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    Clinical Trial Results:
    An open label multicenter Phase Ib/II trial to determine the dose of BI 836826 in combination with gemcitabine and oxaliplatin (GemOx) and the efficacy of BI 836826-GemOx versus rituximab (R)- GemOx (R-GemOx) in patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for, or have relapsed/progressed after autologous/allogeneic stem cell transplant

    Summary
    EudraCT number
    		 2014-004794-16
    Trial protocol
    		 BE   IT  
    Global end of trial date
    16 Mar 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Dec 2021
    First version publication date
    29 Mar 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1270.11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02624492
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.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
    28 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of Phase Ib of the trial was to investigate the maximum tolerated dose (MTD), safety and tolerability, pharmacokinetics (PK), and preliminary efficacy of BI 836826 in combination with GemOx in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jan 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Spain: 14
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    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)
    22
    From 65 to 84 years
    12
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This trial was designed to consist of 2 parts. First part was an open-label, non-randomised, Phase Ib dose-escalation trial according to a standard 3+3 design to determine the maximum tolerated dose (MTD) of BI 836286 in combination with gemcitabine and oxaliplatin. Second part of the trial, an open-label randomised Phase II, was not conducted.

    Pre-assignment
    Screening details
    		 All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patients) met all inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were violated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BI 836826 25 milligram (mg) + GemOx
    Arm description
    		 Patients were administered (intravenous infusion) BI 836826 25 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 836826
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 25 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 25 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 25 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Arm title
    		 BI 836826 50 mg + GemOx
    Arm description
    		 Patients were administered (intravenous infusion) BI 836826 50 mg on Day 8 and GemOx (gemcitabine 1000 mg/m^2 plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 836826
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 50 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 50 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 50 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Arm title
    		 BI 836826 100 mg + GemOx
    Arm description
    		 Patients were administered (intravenous infusion) BI 836826 100 mg on Day 8 and GemOx (gemcitabine 1000 mg/m^2 plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 836826
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 100 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 100 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered (intravenous infusion) BI 836826 100 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Number of subjects in period 1 [1]
    		BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx
    Started
    5
    8
    8
    Completed
    3
    4
    3
    Not completed
    2
    4
    5
         Adverse event, serious fatal
    -
    1
    -
         Adverse event, non-fatal
    2
    1
    2
         Progressive disease
    -
    2
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication. No Statistical analysis

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BI 836826 25 milligram (mg) + GemOx
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 25 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Reporting group title
    BI 836826 50 mg + GemOx
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 50 mg on Day 8 and GemOx (gemcitabine 1000 mg/m^2 plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Reporting group title
    BI 836826 100 mg + GemOx
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 100 mg on Day 8 and GemOx (gemcitabine 1000 mg/m^2 plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Reporting group values
    		 BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx Total
    Number of subjects
    		 5 8 8 21
    Age categorical
    Units: Subjects
    Age Continuous
    The treated set (TS) includes all randomised patients who received at least 1 dose of trial medication.
    Units: years
        arithmetic mean (standard deviation)
    		 62.4 ( 26.6 ) 56.5 ( 14.3 ) 57.9 ( 14.0 ) -
    Sex: Female, Male
    The treated set (TS) includes all randomised patients who received at least 1 dose of trial medication.
    Units: Subjects
        Female
    		 4 4 3 11
        Male
    		 1 4 5 10
    Race (NIH/OMB)
    The treated set (TS) includes all randomised patients who received at least 1 dose of trial medication.
    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
    		 5 8 8 21
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    The treated set (TS) includes all randomised patients who received at least 1 dose of trial medication.
    Units: Subjects
        Hispanic or Latino
    		 0 3 4 7
        Not Hispanic or Latino
    		 5 5 4 14
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    BI 836826 25 milligram (mg) + GemOx
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 25 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Reporting group title
    BI 836826 50 mg + GemOx
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 50 mg on Day 8 and GemOx (gemcitabine 1000 mg/m^2 plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Reporting group title
    BI 836826 100 mg + GemOx
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 100 mg on Day 8 and GemOx (gemcitabine 1000 mg/m^2 plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Primary: Number of patients with Dose Limiting Toxicities (DLTs) in the maximum tolerated dose (MTD) evaluation period- Phase 1b

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    End point title
    		 Number of patients with Dose Limiting Toxicities (DLTs) in the maximum tolerated dose (MTD) evaluation period- Phase 1b [1]
    End point description
    DLT (non-haematologic & haematologic drug-related adverse events (AEs)).Non-haematologic AEs of Common Toxicity Criteria for AEs Grade 3 or higher qualified for DLTs with following exceptions: laboratory abnormalities (corrected with treatment within 48 h);nausea, vomiting, or diarrhoea(resolved within 48 h with adequate treatment); neuropathy (related to oxaliplatin);or an infusion-related reactions.For haematologic AEs, DLTs: Grade 4 neutropenia lasting >7 days (d) despite growth factors support;any febrile neutropenia(not resolved within 48 hours with appropriate treatment);Grade 4 thrombocytopenia lasting >7 d or Grade 3/4 thrombocytopenia clinically significant bleeding; failure to recover platelets ≥75*10^9/litres (L) by 4 weeks after start of cycle;or failure to recover neutrophils ≥1.0*10^9/L by 4 weeks after start of cycle.MTD evaluation set:All patients who were documented to have received at least 1 dose of BI 836826 and were not replaced for the MTD evaluation.
    End point type
    Primary
    End point timeframe
    14 days from first trial medication
    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: Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    		 BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx
    Number of subjects analysed
    3 [2]
    6 [3]
    6 [4]
    Units: participants
    0
    1
    1
    Notes
    [2] - MTD set
    [3] - MTD set
    [4] - MTD set
    No statistical analyses for this end point

    Primary: The MTD of BI 836826 with GemOx- Phase 1b

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    End point title
    		 The MTD of BI 836826 with GemOx- Phase 1b [5]
    End point description
    MTD defined as the highest dose studied for which the number of patients with dose-limiting toxicity (DLT) was 17% or less (i.e. not more than 1 of 6 patients) during the MTD evaluation period (Cycle 1). The trial was discontinued prematurely before the MTD based on the frequency of patients with DLTs in the MTD evaluation period, i.e. the 1st treatment cycle, was reached.
    End point type
    Primary
    End point timeframe
    14 days from first trial medication
    Notes
    [5] - 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: Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    		 BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    Units: mg
    Notes
    [6] - Trial was discontinued prematurely before the MTD in MTD evaluation period was reached
    [7] - Trial was discontinued prematurely before the MTD in MTD evaluation period was reached
    [8] - Trial was discontinued prematurely before the MTD in MTD evaluation period was reached
    No statistical analyses for this end point

    Primary: Overall response, i.e. CR and PR, by central review assessment- Phase II

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    End point title
    		 Overall response, i.e. CR and PR, by central review assessment- Phase II [9]
    End point description
    Overall response based on central review assessment, i.e. CR and PR by central review assessment; CR: Disappearance of all evidence of disease PR: Regression of measurable disease and no new sites. Sponsor discontinued the trial for strategic reasons. Consequently, Phase II of the trial was not conducted and hence the endpoint is not evaluated.
    End point type
    Primary
    End point timeframe
    up to 32 weeks from first trial medication administration
    Notes
    [9] - 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: Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    		 BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx
    Number of subjects analysed
    0 [10]
    0 [11]
    0 [12]
    Units: participants
    Notes
    [10] - Primary & secondary endpoints of Phase II are not applicable since Phase II has not been conducted
    [11] - Primary & secondary endpoints of Phase II are not applicable since Phase II has not been conducted
    [12] - Primary & secondary endpoints of Phase II are not applicable since Phase II has not been conducted
    No statistical analyses for this end point

    Secondary: Overall response based on investigator’s assessment- Phase 1b

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    End point title
    		 Overall response based on investigator’s assessment- Phase 1b
    End point description
    Overall response based on investigator’s assessment, i.e. partial remission (PR) and complete remission (CR) by investigator assessment; CR: Disappearance of all evidence of disease PR: Regression of measurable disease and no new sites
    End point type
    Secondary
    End point timeframe
    up to 32 weeks from first trial medication administration.
    End point values
    		 BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx
    Number of subjects analysed
    5 [13]
    8 [14]
    8 [15]
    Units: participants
        CR|
    1
    0
    1
        PR|
    2
    3
    1
    Notes
    [13] - Treated set
    [14] - Treated set
    [15] - Treated set
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve over the time interval from 0 to the time of the last quantifiable data point after drug administration (AUC0-tz) of BI 836826- Phase 1b

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    End point title
    		 Area under the plasma concentration-time curve over the time interval from 0 to the time of the last quantifiable data point after drug administration (AUC0-tz) of BI 836826- Phase 1b
    End point description
    Pharmacokinetic analyses were planned to be performed. However, after encountering technical difficulties and discontinuation of the BI 836826 programme, the sponsor decided not to re-analyse the samples.
    End point type
    Secondary
    End point timeframe
    up to 32 weeks from first trial medication administration.
    End point values
    		 BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx
    Number of subjects analysed
    0 [16]
    0 [17]
    0 [18]
    Units: nanomole*hours/litre (nmol*h/L)
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    Notes
    [16] - PK parameters were not calculated because the sponsor discontinued development of BI 836826
    [17] - PK parameters were not calculated because the sponsor discontinued development of BI 836826
    [18] - PK parameters were not calculated because the sponsor discontinued development of BI 836826
    No statistical analyses for this end point

    Secondary: Maximum measured plasma concentration of BI 836826 (Cmax)- Phase 1b

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    End point title
    		 Maximum measured plasma concentration of BI 836826 (Cmax)- Phase 1b
    End point description
    Pharmacokinetic analyses were planned to be performed. However, after encountering technical difficulties and discontinuation of the BI 836826 programme, the sponsor decided not to re-analyse the samples.
    End point type
    Secondary
    End point timeframe
    up to 32 weeks from first trial medication administration.
    End point values
    		 BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    Units: nmol/L
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    Notes
    [19] - PK parameters were not calculated because the sponsor discontinued development of BI 836826
    [20] - PK parameters were not calculated because the sponsor discontinued development of BI 836826
    [21] - PK parameters were not calculated because the sponsor discontinued development of BI 836826
    No statistical analyses for this end point

    Secondary: Complete Response (CR) by central review assessment- Phase II

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    End point title
    		 Complete Response (CR) by central review assessment- Phase II
    End point description
    Complete Response (CR) by central review assessment- Phase II; CR: Disappearance of all evidence of disease. Sponsor discontinued the trial for strategic reasons. Consequently, Phase II of the trial was not conducted and hence the endpoint is not evaluated.
    End point type
    Secondary
    End point timeframe
    up to 32 weeks from first trial medication administration.
    End point values
    		 BI 836826 25 milligram (mg) + GemOx BI 836826 50 mg + GemOx BI 836826 100 mg + GemOx
    Number of subjects analysed
    0 [22]
    0 [23]
    0 [24]
    Units: participants
    Notes
    [22] - Primary & secondary endpoints of Phase II are not applicable since Phase II has not been conducted
    [23] - Primary & secondary endpoints of Phase II are not applicable since Phase II has not been conducted
    [24] - Primary & secondary endpoints of Phase II are not applicable since Phase II has not been conducted
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Enter time frame.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    BI 836826 25 milligram (mg) + GemOx‌
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 25 mg on Day 8 and GemOx (gemcitabine 1000 mg/metre square (m^2) plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Reporting group title
    BI 836826 100 mg + GemOx‌
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 100 mg on Day 8 and GemOx (gemcitabine 1000 mg/m^2 plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Reporting group title
    BI 836826 50 mg + GemOx‌
    Reporting group description
    		 Patients were administered (intravenous infusion) BI 836826 50 mg on Day 8 and GemOx (gemcitabine 1000 mg/m^2 plus oxaliplatin 100 mg/m^2) on Day 1 (up to 6 cycles of treatment); the duration of each cycle was 14 days.

    Serious adverse events
    		 BI 836826 25 milligram (mg) + GemOx‌ BI 836826 100 mg + GemOx‌ BI 836826 50 mg + GemOx‌
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    3 / 8 (37.50%)
    5 / 8 (62.50%)
         number of deaths (all causes)
    0
    1
    2
         number of deaths resulting from adverse events
    0
    1
    2
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (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
    Injury, poisoning and procedural complications
    Febrile nonhaemolytic transfusion reaction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 8 (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
    Infusion related reaction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (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
    Neutropenia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Aspergillus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BI 836826 25 milligram (mg) + GemOx‌ BI 836826 100 mg + GemOx‌ BI 836826 50 mg + GemOx‌
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    8 / 8 (100.00%)
    8 / 8 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Pallor
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 8 (37.50%)
    2 / 8 (25.00%)
         occurrences all number
    5
    3
    2
    Chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    2
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Infusion site extravasation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 5 (20.00%)
    5 / 8 (62.50%)
    4 / 8 (50.00%)
         occurrences all number
    3
    5
    6
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Cough
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 8 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    2
    0
    4
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
         occurrences all number
    0
    1
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 8 (37.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    7
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 8 (37.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    9
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    5
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    3
    0
    Transaminases increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
         occurrences all number
    0
    1
    2
    White blood cell count decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 8 (37.50%)
    3 / 8 (37.50%)
         occurrences all number
    8
    9
    8
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 8 (37.50%)
    3 / 8 (37.50%)
         occurrences all number
    1
    4
    7
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Dysaesthesia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    2
    0
    2
    Neuropathy peripheral
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
         occurrences all number
    1
    1
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 5 (60.00%)
    7 / 8 (87.50%)
    4 / 8 (50.00%)
         occurrences all number
    13
    14
    7
    Leukocytosis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Leukopenia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    4
    0
    Lymphopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 8 (37.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    7
    0
    Neutropenia
         subjects affected / exposed
    4 / 5 (80.00%)
    8 / 8 (100.00%)
    4 / 8 (50.00%)
         occurrences all number
    17
    21
    16
    Thrombocytopenia
         subjects affected / exposed
    3 / 5 (60.00%)
    7 / 8 (87.50%)
    4 / 8 (50.00%)
         occurrences all number
    10
    12
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Constipation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 8 (25.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    3
    3
    Dyspepsia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Melaena
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 8 (37.50%)
    2 / 8 (25.00%)
         occurrences all number
    2
    7
    4
    Oral dysaesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Stomatitis
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
         occurrences all number
    0
    3
    3
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 8 (37.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    5
    0
    Muscle spasms
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Influenza
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 8 (25.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Tetany
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2016
    - Biochemistry test was added on Day 1 of Cycle 1 on request of Belgian health authority - Other changes were made to make the protocol more clear, correct some mistakes, as well as add consistency and clarity
    03 Nov 2016
    - Weight assessment was moved to End of Treatment Visit because of an error in a previous version of the Clinical trial Protocol (CTP) - Regular Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) tests were required in case a patient was positive for Hepatitis B surface antigen (HBsAg) or anti- HBc at screening
    10 Jan 2017
    A clarification was added that the MTD can only be determined based on 'evaluable' patients
    09 Jun 2017
    - Two additional dose cohorts (150 and 200 mg) were added - Six to 9 patients were to be recruited at the established MTD to have a total of 12 patients treated at this MTD
    14 Sep 2017
    Inclusion criterion 4 was changed to allow patients with 1 large single lesion to participate to the trial

    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.
    Because of discontinuation of BI 836826 programme, Phase II of the trial and PK analysis in Phase Ib were not conducted.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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