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    Clinical Trial Results:
    A Randomized, Open-Label, Phase 3 Trial of Brentuximab Vedotin (SGN-35) Versus Physician’s Choice (Methotrexate or Bexarotene) in Patients With CD30-Positive Cutaneous T-Cell Lymphoma

    Summary
    EudraCT number
    2010-024215-14
    Trial protocol
    BE   GB   ES   DE   AT   IT   PL  
    Global end of trial date
    06 Jul 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    17 Jul 2019
    First version publication date
    07 Jan 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    C25001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01578499
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Takeda Oncology
    Sponsor organisation address
    40 Lansdowne Street, Cambridge MA, United States, 02139
    Public contact
    Medical Director, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine ORR, lasting at least 4 months (ORR4), with brentuximab vedotin in participants with CD30+ MF or pcALCL compared to that achieved with therapy in the control arm.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Jun 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    United States: 33
    Worldwide total number of subjects
    131
    EEA total number of subjects
    68
    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)
    79
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 34 investigative sites in Australia, Belgium, Brazil, France, Germany, Italy, Poland, Spain, Switzerland, United Kingdom, United States from 11 June 2012 to the Primary Completion data of 06 July 2018.

    Pre-assignment
    Screening details
    Participants with a diagnosis of cluster of differentiation antigen 30 (CD30)-Positive Cutaneous T-Cell Lymphoma were enrolled equally in 1 of 2 arms: brentuximab vedotin 1.8 mg/kg or physician’s choice (Methotrexate or Bexarotene).

    Pre-assignment period milestones
    Number of subjects started
    131
    Number of subjects completed
    128

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Did not Receive Study Drug: 3
    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
    Brentuximab vedotin
    Arm description
    Brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).
    Arm type
    Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    SGN-35
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1.8 milligram per kilogram (mg/kg) intravenous (IV) infusion over approximately 30 minutes on Day 1 of each 21-day cycle.

    Arm title
    Methotrexate or Bexarotene
    Arm description
    Methotrexate 5 to 50 mg, tablets, orally, once weekly (dose adjustment is guided by patient response and toxicity) or Bexarotene 300 mg/m^2, tablets, orally, once daily with meals for up to 48 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Bexarotene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participant received single oral daily dose of 300 mg/m^2/day

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participant received a single dose of 5 to 50 mg methotrexate orally once weekly.

    Number of subjects in period 1 [1]
    Brentuximab vedotin Methotrexate or Bexarotene
    Started
    66
    62
    Completed
    32
    19
    Not completed
    34
    43
         Death
    20
    25
         Withdrawal by Subject
    10
    16
         Died and End of Study Page not Completed
    2
    -
         Reason not Specified
    -
    1
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to be in the baseline period is based on the Safety Population that included all participants who received at least one dose of study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brentuximab vedotin
    Reporting group description
    Brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

    Reporting group title
    Methotrexate or Bexarotene
    Reporting group description
    Methotrexate 5 to 50 mg, tablets, orally, once weekly (dose adjustment is guided by patient response and toxicity) or Bexarotene 300 mg/m^2, tablets, orally, once daily with meals for up to 48 weeks.

    Reporting group values
    Brentuximab vedotin Methotrexate or Bexarotene Total
    Number of subjects
    66 62 128
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    38 39 77
        From 65-84 years
    28 23 51
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    59.4 ± 13.80 56.6 ± 14.43 -
    Gender, Male/Female
    Units: Subjects
        Female
    33 28 61
        Male
    33 34 67
    Region of Enrollment
    Safety population included participants who received at least 1 dose of study drug, analyzed according to the actual treatment received.
    Units: Subjects
        Australia
    12 8 20
        Belgium
    4 2 6
        France
    4 3 7
        Germany
    3 2 5
        Italy
    12 6 18
        Poland
    2 1 3
        Spain
    2 3 5
        Switzerland
    3 3 6
        United Kingdom
    8 15 23
        United States
    14 17 31
        Brazil
    2 2 4

    End points

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    End points reporting groups
    Reporting group title
    Brentuximab vedotin
    Reporting group description
    Brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

    Reporting group title
    Methotrexate or Bexarotene
    Reporting group description
    Methotrexate 5 to 50 mg, tablets, orally, once weekly (dose adjustment is guided by patient response and toxicity) or Bexarotene 300 mg/m^2, tablets, orally, once daily with meals for up to 48 weeks.

    Subject analysis set title
    pcALCL: Brentuximab vedotin
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with pcALCL received brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

    Subject analysis set title
    MF: Brentuximab vedotin 1.8 mg/kg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with MF received brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

    Subject analysis set title
    Brentuximab vedotin
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

    Subject analysis set title
    Methotrexate or Bexarotene
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Methotrexate 5 to 50 mg, tablets, orally, once weekly (dose adjustment is guided by patient response and toxicity) or Bexarotene 300 mg/m^2, tablets, orally, once daily with meals for up to 48 weeks.

    Primary: Percentage of Participants Achieving an Objective Response that Lasts at Least 4 Months (ORR4)

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    End point title
    Percentage of Participants Achieving an Objective Response that Lasts at Least 4 Months (ORR4)
    End point description
    ORR4 was determined by an Independent Review Facility (IRF) based on Global Response Score (GRS) which consisted of a skin assessment by the investigator using the modified severity-weighted assessment tool (mSWAT), nodal and visceral radiographic assessment by an IRF and for the participants with mycosis fungoides (MF) only, detection of circulation Sezary cells. Participants whose first response occurred after the start of subsequent anticancer therapy were excluded. Response Criteria was based on International Society for Cutaneous Lymphomas (ISCL), United States Cutaneous Lymphoma Consortium (USCLC) and Cutaneous Lymphoma Task Force (CLTF) of the European Organisation for Research and Treatment of Cancer (EORTC) Consensus guidelines (Olsen, 2011). The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment.
    End point type
    Primary
    End point timeframe
    Each Cycle until disease progression, death End of treatment (Median overall follow-up 38.8 months)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    64
    64
    Units: percentage of participants
        number (confidence interval 95%)
    54.7 (42.5 to 66.9)
    12.5 (4.4 to 20.6)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Brentuximab vedotin v Methotrexate or Bexarotene
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    42.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.5
         upper limit
    56.8
    Notes
    [1] - Based on a two-sided Χ² test with a significance level of 0.05, and a 10% dropout rate, a sample size of approximately 124 participants was calculated to provide 90% power to detect a 30% improvement in ORR4 in the brentuximab vedotin group.
    [2] - P-value was stratified by baseline disease diagnosis (pcALCL and MF).

    Secondary: Percentage of Participants achieving a CR

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    End point title
    Percentage of Participants achieving a CR
    End point description
    Complete Response (CR) was determined by the IRF based on Global Response Score (GRS) which consisted of a skin assessment by the investigator using the modified severity-weighted assessment tool (mSWAT), nodal and visceral radiographic and for the participants with mycosis fungoides (MF) only, detection of circulation Sezary cells. Response Criteria was based on ISCL, USCLC and CLTF of the EORTC Consensus guidelines (Olsen, 2011). The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment.
    End point type
    Secondary
    End point timeframe
    Each Cycle until disease progression, death or data cutoff (Median overall follow-up 38.8 months)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    64
    64
    Units: percentage of participants
        number (confidence interval 95%)
    17.2 (7.9 to 26.4)
    1.6 (0.0 to 8.4)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Brentuximab vedotin v Methotrexate or Bexarotene
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    15.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    33
    Notes
    [3] - P-value was stratified by baseline disease diagnosis (pcALCL and MF).

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS was assessed by the IRF and is defined as the time from randomization until disease progression or death due to any cause, whichever occurs first. Disease progression was based on ISCL, USCLC and CLTF of the EORTC Consensus guidelines (Olsen, 2011). The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment.
    End point type
    Secondary
    End point timeframe
    Until disease progression, death or data cutoff (Median PFS follow-up of 38.8 months)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    64
    64
    Units: months
        median (confidence interval 95%)
    16.7 (15.4 to 21.6)
    3.5 (2.4 to 4.6)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Brentuximab vedotin v Methotrexate or Bexarotene
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.378
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.247
         upper limit
    0.577
    Notes
    [4] - Hazard ratio brentuximab vedotin/ comparator (methotrexate or bexarotene) with the 95% CI from a stratified Cox regression model with treatment as the explanatory variable and baseline disease diagnosis (MF or pcALCL) as stratification factor.

    Secondary: Maximum Change from Baseline in Symptom Domain Score of the Skindex-29 Questionnaire

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    End point title
    Maximum Change from Baseline in Symptom Domain Score of the Skindex-29 Questionnaire
    End point description
    Skindex-29 is a 29-item dermatology-specific health-related quality of life (HRQoL). The Skindex-29 incorporates a 28-day recall period and consists of 3 domains: symptoms, emotions, and functioning. The domain scores and an overall score are expressed on a 100-point scale, from 0 to 100 with higher scores indicating lower levels of health- HRQoL. A negative change (reduction) from Baseline indicates improvement. The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Here number of participants analyzed are participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of Treatment (Week 52)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    58
    54
    Units: score on a scale
        arithmetic mean (standard deviation)
    -28.08 ± 26.863
    -8.62 ± 17.013
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    P-value is calculated using the analysis of covariance (ANCOVA) model controlling for baseline symptom domain score, eastern cooperative oncology group (ECOG) performance status score (=0 and ≥1), and disease diagnosis (pcALCL and MF) between the brentuximab vedotin and comparator (methotrexate or bexarotene) arms.
    Comparison groups
    Brentuximab vedotin v Methotrexate or Bexarotene
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Estimate of difference
    Point estimate
    -19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.7
         upper limit
    -11.4

    Secondary: Duration of Response (DOR)

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    End point title
    Duration of Response (DOR)
    End point description
    Duration of response was assessed by the IRF in participants with confirmed response [CR or Partial Response (PR)] and is defined as the time between first documentation of response and disease progression. Response Criteria was based on ISCL, USCLC and CLTF of the EORTC Consensus guidelines (Olsen, 2011). The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Responders in ITT population were analyzed in this outcome measure. 99999: Upper limit of Confidence Interval (CI) was not estimable due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Until disease progression, death or data cutoff (Median follow-up 38.8 months)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    42
    13
    Units: months
        median (confidence interval 95%)
    15.1 (9.8 to 25.5)
    18.4 (3.5 to 99999)
    No statistical analyses for this end point

    Secondary: DOR of Skin Response

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    End point title
    DOR of Skin Response
    End point description
    Duration of skin response (CR and PR) was assessed by investigator and is defined as time between first skin response to progressive disease in skin. Per mSWAT, CR is defined as 100% clearance of skin lesions. PR is defined as 50%-99% clearance of skin disease from Baseline; No new tumors in participants without tumors at Baseline -MF; No new tumors-primary cutaneous anaplastic large cell lymphoma (pcALCL).Progressive disease is defined as ≥ 25% increase in skin disease from baseline, or loss of response: in those with CR or PR, increase of skin score of greater than sum of nadir plus 50% baseline score, or new tumors in patients without tumors at baseline (MF).ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Skin responders in ITT population were analyzed in this outcome measure. 99999: Upper limit of Confidence Interval (CI) was not estimable due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Until disease progression, death or data cutoff (Median follow-up 38.8 months)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    47
    19
    Units: months
        median (confidence interval 95%)
    18.9 (15.0 to 25.7)
    18.3 (3.5 to 99999)
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS)

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    End point title
    Event-Free Survival (EFS)
    End point description
    EFS was assessed by the IRF and is defined as the time from randomization until any cause of treatment failure: disease progression, discontinuation of treatment for any reason, or death due to any cause, whichever occurs first. Disease progression was based on ISCL, USCLC and CLTF of the EORTC Consensus guidelines (Olsen, 2011). The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression, death or data cutoff (Median follow-up 36.8 months)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    64
    64
    Units: months
        median (full range (min-max))
    9.4 (5.9 to 11.7)
    2.3 (1.7 to 3.5)
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Concentration for Brentuximab Vedotin

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    End point title
    Cmax: Maximum Observed Concentration for Brentuximab Vedotin
    End point description
    The pharmacokinetic (PK) population included participants with sufficient dose and PK data to reliably estimate PK parameters as determined by a clinical pharmacologist. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose and 30 minutes after infusion in Cycles 1 and 3
    End point values
    pcALCL: Brentuximab vedotin MF: Brentuximab vedotin 1.8 mg/kg
    Number of subjects analysed
    16
    50
    Units: ug/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n= 15, 50)
    38.36 ± 9.427
    38.40 ± 8.912
        Cycle 3 Day 1 (n= 12, 41)
    40.14 ± 12.697
    36.69 ± 14.249
    No statistical analyses for this end point

    Secondary: Ctrough: Observed Concentration at the End of a Dosing Interval for Brentuximab Vedotin

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    End point title
    Ctrough: Observed Concentration at the End of a Dosing Interval for Brentuximab Vedotin
    End point description
    The PK population included participants with sufficient dose and PK data to reliably estimate PK parameters as determined by a clinical pharmacologist. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose of Cycles 2 and 4
    End point values
    pcALCL: Brentuximab vedotin MF: Brentuximab vedotin 1.8 mg/kg
    Number of subjects analysed
    16
    50
    Units: ug/mL
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n= 11, 31)
    3.57 ± 10.101
    0.58 ± 0.517
        Cycle 4 Day 1 (n= 8, 28)
    0.99 ± 0.528
    0.78 ± 0.446
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Concentration for Monomethyl Auristatin (MMAE) for Brentuximab Vedotin

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    End point title
    Cmax: Maximum Observed Concentration for Monomethyl Auristatin (MMAE) for Brentuximab Vedotin
    End point description
    The PK population included participants with sufficient dose and PK data to reliably estimate PK parameters as determined by a clinical pharmacologist. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose and 30 minutes after infusion ended in Cycles 1 and 3
    End point values
    pcALCL: Brentuximab vedotin MF: Brentuximab vedotin 1.8 mg/kg
    Number of subjects analysed
    16
    50
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n= 13, 46)
    2.53 ± 1.382
    3.34 ± 1.901
        Cycle 3 Day 1 (n= 12, 36)
    2.96 ± 1.176
    3.08 ± 1.276
    No statistical analyses for this end point

    Secondary: Ctrough: Observed Concentration at the End of a Dosing Interval for MMAE for Brentuximab Vedotin

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    End point title
    Ctrough: Observed Concentration at the End of a Dosing Interval for MMAE for Brentuximab Vedotin
    End point description
    The PK population included participants with sufficient dose and PK data to reliably estimate PK parameters as determined by a clinical pharmacologist. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose of Cycles 2 and 4
    End point values
    pcALCL: Brentuximab vedotin MF: Brentuximab vedotin 1.8 mg/kg
    Number of subjects analysed
    16
    50
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n= 11, 33)
    0.11 ± 0.095
    0.09 ± 0.060
        Cycle 4 Day 1 (n= 10, 34)
    0.14 ± 0.113
    0.11 ± 0.091
    No statistical analyses for this end point

    Secondary: Number of Participants with Antitherapeutic Antibodies (ATA) to Brentuximab Vedotin

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    End point title
    Number of Participants with Antitherapeutic Antibodies (ATA) to Brentuximab Vedotin
    End point description
    Blood was collected and evaluated for ATA and neutralizing ATA in all participants who received brentuximab vedotin to assess immunogenicity. The Safety population included participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of Treatment (Week 52)
    End point values
    pcALCL: Brentuximab vedotin MF: Brentuximab vedotin 1.8 mg/kg
    Number of subjects analysed
    16
    50
    Units: participants
        Immunogenicity-evaluable participants
    14
    46
        Baseline Negative: ATA negative
    8
    23
        Baseline Negative: ATA positive
    6
    19
        Baseline Negative: Transiently Positive
    4
    9
        Baseline Negative: Persistently Positive
    2
    10
        Baseline Negative: Neutralizing ATA Positive
    4
    14
        Baseline Positive: ATA Negative
    0
    1
        Baseline Positive: ATA Positive
    0
    3
        Baseline Positive: Transiently Positive
    0
    3
        Baseline Positive: Persistently Positive
    0
    0
        Baseline Positive: Neutralizing ATA Positive
    0
    2
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Skindex-29 Questionnaire Total Score

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    End point title
    Change from Baseline in the Skindex-29 Questionnaire Total Score
    End point description
    Skindex-29 is a 29-item dermatology-specific health-related quality of life (HRQoL). The Skindex-29 incorporates a 28-day recall period and consists of 3 domains: symptoms, emotions, and functioning. The domain scores and an overall score are expressed on a 100-point scale, 0 to 100 with higher scores indicating lower levels of health- HRQoL. A negative change (reduction) from Baseline indicates improvement. The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycles 1, 2, 4, 6, 8, 10, 12, 14, 16, at End of Treatment (EOT) and during posttreatment long treatment follow-up (LTFU) - (Median follow-up 38.8 months)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    64
    64
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Cycle 2 (n= 55, 45)
    -5.44 ± 11.055
    -2.49 ± 11.959
        Change at Cycle 4 (n= 49, 30)
    -14.60 ± 17.488
    -6.71 ± 9.755
        Change at Cycle 6 (n= 40, 25)
    -17.59 ± 17.770
    -5.40 ± 9.758
        Change at Cycle 8 (n= 37, 14)
    -21.73 ± 18.882
    -7.28 ± 16.769
        Change at Cycle 10 (n= 35, 13)
    -22.47 ± 21.722
    -3.71 ± 21.752
        Change at Cycle 12 (n= 25, 8)
    -23.37 ± 21.555
    -5.22 ± 17.704
        Change at Cycle 14 (n= 25, 5)
    -19.72 ± 20.980
    -7.49 ± 22.463
        Change at Cycle 16 (n= 22, 3)
    -19.35 ± 18.911
    0.75 ± 10.308
        Change at End of Treatment (n= 47, 37)
    -16.26 ± 23.281
    -0.96 ± 18.973
        Change at 3-6 months LTFU (n= 2, 3)
    -1.07 ± 3.704
    -9.48 ± 21.629
        Change at 6-9 months LTFU (n= 6, 11)
    -8.04 ± 8.800
    -9.68 ± 17.789
        Change at 9-12 months LTFU (n= 7, 10)
    -7.94 ± 15.582
    -4.93 ± 14.516
        Change at 12-15 months LTFU (n= 25, 21)
    -16.21 ± 18.438
    -11.16 ± 18.183
        Change at 15-18 months LTFU (n= 25, 18)
    -19.18 ± 19.475
    -8.53 ± 12.768
        Change at 18-21 months LTFU (n= 22, 17))
    -19.27 ± 20.962
    -5.46 ± 16.679
        Change at 21-24 months LTFU (n= 18, 19)
    -16.60 ± 19.875
    -6.86 ± 14.991
        Change at 24-27 months LTFU (n= 20, 18)
    -17.04 ± 15.982
    -9.05 ± 23.990
        Change at 27-30 months LTFU (n= 20, 18)
    -12.45 ± 19.639
    -7.97 ± 16.401
        Change at >30 months LTFU (n= 23, 20)
    -11.49 ± 22.470
    -1.07 ± 18.886
    No statistical analyses for this end point

    Secondary: Change from Baseline in Functional Assessment of Cancer Therapy General Questionnaire (FACT-G) Score

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    End point title
    Change from Baseline in Functional Assessment of Cancer Therapy General Questionnaire (FACT-G) Score
    End point description
    FACT-G is a 27-item general cancer QOL instrument completed by participants receiving cancer treatment. FACT-G incorporates a 7-day recall period and contains 4 primary subscales: Physical Well-Being (PWB; sum of 7 items, point range 0-28); Social/Family Well-Being (SWB, sum of 7-items, point range 0-28); Emotional Well-Being (EWB; sum of 6-items, point range 0-24); Functional Well-Being (FWB; sum of 7-items, point range 0-28); Fact-G total score=sum of PWB, SWB, EWB, FWB, point range 0-108. Higher scores for the total scales and subscales indicate better quality of life. A negative change (reduction) from Baseline indicates improvement. The ITT population included all participants who were identified as CD30+ by the Ventana anti-CD30 (Ber-H2) assay and were randomized to treatment. Here 'Number analyzed' is the number of participants with evaluable data at the specified time-point.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycles 1, 2, 4, 6, 8, 10, 12, 14, 16, at EOT and during posttreatment (LTFU) - (Median follow-up 38.8 months)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    64
    64
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Cycle 2 (n= 56, 46)
    1.43 ± 10.168
    -0.37 ± 11.723
        Change at Cycle 4 (n= 50, 32)
    1.75 ± 12.014
    1.78 ± 10.740
        Change at Cycle 6 (n= 40, 25)
    4.23 ± 14.257
    2.24 ± 13.108
        Change at Cycle 8 (n= 37, 13)
    5.96 ± 16.030
    2.54 ± 10.809
        Change at Cycle 10 (n= 35, 13)
    6.61 ± 16.971
    4.38 ± 15.040
        Change at Cycle 12 (n= 27, 8)
    7.94 ± 18.837
    8.61 ± 21.024
        Change at Cycle 14 (n= 26, 6)
    9.04 ± 14.104
    10.75 ± 13.615
        Change at Cycle 16 (n= 22, 4)
    5.08 ± 9.230
    7.88 ± 23.432
        Change at End of Treatment (n= 47, 37)
    0.35 ± 16.067
    -2.29 ± 17.171
        Change at 3-6 months LTFU (n= 2, 2)
    16.00 ± 18.385
    -2.92 ± 8.367
        Change at 6-9 months LTFU (n= 6, 12)
    -0.19 ± 19.648
    -2.59 ± 12.473
        Change at 9-12 months LTFU (n= 7, 10)
    3.62 ± 17.651
    -5.32 ± 10.555
        Change at 12-15 months LTFU (n= 20, 16)
    8.33 ± 14.918
    -1.34 ± 11.905
        Change at 15-18 months LTFU (n= 24, 18)
    3.03 ± 12.618
    2.94 ± 14.756
        Change at 18-21 months LTFU (n= 24, 16)
    3.35 ± 11.117
    -0.19 ± 14.316
        Change at 21-24 months LTFU (n= 17, 18)
    1.51 ± 5.471
    0.61 ± 14.505
        Change at 24-27 months LTFU (n= 20, 15)
    4.20 ± 7.952
    1.42 ± 17.870
        Change at 27-30 months LTFU (n= 19, 17)
    -1.57 ± 17.488
    1.93 ± 8.716
        Change at >30 months LTFU (n= 22, 19)
    -6.22 ± 15.222
    -2.85 ± 5.518
    No statistical analyses for this end point

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

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    End point title
    Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    AEs and SAEs were assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. An Adverse Event (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 AE that results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. The Safety population included participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    First dose of study drug through 30 days after last dose of study drug (Up to 450 days)
    End point values
    Brentuximab vedotin Methotrexate or Bexarotene
    Number of subjects analysed
    66
    62
    Units: participants
        AEs (n= 66, 62)
    63
    56
        SAEs (n= 66, 62)
    18
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug through 30 days after last dose of study drug (Up to 450 days)
    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
    21.0
    Reporting groups
    Reporting group title
    Brentuximab vedotin
    Reporting group description
    Brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks).

    Reporting group title
    Methotrexate or Bexarotene
    Reporting group description
    Methotrexate 5 to 50 mg, tablets, orally, once weekly (dose adjustment is guided by patient response and toxicity) or Bexarotene 300 mg/m^2, tablets, orally, once daily with meals for up to 48 weeks.

    Serious adverse events
    Brentuximab vedotin Methotrexate or Bexarotene
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 66 (27.27%)
    18 / 62 (29.03%)
         number of deaths (all causes)
    4
    0
         number of deaths resulting from adverse events
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
    Additional description: One treatment-emergent death occurred in participant with lymphoma during treatment with brentuximab vedotin and is not related.
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 66 (3.03%)
    4 / 62 (6.45%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
    Additional description: One treatment-emergent death occurred in participant with pcALCL during treatment with brentuximab vedotin and is related.
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Stress
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (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
    Fracture
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolytic uraemic syndrome
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (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
    Pulmonary embolism
    Additional description: One treatment-emergent death occurred in participant with pulmonary embolism during treatment with brentuximab vedotin and is not related.
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin erosion
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crystal arthropathy
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 66 (3.03%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    Additional description: One treatment-emergent death occurred in participant with sepsis during treatment with brentuximab vedotin and is not related.
         subjects affected / exposed
    1 / 66 (1.52%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital infection
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Brentuximab vedotin Methotrexate or Bexarotene
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 66 (90.91%)
    51 / 62 (82.26%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 66 (9.09%)
    0 / 62 (0.00%)
         occurrences all number
    7
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 66 (1.52%)
    5 / 62 (8.06%)
         occurrences all number
    1
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 66 (27.27%)
    18 / 62 (29.03%)
         occurrences all number
    22
    19
    Asthenia
         subjects affected / exposed
    7 / 66 (10.61%)
    5 / 62 (8.06%)
         occurrences all number
    10
    9
    Pyrexia
         subjects affected / exposed
    9 / 66 (13.64%)
    8 / 62 (12.90%)
         occurrences all number
    17
    9
    Peripheral swelling
         subjects affected / exposed
    1 / 66 (1.52%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    Oedema peripheral
         subjects affected / exposed
    7 / 66 (10.61%)
    6 / 62 (9.68%)
         occurrences all number
    9
    6
    Chills
         subjects affected / exposed
    4 / 66 (6.06%)
    2 / 62 (3.23%)
         occurrences all number
    4
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 66 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Insomnia
         subjects affected / exposed
    2 / 66 (3.03%)
    6 / 62 (9.68%)
         occurrences all number
    2
    6
    Investigations
    Weight decreased
         subjects affected / exposed
    6 / 66 (9.09%)
    2 / 62 (3.23%)
         occurrences all number
    6
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 66 (4.55%)
    5 / 62 (8.06%)
         occurrences all number
    3
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 66 (1.52%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    Blood cholesterol increased
         subjects affected / exposed
    0 / 66 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Blood triglycerides increased
         subjects affected / exposed
    0 / 66 (0.00%)
    5 / 62 (8.06%)
         occurrences all number
    0
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 66 (10.61%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    Cough
         subjects affected / exposed
    2 / 66 (3.03%)
    4 / 62 (6.45%)
         occurrences all number
    2
    12
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    5 / 66 (7.58%)
    4 / 62 (6.45%)
         occurrences all number
    11
    6
    Anaemia
         subjects affected / exposed
    3 / 66 (4.55%)
    6 / 62 (9.68%)
         occurrences all number
    3
    8
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    31 / 66 (46.97%)
    1 / 62 (1.61%)
         occurrences all number
    53
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    4 / 66 (6.06%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    Paraesthesia
         subjects affected / exposed
    6 / 66 (9.09%)
    1 / 62 (1.61%)
         occurrences all number
    8
    1
    Headache
         subjects affected / exposed
    5 / 66 (7.58%)
    6 / 62 (9.68%)
         occurrences all number
    5
    6
    Dysgeusia
         subjects affected / exposed
    5 / 66 (7.58%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    Dizziness
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 62 (1.61%)
         occurrences all number
    4
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 66 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    24 / 66 (36.36%)
    9 / 62 (14.52%)
         occurrences all number
    32
    9
    Vomiting
         subjects affected / exposed
    11 / 66 (16.67%)
    3 / 62 (4.84%)
         occurrences all number
    14
    3
    Diarrhoea
         subjects affected / exposed
    18 / 66 (27.27%)
    4 / 62 (6.45%)
         occurrences all number
    24
    4
    Constipation
         subjects affected / exposed
    3 / 66 (4.55%)
    5 / 62 (8.06%)
         occurrences all number
    5
    5
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    7 / 66 (10.61%)
    3 / 62 (4.84%)
         occurrences all number
    7
    3
    Alopecia
         subjects affected / exposed
    10 / 66 (15.15%)
    2 / 62 (3.23%)
         occurrences all number
    10
    2
    Dry skin
         subjects affected / exposed
    1 / 66 (1.52%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    Urticaria
         subjects affected / exposed
    5 / 66 (7.58%)
    1 / 62 (1.61%)
         occurrences all number
    6
    1
    Pruritus generalised
         subjects affected / exposed
    7 / 66 (10.61%)
    1 / 62 (1.61%)
         occurrences all number
    8
    1
    Pruritus
         subjects affected / exposed
    11 / 66 (16.67%)
    8 / 62 (12.90%)
         occurrences all number
    11
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 66 (12.12%)
    4 / 62 (6.45%)
         occurrences all number
    13
    4
    Pain in extremity
         subjects affected / exposed
    6 / 66 (9.09%)
    4 / 62 (6.45%)
         occurrences all number
    6
    4
    Muscle spasms
         subjects affected / exposed
    4 / 66 (6.06%)
    3 / 62 (4.84%)
         occurrences all number
    4
    3
    Myalgia
         subjects affected / exposed
    8 / 66 (12.12%)
    2 / 62 (3.23%)
         occurrences all number
    9
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 66 (0.00%)
    5 / 62 (8.06%)
         occurrences all number
    0
    6
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 66 (7.58%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    Decreased appetite
         subjects affected / exposed
    10 / 66 (15.15%)
    3 / 62 (4.84%)
         occurrences all number
    15
    3
    Hyperuricaemia
         subjects affected / exposed
    4 / 66 (6.06%)
    2 / 62 (3.23%)
         occurrences all number
    6
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 66 (1.52%)
    11 / 62 (17.74%)
         occurrences all number
    1
    21
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 66 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Infections and infestations
    Skin infection
         subjects affected / exposed
    2 / 66 (3.03%)
    6 / 62 (9.68%)
         occurrences all number
    3
    6
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 66 (6.06%)
    2 / 62 (3.23%)
         occurrences all number
    4
    2
    Urinary tract infection
         subjects affected / exposed
    4 / 66 (6.06%)
    4 / 62 (6.45%)
         occurrences all number
    4
    4
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 66 (1.52%)
    5 / 62 (8.06%)
         occurrences all number
    1
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2011
    Amendment 1: • The primary objective was revised to define ORR as lasting at least 4 months, and specify the study population. • The study population was modified to include only participants with a primary diagnosis of mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL). • The study population was revised to include participants who received at least 1 prior systemic therapy for their disease. • The protocol was revised to require confirmation of CD30 positivity, defined as membranous, cytoplasmic or golgi pattern of expression of the CD30 antigen by 10% or greater of either total lymphocytes or neoplastic cells at any intensity greater than zero on a scale of zero to 3+. • The protocol was revised to exclude patients with signs or symptoms of progressive multifocal leukoencephalopathy (PML) and contains instructions for the suggested management of suspected PML that include brentuximab vedotin discontinuation. • The schedule for modified severity weighted assessment tool (mSWAT) assessments was changed to include the following time points: before dose administration at Cycle 1, Day 1; at the end of every treatment cycle; within 30 days of the last dose of study drug; and at posttreatment follow-up visits. • The protocol was revised to exclude patients with known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
    24 Feb 2012
    Amendment 2: • The protocol was revised to include information on the occurrence of pulmonary toxicity and specifies that the concomitant use of bleomycin with brentuximab vedotin is contraindicated. • Revised recommendations for subsequent treatment for patients who complete 48 weeks of treatment with reference therapy or 16 cycles of brentuximab vedotin. • The protocol was revised to remove plan to reallocate patients to low-enrolling treatment arms for strata analysis.
    04 Mar 2013
    Amendment 3: • The protocol was revised to allow patients with stable disease (SD) to continue to receive study treatment up to the maximum treatment period (16 cycles of brentuximab vedotin or 48 weeks with methotrexate or bexarotene) at the discretion of the investigator. • The eligibility criteria was revised to allow for the enrollment of patients with pcALCL who have received prior radiation therapy or at least 1 prior systemic therapy for their disease. • A secondary objective was added to the protocol to assess duration of skin response with brentuximab vedotin. • The inclusion criterion requiring fasting serum triglycerides of <150 mg/dL before study entry was removed. • The timing of computed tomography (CT) scans was revised to align with current standard practice. • The planned analysis populations were revised to accommodate the change to the Ventana CD30 (Ber-H2) assay to determine CD30 expression for patient eligibility. • A real-time independent review performed at the time of anticipated treatment discontinuation for all patients, regardless of reason, was added. • References to ECGs were removed from the list of safety assessments in the protocol.
    03 Jul 2013
    Amendment 4: • Reverted to the text that stated that the sponsor was to be notified in the event that a participant was withdrawn from study treatment or from the study. • Revised instructions for calculating body surface area (BSA) to determine the dose of bexarotene. • The protocol was revised to require all events of peripheral neuropathy to be followed for changes in severity until resolution to baseline or study closure, whichever occurred first. • The protocol was revised to remove requirement to end safety monitoring when a patient received subsequent anticancer therapy.
    02 Dec 2014
    Amendment 5: • Updated safety information and revised the existing eligibility criteria regarding patients at risk for pancreatitis. • Language was added to the benefit and risk section summarizing the potential risk of pancreatitis in the population of patients at risk of pancreatitis and with cutaneous T-cell lymphoma (CTCL). • Eligibility criteria were updated to exclude patients with an elevated lipase value ≥3 times the upper limit of normal (ULN) with an amylase value > ULN. Allowed for Fludeoxyglucose-positron emission tomography (FDG-PET) scans and computed tomography (CT) taken within 8 weeks before signing the informed consent form (ICF) to be used as the subject FDG-PET scan, and CT scans taken within 4 weeks before signing the ICF to be used as the screening CT scan provided pre-specified conditions were met.

    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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