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    Clinical Trial Results:
    A randomized, double-blind, placebo controlled, multicenter, phase II study of adding AMG 479, a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R) to first line chemotherapy in patients with optimally debulked ( < 1cm) epithelial ovarian cancer.

    Summary
    EudraCT number
    		 2008-001551-22
    Trial protocol
    		 FR   DE   ES   IE   GB  
    Global end of trial date
    07 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Aug 2016
    First version publication date
    07 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TRIO 014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00718523
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Translational Research In Oncology (TRIO)
    Sponsor organisation address
    Suite 1100, 9925-109th Street, Edmonton , Canada, T5K2J8
    Public contact
    Matthieu Rupin, Translational Research In Oncology (TRIO), +33 1 58 10 08 89, matthieu.rupin@trioncology.org
    Scientific contact
    Matthieu Rupin, Translational Research In Oncology (TRIO), +33 1 58 10 08 89, matthieu.rupin@trioncology.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
    06 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate whether the addition of AMG 479 to paclitaxel and carboplatin chemotherapy improves progression free survival (PFS) when compared to paclitaxel and carboplatin chemotherapy alone.
    Protection of trial subjects
    The clinical trial was conducted in accordance with the recommendation of the Declaration of Helsinki (Helsinki 1964 as amended) and with the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP). The study also complied with the laws and regulations, as well as any applicable guidelines of the countries where the study was conducted. A Data Monitoring Committee (DMC) was appointed for this trial.
    Background therapy
    		 Paclitaxel Carboplatin
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 82
    Country: Number of subjects enrolled
    United States: 59
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Israel: 4
    Worldwide total number of subjects
    170
    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)
    120
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted over a total of 55 sites in 8 countries.

    Pre-assignment
    Screening details
    		 Female, 18 years of age/older/legal age with optimally debulked (<1 cm) FIGO stage III and IV (positive pleural cytology only) ovarian epithelial carcinoma. ECOG performance status ≤ 2, non diabetics patients type 1 or 2, adequate coagulation parameters, INR≤1,5 and prothrombin time or (activated) partial thromboplastin time ≤ 1,5 ULN.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 Placebo plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of placebo administered on Day 1 of each 21-day cycle.
    Arm type
    		 Placebo

    Investigational medicinal product name
    AMG 479 Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AMG 479 placebo: matching placebo administered Day 1 of each 21 day cycle

    Arm title
    		 Experimental
    Arm description
    		 AMG 479 plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of AMG 479 single agent administered on Day 1 of each 21-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 479
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AMG 479: solution for infusion - 18 mg/kg on day 1 of each 21-day cycle

    Number of subjects in period 1
    		Control Experimental
    Started
    84
    86
    Completed
    66
    62
    Not completed
    18
    24
         Adverse event, serious fatal
    13
    17
         Consent withdrawn by subject
    5
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Placebo plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of placebo administered on Day 1 of each 21-day cycle.

    Reporting group title
    Experimental
    Reporting group description
    		 AMG 479 plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of AMG 479 single agent administered on Day 1 of each 21-day cycle

    Reporting group values
    		 Control Experimental Total
    Number of subjects
    		 84 86 170
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 59 61 120
        From 65-84 years
    		 25 25 50
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.1 ( 10 ) 57.2 ( 12.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 84 86 170
        Male
    		 0 0 0
    Region of enrollment
    Units: Subjects
        United States
    		 25 34 59
        United Kingdom
    		 1 2 3
        Canada
    		 4 6 10
        France
    		 7 3 10
        Israel
    		 2 2 4
        Spain
    		 1 1 2
        Germany
    		 44 38 82
    Eastern Cooperative Oncology Group Performance Status
    Units: Subjects
        PS 0 (fully active)
    		 36 32 68
        PS 1 (restricted in physically strenuous activity)
    		 43 46 89
        PS 2 (ambulatory and capable of all selfcare)
    		 5 6 11
        Missing
    		 0 2 2
    Origin of tumor
    Units: Subjects
        Primary peritoneal
    		 8 4 12
        Fallopian tube
    		 4 4 8
        Ovarian
    		 69 77 146
        Ovarian + Primary peritoneal
    		 0 1 1
        Ovarian + Fallopian tube
    		 2 0 2
        Missing
    		 1 0 1
    Stage at first diagnosis (International Federation of Gynecology and Obstetrics (FIGO))
    Units: Subjects
        IIIA
    		 3 2 5
        IIIB
    		 10 6 16
        IIIC
    		 65 72 137
        IV
    		 6 6 12
    Histopathologic type
    Units: Subjects
        papillary serous
    		 69 72 141
        mucinous
    		 0 1 1
        endometroid
    		 4 5 9
        clear cell
    		 2 2 4
        mixed
    		 5 3 8
        other
    		 4 3 7
    Histologic Grade
    Units: Subjects
        G1 (well differentiated)
    		 1 5 6
        G2 (moderately differentiated)
    		 15 18 33
        G3 (poorly differentiated)
    		 65 57 122
        Not done
    		 3 6 9
    Number of prior therapies
    Units: Subjects
        1 therapy
    		 80 78 158
        2 therapies
    		 4 8 12
    CA 125 status
    Units: Subjects
        with elevated CA 125
    		 67 70 137
        with CA 125 in the normal range
    		 17 15 32
        missing
    		 0 1 1
    Time from surgery to first treatment dose
    Units: weeks
        arithmetic mean (standard deviation)
    		 5.1 ( 1.2 ) 5.1 ( 1.4 ) -
    Time from diagnosis to randomization
    Units: weeks
        arithmetic mean (standard deviation)
    		 5.2 ( 2.3 ) 5.4 ( 3.4 ) -
    Subject analysis sets

    Subject analysis set title
    Intent To treat Population (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized in the study regardless whether they actually received treatment or not. Patients were analyzed according to their treatment arm at randomization.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of all treated patients who received at least one dose of study treatment. Patients were analyzed according to the treatment actually received.

    Subject analysis sets values
    		 Intent To treat Population (ITT) Safety Population
    Number of subjects
    170
    165
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    120
    115
        From 65-84 years
    50
    50
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.6 ( 11.2 )
    57.6 ( 11.4 )
    Gender categorical
    Units: Subjects
        Female
    170
    165
        Male
    0
    0
    Region of enrollment
    Units: Subjects
        United States
    59
        United Kingdom
    3
        Canada
    10
        France
    10
        Israel
    4
        Spain
    2
        Germany
    82
    Eastern Cooperative Oncology Group Performance Status
    Units: Subjects
        PS 0 (fully active)
    68
    67
        PS 1 (restricted in physically strenuous activity)
    89
    87
        PS 2 (ambulatory and capable of all selfcare)
    11
    9
        Missing
    2
    2
    Origin of tumor
    Units: Subjects
        Primary peritoneal
    12
    12
        Fallopian tube
    8
    7
        Ovarian
    146
    142
        Ovarian + Primary peritoneal
    1
    1
        Ovarian + Fallopian tube
    2
    2
        Missing
    1
    1
    Stage at first diagnosis (International Federation of Gynecology and Obstetrics (FIGO))
    Units: Subjects
        IIIA
    5
    4
        IIIB
    16
    16
        IIIC
    137
    134
        IV
    12
    11
    Histopathologic type
    Units: Subjects
        papillary serous
    141
    137
        mucinous
    1
    1
        endometroid
    9
    9
        clear cell
    4
    4
        mixed
    8
    7
        other
    7
    7
    Histologic Grade
    Units: Subjects
        G1 (well differentiated)
    6
    6
        G2 (moderately differentiated)
    33
    33
        G3 (poorly differentiated)
    122
    117
        Not done
    9
    9
    Number of prior therapies
    Units: Subjects
        1 therapy
    158
    153
        2 therapies
    12
    12
    CA 125 status
    Units: Subjects
        with elevated CA 125
    137
    132
        with CA 125 in the normal range
    32
    32
        missing
    1
    1
    Time from surgery to first treatment dose
    Units: weeks
        arithmetic mean (standard deviation)
    5.1 ( 1.3 )
    5.1 ( 1.3 )
    Time from diagnosis to randomization
    Units: weeks
        arithmetic mean (standard deviation)
    5.3 ( 2.9 )
    5.3 ( 3 )

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Placebo plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of placebo administered on Day 1 of each 21-day cycle.

    Reporting group title
    Experimental
    Reporting group description
    		 AMG 479 plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of AMG 479 single agent administered on Day 1 of each 21-day cycle

    Subject analysis set title
    Intent To treat Population (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized in the study regardless whether they actually received treatment or not. Patients were analyzed according to their treatment arm at randomization.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of all treated patients who received at least one dose of study treatment. Patients were analyzed according to the treatment actually received.

    Primary: Progression Free Survival (PFS): Time from Randomization until date of Progression or Death

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    End point title
    		 Progression Free Survival (PFS): Time from Randomization until date of Progression or Death
    End point description
    A patient may have been declared to have progressive disease on the basis of radiological measurement of tumor lesions assessment or CA125 evaluation (tumor measuremts taking precedence). Radiological progression was defined as per the RECIST guidelines (Therasse et al, JNCI2000) as at least 20% increase in the sum of the longest diameters of target lesions (ref the smallest sum of the longest diam recorded since the treatmt started or since the appearance of at least 1 new lesion). Serum CA125 progression was defined, according to the 2005 GCIG def: patients with: -elevated CA125 pretreatmt and normalization of CA125 has to show evidence of CA125 ≥ 2 X the upper normal limit on 2 occasions at least 1 wk apart OR -elevated CA125 pretreatmt which never normalized must show evidence of CA125 ≥ 2 X the nadir value on 2 occasions at least 1 wk apart OR -CA125 in the normal range pretreatment had to show evidence of CA125 ≥ 2 X the upper normal limit on 2 occasions at least 1 wk apart.
    End point type
    Primary
    End point timeframe
    Radiological tumor assessment: every 12 (+ /- 1) weeks for 3 years after randomization + CA 125: day 1 of each cycle
    End point values
    		 Control Experimental
    Number of subjects analysed
    84
    86
    Units: Months
    median (confidence interval 95%)
        Progression Free Survival (PFS)
    16.69 (14.686 to 28.123)
    15.737 (12.09 to 21.388)
    Statistical analysis title
    		 Kaplan Meier
    Statistical analysis description
    To estimate whether the addition of AMG 479 to paclitaxel and carboplatin chemotherapy improves progression free survival (PFS) when compared to paclitaxel and carboplatin chemotherapy alone.
    Comparison groups
    Control v Experimental
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.338
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.215
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.813
         upper limit
    		 1.816
    Notes
    [1] - The study is designed to provide evidence to either support the null hypothesis H0: λ equals 1 or to reject it in favor of the alternative hypothesis HA: λ does not equal 1, where λ is the hazard ratio for PFS: experimental arm/control arm. However, the study is designed to primarily demonstrate activity and feasibility of AMG 479 in combination with paclitaxel/carboplatin in ovarian cancer, rather than to provide statistical power to support a new standard regimen.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The monitoring period for AEs started from signature of the ICF and continued up to 30 days after last dose.
    Adverse event reporting additional description
    The participant flow module is based on the ITT population, so patients are counted according to their "randomization group". For "participants at risk", patients are grouped by their "actual treatment"; 4 patients were allocated with incorrect treatment and received AMG 479 instead of placebo. The total number of patients treated remains the same.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    UN
    Reporting groups
    Reporting group title
    Arm I
    Reporting group description
    		 Placebo plus paclitaxel/carboplatin administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of placebo administered on Day 1 of each 21-day cycle. AMG479 Placebo: matching placebo administered Day 1 of each 21 day cycle. There were 13 deaths in total with 1 resulting from a serious adverse event (convulsion). 4 patients radomized to recieve placebo actually received AMG 479.

    Reporting group title
    Arm II
    Reporting group description
    		 AMG 479 plus paclitaxel:carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of AMG 479 single agent administered on Day 1 of each 21-day cycle. AMG 479: solution for infusion - 18 mg/kg on day 1 of each 21-day cycle. There were 17 deaths reported in this group, with 2 patient deaths resulting from serious adverse events - UNRELATED TO TREATMENT (1 patient death resulting from aortic aneurysm, and the other patient death resulting from intestinal infarction AND haemorrhage intracranial combined).

    Serious adverse events
    		 Arm I Arm II
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 77 (40.26%)
    30 / 88 (34.09%)
         number of deaths (all causes)
    13
    17
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphocele
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Intestinal infarction
    Additional description: One patient died resulting from 2 events: intracranial hemorrhage AND intestinal infarction. Both events were possibly caused by ovarian cancer and hypertension but NOT related to treatment.
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 77 (1.30%)
    5 / 88 (5.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         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
    Femoral neck fracture
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
    Additional description: Patient in the placebo group died due to convulsion. The event was determined as possibly related to disease progression but NOT related to treatment.
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
    Additional description: One patient died resulting from 2 events: intracranial hemorrhage AND intestinal infarction. Both events were possibly caused by ovarian cancer and hypertension but NOT related to treatment.
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorder
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (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
    Anaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    6 / 88 (6.82%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 77 (1.30%)
    5 / 88 (5.68%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 77 (2.60%)
    2 / 88 (2.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 77 (2.60%)
    3 / 88 (3.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic leak
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 77 (0.00%)
    3 / 88 (3.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 88 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         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
    1 / 77 (1.30%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm I Arm II
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 77 (100.00%)
    86 / 88 (97.73%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    13 / 77 (16.88%)
    7 / 88 (7.95%)
         occurrences all number
    13
    8
    Hypertension
         subjects affected / exposed
    3 / 77 (3.90%)
    6 / 88 (6.82%)
         occurrences all number
    3
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 77 (11.69%)
    5 / 88 (5.68%)
         occurrences all number
    17
    6
    Chills
         subjects affected / exposed
    4 / 77 (5.19%)
    10 / 88 (11.36%)
         occurrences all number
    4
    12
    Fatigue
         subjects affected / exposed
    46 / 77 (59.74%)
    49 / 88 (55.68%)
         occurrences all number
    55
    55
    Oedema peripheral
         subjects affected / exposed
    8 / 77 (10.39%)
    5 / 88 (5.68%)
         occurrences all number
    8
    5
    Pain
         subjects affected / exposed
    9 / 77 (11.69%)
    11 / 88 (12.50%)
         occurrences all number
    10
    11
    Pyrexia
         subjects affected / exposed
    13 / 77 (16.88%)
    9 / 88 (10.23%)
         occurrences all number
    15
    12
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    10 / 77 (12.99%)
    8 / 88 (9.09%)
         occurrences all number
    14
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 77 (9.09%)
    9 / 88 (10.23%)
         occurrences all number
    7
    9
    Dyspnoea
         subjects affected / exposed
    15 / 77 (19.48%)
    12 / 88 (13.64%)
         occurrences all number
    15
    12
    Epistaxis
         subjects affected / exposed
    6 / 77 (7.79%)
    12 / 88 (13.64%)
         occurrences all number
    6
    13
    Oropharyngeal pain
         subjects affected / exposed
    5 / 77 (6.49%)
    4 / 88 (4.55%)
         occurrences all number
    5
    4
    Rhinorrhoea
         subjects affected / exposed
    4 / 77 (5.19%)
    3 / 88 (3.41%)
         occurrences all number
    4
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 77 (5.19%)
    2 / 88 (2.27%)
         occurrences all number
    4
    2
    Depression
         subjects affected / exposed
    6 / 77 (7.79%)
    2 / 88 (2.27%)
         occurrences all number
    6
    2
    Insomnia
         subjects affected / exposed
    6 / 77 (7.79%)
    7 / 88 (7.95%)
         occurrences all number
    6
    7
    Investigations
    Weight increased
         subjects affected / exposed
    2 / 77 (2.60%)
    5 / 88 (5.68%)
         occurrences all number
    2
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 77 (19.48%)
    9 / 88 (10.23%)
         occurrences all number
    16
    9
    Dysgueusia
         subjects affected / exposed
    15 / 77 (19.48%)
    15 / 88 (17.05%)
         occurrences all number
    17
    16
    Headache
         subjects affected / exposed
    15 / 77 (19.48%)
    23 / 88 (26.14%)
         occurrences all number
    17
    30
    Neuropathy peripheral
         subjects affected / exposed
    15 / 77 (19.48%)
    24 / 88 (27.27%)
         occurrences all number
    17
    25
    Paraesthesia
         subjects affected / exposed
    7 / 77 (9.09%)
    3 / 88 (3.41%)
         occurrences all number
    9
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    32 / 77 (41.56%)
    27 / 88 (30.68%)
         occurrences all number
    35
    31
    Polyneuropathy
         subjects affected / exposed
    11 / 77 (14.29%)
    8 / 88 (9.09%)
         occurrences all number
    11
    8
    Syncope
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 88 (1.14%)
         occurrences all number
    4
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    4 / 77 (5.19%)
    3 / 88 (3.41%)
         occurrences all number
    4
    3
    Vertigo
         subjects affected / exposed
    4 / 77 (5.19%)
    8 / 88 (9.09%)
         occurrences all number
    4
    8
    Eye disorders
    Vision blurred
         subjects affected / exposed
    4 / 77 (5.19%)
    4 / 88 (4.55%)
         occurrences all number
    4
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    16 / 77 (20.78%)
    18 / 88 (20.45%)
         occurrences all number
    16
    22
    Abdominal pain upper
         subjects affected / exposed
    14 / 77 (18.18%)
    6 / 88 (6.82%)
         occurrences all number
    16
    6
    Constipation
         subjects affected / exposed
    28 / 77 (36.36%)
    28 / 88 (31.82%)
         occurrences all number
    33
    32
    Diarrhoea
         subjects affected / exposed
    24 / 77 (31.17%)
    37 / 88 (42.05%)
         occurrences all number
    32
    45
    Dry mouth
         subjects affected / exposed
    6 / 77 (7.79%)
    11 / 88 (12.50%)
         occurrences all number
    6
    13
    Nausea
         subjects affected / exposed
    51 / 77 (66.23%)
    46 / 88 (52.27%)
         occurrences all number
    67
    53
    Stomatitis
         subjects affected / exposed
    17 / 77 (22.08%)
    24 / 88 (27.27%)
         occurrences all number
    19
    25
    Vomiting
         subjects affected / exposed
    31 / 77 (40.26%)
    29 / 88 (32.95%)
         occurrences all number
    38
    32
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 77 (1.30%)
    5 / 88 (5.68%)
         occurrences all number
    1
    6
    Alopecia
         subjects affected / exposed
    68 / 77 (88.31%)
    66 / 88 (75.00%)
         occurrences all number
    68
    66
    Dry skin
         subjects affected / exposed
    3 / 77 (3.90%)
    5 / 88 (5.68%)
         occurrences all number
    3
    5
    Nail disorder
         subjects affected / exposed
    2 / 77 (2.60%)
    8 / 88 (9.09%)
         occurrences all number
    2
    8
    Pruritus
         subjects affected / exposed
    11 / 77 (14.29%)
    11 / 88 (12.50%)
         occurrences all number
    15
    12
    Rash
         subjects affected / exposed
    17 / 77 (22.08%)
    24 / 88 (27.27%)
         occurrences all number
    22
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 77 (31.17%)
    30 / 88 (34.09%)
         occurrences all number
    39
    34
    Back pain
         subjects affected / exposed
    14 / 77 (18.18%)
    8 / 88 (9.09%)
         occurrences all number
    16
    8
    Bone pain
         subjects affected / exposed
    13 / 77 (16.88%)
    18 / 88 (20.45%)
         occurrences all number
    15
    21
    Muscle spasms
         subjects affected / exposed
    2 / 77 (2.60%)
    6 / 88 (6.82%)
         occurrences all number
    2
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 77 (5.19%)
    0 / 88 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal pain
         subjects affected / exposed
    5 / 77 (6.49%)
    3 / 88 (3.41%)
         occurrences all number
    6
    3
    Myalgia
         subjects affected / exposed
    20 / 77 (25.97%)
    27 / 88 (30.68%)
         occurrences all number
    26
    33
    Pain in extremity
         subjects affected / exposed
    16 / 77 (20.78%)
    11 / 88 (12.50%)
         occurrences all number
    17
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 77 (6.49%)
    2 / 88 (2.27%)
         occurrences all number
    5
    2
    Cystitis
         subjects affected / exposed
    5 / 77 (6.49%)
    2 / 88 (2.27%)
         occurrences all number
    9
    2
    Nasopharyngitis
         subjects affected / exposed
    12 / 77 (15.58%)
    7 / 88 (7.95%)
         occurrences all number
    13
    10
    Urinary tract infection
         subjects affected / exposed
    11 / 77 (14.29%)
    7 / 88 (7.95%)
         occurrences all number
    15
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 77 (20.78%)
    12 / 88 (13.64%)
         occurrences all number
    17
    14
    Hypomagnesaemia
         subjects affected / exposed
    2 / 77 (2.60%)
    5 / 88 (5.68%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2009
    Correction of typography regarding a time of intensive PK sampling: to be read at 4hours post-infusion instead of 6hours post-infusion. Extension of the rule for withdrawing a patient under stable anticoagulation treatment but suffering of concurrent thrombocytopenia.
    02 Apr 2010
    Adding the audiometry assessment; Adjustment in carboplatin doses; Update of guidelines for treatment modifications; Clarification on timing of study procedures.
    07 Sep 2011
    Update in company name; Removal of central reading of images; Decrease in the follow up period; Clarification on eligibility criteria.

    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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