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    Clinical Trial Results:
    GAMEC-SHORT (S) & GAMEC-ANTHRACYCLINE (A) RISK-ADAPTED PROTOCOL FOR RELAPSED GERM CELL TUMOURS (GCT)

    Summary
    EudraCT number
    2006-001963-52
    Trial protocol
    GB  
    Global end of trial date
    14 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Mar 2019
    First version publication date
    23 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GAMEC II
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Queen Mary University London
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    CECM Trials Team, CECM Trials Team, Queen Mary University of London, bci-cecmmonitoring@qmul.ac.uk
    Scientific contact
    CECM Trials Team, CECM Trials Team, Queen Mary University of London, bci-cecmmonitoring@qmul.ac.uk
    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
    10 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study aimed to address two questions. The first was whether treatment for patients with no identifiable risk factors could be shortened to 6 weeks (GAMEC-S (short)) and whether patients with these risk factors (either raised LDH at relapse or > 35 years old) would benefit from the substitution epirubicin for etoposide (GAMEC-A (anthracycline)).
    Protection of trial subjects
    Not applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Jul 2006
    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
    United Kingdom: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    36
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Between 21/08/2006 and 06/01/2012, 36 patients with relapsed germ cell tumours were recruited.

    Pre-assignment
    Screening details
    Patients who relapsed with germ cell tumours after failure of cisplatin based combination chemotherapy were eligible for study entry. Patients had to have evidence of relapse based on the presence of rising tumour markers and/or the development of radiological progression on CT.

    Pre-assignment period milestones
    Number of subjects started
    36
    Number of subjects completed
    36

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    GAMEC-A
    Arm description
    Patients with either a raised LDH and/or were 35 years or older were allocated to therapy with GAMEC-A ( actinomycin-D 1mg/m2 day 1, methotrexate 8g/m2 ,cisplatin 50mg/m2, day 2 and 3 and 8, epirubicin 37.5mg/m2 days 1 and 2 followed by pegfilgrastim 6mg on day 3), treatment was given on weeks1, 3 ,6 , 8 and 10 . From week 6 onwards day 8 cisplatin was omitted. The dose of methotrexate was adjusted according to glomerular filtration rate as determined by an EDTA clearance as follows:> 120ml/min- 10g/m2, 100-119ml/min 8g/m2, 80-99ml/min 6g/m2, 60-79ml/min 4g/m2, 40-59ml/min 2g/m2, 25-39ml/min.
    Arm type
    Experimental

    Investigational medicinal product name
    Pegfilgrastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 mgs

    Investigational medicinal product name
    Actinomycin - D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/m2

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 g/m2

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m2

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    37.5 mg/m2

    Arm title
    GAMEC-S
    Arm description
    Patients with neither risk factor were treated with GAMEC-S. In this protocol epirubicin was replaced by etoposide 90mg/m2 days 1, 2, 3 and 4. Treatment was stopped after 3 cycles (weeks 1, 3, and 6 only). Dose reductions and treatment administration have been described previously.
    Arm type
    Experimental

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m2

    Number of subjects in period 1
    GAMEC-A GAMEC-S
    Started
    15
    21
    Completed
    15
    21

    Baseline characteristics

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

    Reporting group values
    GAMEC Total
    Number of subjects
    36 36
    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))
    31.5 (18 to 56) -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    36 36
    IGCCCG at diagnosis
    Units: Subjects
        Good
    16 16
        Intermediate
    9 9
        Poor
    11 11
    1st Line Chemotherapy
    Units: Subjects
        BEP/EP
    30 30
        EP
    1 1
        VIP
    2 2
        CBOP/BEP
    2 2
        BEP + IPO at relapse
    1 1
    IPFSG risk group at relapse
    Units: Subjects
        Low risk
    3 3
        Intermediate risk
    24 24
        High Risk
    8 8
        n/a (3rd Line)
    1 1
    Primary
    Units: Subjects
        Testes
    30 30
        Extra gonadal
    5 5
        Mediastinal
    1 1
    Histology
    Units: Subjects
        NSGCT
    33 33
        Pure seminoma
    3 3
    Subject analysis sets

    Subject analysis set title
    GAMEC - S
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with neither risk factor were treated with GAMEC-S. In this protocol epirubicin was replaced by etoposide 90mg/m2 days 1, 2, 3 and 4. Treatment was stopped after 3 cycles (weeks 1, 3, and 6 only). Dose reductions and treatment administration have been described previously.

    Subject analysis set title
    GAMEC-A
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with either a raised LDH and/or 35 years or older were allocated to therapy with GAMEC-A ( actinomycin-D 1mg/m2 day 1, methotrexate 8g/m2 ,cisplatin 50mg/m2, day 2 and 3 and 8, epirubicin 37.5mg/m2 days 1 and 2 followed by pegfilgrastim 6mg on day 3), treatment was given on weeks1, 3 ,6 , 8 and 10 . From week 6 onwards day 8 cisplatin was omitted. The dose of methotrexate was adjusted according to glomerular filtration rate as determined by an EDTA clearance as follows:> 120ml/min- 10g/m2, 100-119ml/min 8g/m2, 80-99ml/min 6g/m2, 60-79ml/min 4g/m2, 40-59ml/min 2g/m2, 25-39ml/min.

    Subject analysis sets values
    GAMEC - S GAMEC-A
    Number of subjects
    21
    15
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    30 (18 to 36)
    38 (25 to 56)
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    36
    36
    IGCCCG at diagnosis
    Units: Subjects
        Good
    7
    9
        Intermediate
    6
    3
        Poor
    8
    3
    1st Line Chemotherapy
    Units: Subjects
        BEP/EP
    18
    12
        EP
    1
    0
        VIP
    0
    2
        CBOP/BEP
    2
    0
        BEP + IPO at relapse
    0
    1
    IPFSG risk group at relapse
    Units: Subjects
        Low risk
    2
    1
        Intermediate risk
    14
    10
        High Risk
    5
    3
        n/a (3rd Line)
    0
    1
    Primary
    Units: Subjects
        Testes
    18
    12
        Extra gonadal
    3
    2
        Mediastinal
    0
    1
    Histology
    Units: Subjects
        NSGCT
    20
    13
        Pure seminoma
    1
    2

    End points

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    End points reporting groups
    Reporting group title
    GAMEC-A
    Reporting group description
    Patients with either a raised LDH and/or were 35 years or older were allocated to therapy with GAMEC-A ( actinomycin-D 1mg/m2 day 1, methotrexate 8g/m2 ,cisplatin 50mg/m2, day 2 and 3 and 8, epirubicin 37.5mg/m2 days 1 and 2 followed by pegfilgrastim 6mg on day 3), treatment was given on weeks1, 3 ,6 , 8 and 10 . From week 6 onwards day 8 cisplatin was omitted. The dose of methotrexate was adjusted according to glomerular filtration rate as determined by an EDTA clearance as follows:> 120ml/min- 10g/m2, 100-119ml/min 8g/m2, 80-99ml/min 6g/m2, 60-79ml/min 4g/m2, 40-59ml/min 2g/m2, 25-39ml/min.

    Reporting group title
    GAMEC-S
    Reporting group description
    Patients with neither risk factor were treated with GAMEC-S. In this protocol epirubicin was replaced by etoposide 90mg/m2 days 1, 2, 3 and 4. Treatment was stopped after 3 cycles (weeks 1, 3, and 6 only). Dose reductions and treatment administration have been described previously.

    Subject analysis set title
    GAMEC - S
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with neither risk factor were treated with GAMEC-S. In this protocol epirubicin was replaced by etoposide 90mg/m2 days 1, 2, 3 and 4. Treatment was stopped after 3 cycles (weeks 1, 3, and 6 only). Dose reductions and treatment administration have been described previously.

    Subject analysis set title
    GAMEC-A
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with either a raised LDH and/or 35 years or older were allocated to therapy with GAMEC-A ( actinomycin-D 1mg/m2 day 1, methotrexate 8g/m2 ,cisplatin 50mg/m2, day 2 and 3 and 8, epirubicin 37.5mg/m2 days 1 and 2 followed by pegfilgrastim 6mg on day 3), treatment was given on weeks1, 3 ,6 , 8 and 10 . From week 6 onwards day 8 cisplatin was omitted. The dose of methotrexate was adjusted according to glomerular filtration rate as determined by an EDTA clearance as follows:> 120ml/min- 10g/m2, 100-119ml/min 8g/m2, 80-99ml/min 6g/m2, 60-79ml/min 4g/m2, 40-59ml/min 2g/m2, 25-39ml/min.

    Primary: PFS at 2 years

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    End point title
    PFS at 2 years
    End point description
    End point type
    Primary
    End point timeframe
    2 years
    End point values
    GAMEC - S GAMEC-A
    Number of subjects analysed
    21
    15
    Units: Percentage
        number (confidence interval 95%)
    57 (33.8 to 74.9)
    27 (8.3 to 49.6)
    Statistical analysis title
    PFS at 2 years
    Statistical analysis description
    Progression free survival of GAMEC-A and GAMEC-S patients were compared using Kaplan Meier curves with log-rank tests.
    Comparison groups
    GAMEC - S v GAMEC-A
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11 [1]
    Method
    Logrank
    Confidence interval
    Notes
    [1] - The log rank p-value is a comparison of the K-M curves of the entire study i.e. not at 2 years.

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    GAMEC - S GAMEC-A
    Number of subjects analysed
    21
    15
    Units: Percentage
        number (confidence interval 95%)
    56 (32 to 74)
    23 (5.9 to 47.3)
    Attachments
    OS
    No statistical analyses for this end point

    Secondary: PFS median

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    End point title
    PFS median
    End point description
    End point type
    Secondary
    End point timeframe
    Until progression or death
    End point values
    GAMEC - S GAMEC-A
    Number of subjects analysed
    21
    15
    Units: years
        median (confidence interval 95%)
    4.94 (0.36 to 99999)
    0.43 (0.16 to 0.62)
    Attachments
    PFS
    No statistical analyses for this end point

    Secondary: Response

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    End point title
    Response
    End point description
    End point type
    Secondary
    End point timeframe
    overall
    End point values
    GAMEC - S GAMEC-A
    Number of subjects analysed
    21
    15
    Units: patients
        CR
    8
    1
        M-ve PR
    8
    9
        M+ve PR
    1
    0
        SD
    0
    1
        PD
    0
    3
        Non-evaluable
    4
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment to 30 days after the last dose.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI
    Dictionary version
    3
    Reporting groups
    Reporting group title
    GAMEC-S
    Reporting group description
    -

    Reporting group title
    GAMEC-A
    Reporting group description
    -

    Serious adverse events
    GAMEC-S GAMEC-A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    4 / 15 (26.67%)
         number of deaths (all causes)
    9
    11
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cerebral metastasis
    Additional description: Convulsions and brain stem death
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Chest pain
    Additional description: Patient was on their way to the hospital for a planned admission, had sudden onset of central burning/pain radiating across chest. ECG showed changes of possible MI. Blood test shows raised Tropinin T- 1.99
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fast atrial fibrilation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
    Additional description: Preceded by renal impairment
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Death due to prolonged neutropenia
    Additional description: Death following prolonged neutropenia leading to infection hypoxia renal failure. ALDs and multiple organ failure.
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Pneumothorax spontaneous
    Additional description: Patient coughed and sustained pneumothorax. Patient is a smoker
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Required ventilation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia sepsis
    Additional description: Neutropenia sepsis leading to renal failure. Required ITU intervention and death in ITU
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Septic shock
    Additional description: Acute repiratory syndrome, refractory to ventilation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    GAMEC-S GAMEC-A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 21 (95.24%)
    15 / 15 (100.00%)
    Investigations
    Weight loss
         subjects affected / exposed
    13 / 21 (61.90%)
    12 / 15 (80.00%)
         occurrences all number
    25
    28
    Neutropenia
         subjects affected / exposed
    20 / 21 (95.24%)
    15 / 15 (100.00%)
         occurrences all number
    54
    40
    Thrombocytopenia
         subjects affected / exposed
    20 / 21 (95.24%)
    15 / 15 (100.00%)
         occurrences all number
    54
    47
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 21 (95.24%)
    15 / 15 (100.00%)
         occurrences all number
    44
    44
    General disorders and administration site conditions
    Skin toxicity
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 15 (6.67%)
         occurrences all number
    4
    1
    Pain
         subjects affected / exposed
    10 / 21 (47.62%)
    5 / 15 (33.33%)
         occurrences all number
    13
    8
    Fatigue
         subjects affected / exposed
    19 / 21 (90.48%)
    14 / 15 (93.33%)
         occurrences all number
    49
    40
    Gastrointestinal disorders
    Mucositis
         subjects affected / exposed
    18 / 21 (85.71%)
    15 / 15 (100.00%)
         occurrences all number
    41
    36
    Nausea
         subjects affected / exposed
    16 / 21 (76.19%)
    11 / 15 (73.33%)
         occurrences all number
    34
    26
    Vomiting
         subjects affected / exposed
    15 / 21 (71.43%)
    11 / 15 (73.33%)
         occurrences all number
    28
    23
    Constipation
         subjects affected / exposed
    6 / 21 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    10
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    19 / 21 (90.48%)
    14 / 15 (93.33%)
         occurrences all number
    43
    42
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    17 / 21 (80.95%)
    13 / 15 (86.67%)
         occurrences all number
    38
    31
    Infections and infestations
    Infection
         subjects affected / exposed
    18 / 21 (85.71%)
    15 / 15 (100.00%)
         occurrences all number
    35
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2008
    Closed Arm GAMEC-A following a relapse rate of 80% in the first 16 patients, which remained unchanged from previous studies. The regimen offered no advantage in terms of toxicity. Change in Sponsor to Queen Mary University of London
    23 Dec 2008
    Supplier change for the IMPs cisplatin and etoposide.

    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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