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    Clinical Trial Results:
    A Phase 1/2 Study of Brentuximab Vedotin (SGN-35) in Pediatric Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma.

    Summary
    EudraCT number
    2011-001240-29
    Trial protocol
    DE   GB   NL   IT   ES  
    Global end of trial date
    12 Apr 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Oct 2018
    First version publication date
    27 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C25002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01492088
    WHO universal trial number (UTN)
    U1111-1158-2613
    Other trial identifiers
    RNEC: 133300410A0384, CCMO: NL38209.078.11
    Sponsors
    Sponsor organisation name
    Takeda Oncology
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000980-PIP01-10
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to assess the safety and pharmacokinetics, and determine the pediatric maximum tolerated dose and/or or recommended phase 2 dose of brentuximab vedotin.
    Protection of trial subjects
    All study participants or their guardians were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Apr 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Regulatory reason
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Mexico: 1
    Worldwide total number of subjects
    36
    EEA total number of subjects
    31
    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)
    12
    Adolescents (12-17 years)
    24
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 12 investigative sites in United States, France, Germany, Netherlands, United Kingdom, Italy, Spain and Mexico from 16-April-2012 to 12-April-2018.

    Pre-assignment
    Screening details
    Participants with diagnosis of relapsed or refractory (r/r) sALCL/HL were enrolled to receive brentuximab vedotin 1.4-1.8 mg/kg, intravenous infusion on Day 1 of every 21-day cycle for up to 16 cycles. Treatment beyond 16 cycles was permitted at joint discretion of sponsor and investigator for participants experiencing continued clinical benefit.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Brentuximab vedotin 1.4 mg/kg: Phase 1
    Arm description
    Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion, Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin Intravenous Infusion

    Arm title
    Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only
    Arm description
    Participants with r/r HL received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.
    Arm type
    Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin Intravenous Infusion

    Arm title
    Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Arm description
    Participants with r/r systemic anaplastic large-cell lymphoma (sALCL) received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.
    Arm type
    Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin Intravenous Infusion

    Number of subjects in period 1
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Started
    3
    16
    17
    Completed
    0
    2
    3
    Not completed
    3
    14
    14
         Death
    1
    6
    2
         Withdrawal by Patient
    -
    2
    -
         Completed Post Treatment Followup (PTFU)
    2
    -
    1
         Alive at Last Follow-up
    -
    6
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brentuximab vedotin 1.4 mg/kg: Phase 1
    Reporting group description
    Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

    Reporting group title
    Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only
    Reporting group description
    Participants with r/r HL received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Reporting group title
    Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Reporting group description
    Participants with r/r systemic anaplastic large-cell lymphoma (sALCL) received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Reporting group values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only Total
    Number of subjects
    3 16 17 36
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 2 10 12
        Adults (18-64 years)
    3 14 7 24
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    14.7 ± 1.15 14.5 ± 2.68 11.5 ± 3.18 -
    Sex: Female, Male
    Units: Subjects
        Female
    1 7 3 11
        Male
    2 9 14 25
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0 4 4
        Not Hispanic or Latino
    3 14 12 29
        Unknown or Not Reported
    0 2 1 3
    Race/Ethnicity, Customized
    Units: Subjects
        White
    2 13 16 31
        Asian
    1 0 0 1
        Other
    0 2 1 3
        Not Reported
    0 1 0 1
    Region of Enrollment
    Units: Subjects
        United States
    2 1 1 4
        France
    0 2 0 2
        Germany
    0 4 1 5
        Netherlands
    0 1 2 3
        United Kingdom
    0 1 2 3
        Italy
    1 7 6 14
        Spain
    0 0 4 4
        Mexico
    0 0 1 1
    Height
    Units: cm
        arithmetic mean (standard deviation)
    167.17 ± 10.865 165.31 ± 14.350 149.54 ± 17.783 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    53.10 ± 9.924 57.85 ± 17.539 42.16 ± 15.162 -
    Body Surface Area
    Units: m^2
        arithmetic mean (standard deviation)
    1.562 ± 0.0967 1.617 ± 0.2938 1.313 ± 0.3103 -

    End points

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    End points reporting groups
    Reporting group title
    Brentuximab vedotin 1.4 mg/kg: Phase 1
    Reporting group description
    Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

    Reporting group title
    Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only
    Reporting group description
    Participants with r/r HL received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Reporting group title
    Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Reporting group description
    Participants with r/r systemic anaplastic large-cell lymphoma (sALCL) received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Subject analysis set title
    Brentuximab vedotin 1.8 mg/kg: Phase 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Subject analysis set title
    Brentuximab vedotin 1.8 mg/kg: Phase 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle starting from Cycle 2 until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Subject analysis set title
    Brentuximab vedotin 1.8 mg/kg: Phase 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle starting from Cycle 2 until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Subject analysis set title
    Brentuximab vedotin 1.8 mg/kg: Phase 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Primary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1)

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    End point title
    Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1) [1] [2]
    End point description
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with treatment. A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. AE severity was graded according to NCI CTCAE version 4.03. Safety population is defined as all participants who received at least 1 dose of study drug. Participants enrolled in Phase 1 of study were evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication (Up to 15 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: Only descriptive statistics were planned for this 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 planned to be assessed in Phase 1 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1
    Number of subjects analysed
    3
    9
    Units: participants
        TEAE
    3
    9
        SAE
    0
    4
    No statistical analyses for this end point

    Primary: Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1)

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    End point title
    Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1) [3] [4]
    End point description
    Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. Safety population is defined as all participants who received at least 1 dose of study drug. Participants enrolled in Phase 1 of study were evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication (Up to 15 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: Only descriptive statistics were planned for this endpoint.
    [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 planned to be assessed in Phase 1 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1
    Number of subjects analysed
    3
    9
    Units: participants
        Gamma-glutamyltransferase increased
    0
    1
        Transaminases increased
    0
    1
        Lymphocyte count decreased
    1
    1
        Neutrophil count decreased
    0
    1
        Blood bicarbonate decreased
    0
    1
        Weight decreased
    0
    1
        Hypocalaemia
    0
    2
        Hyperuricaemia
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants with Clinically Significant Vital Signs Values Reported as AEs (Phase 1)

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    End point title
    Number of Participants with Clinically Significant Vital Signs Values Reported as AEs (Phase 1) [5] [6]
    End point description
    Vital signs measurements included supine (after 3-5 minutes in this position) and standing (after 3-5 minutes in this position) measurements of diastolic and systolic blood pressure, heart rate, and oral temperature. Safety population is defined as all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication (Up to 15 months)
    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: Only descriptive statistics were planned for this endpoint.
    [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 planned to be assessed in Phase 1 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1
    Number of subjects analysed
    3
    9
    Units: participants
    0
    0
    No statistical analyses for this end point

    Primary: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1)

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    End point title
    Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1) [7] [8]
    End point description
    Blood samples were collected and tested for serum concentrations of brentuximab vedotin antibody-drug conjugate. Data for this endpoint was not summarized for Phase 1 participants only, data was summarized together for Phase 1 and 2 participants in brentuximab 1.4 mg/kg and 1.8 mg/kg arms groups.
    End point type
    Primary
    End point timeframe
    Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned for this endpoint.
    [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 planned to be assessed in Phase 1 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1
    Number of subjects analysed
    0 [9]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ±
    Notes
    [9] - Data has been presented in endpoint 19.
    No statistical analyses for this end point

    Primary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated) (Phase 1)

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    End point title
    Serum Concentration of Total Antibodies (Conjugated and Unconjugated) (Phase 1) [10] [11]
    End point description
    Blood samples were collected and tested for conjugated and unconjugated antibodies. Data for thisendpoint was not summarized for Phase 1 participants only, data was summarized together for Phase 1 and 2 participants in brentuximab 1.4 mg/kg and 1.8 mg/kg arms groups.
    End point type
    Primary
    End point timeframe
    Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned for this endpoint.
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed in Phase 1 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1
    Number of subjects analysed
    0 [12]
    Units: ug/mL
        arithmetic mean (standard deviation)
    ±
    Notes
    [12] - Data has been presented in endpoint 20.
    No statistical analyses for this end point

    Primary: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1)

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    End point title
    Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1) [13] [14]
    End point description
    Blood samples were collected and tested for MMAE plasma concentrations. Data for this endpoint was not summarized for Phase 1 participants only, data was summarized together for Phase 1 and 2 participants in brentuximab 1.4 mg/kg and 1.8 mg/kg arms groups.
    End point type
    Primary
    End point timeframe
    Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned for this endpoint.
    [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 planned to be assessed in Phase 1 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1
    Number of subjects analysed
    0 [15]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ±
    Notes
    [15] - Data has been presented in endpoint 21.
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) (Phase 1 and 2)

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    End point title
    Overall Response Rate (ORR) (Phase 1 and 2) [16]
    End point description
    Overall response rate is defined as the percentage of participants with complete remission (CR) or partial remission (PR) as assessed by an independent review facility (IRF) using International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. Response-evaluable population included participants who received at least 1 dose of study drug, have measurable disease at baseline, and 1 postbaseline disease assessment. Data was summarized together for Phase 1 and 2 participants in brentuximab 1.8 mg/kg arm group.
    End point type
    Primary
    End point timeframe
    Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or end of treatment (EOT) (Up to 15 months)
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned for this endpoint.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    15
    17
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 71)
    47 (21 to 73)
    53 (28 to 77)
    No statistical analyses for this end point

    Secondary: Number of Participants with Antitherapeutic Antibodies (ATA) and Neutralizing ATA (nATA) (Phase 1 and 2)

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    End point title
    Number of Participants with Antitherapeutic Antibodies (ATA) and Neutralizing ATA (nATA) (Phase 1 and 2)
    End point description
    Blood samples were collected to assess the immunogenicity of brentuximab vedotin (ATA and nATA development) using a laboratory test. ATA-positive samples were further characterized as transiently ATA positive (defined as 1 or 2 post-Baseline ATA-positive responses), persistently ATA positive (defined as more than 2 post-Baseline ATA positive responses), and nATA positive or negative. Participants from the Safety Population, all enrolled participants who received at least one dose of brentuximab vedotin, with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (Up to 15 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    16
    17
    Units: participants
        ATA status: Transiently positive
    1
    4
    7
        ATA status: Persistently positive
    0
    2
    0
        nATA status: Positive
    0
    5
    4
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) (Phase 1)

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    End point title
    Overall Response Rate (ORR) (Phase 1) [17]
    End point description
    Overall response rate is defined as the percentage of participants with CR or PR as assessed by an IRF using IWG Revised Response Criteria for Malignant Lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. Response-evaluable population included participants who received at least 1 dose of study drug, have measurable disease at baseline, and 1 postbaseline disease assessment. Participants enrolled in Phase 1 of the study were evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months)
    Notes
    [17] - 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 planned to be assessed in Phase 1 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1
    Number of subjects analysed
    3
    8
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 71)
    63 (24 to 91)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP) (Phase 1 and 2)

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    End point title
    Time to Progression (TTP) (Phase 1 and 2)
    End point description
    TTP is defined as the time in months from first dose until the first subsequent documentation of objective tumor progression. Progressive disease (PD) is defined as any new lesion or increase by ≥50% of previously involved sites from nadir. Safety population is defined as all participants who received at least 1 dose of study drug. TTP was censored on last radiological assessment of measured lesions documenting absence of PD for participants who did not have tumor progression. Safety population is defined as all participants who received at least 1 dose of study drug. TTP was censored on last radiological assessment of measured lesions documenting absence of PD for participants who did not have tumor progression. Here, 9999 indicates upper limit of confidence interval was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death (Up to 27 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    16
    17
    Units: months
        median (confidence interval 95%)
    2.7 (1.4 to 2.8)
    4.8 (1.2 to 9999)
    6.2 (2.8 to 9999)
    No statistical analyses for this end point

    Secondary: Time to Response (Phase 1 and 2)

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    End point title
    Time to Response (Phase 1 and 2)
    End point description
    Time to response is defined as the time in months from the first dose of study treatment until the date of the first assessment of confirmed CR or PR. as assessed by an IRF using IWG revised response criteria for malignant lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. Response-evaluable population included participants who received at least 1 dose of study drug, have measurable disease at baseline, and 1 postbaseline disease assessment. Time to response was censored on the last radiological assessment of measured lesions documenting absence of CR or PR for participants who did not have CR or PR. Here, 9999 indicates upper limit of confidence interval was not reached due to low number of participants with events. 99999 indicates median was not reached as no participant had response.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    15
    17
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    2.7 (1.3 to 9999)
    1.5 (1.2 to 9999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) (Phase 1 and 2)

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    End point title
    Duration of Response (DOR) (Phase 1 and 2)
    End point description
    DOR is defined as the time in months from the date of first documentation of a CR or PR to the date of first documentation of tumor progression or PD per IRF assessment according to IWG criteria or to death due to any cause, whichever comes first. CR is defined as the disappearance of all evidence of disease and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. Participants with response from the Safety Population, all enrolled participants who received at least one dose of brentuximab vedotin, with data available for analysis. Duration of response was censored at last observation documenting absence of PD for participants who did not have tumor progression. Here, 99999 indicates median and CI limits were not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death or end of study (Up to 72 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    0 [18]
    7
    9
    Units: months
        median (confidence interval 95%)
    ( to )
    99999 (2.2 to 99999)
    30.3 (3.4 to 30.3)
    Notes
    [18] - Number of Subjects Analyzed were Zero.
    No statistical analyses for this end point

    Secondary: Event Free Survival (EFS) (Phase 1 and 2)

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    End point title
    Event Free Survival (EFS) (Phase 1 and 2)
    End point description
    EFS is defined as the time in months from first dose until any cause of treatment failure: disease progression, premature discontinuation of treatment for any reason, or death due to any cause, whichever occurs first. PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. Safety population is defined as all participants who received at least 1 dose of study drug. EFS was censored on the last follow-up date if none of the above events occur during the study.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death (Up to 27 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    16
    17
    Units: months
        median (confidence interval 95%)
    2.7 (1.4 to 2.8)
    2.1 (1.2 to 4.8)
    4.8 (2.8 to 7.4)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) (Phase 1 and 2)

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    End point title
    Progression Free Survival (PFS) (Phase 1 and 2)
    End point description
    PFS is defined as time in months from start of study treatment to first documentation of objective tumor progression per IRF assessment or up to death due to any cause, whichever occurs first. and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. Safety population is defined as all participants who received at least 1 dose of study drug. PFS was censored on the day following the date of last radiological assessment of measured lesions documenting absence of PD for participants who did not have tumor progression. Here, 9999 indicates upper limit of CI was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death or end of study (Up to 72 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    16
    17
    Units: months
        median (confidence interval 95%)
    2.7 (1.4 to 2.8)
    3.8 (1.2 to 9999)
    6.2 (2.8 to 31.5)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) (Phase 1 and 2)

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    End point title
    Overall Survival (OS) (Phase 1 and 2)
    End point description
    OS is the time in months from start of study treatment to date of death due to any cause. Safety population is defined as all participants who received at least 1 dose of study drug. Here, 99999 indicates median was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Every 6 months after EOT, until the sooner of death, study closure, or 2 years after enrolment of the last participant (Up to 72 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    16
    17
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1 and 2)

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    End point title
    Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1 and 2)
    End point description
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. AE severity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Safety population is defined as all participants who received at least 1 dose of study drug. Data was summarized together for Phase 1 and 2 participants.
    End point type
    Secondary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication (up to 15 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    16
    17
    Units: participants
        TEAEs
    3
    16
    17
        SAEs
    0
    7
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1 and 2)

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    End point title
    Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1 and 2)
    End point description
    Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. Safety population is defined as all participants who received at least 1 dose of study drug. Data was summarized together for Phase 1 and 2 participants in brentuximab 1.8 mg/kg arm group.
    End point type
    Secondary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication (Up to 15 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    16
    17
    Units: participants
        Gamma-glutamyltransferase increased
    0
    2
    0
        Alanine aminotransferase increased
    0
    1
    0
        Aspartate aminotransferase increased
    0
    1
    0
        Transaminases increased
    0
    1
    0
        Lymphocyte count decreased
    1
    0
    2
        Neutrophil count decreased
    0
    0
    2
        White blood cell count decreased
    0
    0
    1
        Blood bicarbonate decreased
    0
    1
    0
        Weight decreased
    0
    0
    1
        C-reactive protein increased
    0
    1
    0
        Blood alkaline phosphatase increased
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Vital Signs Reported as AEs (Phase 1 and 2)

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    End point title
    Number of Participants with Clinically Significant Vital Signs Reported as AEs (Phase 1 and 2)
    End point description
    Vital signs measurements included supine (after 3-5 minutes in this position) and standing (after 3-5 minutes in this position) measurements of diastolic and systolic blood pressure, heart rate, and oral temperature. Safety population is defined as all participants who received at least 1 dose of study drug. Data was summarized together for Phase 1 and 2 participants in brentuximab 1.8 mg/kg arm group.
    End point type
    Secondary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication (Up to 15 months)
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Number of subjects analysed
    3
    16
    17
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1 and 2)

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    End point title
    Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1 and 2) [19]
    End point description
    Blood samples were collected and tested for serum concentrations of brentuximab vedotin antibody-drug conjugate. PK-evaluable population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Cycle 2 Day 2 values are collected in phase 1 participants only. Data was summarized together for all participants in brentuximab vedotin 1.8 mg/kg arm group. Here, 999999 indicates arithmetic mean and standard deviation was not estimable since the number of participants analyzed were '0'. n is the number of participants analyzed at the given time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
    Notes
    [19] - 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: The data for this endpoint was planned to be assessed in combined form for Phase 2 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1
    Number of subjects analysed
    3
    33 [20]
    Units: ug/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose (n=0,33)
    999999 ± 999999
    99999 ± 99999
        Cycle 1 Day 1, 5 Minutes Post-Dose (n=3,33)
    23.1 ± 3.46
    31.8 ± 12.4
        Cycle 1 Day 2, 24 Hours Post-Dose (n=3,32)
    9.50 ± 1.73
    13.0 ± 5.34
        Cycle 1 Day 3, 48 Hours Post-Dose (n=3,31)
    5.67 ± 0.924
    12.0 ± 16.3
        Cycle 1 Day 5, 96 Hours Post-Dose (n=3,31)
    3.50 ± 1.41
    8.68 ± 13.4
        Cycle 1 Day 14, 312 Hours Post-Dose (n=3,31)
    0.844 ± 0.309
    2.19 ± 3.44
        Cycle 2 Day 1, Pre-Dose (n=3,32)
    0.149 ± 0.128
    0.395 ± 0.322
        Cycle 2 Day 1, 5-minutes Post-Dose (n=3,30)
    25.3 ± 7.56
    32.9 ± 9.80
        Cycle 2 Day 2, 24 Hours Post-Dose (n=3,10)
    8.80 ± 6.19
    10.4 ± 8.05
        Cycle 2 Day 3, 48 Hours Post-Dose (n=3,29)
    3.70 ± 1.95
    11.4 ± 16.8
        Cycle 2 Day 5, 96 Hours Post-Dose (n=3,27)
    2.04 ± 1.26
    9.61 ± 17.9
        Cycle 3 Day 1, Pre-Dose (n=2,26)
    0.116 ± 0.163
    0.491 ± 0.387
        Cycle 3 Day 1, 5 minutes Post-Dose (n=2,26)
    23.9 ± 2.83
    31.3 ± 9.79
        Cycle 4 Day 1, Pre-dose (n=2,21)
    0.218 ± 0.271
    0.691 ± 0.492
        Cycle 4 Day 1, 5 minutes Post-Dose (n=2,21)
    22.9 ± 4.60
    30.0 ± 12.2
        Cycle 5 Day 1, Pre-Dose (n=2,21)
    0.264 ± 0.321
    0.845 ± 0.564
        Cycle 5 Day 1, 5 minutes Post-Dose (n=2,21)
    22.5 ± 3.32
    30.6 ± 15.1
        Cycle 6 Day 1, Pre-Dose (n=2,17)
    0.312 ± 0.351
    1.06 ± 0.699
        Cycle 6 Day 1, 5 minutes Post-Dose (n=2,17)
    20.3 ± 4.38
    33.2 ± 16.1
        Cycle 7 Day 1, Pre-Dose (n=2,17)
    0.327 ± 0.337
    1.04 ± 0.618
        Cycle 7 Day 1, 5 minutes Post-Dose (n=2,17)
    17.9 ± 2.40
    32.3 ± 15.4
        Cycle 8 Day 1, Pre-Dose (n=0,14)
    999999 ± 999999
    1.25 ± 0.565
        Cycle 8 Day 1, 5 minutes Post-Dose (n=0,13)
    999999 ± 999999
    35.2 ± 10.5
        Cycle 8 Day 2, 24 Hours Post-Dose (n=0,13)
    999999 ± 999999
    14.0 ± 4.55
        Cycle 8 Day 3, 48 Hours Post-Dose (n=0,13)
    999999 ± 999999
    9.53 ± 2.96
        Cycle 8 Day 5, 96 Hours Post-Dose (n=0,12)
    999999 ± 999999
    6.44 ± 2.35
        Cycle 8 Day 14, 312 Hours Post-Dose (n=0,13)
    999999 ± 999999
    3.30 ± 4.63
        Cycle 9 Day 1, Pre-Dose (n=0,14)
    999999 ± 999999
    4.37 ± 11.7
        Cycle 9 Day 1, 5 Minutes Post-Dose (n=0,13)
    999999 ± 999999
    29.6 ± 11.3
        Cycle 10 Day 1, Pre-Dose (n=0,11)
    999999 ± 999999
    1.20 ± 0.455
        Cycle 10 Day 1, 5 minutes Post-Dose (n=0,12)
    999999 ± 999999
    35.7 ± 9.50
        Cycle 11 Day 1, Pre-Dose (n=0,8)
    999999 ± 999999
    1.84 ± 1.57
        Cycle 11 Day 1, 5 minutes Post-Dose (n=0,8)
    999999 ± 999999
    35.7 ± 10.8
        Cycle 12 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    1.47 ± 0.665
        Cycle 12 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    40.0 ± 10.4
        Cycle 13 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    6.28 ± 11.5
        Cycle 13 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    33.3 ± 16.1
        Cycle 14 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    1.60 ± 0.600
        Cycle 14 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    37.0 ± 7.92
        Cycle 15 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    1.48 ± 0.542
        Cycle 15 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    40.3 ± 10.6
        Cycle 16 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    1.52 ± 0.361
        Cycle 16 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    41.5 ± 4.70
    Notes
    [20] - Here, 99999 indicates data was below the limit of quantification.
    No statistical analyses for this end point

    Secondary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated)

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    End point title
    Serum Concentration of Total Antibodies (Conjugated and Unconjugated) [21]
    End point description
    Blood samples were collected and tested for conjugated and unconjugated antibodies. PK-evaluable population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Cycle 2 Day 2 values are collected in phase 1 participants only. Data was summarized together for all participants in brentuximab vedotin 1.8 mg/kg arm group. Here, 999999 indicates arithmetic mean and standard deviation was not estimable since the number of participants analyzed were '0'. 99999 indicates data was below the limit of quantification. n is the number of participants analyzed at the given time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
    Notes
    [21] - 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: The data for this endpoint was planned to be assessed in combined form for Phase 2 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1
    Number of subjects analysed
    3
    33 [22]
    Units: ug/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose (n=2,32)
    99999 ± 99999
    99999 ± 99999
        Cycle 1 Day 1, 5 Minutes Post-Dose (n=3,33)
    26.3 ± 2.29
    34.7 ± 13.4
        Cycle 1 Day 2, 24 Hours Post-Dose (n=3,33)
    16.7 ± 1.50
    25.0 ± 9.59
        Cycle 1 Day 3, 48 Hours Post-Dose (n=3,33)
    12.7 ± 3.13
    18.5 ± 7.57
        Cycle 1 Day 5, 96 Hours Post-Dose (n=3,33)
    8.63 ± 5.11
    11.8 ± 5.02
        Cycle 1 Day 14, 312 Hours Post-Dose (n=3,32)
    2.23 ± 0.833
    3.50 ± 1.70
        Cycle 2 Day 1, Pre-Dose (n=3,32)
    0.470 ± 0.459
    1.16 ± 0.825
        Cycle 2 Day 1, 5-minutes Post-Dose (n=3,31)
    26.9 ± 7.98
    35.6 ± 12.0
        Cycle 2 Day 2, 24 Hours Post-Dose (n=3,10)
    17.1 ± 10.4
    17.2 ± 7.93
        Cycle 2 Day 3, 48 Hours Post-Dose (n=3,31)
    9.60 ± 5.39
    16.0 ± 6.73
        Cycle 2 Day 3, 96 Hours Post-Dose (n=3,30)
    6.43 ± 3.69
    10.2 ± 5.16
        Cycle 3 Day 1, Pre-Dose (n=2,26)
    0.415 ± 0.586
    1.62 ± 1.07
        Cycle 3 Day 1, 5 minutes Post-Dose (n=2,26)
    30.0 ± 5.87
    38.2 ± 13.1
        Cycle 4 Day 1, Pre-dose (n=2,21)
    0.875 ± 1.03
    1.95 ± 1.26
        Cycle 4 Day 1, 5 minutes Post-Dose (n=2,21)
    29.6 ± 8.13
    37.1 ± 15.6
        Cycle 5 Day 1, Pre-Dose (n=2,21)
    0.844 ± 0.928
    2.45 ± 1.68
        Cycle 5 Day 1, 5 minutes Post-Dose (n=2,21)
    29.4 ± 3.04
    38.0 ± 18.8
        Cycle 6 Day 1, Pre-Dose (n=2,17)
    1.05 ± 1.20
    2.99 ± 1.81
        Cycle 6 Day 1, 5 minutes Post-Dose (n=2,17)
    29.4 ± 5.37
    39.8 ± 19.8
        Cycle 7 Day 1, Pre-Dose (n=2,17)
    0.995 ± 0.998
    2.92 ± 1.62
        Cycle 7 Day 1, 5 minutes Post-Dose (n=2,17)
    24.0 ± 2.69
    41.0 ± 21.2
        Cycle 8 Day 1, Pre-Dose (n=0,14)
    999999 ± 999999
    3.29 ± 1.14
        Cycle 8 Day 1, 5 minutes Post-Dose (n=0,14)
    999999 ± 999999
    41.4 ± 9.47
        Cycle 8 Day 2, 24 Hours Post-Dose (n=0,14)
    999999 ± 999999
    28.2 ± 6.38
        Cycle 8 Day 3, 48 Hours Post-Dose (n=0,14)
    999999 ± 999999
    22.9 ± 5.67
        Cycle 8 Day 5, 96 Hours Post-Dose (n=0,14)
    999999 ± 999999
    17.3 ± 4.93
        Cycle 8 Day 14, 312 Hours Post-Dose (n=0,13)
    999999 ± 999999
    5.74 ± 2.02
        Cycle 9 Day 1, Pre-Dose (n=0,14)
    999999 ± 999999
    6.30 ± 12.0
        Cycle 9 Day 1, 5 Minutes Post-Dose (n=0,13)
    999999 ± 999999
    35.1 ± 11.3
        Cycle 10 Day 1, Pre-Dose (n=0,12)
    999999 ± 999999
    3.48 ± 1.13
        Cycle 10 Day 1, 5 minutes Post-Dose (n=0,12)
    999999 ± 999999
    41.4 ± 8.63
        Cycle 11 Day 1, Pre-Dose (n=0,8)
    999999 ± 999999
    3.96 ± 2.24
        Cycle 11 Day 1, 5 minutes Post-Dose (n=0,8)
    999999 ± 999999
    42.8 ± 8.85
        Cycle 12 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    3.47 ± 1.28
        Cycle 12 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    44.8 ± 10.3
        Cycle 13 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    11.3 ± 17.1
        Cycle 13 Day 1, 5 minutes Post-Dose (n=3,32)
    999999 ± 999999
    40.3 ± 19.2
        Cycle 14 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    3.97 ± 1.14
        Cycle 14 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    44.5 ± 7.05
        Cycle 15 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    4.02 ± 1.40
        Cycle 15 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    49.7 ± 6.88
        Cycle 16 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    4.60 ± 1.67
        Cycle 16 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    49.7 ± 7.61
    Notes
    [22] - Here, 99999 indicates data was below the limit of quantification.
    No statistical analyses for this end point

    Secondary: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1 and 2)

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    End point title
    Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1 and 2) [23]
    End point description
    Blood samples were collected and tested for MMAE plasma concentrations. PK-evaluable population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Cycle 2 Day 2 values are collected in phase 1 participants only. Data was summarized together for all participants in brentuximab vedotin 1.8 mg/kg arm group. Here, 999999 indicates arithmetic mean and standard deviation was not estimable since the number of participants analyzed were '0'. 99999 indicates data was below the limit of quantification. n is the number of participants analyzed at the given time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose
    Notes
    [23] - 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: The data for this endpoint was planned to be assessed in combined form for Phase 2 arm groups.
    End point values
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1
    Number of subjects analysed
    3
    33 [24]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose (n=2,32)
    99999 ± 99999
    99999 ± 99999
        Cycle 1 Day 1, 5 Minutes Post-Dose (n=3,32)
    0.416 ± 0.480
    0.368 ± 0.309
        Cycle 1 Day 2, 24 Hours Post-Dose (n=3,32)
    4.63 ± 3.20
    4.88 ± 3.55
        Cycle 1 Day 3, 48 Hours Post-Dose (n=3,32)
    4.20 ± 1.95
    5.36 ± 3.72
        Cycle 1 Day 5, 96 Hours Post-Dose (n=3,32)
    2.80 ± 0.300
    4.43 ± 3.04
        Cycle 1 Day 14, 312 Hours Post-Dose (n=3,31)
    0.196 ± 0.0641
    0.530 ± 0.552
        Cycle 2 Day 1, Pre-Dose (n=3,29)
    0.0647 ± 0.0358
    0.0739 ± 0.0640
        Cycle 2 Day 1, 5-minutes Post-Dose (n=3,29)
    0.556 ± 0.562
    0.478 ± 0.461
        Cycle 2 Day 2, 24 Hours Post-Dose (n=3,8)
    5.63 ± 5.72
    3.71 ± 3.94
        Cycle 2 Day 3, 48 Hours Post-Dose (n=3,30)
    4.60 ± 3.70
    3.86 ± 3.18
        Cycle 2 Day 5, 96 Hours Post-Dose (n=3,29)
    2.60 ± 1.04
    2.70 ± 1.69
        Cycle 3 Day 1, Pre-Dose (n=2,26)
    0.0250 ± 0.0354
    0.0650 ± 0.0590
        Cycle 3 Day 1, 5 minutes Post-Dose (n=2,25)
    0.216 ± 0.0361
    0.514 ± 0.684
        Cycle 4 Day 1, Pre-dose (n=2,19)
    0.0565 ± 0.00495
    0.0866 ± 0.0784
        Cycle 4 Day 1, 5 minutes Post-Dose (n=2,19)
    0.234 ± 0.0742
    0.376 ± 0.449
        Cycle 5 Day 1, Pre-Dose (n=2,18)
    0.0820 ± 9999
    0.0862 ± 0.0729
        Cycle 5 Day 1, 5 minutes Post-Dose (n=2,18)
    0.334 ± 0.0955
    0.301 ± 0.248
        Cycle 6 Day 1, Pre-Dose (n=2,15)
    0.0680 ± 0.0156
    0.0841 ± 0.0632
        Cycle 6 Day 1, 5 minutes Post-Dose (n=2,15)
    0.247 ± 0.00707
    0.450 ± 0.663
        Cycle 7 Day 1, Pre-Dose (n=2,16)
    0.104 ± 0.0389
    0.0830 ± 0.0578
        Cycle 7 Day 1, 5 minutes Post-Dose (n=2,15)
    0.326 ± 0.0361
    0.310 ± 0.282
        Cycle 8 Day 1, Pre-Dose (n=0,13)
    999999 ± 999999
    0.101 ± 0.934
        Cycle 8 Day 1, 5 minutes Post-Dose (n=0,12)
    999999 ± 999999
    0.295 ± 0.151
        Cycle 8 Day 2, 24 Hours Post-Dose (n=0,13)
    999999 ± 999999
    1.96 ± 1.31
        Cycle 8 Day 3, 48 Hours Post-Dose|
    999999 ± 999999
    1.91 ± 1.29
        Cycle 8 Day 5, 96 Hours Post-Dose (n=0,13)
    999999 ± 999999
    2.00 ± 1.05
        Cycle 8 Day 14, 312 Hours Post-Dose (n=0,12)
    999999 ± 999999
    0.325 ± 0.214
        Cycle 9 Day 1, Pre-Dose (n=0,13)
    999999 ± 999999
    0.0819 ± 0.0496
        Cycle 9 Day 1, 5 Minutes Post-Dose (n=0,12)
    999999 ± 999999
    0.218 ± 0.128
        Cycle 10 Day 1, Pre-Dose (n=0,12)
    999999 ± 999999
    0.727 ± 0.0517
        Cycle 10 Day 1, 5 minutes Post-Dose (n=0,12)
    999999 ± 999999
    0.204 ± 0.0982
        Cycle 11 Day 1, Pre-Dose (n=0,7)
    999999 ± 999999
    0.0763 ± 0.0368
        Cycle 11 Day 1, 5 minutes Post-Dose (n=0,7)
    999999 ± 999999
    0.255 ± 0.133
        Cycle 12 Day 1, Pre-Dose (n=0,5)
    999999 ± 999999
    0.105 ± 0.0983
        Cycle 12 Day 1, 5 minutes Post-Dose (n=0,5)
    999999 ± 999999
    0.252 ± 0.116
        Cycle 13 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    0.110 ± 0.0629
        Cycle 13 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    0.244 ± 0.130
        Cycle 14 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    0.109 ± 0.0529
        Cycle 14 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    0.320 ± 0.138
        Cycle 15 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    0.0843 ± 0.0548
        Cycle 15 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    0.404 ± 0.192
        Cycle 16 Day 1, Pre-Dose (n=0,6)
    999999 ± 999999
    0.139 ± 0.0926
        Cycle 16 Day 1, 5 minutes Post-Dose (n=0,6)
    999999 ± 999999
    0.381 ± 0.277
    Notes
    [24] - Here, 99999 indicates data was below the limit of quantification.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose through 30 days after the last dose of study medication (Up to 15 months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Brentuximab vedotin 1.4 mg/kg: Phase 1
    Reporting group description
    Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

    Reporting group title
    Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only
    Reporting group description
    Participants with r/r HL received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Reporting group title
    Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Reporting group description
    Participants with r/r systemic anaplastic large-cell lymphoma (sALCL) received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

    Serious adverse events
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 16 (43.75%)
    1 / 17 (5.88%)
         number of deaths (all causes)
    1
    6
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (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
    Cardiac arrest
    Additional description: One treatment-emergent death occurred during treatment with brentuximab 1.8 mg/kg and was not related.
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (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
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Brentuximab vedotin 1.4 mg/kg: Phase 1 Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    16 / 16 (100.00%)
    17 / 17 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    8 / 16 (50.00%)
    7 / 17 (41.18%)
         occurrences all number
    1
    11
    10
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    1
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    3
    Feeling hot
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Muscle strain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Head injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Facial bones fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    0
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    0
    3
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    2
    C-reactive protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 16 (25.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    6
    3
    Lymph node pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    1
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    6
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    1 / 17 (5.88%)
         occurrences all number
    0
    4
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 16 (31.25%)
    1 / 17 (5.88%)
         occurrences all number
    2
    5
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    8
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    3 / 17 (17.65%)
         occurrences all number
    0
    0
    3
    Migraine
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Eye discharge
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    7 / 16 (43.75%)
    4 / 17 (23.53%)
         occurrences all number
    2
    9
    5
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    0
    3
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    1
    2
    2
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    1
    2
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    0
    3
    3
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Toothache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Odynophagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Hepatic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    2
    Blister
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    2
    Dermatosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Urticaria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    2
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Drug eruption
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Erythema multiforme
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 16 (25.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    5
    0
    Arthralgia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Groin pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    3
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    4 / 17 (23.53%)
         occurrences all number
    0
    3
    5
    Pharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    3 / 17 (17.65%)
         occurrences all number
    0
    4
    4
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    Herpes zoster
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2011
    The amendment promoted participant safety by reducing the opportunity for potential drug-drug interactions, using an objective definition of dose-limiting toxicity (DLT), and specifying administration equipment that ensures drug compatibility.
    06 Feb 2012
    • The protocol excluded participants with signs or symptoms of progressive multifocal leukoencephalopathy (PML) and instructed for management of suspected PML as brentuximab vedotin discontinuation. • Information was added on management of infusion-related reactions, including instructions to immediately and permanently discontinue administration of brentuximab vedotin for Grade 3 or higher infusion-related reactions consistent with anaphylaxis. • Included information on occurrence of pulmonary toxicity and specifies that concomitant use of bleomycin with brentuximab vedotin is contraindicated. • The original protocol stated that brentuximab vedotin dose should be held in case of new or worsening events of Grade 2 or 3 neuropathy. To ensure participant’s safety and conform to dosing guidelines, an exclusion criterion was added for participants with Grade 2/higher peripheral neuropathy at the time of screening. • Participants who were pregnant or both lactating and breastfeeding were not eligible for the study. This exclusion criterion was inadvertently omitted from original protocol and was added to this amendment. • A washout period of at least 14 days was required for participants who received local palliative radiation therapy; a washout period of at least 84 days was required for participants who received radiation therapy to more than 25% of bone marrow-containing spaces. Exclusion criteria was added to specify the restrictions on receiving radiation therapy prior to first dose of study drug. • Planned imaging assessments were revised in order to minimize radiation exposure in this pediatric population. Magnetic resonance imaging (MRI) was to be performed for neck, abdomen, and pelvis evaluations; computed tomography (CT) scans were to be used for chest evaluations only. • The definition of enrollment was changed to at the time of first dose of study drug. • The contact information for serious adverse events (SAEs) and events of pregnancy was revised.
    12 Jun 2014
    • Duration of follow-up was changed to align with content of pediatric investigation plan. PIP states that participants will be followed for safety and survival for 2 years after enrollment. References to follow-up revised to state that participants will be followed for progression-free survival and overall survival every 12 weeks for 12 months after End of Treatment visit. Thereafter, assessment for OS was to continue every 6 months until sooner of death or study closure or a maximum of 2 years after enrollment of last participant. • Described study procedures for participants who continue to receive brentuximab vedotin after Cycle 16 and further clarifies other study procedures associated with study conduct. • Clarified primary endpoint for phase 2 of study is best overall response rate Inclusion criterion for total bilirubin has been revised to include participants with total serum bilirubin ≤ 3 times upper limit of normal range (ULN) if abnormal value is due to indirect hyperbilirubinemia due to Gilbert’s disease. • Participants with elevated alanine aminotransferase or aspartate aminotransferase values 5 times ULN may be enrolled if elevation can be reasonably ascribed to presence of metastatic disease in liver. • Exclusions of previous allogeneic stem cell transplant or autologous stem cell infusion was changed from within 6 months and 6 weeks before first dose of study drug, respectively, to within 3 months and 4 weeks before first dose of study drug, respectively. • Exclusion criterion for cytochrome P450 3A4 inhibitors was changed to exclude both strong and listed moderate inhibitors of CYP3A4 within 2 weeks before first dose of study drug, and a change to timing for exclusion of corticosteroids. • Following potential risks were added to Risks in Children section to align with updates to safety profile of brentuximab vedotin: Stevens-Johnson syndrome, pancreatitis, hepatotoxicity (elevated AST and ALT).

    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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