ever-positive
    0
    0
        nAb never-positive
    1
    2
    No statistical analyses for this end point

    Secondary: Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline

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    End point title
    		 Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline
    End point description
    Percentage of Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline. FAS analysed. Here, N=subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Screening (prior to first dose of study treatment)
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    6
    8
    6
    Units: Percentage of cells staining positive
    median (full range (min-max))
        Tumor Cells (membrane)
    0 (0 to 5)
    0.5 (0.0 to 10.0)
    0 (0 to 30)
        Immune Cells
    7.5 (0.0 to 30.0)
    7.5 (0.0 to 70.0)
    17.5 (0.0 to 50.0)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Minimal Residual Disease Burden (MRD) Positive, Negative and Not Evaluable (NE) Status

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    End point title
    		 Number of Subjects With Minimal Residual Disease Burden (MRD) Positive, Negative and Not Evaluable (NE) Status
    End point description
    Number of participants with MRD positive, negative and not evaluable status were reported in this endpoint. Safety analysis set population included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycle 3, 6, 9, 12 and 18
    End point values
    		 Avelumab+Rituximab+Utomilumab Avelumab+Azacitidine+Utomilumab Avelumab+Bendamustine+Rituximab
    Number of subjects analysed
    8
    9
    11
    Units: Subjects
        Baseline: Positive
    3
    1
    3
        Baseline: Negative
    0
    0
    2
        Baseline: NE
    5
    8
    6
        Cycle 3 Day 1: Positive
    3
    1
    1
        Cycle 3 Day 1: Negative
    0
    0
    3
        Cycle 3 Day 1: NE
    2
    1
    1
        Cycle 6 Day 1: Positive
    0
    1
    0
        Cycle 6 Day 1: Negative
    0
    0
    2
        Cycle 6 Day 1: NE
    0
    0
    2
        Cycle 9 Day 1: Positive
    0
    0
    0
        Cycle 9 Day 1: Negative
    0
    0
    1
        Cycle 9 Day 1: NE
    0
    0
    2
        Cycle 12 Day 1: Positive
    0
    0
    0
        Cycle 12 Day 1: Negative
    0
    0
    1
        Cycle 12 Day 1: NE
    0
    0
    2
        Cycle 18 Day 1: Positive
    0
    0
    0
        Cycle 18 Day 1: Negative
    0
    0
    0
        Cycle 18 Day 1: NE
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to follow up (36 months)
    Adverse event reporting additional description
    Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 subject and as non-serious in another subject or 1 subject may have experienced both serious and non-serious event during study. Safety analysis set population included all subjects who were randomised in the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Avelumab+Rituximab+Utomilumab
    Reporting group description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycle 1 and 2, if well tolerated than continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab tolerated well than it continued to administer on Day 1 in Cycle 3 and in all subsequent cycles until the subject no longer received clinical benefit. Each treatment cycle was of 28 days.

    Reporting group title
    Avelumab+Bendamustine+Rituximab
    Reporting group description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycle 1 and 2, if well tolerated than continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine tolerated well than it continued to administer on Day 1 and Day 2 in Cycle 3 and in all subsequent cycles for a maximum of 6 cycles. Each treatment cycle was of 28 days.

    Reporting group title
    Avelumab+Azacitidine+Utomilumab
    Reporting group description
    		 Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycle 1 and 2, if well tolerated than continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the subject no longer received clinical benefit. Azacitidine 40 mg/m^2 sub-cutaneous (SC) dose was administered on Day 1 to 5 of each treatment cycle, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab tolerated well, than it continued to administer on Day 1 in Cycle 3 and in all subsequent cycles until the subject no longer received clinical benefit. Each treatment cycle was of 28 days.

    Serious adverse events
    		 Avelumab+Rituximab+Utomilumab Avelumab+Bendamustine+Rituximab Avelumab+Azacitidine+Utomilumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    7 / 11 (63.64%)
    6 / 9 (66.67%)
         number of deaths (all causes)
    4
    6
    8
         number of deaths resulting from adverse events
    2
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (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
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (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
    Pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (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
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (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
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (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
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         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
    		 Avelumab+Rituximab+Utomilumab Avelumab+Bendamustine+Rituximab Avelumab+Azacitidine+Utomilumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    11 / 11 (100.00%)
    9 / 9 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    1
    Hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Chills
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    5
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 11 (36.36%)
    1 / 9 (11.11%)
         occurrences all number
    1
    6
    1
    Generalised oedema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Injection site reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 11 (27.27%)
    1 / 9 (11.11%)
         occurrences all number
    4
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    3
    2
    1
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    2
    Amylase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    2
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Blood alkaline phosphatase
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Blood calcium
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    0
    6
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    2
    Haemoglobin decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Lipase decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 11 (27.27%)
    1 / 9 (11.11%)
         occurrences all number
    0
    11
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    0 / 9 (0.00%)
         occurrences all number
    0
    9
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    4
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    2
    Infusion related reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Transfusion reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Head discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Somnolence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Taste disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 11 (36.36%)
    2 / 9 (22.22%)
         occurrences all number
    3
    8
    2
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    Lymph node pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    2 / 8 (25.00%)
    5 / 11 (45.45%)
    1 / 9 (11.11%)
         occurrences all number
    5
    16
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 11 (27.27%)
    0 / 9 (0.00%)
         occurrences all number
    1
    8
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Dry eye
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 11 (36.36%)
    5 / 9 (55.56%)
         occurrences all number
    1
    5
    6
    Diarrhoea
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    3
    2
    1
    Hiatus hernia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 11 (36.36%)
    2 / 9 (22.22%)
         occurrences all number
    2
    6
    3
    Oesophageal obstruction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Toothache
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    1
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    3
    Rash erythematous
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Rash papular
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Microalbuminuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Nocturia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    5
    0
    Renal failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Primary hypothyroidism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Back pain
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 11 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    2
    0
    4
    Bone pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    1
    Myalgia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    0
    Herpes zoster
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 11 (27.27%)
    0 / 9 (0.00%)
         occurrences all number
    3
    4
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    3
    2
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2017
    Futility Interim Analysis added in Phase 1b to allow for early stopping of any treatment arm for futility.

    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.
    Data for Phase 3 endpoints were not collected as study was terminated early and phase 3 was not conducted.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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