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    Clinical Trial Results:
    A phase 2 study of brentuximab vedotin in combination with standard of care treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [RCHOP]) or RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) as front-line therapy in patients with diffuse large B-cell lymphoma (DLBCL)

    Summary
    EudraCT number
    		 2015-004741-54
    Trial protocol
    		 CZ   ES   IT  
    Global end of trial date
    01 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2018
    First version publication date
    13 May 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SGN35-017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01925612
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Seattle Genetics, Inc
    Sponsor organisation address
    21823 30th Dr SE, Bothell, United States, 98021-3907
    Public contact
    Chief Medical Officer, Seattle Genetics, Inc, 001 855-473-2436, medinfo@seagen.com
    Scientific contact
    Chief Medical Officer, Seattle Genetics, Inc, 001 855-473-2436, medinfo@seagen.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
    15 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the antitumor activity of brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone, as measured by the CR rate at the end of treatment per investigator assessment in treatment-naive patients with high-intermediate or high risk systemic DLBCL To assess the safety profile of brentuximab vedotin administered at dose levels of 1.2 mg/kg versus 1.8 mg/kg in combination with RCHOP or brentuximab vedotin 1.8 mg/kg in combination with RCHP in treatment-naive patients with high-intermediate or high risk systemic DLBCL
    Protection of trial subjects
    The protocol for this study was designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. The conduct of all aspects of the study, including methods for obtaining informed consent, were also in accordance with principles enunciated in the declaration, the International Conference on Harmonisation (ICH) Good Clinical Practices (GCP), and applicable Food and Drug Administration (FDA) regulations/guidelines set forth in Title 21 CFR Parts 11, 50, 54, 56, and 312. The consent form approved by each IRB/IEC included all elements required by the applicable regional laws and regulations, including a statement that Seattle Genetics, Inc. and authorities had access to patient records. Consent was obtained from all patients before any protocol-required procedures were performed, including any procedure not part of normal patient care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    United States: 80
    Worldwide total number of subjects
    85
    EEA total number of subjects
    5
    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)
    39
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were enrolled from 30-Aug-2013 through 28-Nov-2016.

    Pre-assignment
    Screening details
    		 The population to be studied includes treatment-naive patients with systemic de novo or transformed DLBCL or follicular non-Hodgkin lymphoma (NHL) grade 3b.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Part 1 was randomized and open-label. Part 2 was non-randomized and open-label. Part 3 was randomized and open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: BV (1.2 mg/kg) + RCHOP
    Arm description
    		 Part 1 of the study is randomized and open-label. Brentuximab vedotin was administered at 1.2mg/kg in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    Adcetris, SGN-35
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.2mg/kg every 3 weeks by IV infusion

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    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
    1.4 mg/m2 every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total).

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles.

    Arm title
    		 Part 1: BV (1.8 mg/kg) + RCHOP
    Arm description
    		 Part 1 of the study is a randomized and open-label. Brentuximab vedotin was administered at 1.8 mg/kg in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    Adcetris, SGN-35
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.8mg/kg every 3 weeks by IV infusion

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    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
    1.4 mg/m2 every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total).

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles.

    Arm title
    		 Part 2: BV (1.8 mg/kg) + RCHP
    Arm description
    		 Part 2 of the study was non-randomized and open-label. Brentuximab vedotin (1.8 mg/kg) was administered in combination with RCHP chemotherapy (rituximab, cyclophosphamide, doxorubicin, and prednisone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    Adcetris, SGN-35
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.8mg/kg every 3 weeks by IV infusion

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles.

    Arm title
    		 Part 3: BV (1.8 mg/kg) + RCHP
    Arm description
    		 Part 3 of the study was randomized and open-label. Brentuximab vedotin (1.8 mg/kg) was administered in combination with RCHP chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    Adcetris, SGN-35
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.8mg/kg every 3 weeks by IV infusion

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles.

    Arm title
    		 Part 3: RCHOP
    Arm description
    		 Part 3 of the study was randomized and open-label. RCHOP chemotherapy was administered alone.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles.

    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
    1.4 mg/m2 every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total).

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles.

    Number of subjects in period 1
    		Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Started
    29
    22
    11
    11
    12
    Completed
    25
    18
    10
    10
    10
    Not completed
    4
    4
    1
    1
    2
         Adverse event, serious fatal
    1
    1
    -
    1
    2
         Adverse event, non-fatal
    2
    2
    -
    -
    -
         Progressive Disease
    1
    1
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: BV (1.2 mg/kg) + RCHOP
    Reporting group description
    		 Part 1 of the study is randomized and open-label. Brentuximab vedotin was administered at 1.2mg/kg in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

    Reporting group title
    Part 1: BV (1.8 mg/kg) + RCHOP
    Reporting group description
    		 Part 1 of the study is a randomized and open-label. Brentuximab vedotin was administered at 1.8 mg/kg in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

    Reporting group title
    Part 2: BV (1.8 mg/kg) + RCHP
    Reporting group description
    		 Part 2 of the study was non-randomized and open-label. Brentuximab vedotin (1.8 mg/kg) was administered in combination with RCHP chemotherapy (rituximab, cyclophosphamide, doxorubicin, and prednisone).

    Reporting group title
    Part 3: BV (1.8 mg/kg) + RCHP
    Reporting group description
    		 Part 3 of the study was randomized and open-label. Brentuximab vedotin (1.8 mg/kg) was administered in combination with RCHP chemotherapy.

    Reporting group title
    Part 3: RCHOP
    Reporting group description
    		 Part 3 of the study was randomized and open-label. RCHOP chemotherapy was administered alone.

    Reporting group values
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP Total
    Number of subjects
    		 29 22 11 11 12 85
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 10 11 7 5 6 39
        65 years and over
    		 19 11 4 6 6 46
    Age continuous
    Units: years
        median (full range (min-max))
    		 70 (33 to 80) 64 (21 to 81) 59 (22 to 78) 68 (46 to 74) 65 (41 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 13 6 4 10 6 39
        Male
    		 16 16 7 1 6 46
    Ethnicity
    NIH/OMB
    Units: Subjects
        Hispanic or Latino
    		 4 2 1 0 1 8
        Not Hispanic or Latino
    		 25 18 8 11 11 73
        Unknown or Not Reported
    		 0 2 2 0 0 4
    Race
    NIH/OMB
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 1 1 0 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 1 1 1 1 0 4
        White
    		 27 17 8 10 12 74
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 1 3 1 0 0 5
    Region of Enrollment
    Units: Subjects
        United States
    		 29 22 11 8 10 80
        Czechia
    		 0 0 0 1 1 2
        Poland
    		 0 0 0 2 0 2
        Italy
    		 0 0 0 0 1 1
    ECOG Performance Status
    Units: Subjects
        Zero
    		 5 4 1 4 4 18
        One
    		 16 12 4 4 3 39
        Two
    		 8 6 6 3 5 28

    End points

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    End points reporting groups
    Reporting group title
    Part 1: BV (1.2 mg/kg) + RCHOP
    Reporting group description
    		 Part 1 of the study is randomized and open-label. Brentuximab vedotin was administered at 1.2mg/kg in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

    Reporting group title
    Part 1: BV (1.8 mg/kg) + RCHOP
    Reporting group description
    		 Part 1 of the study is a randomized and open-label. Brentuximab vedotin was administered at 1.8 mg/kg in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

    Reporting group title
    Part 2: BV (1.8 mg/kg) + RCHP
    Reporting group description
    		 Part 2 of the study was non-randomized and open-label. Brentuximab vedotin (1.8 mg/kg) was administered in combination with RCHP chemotherapy (rituximab, cyclophosphamide, doxorubicin, and prednisone).

    Reporting group title
    Part 3: BV (1.8 mg/kg) + RCHP
    Reporting group description
    		 Part 3 of the study was randomized and open-label. Brentuximab vedotin (1.8 mg/kg) was administered in combination with RCHP chemotherapy.

    Reporting group title
    Part 3: RCHOP
    Reporting group description
    		 Part 3 of the study was randomized and open-label. RCHOP chemotherapy was administered alone.

    Primary: Complete Remission Rate

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    End point title
    		 Complete Remission Rate [1]
    End point description
    Number (count) of participants that achieved complete remission according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).
    End point type
    Primary
    End point timeframe
    Up to 6 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Within-group analysis
    End point values
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Number of subjects analysed
    29
    22
    11
    11
    12
    Units: Count of Participants
    20
    16
    9
    6
    8
    No statistical analyses for this end point

    Primary: Incidence of Adverse Events

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    End point title
    		 Incidence of Adverse Events [2]
    End point description
    Number (count) of participants that experienced at least 1 adverse event.
    End point type
    Primary
    End point timeframe
    Up to 6 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Data for this end point were summarized per protocol.
    End point values
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Number of subjects analysed
    29
    22
    11
    11
    12
    Units: Count of Participants
    29
    22
    11
    11
    12
    No statistical analyses for this end point

    Primary: Incidence of Laboratory Abnormalities

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    End point title
    		 Incidence of Laboratory Abnormalities [3]
    End point description
    Number (count) of participants that experienced a Grade 3 or higher maximum post-baseline laboratory toxicity (hematology and chemistry)
    End point type
    Primary
    End point timeframe
    Up to 6 months
    Notes
    [3] - 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: Data for this end point were summarized per protocol.
    End point values
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Number of subjects analysed
    29
    22
    11
    11
    12
    Units: Count of Participants
        Any Hematology Test
    10
    16
    4
    6
    4
        Lymphocytes (x10^3/uL)
    8
    15
    3
    4
    4
        Absolute Neutrophil Count (x10^3/uL)
    4
    4
    1
    2
    0
        Neutrophils (x10^3/uL)
    4
    4
    1
    2
    0
        Leukocytes (x10^3/uL)
    3
    2
    1
    1
    1
        Hemoglobin (x10^3/uL)
    0
    1
    0
    1
    0
        Platelets (x10^3/uL)
    1
    1
    0
    0
    0
        Any Chemistry Test
    4
    7
    2
    1
    3
        Glucose (mg/dL)
    3
    5
    0
    0
    1
        Potassium (mEq)/L
    0
    2
    1
    1
    2
        Calcium (mg/dL)
    1
    1
    0
    0
    0
        Sodium (mEq/L)
    0
    2
    0
    0
    0
        Alanine Aminotransferase (IU/L)
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Number (count) of participants that achieved complete or partial remission at the end of treatment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    End point values
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Number of subjects analysed
    29
    22
    11
    11
    12
    Units: Count of Participants
    23
    19
    10
    10
    9
    No statistical analyses for this end point

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Median progression-free survival (in months) and observed minimum-maximum range. Insufficient data to determine median value in all arms. Arms and full ranges listed below: Part 1: BV (1.2 mg/kg) + RCHOP (0.62, 40.21+) Part 1: BV (1.8mg/kg) + RCHOP (1.28, 39.85+) Part 2: BV (1.8 mg/kg) + RCHP (3.35, 24.34+) Part 3: BV (1.8 mg/kg) + RCHP (3.25, 15.41+) Part 3: RCHOP (1.25, 16.43+)
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Number of subjects analysed
    29
    22
    11
    11
    12
    Units: Months
        median (full range (min-max))
    999 (0.62 to 999)
    999 (1.28 to 999)
    999 (3.35 to 999)
    999 (3.25 to 999)
    999 (1.25 to 999)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Median progression-free survival (in months) and observed minimum-maximum range. Insufficient data to calculate median for 3 arms. Arms and full ranges are listed here: Part 1: BV (1.2 mg/kg) + RCHOP (0.62, 42.79) Part 2: BV (1.8 mg/kg) + RCHP (16.56, 25.76) Part 3: BV (1.8 mg/kg) + RCHP (3.25, 16.85)
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Number of subjects analysed
    29
    22
    11
    11
    12
    Units: Months
        median (full range (min-max))
    999 (0.62 to 999)
    18.1 (1.28 to 44.29)
    999 (16.56 to 999)
    999 (3.25 to 999)
    4.6 (1.25 to 19.22)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from study Day 1 (predose) though the EOT visit or 30 days after the last study treatment (mono- or combination therapy), whichever was later. However, all protocol-related AEs were collected from the time of informed consent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Part 1: BV (1.2 mg/kg) + RCHOP
    Reporting group description
    		 -

    Reporting group title
    Part 1: BV (1.8 mg/kg) + RCHOP
    Reporting group description
    		 -

    Reporting group title
    Part 2: BV (1.8 mg/kg) + RCHP
    Reporting group description
    		 -

    Reporting group title
    Part 3: BV (1.8 mg/kg) + RCHP
    Reporting group description
    		 -

    Reporting group title
    Part 3: RCHOP
    Reporting group description
    		 -

    Serious adverse events
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 29 (55.17%)
    14 / 22 (63.64%)
    5 / 11 (45.45%)
    4 / 11 (36.36%)
    4 / 12 (33.33%)
         number of deaths (all causes)
    6
    7
    1
    1
    2
         number of deaths resulting from adverse events
    1
    2
    0
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer metastatic
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    8 / 29 (27.59%)
    8 / 22 (36.36%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    10 / 13
    9 / 13
    2 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pantoea agglomerans infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: BV (1.2 mg/kg) + RCHOP Part 1: BV (1.8 mg/kg) + RCHOP Part 2: BV (1.8 mg/kg) + RCHP Part 3: BV (1.8 mg/kg) + RCHP Part 3: RCHOP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 29 (100.00%)
    22 / 22 (100.00%)
    11 / 11 (100.00%)
    11 / 11 (100.00%)
    12 / 12 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 29 (3.45%)
    6 / 22 (27.27%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    9
    0
    0
    0
    Flushing
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Hot flush
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    1
    Hypertension
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    5
    0
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 29 (58.62%)
    16 / 22 (72.73%)
    7 / 11 (63.64%)
    2 / 11 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    28
    30
    7
    2
    4
    Asthenia
         subjects affected / exposed
    8 / 29 (27.59%)
    7 / 22 (31.82%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    19
    8
    0
    0
    3
    Chills
         subjects affected / exposed
    7 / 29 (24.14%)
    4 / 22 (18.18%)
    3 / 11 (27.27%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    12
    4
    3
    2
    0
    Oedema peripheral
         subjects affected / exposed
    7 / 29 (24.14%)
    7 / 22 (31.82%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    9
    8
    2
    2
    0
    Pyrexia
         subjects affected / exposed
    6 / 29 (20.69%)
    6 / 22 (27.27%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    9
    6
    1
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    3
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Pain
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    0
    0
    0
    Malaise
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Throat irritation
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    4 / 11 (36.36%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    4
    1
    0
    Dyspnoea
         subjects affected / exposed
    7 / 29 (24.14%)
    9 / 22 (40.91%)
    0 / 11 (0.00%)
    3 / 11 (27.27%)
    4 / 12 (33.33%)
         occurrences all number
    7
    12
    0
    3
    4
    Cough
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 22 (18.18%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    3
    7
    1
    1
    2
    Nasal congestion
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    3
    0
    0
    1
    2
    Oropharyngeal pain
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    1
    0
    0
    1
    Respiratory tract irritation
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    1
    3
    0
    Sinus congestion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Pleural effusion
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    1
    0
    Hiccups
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 29 (24.14%)
    8 / 22 (36.36%)
    2 / 11 (18.18%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    7
    8
    2
    1
    0
    Anxiety
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 22 (18.18%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    3
    5
    0
    1
    1
    Confusional state
         subjects affected / exposed
    4 / 29 (13.79%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    Depression
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    0
    0
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    10 / 29 (34.48%)
    8 / 22 (36.36%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    16
    13
    1
    0
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    2
    2
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    5
    1
    0
    2
    0
    Contusion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    3
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    8 / 29 (27.59%)
    4 / 22 (18.18%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    9
    4
    0
    1
    0
    Palpitations
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    1
    5
    0
    1
    0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    16 / 29 (55.17%)
    15 / 22 (68.18%)
    6 / 11 (54.55%)
    4 / 11 (36.36%)
    4 / 12 (33.33%)
         occurrences all number
    25
    27
    6
    6
    4
    Headache
         subjects affected / exposed
    6 / 29 (20.69%)
    6 / 22 (27.27%)
    3 / 11 (27.27%)
    2 / 11 (18.18%)
    1 / 12 (8.33%)
         occurrences all number
    7
    6
    5
    3
    1
    Dizziness
         subjects affected / exposed
    4 / 29 (13.79%)
    8 / 22 (36.36%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    6
    9
    1
    2
    3
    Peripheral motor neuropathy
         subjects affected / exposed
    4 / 29 (13.79%)
    8 / 22 (36.36%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    11
    14
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    4 / 29 (13.79%)
    5 / 22 (22.73%)
    2 / 11 (18.18%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    6
    5
    2
    1
    2
    Restless legs syndrome
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 22 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    2
    0
    0
    Balance disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Hypoaesthesia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    10 / 29 (34.48%)
    7 / 22 (31.82%)
    4 / 11 (36.36%)
    4 / 11 (36.36%)
    2 / 12 (16.67%)
         occurrences all number
    27
    20
    5
    4
    4
    Anaemia
         subjects affected / exposed
    9 / 29 (31.03%)
    7 / 22 (31.82%)
    2 / 11 (18.18%)
    3 / 11 (27.27%)
    1 / 12 (8.33%)
         occurrences all number
    26
    20
    5
    8
    1
    Thrombocytopenia
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 22 (13.64%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    20
    19
    2
    0
    0
    Leukopenia
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 22 (18.18%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    13
    16
    0
    0
    0
    Febrile neutropenia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    0
    0
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    1
    4
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    14 / 29 (48.28%)
    15 / 22 (68.18%)
    8 / 11 (72.73%)
    4 / 11 (36.36%)
    2 / 12 (16.67%)
         occurrences all number
    24
    23
    9
    6
    2
    Diarrhoea
         subjects affected / exposed
    14 / 29 (48.28%)
    15 / 22 (68.18%)
    3 / 11 (27.27%)
    6 / 11 (54.55%)
    1 / 12 (8.33%)
         occurrences all number
    19
    23
    4
    8
    1
    Constipation
         subjects affected / exposed
    8 / 29 (27.59%)
    9 / 22 (40.91%)
    6 / 11 (54.55%)
    1 / 11 (9.09%)
    5 / 12 (41.67%)
         occurrences all number
    9
    12
    6
    1
    5
    Vomiting
         subjects affected / exposed
    7 / 29 (24.14%)
    14 / 22 (63.64%)
    2 / 11 (18.18%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    9
    17
    2
    2
    0
    Stomatitis
         subjects affected / exposed
    8 / 29 (27.59%)
    3 / 22 (13.64%)
    3 / 11 (27.27%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    10
    4
    3
    1
    1
    Abdominal pain
         subjects affected / exposed
    6 / 29 (20.69%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    6
    3
    0
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Haemorrhoids
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 22 (4.55%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    Oral pain
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 22 (9.09%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    2
    0
    1
    Dyspepsia
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 22 (13.64%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    5
    3
    2
    1
    0
    Dry mouth
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    3
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    2
    3
    0
    1
    1
    Dysphagia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    2
    0
    Epigastric discomfort
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tongue discolouration
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Toothache
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 29 (17.24%)
    9 / 22 (40.91%)
    8 / 11 (72.73%)
    3 / 11 (27.27%)
    3 / 12 (25.00%)
         occurrences all number
    6
    10
    10
    3
    4
    Dry skin
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 22 (4.55%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    2
    0
    1
    Night sweats
         subjects affected / exposed
    4 / 29 (13.79%)
    2 / 22 (9.09%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    2
    2
    0
    1
    Skin hyperpigmentation
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 22 (13.64%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    3
    3
    2
    1
    2
    Blister
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Rash
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    1
    0
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Renal failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 22 (18.18%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    6
    4
    1
    1
    3
    Muscle spasms
         subjects affected / exposed
    6 / 29 (20.69%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    7
    2
    0
    0
    0
    Myalgia
         subjects affected / exposed
    4 / 29 (13.79%)
    4 / 22 (18.18%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    5
    7
    0
    0
    0
    Back pain
         subjects affected / exposed
    5 / 29 (17.24%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    5
    2
    0
    1
    0
    Bone pain
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    3
    3
    0
    1
    0
    Flank pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    0
    1
    1
    Muscular weakness
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Infections and infestations
    Candida infection
         subjects affected / exposed
    5 / 29 (17.24%)
    5 / 22 (22.73%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    8
    7
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    1
    2
    1
    Oral candidiasis
         subjects affected / exposed
    4 / 29 (13.79%)
    2 / 22 (9.09%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    2
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Fungal infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 29 (24.14%)
    10 / 22 (45.45%)
    2 / 11 (18.18%)
    2 / 11 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    10
    15
    2
    2
    3
    Dehydration
         subjects affected / exposed
    3 / 29 (10.34%)
    9 / 22 (40.91%)
    2 / 11 (18.18%)
    2 / 11 (18.18%)
    1 / 12 (8.33%)
         occurrences all number
    3
    11
    3
    3
    1
    Hypokalaemia
         subjects affected / exposed
    6 / 29 (20.69%)
    5 / 22 (22.73%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
    2 / 12 (16.67%)
         occurrences all number
    10
    8
    1
    3
    3
    Hypomagnesaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    5 / 22 (22.73%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    8
    0
    2
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 22 (9.09%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    6
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    0
    0
    4
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    11
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2013
    • Removed CD30 expression by local pathology laboratory as a screening assessment, for operational ease. CD30 expression was still evaluated by central pathology laboratory. • Removed randomization stratification by CD30 expression because it was unlikely that significant imbalances would be observed between treatment arms. • Clarified that the optional malignant lymphoma biopsy may be requested for patients who progress at any time during their participation on the study. • Clarified the definition of PFS and associated censoring rules.
    04 Nov 2013
    • Clarified the permissible use of corticosteroids prior to first dose • Clarified that routine vaccination was permitted as long as the vaccine did not contain live microorganisms • Added serology for hepatitis B surface antigen and anti-hepatitis B core antibody to the screening assessments to ensure exclusion of patients who are positive for either hepatitis B surface antigen or anti-hepatitis B core antibody because of the risk of hepatitis B reactivation in patients treated with rituximab • Clarified the definition of study treatment-related AEs • Clarified that certain AEs may be followed until resolution, return to baseline, or study closure
    26 Feb 2014
    • Revised protocol to define high-intermediate and high risk patients based on standard IPI or age-adjusted IPI • Clarified to show that all samples provided by patients may be used to evaluate disease-related biomarkers, including baseline tumor specimens and not just those specimens taken on treatment
    14 Jan 2015
    • Added new part to the study (Part 2) to assess safety, efficacy, and PK of BV + RCHP; numerous sections of the protocol were updated
    10 Aug 2015
    • Added new part to the study (Part 3) to assess safety and antitumor activity of BV + RCHP versus RCHOP alone; numerous sections of the protocol were updated • Revised Inclusion criterion No. 7 to clarify patients must use 2 effective contraception methods during the study • Revised Exclusion criterion No. 12 to allow patients with negative PCR assay • Added instructions regarding testing for hepatitis B PCR assay and concomitant therapy with antiviral prophylaxis

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

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