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    Clinical Trial Results:
    Ensayo clínico fase II de un solo brazo, multicéntrico y prospectivo para la validación de biomarcadores en pacientes con cáncer colorrectal avanzado y/o metastásico con gen KRAS no mutado tratados con quimioterapia más cetuximab bisemanal como terapia de primera línea.

    Summary
    EudraCT number
    		 2010-019236-12
    Trial protocol
    		 ES  
    Global end of trial date
    20 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2021
    First version publication date
    02 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GEMCAD-1002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01276379
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)
    Sponsor organisation address
    Ronda General Mitre 200, entresuelo 3a, Barcelona, Spain,
    Public contact
    Joan Maurel Santasusana, Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD), jmaurel@clinic.cat
    Scientific contact
    Joan Maurel Santasusana, Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD), jmaurel@clinic.cat
    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
    29 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Validación de los biomarcadores BRAF, IGF1P/MMp7 (DP) y PI3K-PTEN para predecir la SLP en pacientes con cáncer colorrectal avanzado y/o metastásico con KRAS no mutado tratados con quimioterapia estándar más cetuximab bisemanal como terapia de primera línea. Identificar nuevos biomarcadores que puedan predecir la supervivencia libre de progresión (SLP) en pacientes KRAS no mutado tratados con quimioterapia (QT) y cetuximab bisemanal en terapia de primera línea. La necesidad de identificar biomarcadores adicionales de la eficacia de cetuximab proviene del pequeño valor predictivo de la clasificación actual, basada en el estado mutacional de KRAS, de la eficacia de la administración de cetuximab bisemanal en el grupo de pacientes de la enfermedad a estudio. Los biomarcadores propuestos son: 1.Mutaciones BRAF 2.IGF-1Rp/MMP-7 (DP) 3.PIK3CA-PTEN.
    Protection of trial subjects
    The protocol provided all measures needed to grant the integrity of human patients enrolled and the conservation of their rights.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 221
    Worldwide total number of subjects
    221
    EEA total number of subjects
    221
    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)
    221
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 221 recruited, 40 do not comply with all protocol specifications, total of 181 patients enrolled and evaluable

    Pre-assignment
    Screening details
    		 221 recruited, 40 do not comply with all protocol specifications, total of 181 patients enrolled and evaluable

    Period 1
    Period 1 title
    Evaluable population (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Single-arm

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BRAF WT
    Arm description
    		 FOLFIRI (m): FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. FOLFOX-6 (m): FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. Cetuximab: - 500 mg/m2 i.v. Every 2 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    administered on day 1 of each 14-days-cycle. The administered doses will be: - Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. - l-Leucovorin 200 mg/ m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1.- One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. - 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours

    Investigational medicinal product name
    FOLFOX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Intravenous bolus use
    Dosage and administration details
    Administered on day 1 of each 14-days-cycle. The administered doses will be: -Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. - l-Leucovorin 200 mg/ m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. -One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. -5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2 i.v. Every 2 weeks.

    Arm title
    		 Mutant BRAF
    Arm description
    		 FOLFIRI (m): FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. FOLFOX-6 (m): FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. Cetuximab: - 500 mg/m2 i.v. Every 2 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Intravenous bolus use
    Dosage and administration details
    administered on day 1 of each 14-days-cycle. The administered doses will be: - Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. - l-Leucovorin 200 mg/ m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1.- One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. - 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours

    Investigational medicinal product name
    FOLFOX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    Administered on day 1 of each 14-days-cycle. The administered doses will be: -Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. - l-Leucovorin 200 mg/ m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. -One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. -5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2 i.v. Every 2 weeks.

    Number of subjects in period 1 [1]
    		BRAF WT Mutant BRAF
    Started
    161
    20
    Completed
    161
    20
    Notes
    [1] - 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: 221 recruited, 40 do not comply with all protocol specifications, total of 181 patients enrolled and evaluable

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BRAF WT
    Reporting group description
    		 FOLFIRI (m): FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. FOLFOX-6 (m): FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. Cetuximab: - 500 mg/m2 i.v. Every 2 weeks.

    Reporting group title
    Mutant BRAF
    Reporting group description
    		 FOLFIRI (m): FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. FOLFOX-6 (m): FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. Cetuximab: - 500 mg/m2 i.v. Every 2 weeks.

    Reporting group values
    		 BRAF WT Mutant BRAF Total
    Number of subjects
    		 161 20 181
    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
        arithmetic mean (standard deviation)
    		 62 ± 10.5 67 ± 7.4 -
    Gender categorical
    Units: Subjects
        Female
    		 46 7 53
        Male
    		 115 13 128
    Stage
    Measure Description: The stage of a cancer describes the size and spread of a tumour: stage I – The cancer has grown through the mucosa and has invaded the muscular layer of the colon or rectum. stage II – The cancer has grown through the wall of the colon or rectum stage III – The cancer has grown through the inner lining or into the muscle layers of the intestine. It has spread to lymph nodes stage IV – The cancer has spread to a distant part of the body
    Units: Subjects
        Stage I
    		 1 0 1
        Stage II
    		 13 0 13
        Stage III
    		 30 5 35
        Stage IV
    		 117 15 132
    Primary location
    Measure Description: Part of the colon where the primary tumor was located
    Units: Subjects
        Ascending colon
    		 23 9 32
        Transverse colon
    		 12 2 14
        Descending colon
    		 10 4 14
        Sigmoid colon
    		 73 3 76
        Rectum
    		 43 2 45
    Surgery of the primary tumor
    Percentage of patients that had surgery for their primary colorectal tumor
    Units: Subjects
        Yes
    		 91 10 101
        No
    		 70 10 80
    ECOG PS
    Eastern Cooperative Oncology Group (ECOG) performance status (PS). ECOG scale measures the performance status of a patients. It ranges from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (death).
    Units: Subjects
        ECOG 0
    		 112 7 119
        ECOG 1
    		 49 13 62
    Number of metastatic organs
    Percentage of patients presenting metastasis in one or more distant organs. The number of patients with 1,2, 3 or more than 4 affected organs are reported
    Units: Subjects
        1 organ
    		 87 7 94
        2 organs
    		 58 11 69
        3 organs
    		 15 2 17
        4 or higher organs
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    BRAF WT
    Reporting group description
    		 FOLFIRI (m): FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. FOLFOX-6 (m): FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. Cetuximab: - 500 mg/m2 i.v. Every 2 weeks.

    Reporting group title
    Mutant BRAF
    Reporting group description
    		 FOLFIRI (m): FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. FOLFOX-6 (m): FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: • Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. Cetuximab: - 500 mg/m2 i.v. Every 2 weeks.

    Primary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CTscan. Two groups will be defined based on the score built from the proposed clinical variables and biomarkers. Instead of a binomial distribution, a Log-rank method has been used to calculate the sample size in order to include all the incidents during the follow-up. Expecting a minimum 20% difference (60 vs. 40%) on PFS at 12 months between groups and with the following assumptions: Alpha error (bilateral): 5% Beta error: 20%
    End point type
    Primary
    End point timeframe
    4 years
    End point values
    		 BRAF WT Mutant BRAF
    Number of subjects analysed
    161
    20
    Units: Months
        median (confidence interval 95%)
    11.4 (9.9 to 13.1)
    5.9 (3.3 to 7.8)
    Statistical analysis title
    		 Log rank
    Comparison groups
    BRAF WT v Mutant BRAF
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 3.29
    Notes
    [1] - If pvalue <0.05 the null hypothesis is discarded and we asume there are statistically significant diferences between groups

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Proportion of patients alive at the end of study
    End point type
    Secondary
    End point timeframe
    4 years
    End point values
    		 BRAF WT Mutant BRAF
    Number of subjects analysed
    161
    20
    Units: Months
        median (confidence interval 95%)
    32.6 (27.5 to 38.8)
    9.3 (5.3 to 22)
    Statistical analysis title
    		 Log rank
    Comparison groups
    BRAF WT v Mutant BRAF
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 3.96
    Notes
    [2] - If p-value was lower than P<0.05 the null hypothesis was discarded and it is assumed that there are statistically significant diferences among the groups

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    Duration of the partial or total response to the treatment. Evaluation and classification according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors)
    End point type
    Secondary
    End point timeframe
    4 years
    End point values
    		 BRAF WT Mutant BRAF
    Number of subjects analysed
    161
    20
    Units: months
        median (full range (min-max))
    8.66 (1.16 to 53.49)
    8.66 (1.16 to 53.49)
    No statistical analyses for this end point

    Secondary: Tumoral response

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    End point title
    		 Tumoral response
    End point description
    Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT scan
    End point type
    Secondary
    End point timeframe
    4 years
    End point values
    		 BRAF WT Mutant BRAF
    Number of subjects analysed
    161
    20
    Units: Patients
        Complete response (CR)
    16
    1
        Partial response (PR)
    106
    6
        Stable disease (SD)
    25
    6
        Pogression disease (PD)
    8
    4
        Not evaluable (NE)
    6
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 years
    Adverse event reporting additional description
    Safety assessments included patient history and physical examinations, vital signs, ECOG PS, AEs, blood chemistry, and blood counts at each visit. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. Relation to cetuximab or chemotherapy assessed by PI
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    173 / 218 (79.36%)
         number of deaths (all causes)
    136
         number of deaths resulting from adverse events
    12
    Vascular disorders
    Vascular disorders NOS
         subjects affected / exposed
    10 / 218 (4.59%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 218 (8.72%)
         occurrences causally related to treatment / all
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    Edema
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General site reactions NOS
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hand foot syndrome
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    multiorgan failure
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Immune system disorders
    Allergic reaction to excipient
         subjects affected / exposed
    7 / 218 (3.21%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorders NOS
         subjects affected / exposed
    6 / 218 (2.75%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    Cardiac disorders
    Cardiac disorders NOS
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Neuropathy
         subjects affected / exposed
    5 / 218 (2.29%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Paresthesia
         subjects affected / exposed
    5 / 218 (2.29%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    5 / 218 (2.29%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Leucocytopenia
         subjects affected / exposed
    4 / 218 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    53 / 218 (24.31%)
         occurrences causally related to treatment / all
    0 / 53
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 218 (1.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Ocular alterations
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ocular disorders
         subjects affected / exposed
    3 / 218 (1.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 218 (1.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    28 / 218 (12.84%)
         occurrences causally related to treatment / all
    0 / 28
         deaths causally related to treatment / all
    0 / 0
    Fistula
         subjects affected / exposed
    7 / 218 (3.21%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders NOS
         subjects affected / exposed
    5 / 218 (2.29%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    10 / 218 (4.59%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Mucoitis
         subjects affected / exposed
    11 / 218 (5.05%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    9 / 218 (4.13%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Rectal bleeding
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    hepatic toxicity
         subjects affected / exposed
    3 / 218 (1.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Transaminitis
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 218 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Skin reaction
         subjects affected / exposed
    29 / 218 (13.30%)
         occurrences causally related to treatment / all
    0 / 29
         deaths causally related to treatment / all
    0 / 0
    Xerosis
         subjects affected / exposed
    8 / 218 (3.67%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary disorders NOS
         subjects affected / exposed
    4 / 218 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscluloskeletal disorders NOS
         subjects affected / exposed
    5 / 218 (2.29%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infections
         subjects affected / exposed
    9 / 218 (4.13%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 3
    Metabolism and nutrition disorders
    Anemia
         subjects affected / exposed
    4 / 218 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Anorexia
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolic disorders NOS
         subjects affected / exposed
    6 / 218 (2.75%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    198 / 218 (90.83%)
    Vascular disorders
    Vascular disorders NOS
         subjects affected / exposed
    12 / 218 (5.50%)
         occurrences all number
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    101 / 218 (46.33%)
         occurrences all number
    101
    Fever
         subjects affected / exposed
    25 / 218 (11.47%)
         occurrences all number
    25
    Pain NOS
         subjects affected / exposed
    21 / 218 (9.63%)
         occurrences all number
    21
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorders NOS
         subjects affected / exposed
    29 / 218 (13.30%)
         occurrences all number
    29
    Psychiatric disorders
    Psychiatric disorders NOS
         subjects affected / exposed
    12 / 218 (5.50%)
         occurrences all number
    12
    Congenital, familial and genetic disorders
    Trichomegaly
         subjects affected / exposed
    11 / 218 (5.05%)
         occurrences all number
    11
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    22 / 218 (10.09%)
         occurrences all number
    22
    Neuropathy
         subjects affected / exposed
    72 / 218 (33.03%)
         occurrences all number
    72
    Paresthesia
         subjects affected / exposed
    45 / 218 (20.64%)
         occurrences all number
    45
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    34 / 218 (15.60%)
         occurrences all number
    34
    Leucopenia
         subjects affected / exposed
    16 / 218 (7.34%)
         occurrences all number
    16
    Neutropenia
         subjects affected / exposed
    37 / 218 (16.97%)
         occurrences all number
    37
    Thrombocytopenia
         subjects affected / exposed
    22 / 218 (10.09%)
         occurrences all number
    22
    Eye disorders
    Ocular disorders NOS
         subjects affected / exposed
    24 / 218 (11.01%)
         occurrences all number
    24
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    28 / 218 (12.84%)
         occurrences all number
    28
    Constipation
         subjects affected / exposed
    40 / 218 (18.35%)
         occurrences all number
    40
    Diarrhoea
         subjects affected / exposed
    80 / 218 (36.70%)
         occurrences all number
    80
    Fistula
         subjects affected / exposed
    47 / 218 (21.56%)
         occurrences all number
    47
    Mucosa dryness
         subjects affected / exposed
    13 / 218 (5.96%)
         occurrences all number
    13
    Mucositis
         subjects affected / exposed
    87 / 218 (39.91%)
         occurrences all number
    87
    Nausea
         subjects affected / exposed
    60 / 218 (27.52%)
         occurrences all number
    60
    Gastrointestinal disorders NOS
         subjects affected / exposed
    40 / 218 (18.35%)
         occurrences all number
    40
    Hepatobiliary disorders
    Transaminitis
         subjects affected / exposed
    13 / 218 (5.96%)
         occurrences all number
    13
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    29 / 218 (13.30%)
         occurrences all number
    29
    Cutaneous reaction
         subjects affected / exposed
    134 / 218 (61.47%)
         occurrences all number
    134
    Xerosis
         subjects affected / exposed
    36 / 218 (16.51%)
         occurrences all number
    36
    Renal and urinary disorders
    Urinary disorders NOS
         subjects affected / exposed
    13 / 218 (5.96%)
         occurrences all number
    13
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorders NOS
         subjects affected / exposed
    20 / 218 (9.17%)
         occurrences all number
    20
    Infections and infestations
    Infections NOS
         subjects affected / exposed
    17 / 218 (7.80%)
         occurrences all number
    17
    Metabolism and nutrition disorders
    Anorexia and bulimia syndrome
         subjects affected / exposed
    27 / 218 (12.39%)
         occurrences all number
    27
    Metabolic disorders NOS
         subjects affected / exposed
    36 / 218 (16.51%)
         occurrences all number
    36

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2011
    NA
    13 Jul 2011
    NA
    15 Dec 2011
    NA
    17 Apr 2012
    NA
    14 Dec 2012
    NA
    18 Apr 2013
    NA
    15 May 2013
    NA
    04 Jul 2014
    NA

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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