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    Clinical Trial Results:
    PHASE I-II CLINICAL TRIAL FOR THE EVALUATION OF THE ROLE OF BRENTUXIMAB VEDOTIN PLUS ETOPOSIDE, SOLUMODERIN, HIGH DOSE ARA-C AND CIS-PLATIN IN THE TRANSPLANT AND POST-TRANSPLANT MANAGEMENT FOR PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA

    Summary
    EudraCT number
    		 2014-000835-17
    Trial protocol
    		 ES  
    Global end of trial date
    14 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2021
    First version publication date
    16 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BRESHAP-GELTAMO.LH-2013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02243436
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GELTAMO
    Sponsor organisation address
    H. MARQUES DE VALDECILLA SERVICIO DE HEMATOLOGIA, SANTANDER, Spain, 39008
    Public contact
    GELTAMO, Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea, 0034 913195780, dm@geltamo.com
    Scientific contact
    GELTAMO, Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea, 0034 913195780, sc@geltamo.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
    14 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study will be: 1. Search the recommended dose (To determine the Maximum Tolerable Dose of the BV (Brentuximab vedotin) in combination with ESHAP (etoposide, methylprednisolone, high-­dose cytarabine, cisplatin) in relapsed/resistant HODGKIN LYMPHOMA patients) 2. To evaluate the global and complete response rate after BV-ESHAP as salvage regimen prior to APBSCT (autologous peripheral blood stem cell transplant )
    Protection of trial subjects
    Safety was assessed by the type, frequency and severity (grade) of adverse events reported throughout the study period using the NCIC-CTCAE 4.0 criteria and considering all patients who received at least one dose of the investigational treatment. reported throughout the study period using the NCIC-CTCAE 4.0 criteria and considering all patients who received at least one dose of the investigational treatment. The TLDs were assessed in all patients in terms of reported adverse events and their association with treatment with treatment, according to the dose Similar criteria were established for Phase II, and all patients who received at least one dose of the investigational treatment were considered. received at least one dose of the investigational treatment
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Nov 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
    Spain: 66
    Worldwide total number of subjects
    66
    EEA total number of subjects
    66
    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)
    66
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 NUMBER OF PATIENTS PLANNED Phase I: 9-28 Phase II: up to 66 7 NUMBER OF PATIENTS ANALYSED Phase I: 9 Phase I+II: 66 8 DIAGNOSIS Classical Hodgkin's lymphoma (cHL), CD30

    Pre-assignment
    Screening details
    		 To start the therapy, all the conditions above considered have to be observed. Then the therapy can be started preferably by hospitalizing the patient. The Screening visit will be done once the patient provides written informed consent to participate in the study

    Pre-assignment period milestones
    Number of subjects started
    		 66
    Number of subjects completed
    		 66

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

    Arms
    Arm title
    		 Experimental: BV-ESHAP
    Arm description
    		 1) 3 cycles every 21 days: - Brentuximab Vedotin, on day 1 (BV will be administered at three different doses 0.9mg/kg, 1.2mg/kg, 1.8mg/kg) - Etoposide 40 mg/m2/day, on days 1 to 4 - Soludomerin (methylprednisolone) 250 mg/day, on days 1 to 4 - Cisplatin 25 mg/m2/day, on days 1 to 4 - Ara C (cytarabine) 2 g/m2, on day 5 2) A fourth dose of BV will be given 21 days after the third BV dose during the evaluation of response before the transplant. 3) Autologous peripheral blood stem cell transplant 4) A fifth dose of BV (1.8mg/kg) will be given on between day 28 and 35 post-transplant, followed by two additional doses (1.8mg/kg) every 3 weeks, to complete a total of 7 BV infusions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brentuximab Vedotin
    Investigational medicinal product code
    Other name
    ADCETRIS
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab Vedotin, 0.9mg/kg, 1.2mg/kg, 1.8mg/kg, day 1

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenose use, 40mg/m2/day, on days 1 to 4

    Investigational medicinal product name
    Soludomerin
    Investigational medicinal product code
    Other name
    Methylprednisolone
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous use, 250mg/day, on days 1 to 4

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous use, 25mg/m2/day, on days 1 to 4

    Investigational medicinal product name
    Ara C
    Investigational medicinal product code
    Other name
    Cytarabine
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous use, 2g/m2, day 5

    Number of subjects in period 1
    		Experimental: BV-ESHAP
    Started
    66
    Completed
    66

    Baseline characteristics

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

    Reporting group values
    		 OVERALL TRIAL Total
    Number of subjects
    		 66 66
    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)
    		 66 66
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 35 35
        Male
    		 31 31
    Subject analysis sets

    Subject analysis set title
    Overall trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PHASE I: Determine the recommended dose, based on the dose-limiting toxicity (DLT) analysis and safety profile of BV (brentuximab vedotin) in combination with ESHAP (etoposide, solumoderin or methylprednisolone, Ara-C or high-dose cytarabine, cisplatin) in patients with relapsed/refractory classical Hodgkin's lymphoma (cHL). Hodgkin's lymphoma (cHL) relapsed/refractory. PHASE II: To assess the complete response (CR) rate after BV-ESHAP as a salvage regimen before autologous peripheral blood transplantation (APBT)

    Subject analysis sets values
    		 Overall trial
    Number of subjects
    66
    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)
    66
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    35
        Male
    31

    End points

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    End points reporting groups
    Reporting group title
    Experimental: BV-ESHAP
    Reporting group description
    		 1) 3 cycles every 21 days: - Brentuximab Vedotin, on day 1 (BV will be administered at three different doses 0.9mg/kg, 1.2mg/kg, 1.8mg/kg) - Etoposide 40 mg/m2/day, on days 1 to 4 - Soludomerin (methylprednisolone) 250 mg/day, on days 1 to 4 - Cisplatin 25 mg/m2/day, on days 1 to 4 - Ara C (cytarabine) 2 g/m2, on day 5 2) A fourth dose of BV will be given 21 days after the third BV dose during the evaluation of response before the transplant. 3) Autologous peripheral blood stem cell transplant 4) A fifth dose of BV (1.8mg/kg) will be given on between day 28 and 35 post-transplant, followed by two additional doses (1.8mg/kg) every 3 weeks, to complete a total of 7 BV infusions.

    Subject analysis set title
    Overall trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PHASE I: Determine the recommended dose, based on the dose-limiting toxicity (DLT) analysis and safety profile of BV (brentuximab vedotin) in combination with ESHAP (etoposide, solumoderin or methylprednisolone, Ara-C or high-dose cytarabine, cisplatin) in patients with relapsed/refractory classical Hodgkin's lymphoma (cHL). Hodgkin's lymphoma (cHL) relapsed/refractory. PHASE II: To assess the complete response (CR) rate after BV-ESHAP as a salvage regimen before autologous peripheral blood transplantation (APBT)

    Primary: Primary

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    End point title
    		 Primary
    End point description
    1. Number of TLD in different cohorts. 2. Global response rate and complete response. 1. we will evaluate three groups of patients with the standardscheme in 3-patient cohorts. It will be based on the assumption of a stable shape of the dose-toxicity curve with no cumulative toxicity for the four plus three doses of BV. Therefore the decision to escalate to the next dose level will be based solely on toxicity results from the first course administration of the current level. 2. Global and Complete response will be evaluated after the fourth dose of Brentuximab Vedotin
    End point type
    Primary
    End point timeframe
    To determine the MDT is based on an observation period of 21 days, assessing the toxicity results of the administration of the first treatment cycle.
    End point values
    		 Experimental: BV-ESHAP Overall trial
    Number of subjects analysed
    66
    66
    Units: MTD
    66
    66
    Statistical analysis title
    		 Progression free survival
    Comparison groups
    Experimental: BV-ESHAP v Overall trial
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 50
    Method
    		 Logrank
    Parameter type
    		 TTP
    Confidence interval

    Secondary: Secondary

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    End point title
    		 Secondary
    End point description
    As secondary objectives we will also try: - To determine the toxicity of BV-ESHAP regimen - To assess the stem cell mobilization capacity of the BV-ESHAP regimen - To evaluate the final results of the whole procedure (BV-ESHAP followed by high-dose chemotherapy, APBSCT and three doses of BV): transplant-related mortality (TRM), overall survival (OS), and progression free survival (PFS) (Overall Survival, PFS, Event-Free Survival, Time to HL Progression, Disease-Free Survival, Response Duration, Lymphoma-Specific Survival, and Time to Next Treatment)
    End point type
    Secondary
    End point timeframe
    Visits should be done prior every cycle, the day 14th of the first three cycles, pre and post trasplant visits, Final Protocol Treatment Visit aproximately at day +120; follow-up visits for a minimum of 2 years
    End point values
    		 Experimental: BV-ESHAP Overall trial
    Number of subjects analysed
    66
    66
    Units: DLT
    66
    66
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events will be recorded from the time of informed consent Report all AEs and SAEs from the time of informed consent up to 30 days after the last study treatment. All SAEs that occur after the 30-day safety reporting period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 -

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 66 (33.33%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Neutropenia
         subjects affected / exposed
    7 / 66 (10.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    10 / 66 (15.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 66 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 66 (3.03%)
         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
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 66 (100.00%)
    General disorders and administration site conditions
    Vomiting
         subjects affected / exposed
    30 / 66 (45.45%)
         occurrences all number
    1
    Mucositis management
         subjects affected / exposed
    10 / 66 (15.15%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    30 / 66 (45.45%)
         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
    27 Aug 2014
    Any investigator-initiated changes to the protocol (with the exception of changes to eliminate an immediate hazard to a study subject) must be approved by the Sponsor prior to seeking approval from the IRB/IEC/REB, and prior to implementing. The investigator is responsible for enrolling subjects who have met protocol eligibility criteria. Protocol violations must be reported to the Sponsor and the local IRB/IEC/REB in accordance with IRB/IEC/REB policies

    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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