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    Clinical Trial Results:
    GHSG-AFM13 An open-label, randomized, multicenter phase II trial with AFM13 in patients with relapsed or refractory Hodgkin Lymphoma

    Summary
    EudraCT number
    		 2014-004036-19
    Trial protocol
    		 DE  
    Global end of trial date
    28 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Sep 2020
    First version publication date
    19 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-1754
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02321592
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    German Hodgkin Study Group, German Hodgkin Study Group, 0049 22147888200, ghsg@uk-koeln.de
    Scientific contact
    German Hodgkin Study Group, German Hodgkin Study Group, 0049 22147888200, ghsg@uk-koeln.de
    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
    31 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary aim of the AFM13 trial was to demonstrate efficacy of AFM13 with an optimized treatment schedule. This phase II trial also aimed at selecting a treatment schedule, which warrants further investigation in a phase III clinical trial. The primary objectives of the AFM13 trial were to evaluate the tumor response to one 8-week cycle of AFM13 and to select one out of three therapeutic regimens of AFM13 for a potential phase III trial. Further efficacy assessment, evaluation of safety and feasibility and assessment of patient reported outcomes were the secondary objectives of the trial.
    Protection of trial subjects
    Written informed consent prior to study entry; Premedication with paracetamol, dimetindene, ranitidine, and prednisone; Reduced infusion rate for the first infusion and hospitalization during days 1-3 of weeks 1-2 to ensure that adequate measures can be taken in case of adverse events. Management of AFM13-associated infusion-related reactions and other AFM13-related side effects are described in the trial protocol; frequent mandatory safety laboratory examinations during therapy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jun 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    20
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment details: Between June 26, 2015 and May 31, 2019, 25 adult patients with relapsed or refractory classical Hodgkin lymphoma were randomized or assigned to receive AFM13 treatment with the regimen specified for arms A (n=5), B (n=12), or C (n=8), respectively. The trial was terminated before stage-1 analysis.

    Pre-assignment
    Screening details
    		 Medical history (all clinical Symptoms, serious concurrent diseases); physical measurements (ECOG Performance Status, cardial, pulmonary, and thyroid function); laboratory diagnostics; pregnancy test; CT or MRI of neck, thorax and abdomen (obligatory); PET-CT (strongly recommended)

    Period 1
    Period 1 title
    Recruitment groups
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Patients were treated in each cycle with 1.5 mg/kg AFM13 three times per week over 8 weeks. Patients were randomly assigned to receive treatment according to arm A or arm B
    Arm type
    		 Experimental

    Investigational medicinal product name
    AFM13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1-2 cycles of AFM13 according to the regimen specified for Arm A

    Arm title
    		 Arm B
    Arm description
    		 Patients received 1.5 mg/kg AFM13 three times per week for 2 weeks, followed by once Weekly administrations of 7.0 mg/kg over 6 weeks. Patients were randomly assigned to receive treatment according to arm A or arm B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AFM13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1-2 cycles of AFM13 according to the regimen specified for Arm B

    Arm title
    		 Arm C
    Arm description
    		 Patients received a loading dose of 1 mg/kg administered over 1 hour followed by a 5-day continuous Infusion of 6 mg/kg, resulting in a total dose of 7 mg/kg per week. After randomization into arms A and B had been postponed, arm C was introduced and all new patients were allocated to this arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AFM13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1-2 eight-week cycles of AFM13 according to the regimen specified for Arm B

    Number of subjects in period 1
    		Arm A Arm B Arm C
    Started
    5
    12
    8
    Completed
    5
    12
    8
    Period 2
    Period 2 title
    Stage 1 (overall period)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All study patients
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    AFM13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1-2 cycles of AFM13 according to the regimens specified for Arms A, B, and C

    Number of subjects in period 2
    		All study patients
    Started
    25
    Completed
    25

    Baseline characteristics

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

    Reporting group values
    		 Recruitment groups Total
    Number of subjects
    		 25 25
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 20 20
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 45 (21 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 24 24
    ECOG Performance Status
    Units: Subjects
        ECOG 0-1
    		 24 24
        ECOG 2
    		 1 1
    Time since first HL diagnosis
    Years between Primary Hodgkin diagnosis and registration for the GHSG-AFM13 trial
    Units: years
        median (full range (min-max))
    		 7.2 (0.2 to 40.3) -
    HL therapies after first-line
    Units: number
        median (full range (min-max))
    		 3 (1 to 11) -
    Subject analysis sets

    Subject analysis set title
    Arm A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Trial subjects randomised to Arm A

    Subject analysis set title
    Arm B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects randomised to Arm B

    Subject analysis set title
    Arm C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects assigned to Arm C

    Subject analysis sets values
    		 Arm A Arm B Arm C
    Number of subjects
    5
    12
    8
    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)
    4
    9
    7
        From 65-84 years
    1
    3
    1
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    48 (23 to 73)
    43 (21 to 72)
    41 (24 to 64)
    Gender categorical
    Units: Subjects
        Female
    0
    0
    1
        Male
    5
    12
    7
    ECOG Performance Status
    Units: Subjects
        ECOG 0-1
    5
    11
    8
        ECOG 2
    0
    1
    0
    Time since first HL diagnosis
    Years between Primary Hodgkin diagnosis and registration for the GHSG-AFM13 trial
    Units: years
        median (full range (min-max))
    13.7 (4.2 to 40.3)
    6.8 (3.6 to 14.9)
    4.9 (0.2 to 35.8)
    HL therapies after first-line
    Units: number
        median (full range (min-max))
    4 (2 to 6)
    3 (2 to 6)
    3 (1 to 11)

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients were treated in each cycle with 1.5 mg/kg AFM13 three times per week over 8 weeks. Patients were randomly assigned to receive treatment according to arm A or arm B

    Reporting group title
    Arm B
    Reporting group description
    		 Patients received 1.5 mg/kg AFM13 three times per week for 2 weeks, followed by once Weekly administrations of 7.0 mg/kg over 6 weeks. Patients were randomly assigned to receive treatment according to arm A or arm B.

    Reporting group title
    Arm C
    Reporting group description
    		 Patients received a loading dose of 1 mg/kg administered over 1 hour followed by a 5-day continuous Infusion of 6 mg/kg, resulting in a total dose of 7 mg/kg per week. After randomization into arms A and B had been postponed, arm C was introduced and all new patients were allocated to this arm.
    Reporting group title
    All study patients
    Reporting group description
    		 -

    Subject analysis set title
    Arm A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Trial subjects randomised to Arm A

    Subject analysis set title
    Arm B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects randomised to Arm B

    Subject analysis set title
    Arm C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects assigned to Arm C

    Primary: Objective response rate (ORR) after 1 cycle

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    End point title
    		 Objective response rate (ORR) after 1 cycle [1]
    End point description
    Objective response was defined as complete or partial remission in the centrally reviewed restaging after 1 cycle of AFM13. According to the protocol, the null hypothesis H0: ORR <= 10% was to be tested in a 2-stage design. The trial was terminated during stage 1 due to lack of recruitment. Thus, only descriptive analyses of the primary endpoint in the stage-1 intention-to-treat Population were performed.
    End point type
    Primary
    End point timeframe
    PET/CT-based restaging was performed 20 to 22 (arms A and C) or 24 to 26 days (arm B) after the last day with AFM13 infusion in cycle 1.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No confirmative test was performed for the primary endpoint since no trial arm was carried into stage-2. Therefore, only a descriptive analysis of the primary endpoint in the stage-1 population was done. The objective response rate was estimated at 16.6%, 95%-confidence interval [4.5% - 36.1%].
    End point values
    		 All study patients Arm A Arm B Arm C
    Number of subjects analysed
    25
    5
    12
    8
    Units: subjects
        Objective response (Complete or Partial Remission)
    4
    1
    1
    2
        No objective response (No Change or Progression)
    20
    4
    10
    6
        not evaluated
    1
    0
    1
    0
    No statistical analyses for this end point

    Secondary: PET/CT-based remission status after cycle 1

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    End point title
    		 PET/CT-based remission status after cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    PET/CT-based restaging was performed 20 to 22 (arms A and C) or 24 to 26 days (arm B) after the last day with AFM13 infusion in cycles 1 and 2.
    End point values
    		 All study patients Arm A Arm B Arm C
    Number of subjects analysed
    25
    5
    12
    8
    Units: subjects
        Complete Remission
    2
    0
    1
    1
        Partial Remission
    2
    1
    0
    1
        Stable Disease
    3
    1
    1
    1
        Progression
    14
    3
    6
    5
        not evaluated
    4
    0
    4
    0
    No statistical analyses for this end point

    Secondary: PET/CT-base remission status after cycle 2

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    End point title
    		 PET/CT-base remission status after cycle 2
    End point description
    End point type
    Secondary
    End point timeframe
    PET/CT-based restaging was performed 20 to 22 (arms A and C) or 24 to 26 days (arm B) after the last day with AFM13 infusion in cycles 1 and 2.
    End point values
    		 All study patients Arm A Arm B Arm C
    Number of subjects analysed
    5
    2
    2
    1
    Units: subjects
        Complete Remission
    1
    0
    0
    1
        Partial Remission
    1
    1
    0
    0
        Stable Disease
    1
    0
    1
    0
        Progression
    2
    1
    1
    0
        not evaluated
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Time to next salvage therapy

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    End point title
    		 Time to next salvage therapy
    End point description
    First and second new anticancer therapy after the last dose of study drug were to be recorded with the follow-up assessments.
    End point type
    Secondary
    End point timeframe
    The follow-up period was one year measured from the restaging after the last AFM13 cycle. Within the scope of amendment 10 it was decided to shorten the follow-up period for the last arm C patient to 3 months.
    End point values
    		 All study patients Arm A Arm B Arm C
    Number of subjects analysed
    19
    4
    9
    6
    Units: months
        median (full range (min-max))
    3.2 (0.2 to 11.2)
    4.9 (3.0 to 11.2)
    2.1 (0.2 to 6.8)
    3.2 (1.0 to 6.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were assessed during study treatment and within 28 days after end of study treatment or until the first day of a new HL therapy, whatever occurred first.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.2
    Reporting groups
    Reporting group title
    Stage I - Overall period
    Reporting group description
    		 All trial subjects

    Serious adverse events
    		 Stage I - Overall period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 25 (20.00%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Generall physical health deterioration
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Pyloric stenosis
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcemia
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.01%
    Non-serious adverse events
    		 Stage I - Overall period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 25 (40.00%)
    Investigations
    CPK increase
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Aspartate aminotransferase increased
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Lipase increased
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    White blood cell decreased
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Neutrophil count decreased
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Lymphocyte count decreased
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
    Additional description: All grade III-IV non-serious AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    6
    Leukopenia
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Lymphopenia
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
    Additional description: All non-serious grade III-IV AEs
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2015
    Current Information regarding trial medication were taken into account and editorial changes were implemented.
    20 Aug 2015
    Current Information regarding trial medication were taken into account and editorial changes were implemented.
    22 Dec 2015
    Specifications of E-Data-Capture procedures were made and some assessment times were adapted and described in a more detailed way.
    12 Jul 2016
    Update of the Investigational Medicinal Product Dossier
    10 May 2017
    Within the Framework of the 5th, 6th, and 7th Amendment tretment arm C with continuous AFM13 Infusion over 5 days was introduced, while randomization into arms A and B is postponed.
    24 Apr 2019
    A mandatory premedication with Paracetamol, dimetindene, ranitidine and prednisone before the first Administration of AFM13 was included.
    26 Nov 2019
    Recruitment was terminated earlier than planned and with no continuation in stage II due to lack of recruitment. It was also decided to shorten the follow-up period to three months from restaging for the last patient of the trial.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial was terminated without continuation in stage II. All statistical analyses of primary and secondary endpoints are of descriptive nature. A reliable estimate of the ORR cannot be obtained for any arm.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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