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    Clinical Trial Results:
    A Phase 2 Proof-of-Concept Study to Separately Evaluate the Activity of Talacotuzumab (JNJ-56022473) or Daratumumab in Transfusion-Dependent Subjects with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) who are Relapsed or Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

    Summary
    EudraCT number
    		 2016-003328-22
    Trial protocol
    		 BE   NL   ES   IT  
    Global end of trial date
    23 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2022
    First version publication date
    14 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    56022473MDS2002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03011034
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 US Highway 202, Raritan, NJ, United States, 08869-1420
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    23 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the efficacy (transfusion independence [TI]) of daratumumab in red blood cell (RBC) transfusion-dependent subjects with low or intermediate-1-risk myelodysplastic syndromes (MDS) whose disease had relapsed during treatment with or was refractory to erythropoiesis-stimulating agents (ESAs) (after enrollment in the talacotuzumab arm was stopped).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the declaration of helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    34
    EEA total number of subjects
    23
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    6
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Out of 34 enrolled subjects, 33 subjects received daratumumab and 1 subject received talacotuzumab. Due to serious infusion-related reaction (IRR) event that occurred in first subject enrolled in talacotuzumab arm, no further subjects were enrolled and no primary assessments were conducted for the single subject assigned to talacotuzumab arm.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Talacotuzumab
    Arm description
    		 Subjects received a single dose of talacotuzumab 9 milligram per kilogram (mg/kg) intravenously (IV) every two weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talacotuzumab
    Investigational medicinal product code
    Other name
    JNJ-56022473
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Talacotuzumab 9 mg/kg was administered intravenously (IV) as a single dose every two weeks.

    Arm title
    		 Daratumumab
    Arm description
    		 Subjects received daratumumab 16 mg/kg IV weekly on Weeks 1 to 8 (on Days 1, 8, 15, and 22 of Cycles 1 and 2), every 2 weeks from Weeks 9 to 24 (on Days 1 and 15 of Cycles 3 to 6), and every 4 weeks thereafter (on Day 1 for all subsequent cycles). Each treatment cycle was of 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    JNJ-54767414
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Daratumumab 16 mg/kg was administered IV weekly on Weeks 1 to 8 (on Days 1, 8, 15, and 22 of Cycles 1 and 2), every 2 weeks from Weeks 9 to 24 (on Days 1 and 15 of Cycles 3 to 6), and every 4 weeks thereafter (on Day 1 for all subsequent cycles).

    Number of subjects in period 1
    		Talacotuzumab Daratumumab
    Started
    1
    33
    Completed
    0
    33
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Talacotuzumab
    Reporting group description
    		 Subjects received a single dose of talacotuzumab 9 milligram per kilogram (mg/kg) intravenously (IV) every two weeks.

    Reporting group title
    Daratumumab
    Reporting group description
    		 Subjects received daratumumab 16 mg/kg IV weekly on Weeks 1 to 8 (on Days 1, 8, 15, and 22 of Cycles 1 and 2), every 2 weeks from Weeks 9 to 24 (on Days 1 and 15 of Cycles 3 to 6), and every 4 weeks thereafter (on Day 1 for all subsequent cycles). Each treatment cycle was of 28 days.

    Reporting group values
    		 Talacotuzumab Daratumumab Total
    Number of subjects
    		 1 33 34
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 6 6
        From 65 to 84 years
    		 1 27 28
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 67 ( 99999 ) 71.5 ( 6.86 ) -
    Title for Gender
    Units: subjects
        Female
    		 0 8 8
        Male
    		 1 25 26

    End points

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    End points reporting groups
    Reporting group title
    Talacotuzumab
    Reporting group description
    		 Subjects received a single dose of talacotuzumab 9 milligram per kilogram (mg/kg) intravenously (IV) every two weeks.

    Reporting group title
    Daratumumab
    Reporting group description
    		 Subjects received daratumumab 16 mg/kg IV weekly on Weeks 1 to 8 (on Days 1, 8, 15, and 22 of Cycles 1 and 2), every 2 weeks from Weeks 9 to 24 (on Days 1 and 15 of Cycles 3 to 6), and every 4 weeks thereafter (on Day 1 for all subsequent cycles). Each treatment cycle was of 28 days.

    Primary: Percentage of Subjects who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) Lasting at least 8 weeks

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    End point title
    		 Percentage of Subjects who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) Lasting at least 8 weeks [1] [2]
    End point description
    Percentage of subjects who achieved RBC TI lasting at least 8 weeks were reported. The 8-week RBC TI rate is defined as the percentage of subjects without any RBC transfusion during any consecutive 8 weeks (56 days) post randomization. Intent-to-treat (ITT) population included all subjects who received at least 1 dose of daratumumab.
    End point type
    Primary
    End point timeframe
    Up to 2 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: percentage of subjects
        number (confidence interval 95%)
    6.1 (0.7 to 20.2)
    No statistical analyses for this end point

    Secondary: Time to Transfusion Independence (TI)

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    End point title
    		 Time to Transfusion Independence (TI) [3]
    End point description
    Time to transfusion independence (TI) was defined as time to the start of the TI interval. Pertaining only to subjects who achieved TI, time to the 8-week or 24-week RBC TI is defined as the interval from study Day 1 to the first day of the first 8-week or 24-week RBC TI period. ITT population who achieved TI for at least 8 weeks. As less number of subjects were evaluable for this endpoint, the results were not summarized. Hence, subject wise data is reported. Here, N (number of subjects analysed) indicates number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    2
    Units: weeks
        Subject 1
    4
        Subject 2
    5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) Lasting at Least 24 Weeks

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    End point title
    		 Percentage of Subjects who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) Lasting at Least 24 Weeks [4]
    End point description
    Percentage of subjects who achieved RBC TI lasting at least 24 weeks were reported. 24-week RBC TI rate is defined as the percentage of subjects without any RBC transfusion during any consecutive 24 weeks (168 days) post randomisation. ITT population included all subjects who received at least 1 dose of daratumumab.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: percentage of subjects
        number (confidence interval 95%)
    3.0 (0.1 to 15.8)
    No statistical analyses for this end point

    Secondary: Duration of Transfusion Independence (TI)

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    End point title
    		 Duration of Transfusion Independence (TI) [5]
    End point description
    Duration of TI was reported. Pertaining only to subjects who achieved TI, time to the 8-week or 24-week RBC TI is defined as the interval from Study Day 1 to the first day of the first 8-week or 24-week RBC TI period. ITT population who achieved TI for at least 8 weeks. As less number of subjects were evaluable for this outcome measure (OM), the results were not summarized. Hence, subject wise data is reported. Here, N (number of subjects analysed) indicates number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    2
    Units: weeks
        Subject 1
    16
        Subject 2
    65
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who met International Working Group (IWG) Criteria for Transfusion Reduction

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    End point title
    		 Percentage of Subjects who met International Working Group (IWG) Criteria for Transfusion Reduction [6]
    End point description
    Percentage of subjects who met IWG criteria for transfusion reduction were reported. IWG criteria for transfusion reduction: at least 4 units reduction in RBC transfusions in the best 8-week interval. The best 8-week interval was a post-baseline 8-week interval where the subject had the fewest post-baseline RBC transfusion units. ITT population included all subjects who received at least 1 dose of daratumumab.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: percentage of subjects
        number (not applicable)
    54.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with at Least one Dose of Myeloid Growth Factors Usage

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    End point title
    		 Percentage of Subjects with at Least one Dose of Myeloid Growth Factors Usage [7]
    End point description
    Percentage of subjects with Myeloid Growth Factors (MGF) usage (who had used at least 1 dose of MGF) were reported. ITT population included all subjects who received at least 1 dose of daratumumab.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: percentage of subjects
        number (not applicable)
    9.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Hematologic Improvement (HI) per IWG 2006 by Investigator Assessment

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    End point title
    		 Percentage of Subjects with Hematologic Improvement (HI) per IWG 2006 by Investigator Assessment [8]
    End point description
    Percentage of subjects with HI per IWG 2006 by investigator assessment were reported. Response criteria per IWG 2006 for HI: erythroid response (pretreatment, less than [<] 11 gram per deciliter [g/dL]) - hemoglobin (Hb) increase by greater than or equal to (>=) 1.5 g/dL, relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hb of less than or equal to (<=) 9 g/dL pretreatment counted in the RBC transfusion response evaluation; platelet response (pretreatment, <100*10^9/L) - absolute increase of >=30*10^9/L for subjects starting with >20*10^9/L platelets. Increase from <20*10^9/L to >20*10^9/L and by at least 100 percent (%); neutrophil response (pretreatment, <1*10^9/L) - at least 100% increase and an absolute increase >0.5*10^9/L. ITT population included all subjects who received at least 1 dose of daratumumab.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: percentage of subjects
    number (confidence interval 95%)
        Erythroid Response
    9.1 (1.9 to 24.3)
        Platelet Response
    0.0 (0.0 to 10.6)
        Neutrophil Response
    0.0 (0.0 to 10.6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Complete Remission (CR) and Marrow CR

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    End point title
    		 Percentage of Subjects with Complete Remission (CR) and Marrow CR [9]
    End point description
    Percentage of subjects with CR and marrow CR were reported. CR per IWG 2006 response criteria: bone marrow <= 5% myeloblasts with normal maturation of all cell lines, persistent dysplasia noted; peripheral blood - hemoglobin >=11 g/dL; platelets >=100*10^9/L; neutrophils >=1.0*10^9/L; blasts, 0%. Marrow CR: Bone marrow <=5% myeloblasts and decrease by >=50% over pretreatment; peripheral blood - if HI responses, they were noted in addition to marrow CR. ITT population included all subjects who received at least 1 dose of daratumumab.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: percentage of subjects
    number (not applicable)
        CR
    0
        Marrow CR
    3.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Cytogenetic Response

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    End point title
    		 Percentage of Subjects with Cytogenetic Response [10]
    End point description
    Percentage of subjects with cytogenetic response were reported. Cytogenetic response per IWG 2006 response criteria: complete - disappearance of the chromosomal abnormality without appearance of new ones; partial - at least 50% reduction of the chromosomal abnormality. As there were no subjects who had the del(5q) abnormality at baseline, this assessment was not performed. ITT population included all participants who received at least 1 dose of daratumumab.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    0 [11]
    Units: percentage of subjects
    Notes
    [11] - There were no subjects who had del(5q) abnormality at baseline, this assessment was not performed.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Partial Remission (PR)

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    End point title
    		 Percentage of Subjects with Partial Remission (PR) [12]
    End point description
    Percentage of subjects with PR were reported. PR per IWG 2006 response criteria: all CR criteria if abnormal before treatment except: bone marrow blasts decreased by >=50% over pretreatment but still >5%, cellularity and morphology not relevant. ITT population included all subjects who received at least 1 dose of daratumumab.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: percentage of subjects
    0
    No statistical analyses for this end point

    Secondary: Time to Progression to Acute Myeloid Leukemia (AML)

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    End point title
    		 Time to Progression to Acute Myeloid Leukemia (AML) [13]
    End point description
    Time to progression to AML was reported. Time to progression to AML is defined as the interval from study Day 1 to the date of AML progression (bone marrow or peripheral blood blasts ≥20%). Disease progression as per IWG response criteria: for subjects with: <5% blasts: >=50% increase in blasts to >5% blasts; 5%–10% blasts: >=50% increase to >10% blasts; 10%–20% blasts: >=50% increase to >20% blasts; 20%–30% blasts: >=50% increase to >30% blasts. Any of the following: >=50% decrement from maximum remission/response in granulocytes or platelets; reduction in hemoglobin by >=2 g/dL; transfusion dependence. ITT population included all subjects who received at least 1 dose of daratumumab. Here, "99999" signifies that the median, lower and upper limit of Confidence Interval (CI) were not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: weeks
        median (confidence interval 95%)
    99999 (54.7 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival [14]
    End point description
    The overall survival was defined as the time from the date of first dose of study drug to date of death from any cause. Median overall survival was estimated by using the Kaplan-Meier method. ITT population included all subjects who received at least 1 dose of daratumumab. Here, "99999" signifies that the median, lower and upper limit of Confidence Interval (CI) were not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed for the specified arm only as no primary assessments were conducted for other arm.
    End point values
    		 Daratumumab
    Number of subjects analysed
    33
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 2 years
    Adverse event reporting additional description
    The safety analysis set included all subjects who received at least one dose of study drug (daratumumab/ talacotuzumab).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Daratumumab
    Reporting group description
    		 Subjects received daratumumab 16 mg/kg IV weekly on Weeks 1 to 8 (on Days 1, 8, 15, and 22 of Cycles 1 and 2), every 2 weeks from Weeks 9 to 24 (on Days 1 and 15 of Cycles 3 to 6), and every 4 weeks thereafter (on Day 1 for all subsequent cycles). Each treatment cycle was of 28 days.

    Reporting group title
    Talacotuzumab
    Reporting group description
    		 Subjects received a single dose of talacotuzumab 9 milligram per kilogram (mg/kg) intravenously (IV) every two weeks.

    Serious adverse events
    		 Daratumumab Talacotuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 33 (45.45%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    6
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic Cancer
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand Fracture
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis Superficial
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune Disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Oedema
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Corona Virus Infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection Pseudomonal
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic Acidosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Daratumumab Talacotuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    1 / 1 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    Hypotension
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    Pallor
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 33 (18.18%)
    0 / 1 (0.00%)
         occurrences all number
    6
    0
    Chills
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Asthenia
         subjects affected / exposed
    6 / 33 (18.18%)
    0 / 1 (0.00%)
         occurrences all number
    8
    0
    Pyrexia
         subjects affected / exposed
    8 / 33 (24.24%)
    0 / 1 (0.00%)
         occurrences all number
    13
    0
    Peripheral Swelling
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Oedema Peripheral
         subjects affected / exposed
    6 / 33 (18.18%)
    0 / 1 (0.00%)
         occurrences all number
    6
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 33 (18.18%)
    0 / 1 (0.00%)
         occurrences all number
    8
    0
    Dyspnoea
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    Dyspnoea Exertional
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Weight Decreased
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    Blood Creatinine Increased
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    Infusion Related Reaction
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    Paraesthesia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 33 (18.18%)
    0 / 1 (0.00%)
         occurrences all number
    25
    0
    Neutropenia
         subjects affected / exposed
    6 / 33 (18.18%)
    0 / 1 (0.00%)
         occurrences all number
    32
    0
    Thrombocytopenia
         subjects affected / exposed
    9 / 33 (27.27%)
    0 / 1 (0.00%)
         occurrences all number
    18
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Conjunctival Haemorrhage
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 33 (21.21%)
    0 / 1 (0.00%)
         occurrences all number
    9
    0
    Constipation
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    Nausea
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 1 (100.00%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 1 (100.00%)
         occurrences all number
    4
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    10
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    Night Sweats
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Pruritus
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Renal Impairment
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    Arthralgia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    Muscle Spasms
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    Urinary Tract Infection
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    Pneumonia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Herpes Simplex
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Campylobacter Infection
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2017
    The purpose of this amendment was: clarification was provided for subject monitoring and availability of resuscitation equipment in the event of a fatal infusion related reaction (IRR) event during talacotuzumab infusion in study 56022473AML2002. Infusion-rate guidance was changed, and duration of monitoring was increased from 30 minutes to 1-hour post-infusion. Dosing schedules were clarified for talacotuzumab and daratumumab, pre-infusion medications were added for talacotuzumab, pre- and post-infusion medications were added/or clarified for daratumumab. Requirement for blood type assessment and indirect antiglobulin results on Cycle 1 Day 1 for daratumumab and recommendation for herpes zoster (HZ) reactivation prophylaxis were added. Storage and central laboratory information were also included.
    25 Apr 2017
    The purpose of this amendment was: closed the enrollment to the talacotuzumab arm as a precautionary measure due to the benefit/risk considerations in subjects with low-risk myelodysplastic syndromes (MDS) and based on the occurrence of a serious Grade 4 IRR in the first subject who received the first and only dose of talacotuzumab in this study.

    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.
    Analyses in this study are limited to data from daratumumab arm only. Objectives initially designed to explore efficacy, PK and safety in talacotuzumab arm were not pursued as enrollment was stopped due to occurrence of serious Grade 4 IRR.
    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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