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    Clinical Trial Results:
    A randomized, double blind, placebo controlled phase II trial to evaluate the safety and efficacy of recMAGE-A3 + AS15 ASCI in patients with MAGE-A3 positive muscle invasive bladder cancer after cystectomy

    Summary
    EudraCT number
    		 2010-024355-85
    Trial protocol
    		 DE   NL   ES   IT   CZ  
    Global end of trial date
    09 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2017
    First version publication date
    13 Dec 2017
    Other versions
    Summary report(s)
    		 Magnolia_synopsis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2010-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01435356
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NTR Number: NTR2846, EAU-RF: 2010-01
    Sponsors
    Sponsor organisation name
    EAU RF
    Sponsor organisation address
    Mr. E.N. van Kleffensstraat 5, Arnhem, Netherlands, 6842 CV
    Public contact
    Raymond G. Schipper, PhD, EAU RF, +31 263890677, researchfoundation@uroweb.org
    Scientific contact
    Wim P.J. Witjes, MD, PhD, EAU RF, +31 263890677, researchfoundation@uroweb.org
    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
    07 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this Phase II study is to evaluate the clinical efficacy in terms of Disease Free Survival of recMAGE-A3 + AS 15 ASCI versus placebo in the overall population.
    Protection of trial subjects
    Potential risks for recMAGE-A3 + AS15 ASCI were identified during safety evaluation of MAGE-A3 antigen and the AS15 adjuvant in preclinical studies and studies in humans. The first one was the general theoretical concern of acquiring a vaccine induced autoimmune disease after immunization with a product containing Adjuvant Systems (AS). Potential immune-mediated diseases (pIMDs) were specified in the protocol and needed to be reported in the same (expedited) way as SAEs. Second, a potential developmental risk identified from preclinical embryo-foetal developmental toxicity studies in rats and rabbits with CpG 7909 from Pfizer Pharmaceutical Group (manufacturer of CpG 7909). CpG 7909 is one of the immunostimulatory components of GSK Biologicals’ proprietary AS15 Adjuvant System. Any possible risk associated with CpG 7909 exposure in humans is currently unknown, although GSK non-clinical data currently available on AS15 alone and in combination with different antigens shows no adverse reproductive, developmental or fertility effects. Pregnancy was an exclusion criterion to participate in this study. In addition, all women of childbearing potential needed to have a negative pregnancy test before participating in the study, and be using effective contraception during study treatment.
    Background therapy
    		 None
    Evidence for comparator
    		 Currently, the standard treatment for localized muscle invasive bladder cancer is radical cystectomy. • Many patients with muscle invasive bladder cancer will relapse after cystectomy The 10-year disease-specific and overall survival of patients with organ confined (defined as < pT3a) is 72.9% and 49.1%, rapidly decreasing to 33.3% and 22.8% for non-organ confined disease (13). There is thus a clear medical need for an additional anti-tumoral treatment in this population. • There is not enough evidence in favour of the routine use of adjuvant chemotherapy From scientific evidence so far available, it is unclear whether immediate adjuvant chemotherapy or chemotherapy at the time of relapse is superior or if the two approaches are equivalent with respect to the end-point overall survival. There is no additional effective treatment for the patient population at high risk of relapse receiving adjuvant chemotherapy and this represents a significant unmet medical need. • MAGE-A3 is a factor of poor prognosis The interest in recMAGE-A3 ASCI treatment is further reinforced by the possible link between MAGE-A3 expression and shorter survival • MAGE-A3 is tumor-specific, recMAGE-A3 + AS15 ASCI highly tolerated and shows promising Phase II results Taking into account the tumor-specificity of MAGE-A3, the high tolerability of recMAGE-A3 + AS15 and the promising results from the Phase II clinical trials in melanoma and lungcancer, EAU RF proposes to initiate a randomized, placebo-controlled clinical Phase II trial with recombinant MAGE-A3 (recMAGE-A3) combined with the AS15 adjuvant in patients with muscle invasive bladder cancer with MAGE-A3 expression after cystectomy. This trial will assess whether adjuvant treatment with recMAGE-A3 + AS 15 ASCI after cystectomy is safe and effective and improves outcome of MAGE-A3 positive patients after cystectomy.
    Actual start date of recruitment
    01 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 63
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Spain: 156
    Country: Number of subjects enrolled
    Czech Republic: 61
    Country: Number of subjects enrolled
    France: 48
    Country: Number of subjects enrolled
    Germany: 133
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    Russian Federation: 15
    Worldwide total number of subjects
    529
    EEA total number of subjects
    506
    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)
    199
    From 65 to 84 years
    328
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 From September 2011 to August 2014 529 patients were screened. Ten European countries participated with a total of 50 sites. As of 23 September 2014, the recruitment was put on hold. As of Protocol Amendment 4.0 , the recruitment was stopped and the study was unblinded.

    Pre-assignment
    Screening details
    		 Patients enter Screening S1 (pre-assignment period) during which it is checked whether the tumor tissue expresses the MAGE-A3 protein (=MAGE-A3 positive). MAGE-A3 positive patients enter Screening S2 and in case they comply to all in/exclusioncriteria they can be randomised.

    Pre-assignment period milestones
    Number of subjects started
    		 529
    Number of subjects completed
    		 205

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 not MAGE-A3 positive: 243
    Reason: Number of subjects
    		 no FFPE sample taken: 81
    Period 1
    Period 1 title
    Screening S2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Screening S2 patients
    Arm description
    		 Patients who were MAGE-A3 positive (at S1) underwent Screening S2. In case they were eligible they were randomised
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Screening S2 patients
    Started
    205
    Completed
    83
    Not completed
    122
         Consent withdrawn by subject
    29
         Eligibility criteria not fulfilled
    91
         Lost to follow-up
    2
    Period 2
    Period 2 title
    Randomisation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    As of Protocol Amendment 4.0 , the recruitment was stopped and the study was unblinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 recMAGE-A3 +AS15
    Arm description
    		 recombinant antigen ProtD-MAGE-A3/His (recMAGE-A3) and the GSK proprietary immunological adjuvant AS15
    Arm type
    		 Experimental

    Investigational medicinal product name
    recombinant antigen ProtD-MAGE-A3/His (recMAGE-A3) + AS15
    Investigational medicinal product code
    Other name
    recMAGE-A3 + AS15
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    recMAGE-A3 + AS 15 ASCI was administered by using a sterile two vial set comprising: • One vial with the lyophilized preparation containing 300 μg recMAGE-A3 antigen plus 420 μg of CpG7909 (a part of the adjuvant system AS15), • One vial with liquid adjuvant diluent AS01B (containing liposomes), along with 50 μg of MPL combined with 50 μg of QS21 in phosphate buffered saline), making up the remainder of the adjuvant system AS15. The final recMAGE-A3 + AS15 ASCI for administration was obtained by reconstitution of the lyophilized preparation with the adjuvant diluent. A recMAGE-A3 + AS15 ASCI dose consisted of 0.5 ml. A standard dose of recMAGE-A3 (300 ug) + AS15, or of placebo, was administered every 3 weeks from Visit 1 to Visit 5 and every 12 weeks from Visit 6 to Visit 13

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The placebo consisted of sucrose reconstituted with a 1/500 dilution of SB62 oil-inwater emulsion (pH = 6.8) in a total volume of 0.5 ml. It was administered by using a sterile two-vial set comprising: • One vial with the lyophilized sucrose preparation, • One vial with the diluted oil-in-water emulsion diluent. 0.5 ml of sucrose reconstituted in a diluted oil-in-water emulsion was administered every 3 weeks from Visit 1 to Visit 5 and every 12 weeks from Visit 6 to Visit 13

    Number of subjects in period 2
    		recMAGE-A3 +AS15 Placebo
    Started
    52
    31
    Completed
    48
    29
    Not completed
    4
    2
         ineligible, incorrectly randomised, not treated
    4
    2
    Period 3
    Period 3 title
    Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 recMAGE-A3 + AS15
    Arm description
    		 recMAGE-A3 + AS15
    Arm type
    		 Experimental

    Investigational medicinal product name
    recombinant antigen ProtD-MAGE-A3/His (recMAGE-A3) + AS15
    Investigational medicinal product code
    Other name
    recMAGE-A3 + AS15
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    recMAGE-A3 + AS 15 ASCI was administered by using a sterile two vial set comprising: • One vial with the lyophilized preparation containing 300 μg recMAGE-A3 antigen plus 420 μg of CpG7909 (a part of the adjuvant system AS15), • One vial with liquid adjuvant diluent AS01B (containing liposomes), along with 50 μg of MPL combined with 50 μg of QS21 in phosphate buffered saline), making up the remainder of the adjuvant system AS15. The final recMAGE-A3 + AS15 ASCI for administration was obtained by reconstitution of the lyophilized preparation with the adjuvant diluent. A recMAGE-A3 + AS15 ASCI dose consisted of 0.5 ml. A standard dose of recMAGE-A3 (300 ug) + AS15, or of placebo, was administered every 3 weeks from Visit 1 to Visit 5 and every 12 weeks from Visit 6 to Visit 13

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The placebo consisted of sucrose reconstituted with a 1/500 dilution of SB62 oil-inwater emulsion (pH = 6.8) in a total volume of 0.5 ml. It was administered by using a sterile two-vial set comprising: • One vial with the lyophilized sucrose preparation, • One vial with the diluted oil-in-water emulsion diluent. 0.5 ml of sucrose reconstituted in a diluted oil-in-water emulsion was administered every 3 weeks from Visit 1 to Visit 5 and every 12 weeks from Visit 6 to Visit 13

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is the number of randomized patients. Baseline data was not available for 6 patients who were incorrectly randomized and not treated. Baseline data provided for treated patients.
    Number of subjects in period 3 [2]
    		recMAGE-A3 + AS15 Placebo
    Started
    48
    29
    Completed
    16
    5
    Not completed
    32
    24
         Consent withdrawn by subject
    6
    1
         Adverse event, non-fatal
    3
    -
         study discontinuation (amendment 4)
    5
    11
         patient moved to another city
    1
    1
         Lack of efficacy
    17
    10
         Protocol deviation
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled in this trial is the number of patients who entered Screening S1 (pre-assignment period, n=529) during which it was checked whether the tumor tissue expressed the MAGE-A3 protein (=MAGE-A3 positive). Only MAGE-A3 positive patients (n=205) entered Screening S2 and in case they complied to all in/exclusioncriteria they were randomised (n=83).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    recMAGE-A3 + AS15
    Reporting group description
    		 recMAGE-A3 + AS15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 recMAGE-A3 + AS15 Placebo Total
    Number of subjects
    		 48 29 77
    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
    Age at Screening S1
    Units: years
        arithmetic mean (standard deviation)
    		 65.7 ± 8.4 65.5 ± 9.6 -
    Gender categorical
    Units: Subjects
        Female
    		 8 8 16
        Male
    		 40 21 61
    T-category
    T-category of bladder cancer at diagnosis
    Units: Subjects
        T2
    		 22 13 35
        T3
    		 21 13 34
        T4
    		 5 3 8
    N-category
    N-category of bladder cancer at diagnosis
    Units: Subjects
        N0
    		 36 22 58
        N1
    		 7 4 11
        N2
    		 5 3 8
    M-category
    M-category of bladder cancer at diagnosis
    Units: Subjects
        M0
    		 48 29 77
    dominant histopathological type
    Dominant histopathological type of bladder tumor
    Units: Subjects
        transitional (urothelial) cell carcinoma
    		 43 29 72
        squamous cell carcinoma
    		 3 0 3
        adenocarcinoma
    		 1 0 1
        not available
    		 1 0 1
    tumor size
    macrosopic tumor size of primary tumor
    Units: centimeter
        arithmetic mean (standard deviation)
    		 3.4 ± 2.5 3.2 ± 2.3 -

    End points

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    End points reporting groups
    Reporting group title
    Screening S2 patients
    Reporting group description
    		 Patients who were MAGE-A3 positive (at S1) underwent Screening S2. In case they were eligible they were randomised
    Reporting group title
    recMAGE-A3 +AS15
    Reporting group description
    		 recombinant antigen ProtD-MAGE-A3/His (recMAGE-A3) and the GSK proprietary immunological adjuvant AS15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo
    Reporting group title
    recMAGE-A3 + AS15
    Reporting group description
    		 recMAGE-A3 + AS15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Primary: disease free survival

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    End point title
    		 disease free survival [1]
    End point description
    Disease-free Survival (DFS) was defined as the time from randomization to either the date of first recurrence of the disease or the date of death (whatever the cause), whichever occurred first. Types of recurrence considered as an event included loco-regional and distant metastases. In addition, any death occurring without prior documentation of tumor recurrence was considered as an event (and was not censored in the statistical analysis) as this approach is less prone to introduce bias.
    End point type
    Primary
    End point timeframe
    Disease-free Survival (DFS) was defined as the time from randomization to either the date of first recurrence of the disease or the date of death (whatever the cause), whichever occurred first.
    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: Following amendment 4, the primary and secondary endpoints were not assessed as planned. All clinical data collected in the study were analysed descriptively. No formal statistical analysis were performed.
    End point values
    		 recMAGE-A3 + AS15 Placebo
    Number of subjects analysed
    48
    29
    Units: months
        least squares mean (confidence interval 95%)
    27.5 (22.7 to 32.3)
    19.8 (15.7 to 23.9)
    Attachments
    		 Disease free survival
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall Survival was defined as the interval from randomization to the date of death, irrespective of the cause of death; patients still alive were censored at the date of the last assessment.
    End point values
    		 recMAGE-A3 + AS15 Placebo
    Number of subjects analysed
    48
    29
    Units: months
        least squares mean (confidence interval 95%)
    35.5 (32.1 to 39.9)
    24.1 (21 to 27.2)
    Attachments
    		 Overall survival
    No statistical analyses for this end point

    Secondary: Distant metastasis-free survival

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    End point title
    		 Distant metastasis-free survival
    End point description
    Distant metastasis-free survival (DMFS) was defined as the interval from randomization to the date of first distant metastasis or date of death, whichever occurred first. Patients alive and without distant metastasis were censored at the date of last assessment.
    End point type
    Secondary
    End point timeframe
    Distant metastasis-free survival (DMFS) was defined as the interval from randomization to the date of first distant metastasis or date of death, whichever occurred first.
    End point values
    		 recMAGE-A3 + AS15 Placebo
    Number of subjects analysed
    48
    29
    Units: months
        least squares mean (confidence interval 95%)
    31.5 (27.2 to 35.9)
    21.4 (17.5 to 25.2)
    Attachments
    		 Distant Metastasis-free survival
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs occurring within the period beginning at the first administration of study treatment and ending 30 days after the last administration of study treatment were recorded.
    Adverse event reporting additional description
    All AEs either observed by the investigator or one of his clinical collaborators or reported by the patient spontaneously or in response to a direct question were evaluated by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    recMAGE-A3 + AS15
    Reporting group description
    		 recMAGE-A3 + AS15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 recMAGE-A3 + AS15 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 48 (27.08%)
    5 / 29 (17.24%)
         number of deaths (all causes)
    6
    5
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Diagnostic procedure
    Additional description: RADIOGRAPHIC EVIDENCE OF CENTRAL TUMOR RENAL PELVIS LEFT
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Femoral artery aneurysm
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    femoral artery occlusion
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    massive progression of lymphadenopathy
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral stenosis
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    		 recMAGE-A3 + AS15 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 48 (79.17%)
    21 / 29 (72.41%)
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    29 / 48 (60.42%)
    12 / 29 (41.38%)
         occurrences all number
    187
    23
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    11 / 48 (22.92%)
    6 / 29 (20.69%)
         occurrences all number
    13
    8
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    8 / 48 (16.67%)
    3 / 29 (10.34%)
         occurrences all number
    11
    7
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    5 / 48 (10.42%)
    5 / 29 (17.24%)
         occurrences all number
    6
    7
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    9 / 48 (18.75%)
    4 / 29 (13.79%)
         occurrences all number
    13
    6
    Infections and infestations
    infections and infestations
         subjects affected / exposed
    15 / 48 (31.25%)
    11 / 29 (37.93%)
         occurrences all number
    28
    21

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2011
    1) Broadening the time frame of inclusion criterion no. 3 for giving consent: Consent can be given before or after cystectomy since this is not a study-specific procedure. However, (optional) urine collection should be done before cystectomy 2) Additional inclusion criterion no. 10: The patient should be affiliated to health insurance or benefit of such an insurance 3) Additional exclusion criterion no. 14: Adults under legal supervision 4) Additional example to exclusion criterion no. 12: patients taking anticoagulant treatment or having a coagulation disorder 5) Additional condition of the tumor stage of the remaining tissue in the bladder in case tumor tissue derived during a TUR will be sent to the central laboratory for testing: when the bladder tumor is removed during a TUR preceding the cystectomy and the stage of the remaining tissue in the bladder is T0 or T1, the tumor tissue derived during the TUR may be sent to the central laboratory for testing 6) Clarification of the text: either images with or images without contrast material are required 7) Clarification of the nature of the gene profiling tests during recurrence: participation in the part of the study during recurrence is optional. Therefore gene profiling during recurrence should be labelled optional, not mandatory 8) Correction of typo: the hazard ratio of disease free survival of recMAGE-A3 + AS 15 ASCI treated patients will be taken against placebo treated patients
    15 May 2012
    1) Compliance with the Declaration of Helsinki 3§ and ICH GCP 4.3 and ICH GCP 5.13.4: the treating physician (investigator) is responsible for the medical care of the individual trial subject and the coding system in blinded trials should include a mechanism that permits rapid unblinding 2) Correction biopsy technique for (recurrent) tumour tissue samples in which MAGE A3 expression can be tested: MAGE A3 expression can only be tested in samples from resected tissue
    06 Jan 2014
    1) Change in exclusion criterion no. 2: Treatment with neo-adjuvant and adjuvant chemotherapy is allowed. Neo-adjuvant- and adjuvant chemotherapy treated subjects will be studied as subpopulations. 2) Broadening the time frame between cystectomy and randomization, from 9 to13 weeks (for patients not scheduled to receive adjuvant chemotherapy) or from 9 to 35 weeks (for patients receiving adjuvant chemotherapy). 3) Additional condition of the tumor tissue to be sent to the central laboratory for testing: As an alternative to the cystectomy specimen, the conditions are widened for a tumor sample collected during the TUR to be sent to the laboratory for testing. 4) Additional research in Translational Research: We also intend to characterize the tumor microenvironment and lymphocyte infiltration in the primary tumor and its recurrence lesions 5) Change in timing of the treatment/observation phase: The total duration of the study will be 7-8 years, starting with a recruitment phase of 4-5 years. 6) Correction of expected events: Expected events after interim analysis are 155. 7) Adaptation of text on potential immune-mediated diseases (pIMD) 8) Change of term “transitional cell carcinoma of bladder urothelium” into “urothelial carcinoma of the bladder” 9) Correction of typo, addition of “or”: Plant extracts or anticancer treatments, including but not exclusively, chemotherapeutic or immunomodulating agents and radiotherapy. 10) Correction of reference to Figure 3
    28 Oct 2014
    Upon release and analysis of the MAGRIT trial results, the rationale of the MAGNOLIA study has been changed. As of 23 September 2014, the recruitment was put on hold. As of Protocol Amendment 4.0: - The recruitment will be stopped and the study population will be unblinded. - For patients randomized to the placebo group, no further protocol visits will be performed except for the concluding visit and no further doses will be administered - As it cannot be excluded that one or more patients may benefit from this treatment on an individual basis, patients receiving active treatment will be offered the option to continue the administration of the study treatment until the last dose is administered or until recurrence, whichever comes first, or until the patient or the investigator decides to stop the study treatment. Therefore, the study will continue only with patients from the active treatment group who will decide to stay in the study. Treatment will not be possible anymore after 30 November 2016. - During the treatment period, safety monitoring will continue as initially foreseen during the treatment period - The primary and secondary objectives will not be assessed as planned. All clinical data collected in the study will be analysed descriptively. Sections of the protocol impacted by amendment 4.0 include the Study Synopsis (Section 1), the Introduction and Rationale (Section 2), the Study Objectives & End Points (Section 3), the Design of the Study (Section 4), Patient Selection Criteria (Section 5), Investigational Products and Administration (Section 6), the Study Assessments and Procedures (Section 7), the Adverse Events and Serious Adverse Events (Section 8), the Patient Completion and Withdrawal (Section 9) and the Statistical Considerations (Section 10). In addition a typo was corrected in section 6.1.2 and in section 8.3 Table 8 was updated.

    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.
    Trial's recruitment was prematurely stopped, the number of patients participating was limited and the recMAGE-A3+AS15 patients were given the opportunity to continue treatment following amendment 4, whereas placebo patients needed to stop treatment.
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