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    Clinical Trial Results:
    A randomized phase II study of prednisone, vinblastine, doxorubicin, and gemcitabine in patients with intermediate stage Hodgkin's lymphoma

    Summary
    EudraCT number
    		 2007-003467-48
    Trial protocol
    		 DE  
    Global end of trial date
    17 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Apr 2020
    First version publication date
    23 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-949
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00512980
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus Magnus-Platz, Köln, Germany, 50923
    Public contact
    Trial Coordination Center of the German Hodgkin Study Group (GHSG), German Hodgkin Study Group (GHSG), 0049 22147888200, ghsg@uk-koeln.de
    Scientific contact
    Trial Coordination Center of the German Hodgkin Study Group (GHSG), German Hodgkin Study Group (GHSG), 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
    05 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of this phase II trial were to assess the toxicity and activity of PVAG-14 in patients with early-stage unfavorable Hodgkin lymphoma.
    Protection of trial subjects
    Written informed consent prior to study entry, G-CSF prophylaxis, weekly blood tests during therapy, dose reduction strategy in case of inadequate recovery of blood values
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Nov 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 41
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    41
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started on 17 Nov 2008, was much slower than expected even after increasing the number of trial sites and extending the recruitment period, and was stopped on 13 May 2011 with a total of 41 patients enrolled, because it was deemed unlikely to reach the planned number of 100 patients in a reasonable time.

    Pre-assignment
    Screening details
    		 Pre-study assessments should be performed within 28 days prior to enrollment. Main inclusion criteria: previously untreated, histologically confirmed Hodgkin lymphoma; CSI-II with ≥1 risk factor; age 18-60 years. Main exclusion criteria: prior chemo- or radiotherapy; concurrent disease preventing protocol treatment; pregnancy, lactation; ECOG >2.

    Period 1
    Period 1 title
    Randomized study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 8x PVAG-14, Doxo=25mg
    Arm description
    		 Eight cycles of the PVAG chemotherapy regimen with a doxorubicin dose of 25 mg/m² BSA recycled every 14 days; involved-field radiotherapy applied 4-6 weeks after the end of chemotherapy with an overall dose of 30 Gy (1.8-2.0 Gy 5 times per week)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg Prednisone administered on days 1-3 of each 14-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg Vinblastine per m² BSA administered on day 1 of each 14-day cycle over 10 minutes

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg Doxorubicin per m² BSA administered on day 1 of each 14-day cycle over 30 minutes

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg Gemcitabine per m² BSA administered on day 1 of each 14-day cycle over 30 minutes

    Arm title
    		 8x PVAG-14, Doxo=35mg
    Arm description
    		 Eight cycles of the PVAG chemotherapy regimen with a doxorubicin dose of 35 mg/m² BSA recycled every 14 days; involved-field radiotherapy applied 4-6 weeks after the end of chemotherapy with an overall dose of 30 Gy (1.8-2.0 Gy 5 times per week)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg Prednisone administered on days 1-3 of each 14-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg Vinblastine per m² BSA administered on day 1 of each 14-day cycle over 10 minutes

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg Doxorubicin per m² BSA administered on day 1 of each 14-day cycle over 30 minutes

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg Gemcitabine per m² BSA administered on day 1 of each 14-day cycle over 30 minutes

    Number of subjects in period 1
    		8x PVAG-14, Doxo=25mg 8x PVAG-14, Doxo=35mg
    Started
    21
    20
    Completed
    20
    20
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    8x PVAG-14, Doxo=25mg
    Reporting group description
    		 Eight cycles of the PVAG chemotherapy regimen with a doxorubicin dose of 25 mg/m² BSA recycled every 14 days; involved-field radiotherapy applied 4-6 weeks after the end of chemotherapy with an overall dose of 30 Gy (1.8-2.0 Gy 5 times per week)

    Reporting group title
    8x PVAG-14, Doxo=35mg
    Reporting group description
    		 Eight cycles of the PVAG chemotherapy regimen with a doxorubicin dose of 35 mg/m² BSA recycled every 14 days; involved-field radiotherapy applied 4-6 weeks after the end of chemotherapy with an overall dose of 30 Gy (1.8-2.0 Gy 5 times per week)

    Reporting group values
    		 8x PVAG-14, Doxo=25mg 8x PVAG-14, Doxo=35mg Total
    Number of subjects
    		 21 20 41
    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)
    		 21 20 41
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 33 (18 to 57) 38.5 (19 to 53) -
    Gender categorical
    Units: Subjects
        Female
    		 11 10 21
        Male
    		 10 10 20
    Ann Arbor Stage
    Units: Subjects
        IA
    		 0 0 0
        IB
    		 0 1 1
        IIA
    		 17 14 31
        IIB
    		 4 5 9
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 15 16 31
        ECOG 1
    		 6 4 10
    Large mediastinal mass
    Units: Subjects
        No
    		 16 17 33
        Yes
    		 5 3 8
    Extranodal disease
    Units: Subjects
        No
    		 20 19 39
        Yes
    		 1 1 2
    Involvement of 3 or more nodal areas
    Units: Subjects
        No
    		 5 11 16
        Yes
    		 16 9 25
    Elevated erythrocyte sedimentation rate
    Units: Subjects
        No
    		 10 10 20
        Yes
    		 11 10 21
    Subject analysis sets

    Subject analysis set title
    Pooled treatment groups
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Secondary efficacy endpoints were analyzed in the pooled treatment groups to increase power.

    Subject analysis sets values
    		 Pooled treatment groups
    Number of subjects
    41
    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)
    41
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    38 (18 to 57)
    Gender categorical
    Units: Subjects
        Female
    21
        Male
    20
    Ann Arbor Stage
    Units: Subjects
        IA
    0
        IB
    1
        IIA
    31
        IIB
    9
    ECOG performance status
    Units: Subjects
        ECOG 0
    31
        ECOG 1
    10
    Large mediastinal mass
    Units: Subjects
        No
    33
        Yes
    8
    Extranodal disease
    Units: Subjects
        No
    39
        Yes
    2
    Involvement of 3 or more nodal areas
    Units: Subjects
        No
    16
        Yes
    25
    Elevated erythrocyte sedimentation rate
    Units: Subjects
        No
    20
        Yes
    21

    End points

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    End points reporting groups
    Reporting group title
    8x PVAG-14, Doxo=25mg
    Reporting group description
    		 Eight cycles of the PVAG chemotherapy regimen with a doxorubicin dose of 25 mg/m² BSA recycled every 14 days; involved-field radiotherapy applied 4-6 weeks after the end of chemotherapy with an overall dose of 30 Gy (1.8-2.0 Gy 5 times per week)

    Reporting group title
    8x PVAG-14, Doxo=35mg
    Reporting group description
    		 Eight cycles of the PVAG chemotherapy regimen with a doxorubicin dose of 35 mg/m² BSA recycled every 14 days; involved-field radiotherapy applied 4-6 weeks after the end of chemotherapy with an overall dose of 30 Gy (1.8-2.0 Gy 5 times per week)

    Subject analysis set title
    Pooled treatment groups
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Secondary efficacy endpoints were analyzed in the pooled treatment groups to increase power.

    Primary: Complete remission rate

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    End point title
    		 Complete remission rate [1]
    End point description
    Complete remission rate was assessed in the CT-based definitive restaging 4-6 weeks after completion of radiotherapy. Two interim analyses and a final analysis were planned. The first interim analysis was scheduled after 19 patients per arm were evaluable. Enrollment was stopped by the time of the interim analyses because of slow recruitment, leaving only 3 patients enrolled in addition to the interim analysis sample. The second interim analysis was thus not done. The final analysis was done descriptively for both arms separately including all enrolled patients.
    End point type
    Primary
    End point timeframe
    4-6 weeks after completion of radiotherapy
    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: Enrollment was stopped after 41 out of 100 planned patients because of slow recruitment. Due to the small sample size, analysis was done descriptively; no confirmative test, no subgroup analyses and no sensitivity analyses were done. The protocol defines a complete remission rate of 83% as benchmark for insufficient efficacy. The 95% CI for the observed overall complete remission rate of 98% ranged from 87% to 100% and thus exceeded the predefined efficacy benchmark.
    End point values
    		 8x PVAG-14, Doxo=25mg 8x PVAG-14, Doxo=35mg
    Number of subjects analysed
    21
    20
    Units: patients
        Partial remission
    1
    0
        Complete remission
    20
    20
    No statistical analyses for this end point

    Primary: Incidence of hematological toxicity grade III/IV

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    End point title
    		 Incidence of hematological toxicity grade III/IV [2]
    End point description
    Hematological toxicity was defined as any case of leukopenia, thrombocytopenia or anemia of CTCAE grade III or IV at any time during chemotherapy. Two interim analyses and a final analysis were planned. The first interim analysis was scheduled after 19 patients per arm were evaluable. Enrollment was stopped by the time of the interim analyses because of slow recruitment, leaving only 3 patients enrolled in addition to the interim analysis sample. The second interim analysis was thus not done. The final analysis was done descriptively for both arms separately including all enrolled patients.
    End point type
    Primary
    End point timeframe
    During chemotherapy
    Notes
    [2] - 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: Enrollment was stopped after 41 out of 100 planned patients because of slow recruitment. Due to the small sample size, analysis was done descriptively; no confirmative test, no subgroup analyses and no sensitivity analyses were done. The protocol defines a hematological toxicity incidence of 62% as benchmark for inacceptable toxicity. The 95% CI for the observed incidence of 10% ranged from 3% to 23% and was thus below the toxicity benchmark.
    End point values
    		 8x PVAG-14, Doxo=25mg 8x PVAG-14, Doxo=35mg
    Number of subjects analysed
    21
    20
    Units: patients
        Hematological toxicity of CTCAE grade III/IV
    1
    3
        No hematological toxicity of CTCAE grade III/IV
    20
    17
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival was calculated from the date of initial staging until progressive disease, relapse, or death from any cause or, if none of these occured, censored at the date of the last determination of continuing remission.
    End point type
    Secondary
    End point timeframe
    Progression-free survival at 2 years
    End point values
    		 Pooled treatment groups
    Number of subjects analysed
    41
    Units: percent
        number (confidence interval 95%)
    94.2 (86.3 to 100)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was calculated from the date of initial staging until death from any cause or, if the patient was alive, censored at the date of the last information about the patient.
    End point type
    Secondary
    End point timeframe
    Overall survival at 2 years
    End point values
    		 Pooled treatment groups
    Number of subjects analysed
    41
    Units: percent
        number (not applicable)
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment until 28 days after last study treatment or until AE resolution; AEs beginning >28 days after final study treatment reported only if considered related to study treatment
    Adverse event reporting additional description
    All AEs greater than CTCAE grade 2 were to be recorded in the source documents and the CRFs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    8x PVAG-14, Doxo=25mg
    Reporting group description
    		 Eight cycles of the PVAG chemotherapy regimen with a doxorubicin dose of 25 mg/m² BSA recycled every 14 days; involved-field radiotherapy applied 4-6 weeks after the end of chemotherapy with an overall dose of 30 Gy (1.8-2.0 Gy 5 times per week)

    Reporting group title
    8x PVAG-14, Doxo=35mg
    Reporting group description
    		 Eight cycles of the PVAG chemotherapy regimen with a doxorubicin dose of 35 mg/m² BSA recycled every 14 days; involved-field radiotherapy applied 4-6 weeks after the end of chemotherapy with an overall dose of 30 Gy (1.8-2.0 Gy 5 times per week)

    Serious adverse events
    		 8x PVAG-14, Doxo=25mg 8x PVAG-14, Doxo=35mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 20 (10.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 8x PVAG-14, Doxo=25mg 8x PVAG-14, Doxo=35mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 21 (33.33%)
    8 / 20 (40.00%)
    Nervous system disorders
    Nervous system disorder
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences all number
    6
    0
    Blood and lymphatic system disorders
    Leukopenia
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 20 (15.00%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    Drug fever
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Nausea or vomiting
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 20 (5.00%)
         occurrences all number
    4
    4
    Mucositis
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    1
    2
    Infections and infestations
    Infection
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 May 2011
    Premature termination of recruitment

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 May 2011
    Premature termination of recruitment
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Enrollment was stopped after 41 out of 100 planned patients because of slow recruitment. Due to the small sample size, analyses were done descriptively; no confirmative tests, no subgroup analyses and no sensitivity analyses were done.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25768996
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