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    Clinical Trial Results:
    A pilot phase II study with BRENTUXIMAB VEDOTIN as pre-ASCT induction therapy in relapsed/refractory Hodgkin’s lymphoma patients non responding to IGEV salvage treatment.

    Summary
    EudraCT number
    		 2013-003934-33
    Trial protocol
    		 IT  
    Global end of trial date
    12 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 May 2021
    First version publication date
    20 May 2021
    Other versions
    Summary report(s)
    		 FIL_Bridge_synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    FIL_BRidge
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02244021
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fondazione Italiana Linfomi Onlus
    Sponsor organisation address
    piazza Turati 5, Alessandria , Italy,
    Public contact
    Secretariat, Fondazione Italiana Linfomi Onlus, 0039 0131206129, segreteria@filinf.it
    Scientific contact
    Secretariat, Fondazione Italiana Linfomi Onlus, 0039 0131206129, segreteria@filinf.it
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the activity of brentuximab vedotin in terms of complete remission (CT scan and FDG-PET negative) in patients with relapsed/refractory Hodgkin’s Lymphoma not responding (FDG-PET positive) to salvage treatment with IGEV.
    Protection of trial subjects
    Appropriate precautions should be taken during infusion of the drug, with regular monitoring of vital signs, drugs available for the treatment of anaphylactic reaction, and a physician in attendance. Patients treated with brentuximab vedotin should be monitored closely during the infusion and be advised of the potential to develop allergy-like symptoms post-infusion. Infusion-related reactions may occur during the infusion of brentuximab vedotin. The infusion should be administered at a site properly equipped and staffed to manage anaphylaxis should it occur. The patient should be observed for 60 minutes following the first infusion of brentuximab vedotin. During this observation period, the IV line should remain open for at least 1 hour to allow administration of IV drugs if necessary. All supportive measures consistent with optimal patient care will be given throughout the study according to medical judgment and institution standards. If anaphylaxis occurs, immediately and permanently discontinue administration of brentuximab vedotin and administer appropriate medical therapy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    12
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Thirteen patients recruited in Italy from first december 2014, with date of last completed at 27 October 2017

    Pre-assignment
    Screening details
    		 Inclusion criteria: 1. Classical Hodgkin Lymphoma according to the World Health Organisation (WHO) classification 2. Patients at the first line salvage therapy 4. FDG-PET positivity after two cycles of IGEV treatment 5. PBPCs should have been collected after the first or the second IGEV cycle 6. Age≥ 18 years 7. ECOG performance status of 0-

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Single Arm
    Arm description
    		 After registration and eligibility check patients will receive a total of 4 courses of the study drug, one every three weeks. Brentuximab vedotin will be administered intravenously at the dose of 1.8 mg/kg. Brentuximab vedotin is to be administered on Day 1 of each 21-day cycle via a 30 minute intravenous (IV) infusion.
    Arm type
    		 Single arm study

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin will be administered intravenously at the dose of 1.8 mg/kg. Brentuximab vedotin is to be administered on Day 1 of each 21-day via a 30 minute intravenous (IV) infusion.

    Number of subjects in period 1
    		Single Arm
    Started
    13
    Completed
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 13 13
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 45 (19 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 4 4
    Stage
    Ann Arbor Stage
    Units: Subjects
        Stage IV
    		 3 3
        Stage I-II
    		 10 10
    ECOG-PS
    ECOG Performance Status
    Units: Subjects
        ECOG-PS >1
    		 0 0
        ECOG 0-1
    		 13 13
    Bulky Disease
    Mediastinal size >6 cm or lymph node >10 cm
    Units: Subjects
        Bulky, Yes
    		 1 1
        Bulky, No
    		 12 12
    Hemoglobin
    Units: g/dL
        median (full range (min-max))
    		 10.7 (9.8 to 13.0) -
    WBC
    White Cell Count
    Units: 10^9/L
        median (full range (min-max))
    		 4.10 (2.30 to 8.20) -
    ALC
    Absolute Lymphocyte Count
    Units: 10^9/L
        median (full range (min-max))
    		 0.80 (0.40 to 1.40) -

    End points

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    End points reporting groups
    Reporting group title
    Single Arm
    Reporting group description
    		 After registration and eligibility check patients will receive a total of 4 courses of the study drug, one every three weeks. Brentuximab vedotin will be administered intravenously at the dose of 1.8 mg/kg. Brentuximab vedotin is to be administered on Day 1 of each 21-day cycle via a 30 minute intravenous (IV) infusion.

    Subject analysis set title
    Comparison
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison for single arm study

    Primary: Efficacy Evaluation

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    End point title
    		 Efficacy Evaluation
    End point description
    Patients will be considered for assessment of efficacy if they have received four courses of Brentuximab vedotin and underwent FDG-PET and CT scan as prescribed by the study protocol. Complete Response will be defined according to recently updated international criteria (Cheson 2007), assuming that a negative PET is defined by Deauville scores 1, 2 and 3.
    End point type
    Primary
    End point timeframe
    Patients assessed for efficacy after 4 cycles of brentuximab vedotin and evaluated by FDG-PET and CT scan. Patients was considered in CR with PET defined by Deauville Score from 1 to 3.
    End point values
    		 Single Arm Comparison
    Number of subjects analysed
    10 [1]
    10
    Units: Complete Response (CR)
        Deauville Negative (1-3)
    5
    5
        Deauville Positive (4-5)
    5
    5
    Notes
    [1] - Patients treated with 4 cycles of Brentuximab Vedotin
    Statistical analysis title
    		 Primary Efficacy end-point
    Statistical analysis description
    This study will be managed as a pilot phase II trial with a fixed sample size of 13 patients. We do not have results of previous studies with single agent SGN-35 in patients at first diagnosis. For efficacy we considered as precautionary measure the response from PET greater than 30%, regarded as inferior margin of confidence interval at 95%, according to the binomial distribution. So, we expect to observe 8 responsive patients from 13 enrolled (62%, 95%CI 32-86%)
    Comparison groups
    Single Arm v Comparison
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.179
    Method
    		 One- sample Binomial test
    Parameter type
    		 Exact Binomial Distribution
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.81
    Notes
    [2] - The complete response (CR, according to PET Deauville 1-3) rate was estimated by means of exact binomial distribution, with Clopper-Pearson binomial 95% confidence intervals. For efficacy we considered as precautionary measure the response from PET greater than 30%, regarded as inferior margin of confidence interval at 95%, according to the binomial distribution

    Primary: Safety Evaluation

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    End point title
    		 Safety Evaluation
    End point description
    For safety we considered neurotoxicity as the most significant event with a frequency for any grade ≤50%. Based on the binomial distribution we expect to observe ≤ 2 events for 13 enrolled patients (15%, 95%CI 2-45%), so with toxicity less than 50%, respect to the higher margin of confidence interval at 95%.
    End point type
    Primary
    End point timeframe
    Patients treated with at least 1 cycle of Brentuximab Vedotin.
    End point values
    		 Single Arm Comparison
    Number of subjects analysed
    13 [3]
    13
    Units: Neurotoxicity of any CTACE 4.03
        Neurotoxicity, Yes
    4
    4
    Notes
    [3] - Patients treated with at least 1 cycle of Brentuximab Vedotin
    Statistical analysis title
    		 Primary Safety end-point
    Statistical analysis description
    Result expressed with th exact binomial distribution, with Clopper-Pearson binomial 95% confidence intervals.
    Comparison groups
    Single Arm v Comparison
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Exact Binomial Distribution
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.61
    Notes
    [4] - We observed 4 neurotoxicity: 2 of CTCAE grade 1, both in 3th cycle (hypoesthesia and cramps) and 2 of CTACE grade 2 (1st cycle, dysesthesia and tingling (upper arms); and 4th cycle, paresthesia). Than 4/13, 31% (95%CI 9-61%), with the upper margin greater than 50%.

    Secondary: Response after Brentuximab Vedotine and ASCT

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    End point title
    		 Response after Brentuximab Vedotine and ASCT
    End point description
    End point type
    Secondary
    End point timeframe
    Complete Remission after autologous stem-cell transplantation (ASCT) in the 10 patients evaluable for efficacy
    End point values
    		 Single Arm Comparison
    Number of subjects analysed
    10 [5]
    10
    Units: Complete Response
        CR, Yes
    8
    8
    Notes
    [5] - Patients evaluable for efficacy
    Statistical analysis title
    		 Response after brentuximab vedotin and ASCT
    Statistical analysis description
    Considering the full treatment (4BV + consolidation with ASCT) over the 10 assessable patients, 8 CR and 2 PD, were observed with a CR rate of 80% (95CI 44-97%).
    Comparison groups
    Single Arm v Comparison
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Exact Binomial Distribution
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.97
    Notes
    [6] - Observational

    Secondary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    End point type
    Secondary
    End point timeframe
    The progression-free survival was measured from the start of treatmentt to the date of progressive disease or death for any causa, within one year after the end of treatment of the last patient enrolled.
    End point values
    		 Single Arm Comparison
    Number of subjects analysed
    13
    13
    Units: Kaplan Meier probability
        number (confidence interval 95%)
    0.46 (0.19 to 0.70)
    0.46 (0.19 to 0.70)
    Statistical analysis title
    		 Progression Free Survival
    Statistical analysis description
    Kaplan Meier estimate at 12 months of follow-up, from the date of start treatment.
    Comparison groups
    Single Arm v Comparison
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Kaplan Meier estimates
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.7
    Notes
    [7] - One arm pilot phase 2 study

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Patients were considered for assessment of safety if they have received at least one administration of Brentuximab Vedotin.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTC
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Single Arm
    Reporting group description
    		 Patients treated with at least one administration of Brentuximab Vedotin. Reported patients with of any grade CTCAE.

    Serious adverse events
    		 Single Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Fever
    Additional description: CTCAE grade 2 in post-ASCT, reported as fever.
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Single Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 13 (84.62%)
    Investigations
    gamma-GT increase, AST increase
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    11
    Vascular disorders
    Deep venous thrombosis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    11
    Nervous system disorders
    Hypoesthesia, cramps, Dysesthesia and tingling (upper arms), paresthesia
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    11
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    11
    Leukopenia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    11
    Neutropenia
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    11
    Thrombocytopenia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    11
    Febrile neutropenia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    11
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    11
    Gastrointestinal disorders
    Diarrhoea, Mucositis
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    11
    Skin and subcutaneous tissue disorders
    Cutaneus rash, Eczema
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2017
    It was revised the evaluation of Deauville score. In detail: "11.2 Rules for PET interpretation: Following the international recommendations on the use of the Deauville five point scale (Deauville 5ps) for clinical routine and clinical trials using FDG-PET/CT in the initial staging and assessment of treatment response in Hodgkin Lymphoma (HL) (Barrington et al. 2014; Cheson et al. 2014), FDG-PET negativity will be defined in accord to Deauville five-point scale for the evaluation of primary end points. These criteria have been purposely risen for interim-PET interpretation and rely on visual, semi-quantitative assessment according to a 5-point scale for intensity of residual FDG uptake scoring, with liver as reference organ for positivity cutoff. According to these criteria, a score value equal to 1, 2 and 3 will be considered negative while a value equal to 4 and 5 will be considered positive."

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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