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    Clinical Trial Results:
    Intensified methotrexate, vinblastine, doxorubicin and cisplatin (I-MVAC) with or without panitumumab as first-line treatment of advanced urothelial carcinoma in patients without H-Ras nor K-Ras mutations. Randomised phase II study.

    Summary
    EudraCT number
    		 2009-011882-10
    Trial protocol
    		 FR  
    Global end of trial date
    01 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2022
    First version publication date
    14 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GETUG-AFU 19/0901
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02818725
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Unicancer
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France, 75013
    Public contact
    Nourredine AIT-RAHMOUNE, Unicancer, 33 1 71 93 67 04, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT-RAHMOUNE, Unicancer, 33 1 71 93 67 04, n.ait-rahmoune@unicancer.fr
    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
    30 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the GETUG-AFU19 study was the evaluation of efficacy in terms of progression-free survival at 9 months of the combination of intensified methotrexate, vinblastine, doxorubicin and cisplatin (I-MVAC) with or without panitumumab as first-line treatment of advanced urothelial carcinoma in patients without H-Ras nor K-Ras mutations.
    Protection of trial subjects
    In order to ensure the protection of the rights, safety and well-being of trial subjects, this study was conducted in accordance with the ethical principles that have their origins in the latest version of the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) on the conduct of clinical trials and subsequent texts (Eudralex Vol 10), and the applicable local regulatory requirements and laws (The Huriet Law N°88-1138 of the 20th December 1998 on the protection of persons taking part in biomedical research; The National Informatics and Freedoms Commission – Law N° 78-17 of the 6th January 1978 modified by the law N° 2004-801 of the 6th August 2004 concerning the protection of the person with regards to the use of personal data; Bioethical law N°2011-814 of the 8th July 2011). Furthermore, independent Ethics Committees reviewed and gave favorable opinions to the study documents, including the initial protocol and all subsequent amendments, and all information and documents provided to subjects/patients. Written informed consent was obtained from all patients prior to enrollment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Sep 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, 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
    France: 97
    Worldwide total number of subjects
    97
    EEA total number of subjects
    97
    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)
    52
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The GETUG-AFU 19 was a multicentre, randomised phase II trial that evaluated the efficacy of intensified methotrexate, vinblastine, doxorubicin and cisplatin (I-MVAC) with or without panitumumab as first-line treatment of advanced urothelial carcinoma in patients without H-Ras nor K-Ras mutations.

    Pre-assignment
    Screening details
    		 The study consisted of a 28-day screening phase to establish patients' eligibility and document baseline measurements, a treatment phase (28-day cycle till disease progression - 6 cycles maximum), and a long-term follow-up to monitor the progression-free survival, the response rate, time to progression, overall survival, and toxicity.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 I-MVAC
    Arm description
    		 Standard of care treatment. patients randomized in the I-MVAC arm received intravenous injection of methotrexate, vinblastine, doxorubicin, and cisplatin every two weeks until disease progression for a maximum of 6 cycles. Furthermore, patients received two subcutaneous injection of G-CSF at each cycle to decrease chemotherapy toxicity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 30mg/m² over 30 min in 100 ml of 5% glucose solution

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate and solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 3 mg/m² over 15 min in 50 ml of 0.9% sodium chloride

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate and solution for solution for infusion, Powder for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 30 mg/m² over 30 min in 100 ml of 5% glucose solution

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 70 mg/m² over 2 hours in 250 ml of 0.9% sodium chloride, in between hyperhydration with 3 litres of 0.9% sodium chloride/24 hours, having started 24 hours before the cisplatin infusion and to be continued up to 24 hours after the end of the cisplatin infusion. Administration of magnesium to prevent magnesium loss might be performed

    Arm title
    		 I-MVAC plus panitumumab
    Arm description
    		 Patients randomized in the I-MVAC plus panitumumab arm received intravenous injection of methotrexate, vinblastine, doxorubicin, cisplatin, and panitumumab every two weeks until disease progression for a maximum of 6 cycles. Furthermore, patients received two subcutaneous injection of G-CSF at each cycle to decrease chemotherapy toxicity. After stopping treatment with I-MVAC, if panitumumab is well tolerated and in the absence of disease progression, panitumumab was continued alone as per the same regimen up to disease progression or the end of follow-up at 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 30mg/m² over 30 min in 100 ml of 5% glucose solution

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate and solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 3 mg/m² over 15 min in 50 ml of 0.9% sodium chloride

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate and solution for solution for infusion, Powder for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 30 mg/m² over 30 min in 100 ml of 5% glucose solution

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 70 mg/m² over 2 hours in 250 ml of 0.9% sodium chloride, in between hyperhydration with 3 litres of 0.9% sodium chloride/24 hours, having started 24 hours before the cisplatin infusion and to be continued up to 24 hours after the end of the cisplatin infusion. Administration of magnesium to prevent magnesium loss might be performed

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration at a dose of 6 mg/kg over 1 hour in 100 ml of 0.9% sodium chloride solution, 1 hour after cisplatin

    Number of subjects in period 1
    		I-MVAC I-MVAC plus panitumumab
    Started
    33
    64
    Completed
    25
    38
    Not completed
    8
    26
         Patient decision
    1
    2
         Physician decision
    1
    1
         Disease progression
    -
    6
         Adverse event, non-fatal
    5
    15
         Death
    -
    1
         Radiotherapy
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    I-MVAC
    Reporting group description
    		 Standard of care treatment. patients randomized in the I-MVAC arm received intravenous injection of methotrexate, vinblastine, doxorubicin, and cisplatin every two weeks until disease progression for a maximum of 6 cycles. Furthermore, patients received two subcutaneous injection of G-CSF at each cycle to decrease chemotherapy toxicity.

    Reporting group title
    I-MVAC plus panitumumab
    Reporting group description
    		 Patients randomized in the I-MVAC plus panitumumab arm received intravenous injection of methotrexate, vinblastine, doxorubicin, cisplatin, and panitumumab every two weeks until disease progression for a maximum of 6 cycles. Furthermore, patients received two subcutaneous injection of G-CSF at each cycle to decrease chemotherapy toxicity. After stopping treatment with I-MVAC, if panitumumab is well tolerated and in the absence of disease progression, panitumumab was continued alone as per the same regimen up to disease progression or the end of follow-up at 24 months.

    Reporting group values
    		 I-MVAC I-MVAC plus panitumumab Total
    Number of subjects
    		 33 64 97
    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))
    		 65.4 (39.9 to 75.3) 63.8 (35.5 to 73.9) -
    Gender categorical
    Units: Subjects
        Female
    		 8 15 23
        Male
    		 25 49 74
    ECOG PS
    Units: Subjects
        PS 0
    		 13 25 38
        PS 1
    		 17 30 47
        PS 2
    		 0 1 1
        Missing
    		 3 8 11
    Primary tumor
    Units: Subjects
        Upper urinary tract
    		 6 15 21
        Bladder
    		 22 46 68
        Both
    		 5 3 8
    Histological variant
    Units: Subjects
        Pure urothelial
    		 27 56 83
        Squamous
    		 3 1 4
        Glandular
    		 0 1 1
        Unknown
    		 3 6 9
    Disease stage
    Units: Subjects
        Locally advanced
    		 4 6 10
        Metastatic
    		 29 58 87
    Bajorin risk group
    Units: Subjects
        Favorable
    		 7 15 22
        Intermediate
    		 23 40 63
        Poor
    		 0 1 1
        Unknown
    		 3 8 11

    End points

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    End points reporting groups
    Reporting group title
    I-MVAC
    Reporting group description
    		 Standard of care treatment. patients randomized in the I-MVAC arm received intravenous injection of methotrexate, vinblastine, doxorubicin, and cisplatin every two weeks until disease progression for a maximum of 6 cycles. Furthermore, patients received two subcutaneous injection of G-CSF at each cycle to decrease chemotherapy toxicity.

    Reporting group title
    I-MVAC plus panitumumab
    Reporting group description
    		 Patients randomized in the I-MVAC plus panitumumab arm received intravenous injection of methotrexate, vinblastine, doxorubicin, cisplatin, and panitumumab every two weeks until disease progression for a maximum of 6 cycles. Furthermore, patients received two subcutaneous injection of G-CSF at each cycle to decrease chemotherapy toxicity. After stopping treatment with I-MVAC, if panitumumab is well tolerated and in the absence of disease progression, panitumumab was continued alone as per the same regimen up to disease progression or the end of follow-up at 24 months.

    Subject analysis set title
    Efficacy population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients without major violations of eligibility criteria, and evaluable

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients that received at least administration of a study drugs (MVAC or panitumumab). The patients were analysed according to the actual treatment they received

    Primary: 9-month progression-free survival

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    End point title
    		 9-month progression-free survival [1]
    End point description
    End point type
    Primary
    End point timeframe
    The primary endpoint PFS was evaluated at 9 months
    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: For this study, no formal statistical analysis between arms was planned. The treatment would be considered to be active if at least 37 patients among 62 did not show tumour progression at 9 months. Only 10 out of 63 patients were alive without disease progression at 9 months in the arm I-MVAC plus panitumumab. Thus, the combination of I-MVAC and panitumumab as first-line treatment of advanced urothelial carcinoma in patients without H-Ras nor K-Ras mutations is not considered sufficiently active
    End point values
    		 I-MVAC I-MVAC plus panitumumab
    Number of subjects analysed
    33
    63 [2]
    Units: Patients
        No
    22
    53
        Yes
    11
    10
    Notes
    [2] - 1 patient died before treatment end was not analysed
    No statistical analyses for this end point

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Survival rates will be estimated according to Kaplan-Meier. Patients alive at last follow-up news will be censored at the last visit date.
    End point type
    Primary
    End point timeframe
    The event times for the analyse of OS were calculated from the date of randomisation to the date of death (up to 24 months)
    End point values
    		 I-MVAC I-MVAC plus panitumumab
    Number of subjects analysed
    33
    63 [3]
    Units: year
        median (confidence interval 95%)
    20.2 (14.7 to 27.8)
    12.5 (9.5 to 17.3)
    Notes
    [3] - 1 patient died before treatment end was not analysed
    Statistical analysis title
    		 OS analysis
    Comparison groups
    I-MVAC v I-MVAC plus panitumumab
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 3

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Tumour evaluations were performed by chest-abdominal-pelvic CT scan and response to treatment were evaluated according to RECIST criteria v1.1.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed at baseline, every 6 weeks during and the treatment period (up to disease progression), then every 3 months for 2 years thereafter.
    End point values
    		 I-MVAC I-MVAC plus panitumumab
    Number of subjects analysed
    33
    63 [4]
    Units: Percent
        number (confidence interval 95%)
    69.7 (51 to 84)
    47.6 (35 to 61)
    Notes
    [4] - 1 patient died before treatment end was not analysed
    No statistical analyses for this end point

    Secondary: Time to progression

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    End point title
    		 Time to progression
    End point description
    Survival rates were estimated according to Kaplan-Meier. Patients alive at last follow-up news were censored at the date of last tumour assessment. Patients who died from causes other than disease progression were censored at the date of death. Patients who did not progress nor die were censored at the date of last tumour assessment, or at the date of a secondary treatment initiation in the case of absence of disease progression.
    End point type
    Secondary
    End point timeframe
    The event times for the analysis of time to progression (TTP) were calculated from the date of randomisation to the date of progression (up to 24 months).
    End point values
    		 I-MVAC I-MVAC plus panitumumab
    Number of subjects analysed
    33
    63 [5]
    Units: month
        median (confidence interval 95%)
    6.8 (6.3 to 10.0)
    5.7 (4.6 to 6.4)
    Notes
    [5] - 1 patient died before treatment end was not analysed
    Statistical analysis title
    		 TTP analysis
    Comparison groups
    I-MVAC v I-MVAC plus panitumumab
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.028
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 2.61

    Post-hoc: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Tumour evaluations were performed by chest-abdominal-pelvic CT scan and response to treatment were evaluated according to RECIST criteria v1.1.
    End point type
    Post-hoc
    End point timeframe
    Tumor assessment were performed every 6 weeks during and the treatment period (up to disease progression), then every 3 months for 2 years thereafter.
    End point values
    		 I-MVAC I-MVAC plus panitumumab
    Number of subjects analysed
    33
    63 [6]
    Units: month
        median (confidence interval 95%)
    6.8 (6.3 to 9.2)
    5.7 (4.6 to 6.4)
    Notes
    [6] - 1 patient died before treatment end was not analysed
    Statistical analysis title
    		 PFS analysis
    Comparison groups
    I-MVAC v I-MVAC plus panitumumab
    Number of subjects included in analysis
    96
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.038
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.51

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion until 30 days after end of treatment (up to 2 years).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    I-MVAC
    Reporting group description
    		 -

    Reporting group title
    I-MVAC plus panitumumab
    Reporting group description
    		 -

    Serious adverse events
    		 I-MVAC I-MVAC plus panitumumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 33 (42.42%)
    47 / 63 (74.60%)
         number of deaths (all causes)
    20
    50
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningeal carcinomatosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Muscle neoplasm
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Nephrostomy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter occlusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 63 (7.94%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumopathy
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Left ventricular ejection fraction decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Drug administration error
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplasia bone marrow
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplasia anaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 63 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile aplasia
         subjects affected / exposed
    2 / 33 (6.06%)
    7 / 63 (11.11%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Melaena
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pustular skin eruption
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute renal failure
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute renal insufficiency
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematuria
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal insufficiency
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 63 (7.94%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in spine
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 63 (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
    Candida sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter infection
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatophytosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panaritium
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septicaemia staphylococcal
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septicaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus epidermidis infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary infection
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 I-MVAC I-MVAC plus panitumumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    63 / 63 (100.00%)
    Vascular disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Thrombosis
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 63 (7.94%)
         occurrences all number
    2
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    29 / 33 (87.88%)
    50 / 63 (79.37%)
         occurrences all number
    29
    50
    Fever
         subjects affected / exposed
    8 / 33 (24.24%)
    16 / 63 (25.40%)
         occurrences all number
    8
    16
    Weight
         subjects affected / exposed
    17 / 33 (51.52%)
    41 / 63 (65.08%)
         occurrences all number
    17
    41
    Chills
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 63 (1.59%)
         occurrences all number
    4
    1
    Oedema peripheral
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 63 (4.76%)
         occurrences all number
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 33 (21.21%)
    12 / 63 (19.05%)
         occurrences all number
    7
    12
    Dyspnoea
         subjects affected / exposed
    4 / 33 (12.12%)
    11 / 63 (17.46%)
         occurrences all number
    4
    11
    Thoracic pain
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 63 (0.00%)
         occurrences all number
    4
    0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Peripheral neuropathy
         subjects affected / exposed
    9 / 33 (27.27%)
    10 / 63 (15.87%)
         occurrences all number
    9
    10
    Insomnia
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 63 (4.76%)
         occurrences all number
    1
    3
    Somnolence
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    Haemoglobin
         subjects affected / exposed
    31 / 33 (93.94%)
    62 / 63 (98.41%)
         occurrences all number
    31
    62
    Neutrophil
         subjects affected / exposed
    21 / 33 (63.64%)
    36 / 63 (57.14%)
         occurrences all number
    21
    36
    Febrile neutropenia
         subjects affected / exposed
    2 / 33 (6.06%)
    11 / 63 (17.46%)
         occurrences all number
    2
    11
    Platelet
         subjects affected / exposed
    25 / 33 (75.76%)
    42 / 63 (66.67%)
         occurrences all number
    25
    42
    Ear and labyrinth disorders
    Audition
         subjects affected / exposed
    8 / 33 (24.24%)
    6 / 63 (9.52%)
         occurrences all number
    8
    6
    Eye disorders
    Visual impairment
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 63 (3.17%)
         occurrences all number
    2
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 33 (36.36%)
    28 / 63 (44.44%)
         occurrences all number
    12
    28
    Diarrhoea
         subjects affected / exposed
    10 / 33 (30.30%)
    27 / 63 (42.86%)
         occurrences all number
    10
    27
    Nausea
         subjects affected / exposed
    25 / 33 (75.76%)
    46 / 63 (73.02%)
         occurrences all number
    25
    46
    Stomatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    14 / 33 (42.42%)
    27 / 63 (42.86%)
         occurrences all number
    14
    27
    Mucositis
         subjects affected / exposed
    11 / 33 (33.33%)
    41 / 63 (65.08%)
         occurrences all number
    11
    41
    Abdominal pain
         subjects affected / exposed
    6 / 33 (18.18%)
    8 / 63 (12.70%)
         occurrences all number
    6
    8
    Hepatobiliary disorders
    Bilirubin
         subjects affected / exposed
    4 / 33 (12.12%)
    6 / 63 (9.52%)
         occurrences all number
    4
    6
    Alkaline phosphatase
         subjects affected / exposed
    11 / 33 (33.33%)
    30 / 63 (47.62%)
         occurrences all number
    11
    30
    Alanine aminotransferase
         subjects affected / exposed
    6 / 33 (18.18%)
    15 / 63 (23.81%)
         occurrences all number
    6
    15
    Aspartate aminotransferase
         subjects affected / exposed
    6 / 33 (18.18%)
    10 / 63 (15.87%)
         occurrences all number
    6
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    12 / 33 (36.36%)
    20 / 63 (31.75%)
         occurrences all number
    12
    20
    Desquamation
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 63 (9.52%)
         occurrences all number
    0
    6
    Dry skin
         subjects affected / exposed
    2 / 33 (6.06%)
    20 / 63 (31.75%)
         occurrences all number
    2
    20
    Erythema
         subjects affected / exposed
    0 / 33 (0.00%)
    20 / 63 (31.75%)
         occurrences all number
    0
    20
    Hand-foot syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    7 / 63 (11.11%)
         occurrences all number
    0
    7
    Rash
         subjects affected / exposed
    0 / 33 (0.00%)
    37 / 63 (58.73%)
         occurrences all number
    0
    37
    Skin fissures
         subjects affected / exposed
    0 / 33 (0.00%)
    8 / 63 (12.70%)
         occurrences all number
    0
    8
    Renal and urinary disorders
    Creatine
         subjects affected / exposed
    13 / 33 (39.39%)
    27 / 63 (42.86%)
         occurrences all number
    13
    27
    Haematuria
         subjects affected / exposed
    4 / 33 (12.12%)
    14 / 63 (22.22%)
         occurrences all number
    4
    14
    Proteinuria
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Infections and infestations
    Infection with neutropenia
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 63 (4.76%)
         occurrences all number
    3
    3
    Infection without neutropenia
         subjects affected / exposed
    6 / 33 (18.18%)
    12 / 63 (19.05%)
         occurrences all number
    6
    12
    Paronychia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    12 / 33 (36.36%)
    38 / 63 (60.32%)
         occurrences all number
    12
    38
    Hypomagnesaemia
         subjects affected / exposed
    12 / 33 (36.36%)
    31 / 63 (49.21%)
         occurrences all number
    12
    31
    Hypocalcaemia
         subjects affected / exposed
    9 / 33 (27.27%)
    33 / 63 (52.38%)
         occurrences all number
    9
    33
    Hypokalaemia
         subjects affected / exposed
    10 / 33 (30.30%)
    23 / 63 (36.51%)
         occurrences all number
    10
    23
    Dehydration
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 63 (4.76%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2011
    * In order not to exclude patients with bone metastases due to alkaline phosphatases exceeding the limits mentioned in the protocol, the inclusion criterion #10 was added so that patients with bone metastases and ALP < grade 3 according to CTC-AE v 4 were eligible. * Approximately 30% of patients with urothelial cancer for whom prostate cancer is diagnosed during histopathological analysis of the cystectomy specimen. In order not to exclude patients with low-risk prostate cancer, and therefore without impact on the survival prognosis of these patients who also have urothelial cancer, the inclusion criterion #2 was reworded to specify the eligibility of these patients in this protocol.
    22 May 2012
    Patients with brain metastasis require special management, particularly radiotherapy, which is not compatible with the chemotherapy proposed in the protocol. Thus, the non-inclusion criterion #2 was modified to include this parameter and the inclusion criterion #4 reworded.
    11 Sep 2012
    The inclusion period was extended by 2 years to allow inclusion of the last 50 patients.
    15 Jul 2014
    * Initially, the protocol planned to register 107 patients and randomize 93, with a rate of 20% of patients not eligible for randomization and analysis. However, it has been observed that about 30% of the registered patients were not randomized (screening failure, death before randomization, deterioration of the general state before randomization, etc.) and that 15% of the randomized patients could not be taken into account in the analysis (absence of measurable lesions and/or untreated patients). Thus, the population to be screened was increased to 135 registered patients to reach 93 evaluable patients. * Given the need to increase the number of patients to be registered and given the average inclusion rate (3 patients/month), the inclusion period was extended by 8 months.
    26 Mar 2015
    * The inclusion period was extended by 8 months to allow inclusion of the last patients. * The calculation of the number of patients to be registered necessary to reach the objective of 93 analyzable patients was incorrect. Indeed, the estimated percentage of non-analyzable patients being 45% (30% of patients not randomizedand 15% of patients randomized but not evaluable), the required number of patients to be registrered was 170 patients and not 135 as specified in the amendment approved on 15-Jul-2014 .

    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.
    For adverse events, the "total number of occurrences" was not reported, so the number of patients is noted in this field.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33753043
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