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    Clinical Trial Results:
    Open Label Randomized, Multi-centre Phase III Trial of TPF Plus Concomitant Treatment With Cisplatin and Radiotherapy Versus Concomitant Cetuximab and Radiotherapy in Locally Advanced, Unresectable Head and Neck Cancer

    Summary
    EudraCT number
    		 2007-005540-24
    Trial protocol
    		 ES  
    Global end of trial date
    23 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Nov 2019
    First version publication date
    28 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TTCC-2007-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC)
    Sponsor organisation address
    SEOM, Calle Velázquez, 7-3º, Madrid, Spain, 28001
    Public contact
    Juan Jesús Cruz, TTCC- Grupo Español de Tratamiento de Tumores de Cabeza y Cuello, jjcruz@usal.es
    Scientific contact
    Juan Jesús Cruz / Ricardo Hitt Sabag (rhitt@telefonica.net), TTCC- Grupo Español de Tratamiento de Tumores de Cabeza y Cuello, jjcruz@usal.es
    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
    05 Jul 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that induction (TPF) chemotherapy followed by RT + Cetuximab is at least non-inferior to chemotherapy with TPF followed by RT + Cisplatin in terms of OS in patients with unresectable SCCHN.
    Protection of trial subjects
    All patients were offered supportive measures for disease-related symptoms and treatment-associated toxicity. Any concomitant medication, procedures or blood products administered during the study and in the 2 weeks prior to its start were recording the CRF. The patients had to be premedicated with: antihistamines and corticosteroids before they received the first dose of cetuximab, dexamethasone before the administration of docetaxel. Palliative RT could not be administered for pain management or other non-curative purposes. Surgery to remove tumours was not permitted. The study patient was withdrawn if this surgery was carried out. If, at the end of the study, tumour persistence, relapse or progression (exit from the study) was observed, the investigator could then make a decision regarding the appropriateness or not of performing rescue and/or palliative surgery.Sedatives, antiemetics, antibiotics, analgesics, antihistamines, steroids, red blood cell concentrates, or fresh-frozen plasma or platelet transfusions could be administered to help the treatment of pain, infection or other complications of the neoplasia. In the case of documented febrile neutropenia or infection, IV antibiotics could be administered for curative purposes. Only the administration of haematopoietic growth factors was accepted. Erythropoietin was only administered in patients with a haemoglobin value below 10 g/dL and at the lowest possible dose so as to avoid a transfusion. Furthermore, the administration of erythropoietin was stopped if, after 8 weeks of treatment, the patient's haemoglobin levels did not recover to the levels necessary or if they still required transfusions. Prophylactic treatment with an antihistamine and a corticosteroid was administered before the initial dose of cetuximab was administered. Similarly, the patients had to be premedicated with corticosteroids before all the docetaxel doses.
    Background therapy
    		 The combination of TPF induction chemotherapy followed by concomitant chemoradiotherapy with cisplatin currently appears to be the new standard treatment in unresectable cancer. However, increased acute and particularly chronic toxicity lead us to reconsider continuing a chemoradiotherapy regimen after induction chemotherapy. In particular, due to the onset of cetuximab and the finding that cetuximab has been shown to increase the efficacy of RT with a significant increase in locoregional disease control and survival in locally advanced SCCHN, without increasing the acute and/or chronic toxicity associated with RT.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jul 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 519
    Worldwide total number of subjects
    519
    EEA total number of subjects
    519
    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)
    434
    From 65 to 84 years
    85
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total, 530 patients with locally advanced, unresectable head and neck cancer were recruited at 43 sites in Spain between 2008-2013.

    Pre-assignment
    Screening details
    		 Prior to start date of the TPF induction chemotherapy treatment, the patients signed informed consent and were assessed for e.g. diagnosis and inclusion/exclusion critera. Eligible patients were recruited to an induction period (ITT1). Those still eligible after this period were randomized to either of the two radical treatment arms (ITT2).

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

    Arms
    Arm title
    		 Induction treatment following Radical treatment
    Arm description
    		 - Induction treatment (ITT1): Chemotherapy with TPF (docetaxel, cisplatin, 5-fluorouracil) - Radical treatment (ITT2) - Group A: Cisplatin + Radiotherapy - Radical treatment (ITT2) - Group B: Cetuximab + Radiotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    TPF (docetaxel, cisplatin, 5-fluorouracil)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The treatment was started with 3 cycles of TPF (docetaxel, cisplatin and 5-fluorouracil) every 3 weeks supported with G-CSF and ciprofloxacin (or its equivalent). Docetaxel (75 mg/m2/d; IV 1 hour; 1 day) Cisplatin (75 mg/m2/d; IV 1 hour; 1 day) 5-FU (750 mg/m2/d; 24-hour infusion; 1-5 day)

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At 3-4 weeks (5 weeks at most) from the end of the 3rd TPF cycle, conventionally fractionated RT concomitant with chemotherapy was started (cisplatin 100 mg/m2). Patients received cisplatin 100 mg/m2 on day 1 (IV infusion of 1 hour), coinciding with the first day of RT, and subsequently on days 22 and 43 of RT.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At 3-4 weeks (5 weeks at most) from the end of the 3rd TPF cycle, conventionally fractionated RT started. Cetuximab was administered at an initial dose of 400 mg/m2/day in the first infusion for 120 minutes, followed by weekly doses of 250 mg/m2/day for 60 minutes.

    Number of subjects in period 1
    		Induction treatment following Radical treatment
    Started
    519
    Completed
    407
    Not completed
    112
         Consent withdrawn by subject
    4
         Physician decision
    6
         Adverse event, non-fatal
    42
         Death
    15
         Lost to follow-up
    2
         Progressive disease
    23
         Protocol deviation
    13
         Not treated
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction treatment following Radical treatment
    Reporting group description
    		 - Induction treatment (ITT1): Chemotherapy with TPF (docetaxel, cisplatin, 5-fluorouracil) - Radical treatment (ITT2) - Group A: Cisplatin + Radiotherapy - Radical treatment (ITT2) - Group B: Cetuximab + Radiotherapy

    Reporting group values
    		 Induction treatment following Radical treatment Total
    Number of subjects
    		 519 519
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 434 434
        From 65-84 years
    		 85 85
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 56.9 (29.4 to 72.7) -
    Gender categorical
    Units: Subjects
        Female
    		 56 56
        Male
    		 463 463
    ECOG
    Units: Subjects
        ECOG 0
    		 135 135
        ECOG 1
    		 383 383
        ECOG NA
    		 1 1
    Anatomic location
    Units: Subjects
        Oropharynx
    		 222 222
        Larynx
    		 88 88
        Hypopharynx
    		 120 120
        Oral cavity
    		 89 89
    Tumour category
    Units: Subjects
        T 1-3
    		 183 183
        T4
    		 333 333
        UK
    		 3 3
    Nodule Status
    Units: Subjects
        N0/1
    		 126 126
        N2
    		 329 329
        N3
    		 62 62
        UK
    		 2 2
    Smoking history
    Units: Subjects
        Smoker
    		 399 399
        Non smoker
    		 120 120
    Alcohol
    Units: Subjects
        Drinker
    		 349 349
        Non drinker
    		 170 170
    Race
    Units: Subjects
        Caucasic/white
    		 518 518
        Asiatic
    		 1 1
    Squamous Carcinoma grade
    Units: Subjects
        Grade I
    		 40 40
        Grade II
    		 142 142
        Grade III
    		 67 67
        UNK
    		 270 270
    Stage
    Units: Subjects
        III
    		 44 44
        IVA
    		 372 372
        IVB
    		 102 102
        UK
    		 1 1
    TNM (Clinical+Radiological)
    Units: Subjects
        T1-3N0/1
    		 28 28
        T1-3N2
    		 118 118
        T1-3N3
    		 37 37
        T4N0/1
    		 99 99
        T4N2
    		 210 210
        T4N3
    		 25 25
        UK
    		 1 1
        N2
    		 1 1
    Scintigraphy
    Units: Subjects
        Abnormal
    		 2 2
        Normal
    		 12 12
        UKN
    		 505 505
    Dental evaluation
    Units: Subjects
        Abnormal
    		 192 192
        Normal
    		 66 66
        UKN
    		 261 261
    X-ray
    Units: Subjects
        Abnormal
    		 42 42
        Normal
    		 390 390
        UKN
    		 87 87
    Physical condition - head and neck - primary lesion
    Units: Subjects
        Oropharynx
    		 196 196
        Larynx
    		 75 75
        Hypopharynx
    		 110 110
        Oral cavity
    		 67 67
        UKN
    		 71 71
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 166.9 ± 8.33 -
    Theorical weight
    Units: kg
        arithmetic mean (standard deviation)
    		 69.5 ± 13.99 -
    Body surface
    Units: m2
        arithmetic mean (standard deviation)
    		 1.76 ± 0.22 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 67.8 ± 14.9 -
    Exposure G-CSF
    Units: Subjects
        arithmetic mean (standard deviation)
    		 0 ± 0 -
    Subject analysis sets

    Subject analysis set title
    Cisplatin+RT (Standard arm)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    After randomization: Cisplatin + Radiotherapy

    Subject analysis set title
    Cetuximab+RT (Experimental arm)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    After randomization: Cetuximab + Radiotherapy

    Subject analysis sets values
    		 Cisplatin+RT (Standard arm) Cetuximab+RT (Experimental arm)
    Number of subjects
    205
    202
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    181
    168
        From 65-84 years
    25
    40
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    56.1 (39.6 to 72.7)
    57.4 (29.4 to 70.7)
    Gender categorical
    Units: Subjects
        Female
    19
    25
        Male
    186
    177
    ECOG
    Units: Subjects
        ECOG 0
    49
    61
        ECOG 1
    155
    141
        ECOG NA
    1
    0
    Anatomic location
    Units: Subjects
        Oropharynx
    90
    86
        Larynx
    38
    38
        Hypopharynx
    43
    43
        Oral cavity
    34
    35
    Tumour category
    Units: Subjects
        T 1-3
    71
    85
        T4
    133
    116
        UK
    1
    1
    Nodule Status
    Units: Subjects
        N0/1
    46
    47
        N2
    130
    130
        N3
    29
    24
        UK
    0
    1
    Smoking history
    Units: Subjects
        Smoker
    168
    160
        Non smoker
    37
    42
    Alcohol
    Units: Subjects
        Drinker
    139
    143
        Non drinker
    66
    59
    Race
    Units: Subjects
        Caucasic/white
    205
    201
        Asiatic
    0
    1
    Squamous Carcinoma grade
    Units: Subjects
        Grade I
    18
    16
        Grade II
    48
    58
        Grade III
    27
    20
        UNK
    112
    108
    Stage
    Units: Subjects
        III
    17
    13
        IVA
    147
    149
        IVB
    41
    39
        UK
    0
    1
    TNM (Clinical+Radiological)
    Units: Subjects
        T1-3N0/1
    0
    1
        T1-3N2
    1
    0
        T1-3N3
    9
    12
        T4N0/1
    44
    58
        T4N2
    18
    15
        T4N3
    37
    35
        UK
    85
    72
        N2
    11
    9
    Scintigraphy
    Units: Subjects
        Abnormal
    1
    2
        Normal
    3
    8
        UKN
    198
    397
    Dental evaluation
    Units: Subjects
        Abnormal
    77
    80
        Normal
    28
    24
        UKN
    100
    98
    X-ray
    Units: Subjects
        Abnormal
    13
    12
        Normal
    160
    155
        UKN
    32
    35
    Physical condition - head and neck - primary lesion
    Units: Subjects
        Oropharynx
    83
    75
        Larynx
    35
    33
        Hypopharynx
    40
    41
        Oral cavity
    26
    25
        UKN
    21
    28
    Height
    Units: cm
        arithmetic mean (standard deviation)
    167.7 ± 7.8
    166.6 ± 8.5
    Theorical weight
    Units: kg
        arithmetic mean (standard deviation)
    69.5 ± 13.6
    69.7 ± 13.9
    Body surface
    Units: m2
        arithmetic mean (standard deviation)
    1.8 ± 0.2
    1.8 ± 0.2
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    68.0 ± 14.1
    68.3 ± 14.6
    Exposure G-CSF
    Units: Subjects
        arithmetic mean (standard deviation)
    48.0 ± 33.8
    47.9 ± 22.8

    End points

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    End points reporting groups
    Reporting group title
    Induction treatment following Radical treatment
    Reporting group description
    		 - Induction treatment (ITT1): Chemotherapy with TPF (docetaxel, cisplatin, 5-fluorouracil) - Radical treatment (ITT2) - Group A: Cisplatin + Radiotherapy - Radical treatment (ITT2) - Group B: Cetuximab + Radiotherapy

    Subject analysis set title
    Cisplatin+RT (Standard arm)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    After randomization: Cisplatin + Radiotherapy

    Subject analysis set title
    Cetuximab+RT (Experimental arm)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    After randomization: Cetuximab + Radiotherapy

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival defined as time between the start of treatment with TPF (induction) and death due to any cause, or to the last check-up in the case of living patients.
    End point type
    Primary
    End point timeframe
    Measured from induction until death or time of last check-up.
    End point values
    		 Cisplatin+RT (Standard arm) Cetuximab+RT (Experimental arm)
    Number of subjects analysed
    205
    202
    Units: month
        median (confidence interval 95%)
    63.6 (42.2 to 75.1)
    42.9 (33.6 to 72.2)
    Statistical analysis title
    		 Overall survival
    Statistical analysis description
    Cox proportional hazards regression model to prove non-inferiority.
    Comparison groups
    Cisplatin+RT (Standard arm) v Cetuximab+RT (Experimental arm)
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.05
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.3

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    End point type
    Secondary
    End point timeframe
    From start of induction treatment until the date of progression or death from any cause, whichever occurred first.
    End point values
    		 Induction treatment following Radical treatment Cisplatin+RT (Standard arm) Cetuximab+RT (Experimental arm)
    Number of subjects analysed
    519
    205
    202
    Units: months
        median (confidence interval 95%)
    22.6 (17.6 to 31.1)
    39.9 (26.1 to 62.8)
    20.2 (15.2 to 31.1)
    No statistical analyses for this end point

    Secondary: Disease specific survival

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    End point title
    		 Disease specific survival
    End point description
    End point type
    Secondary
    End point timeframe
    From start of induction treatment until the date of progression.
    End point values
    		 Cisplatin+RT (Standard arm) Cetuximab+RT (Experimental arm)
    Number of subjects analysed
    205
    202
    Units: months
        median (confidence interval 95%)
    75.1 (63.8 to 82)
    85.3 (47.1 to 100.6)
    No statistical analyses for this end point

    Secondary: Overall response rate (RECIST criteria)

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    End point title
    		 Overall response rate (RECIST criteria)
    End point description
    End point type
    Secondary
    End point timeframe
    During the induction and radical treatment periods.
    End point values
    		 Induction treatment following Radical treatment Cisplatin+RT (Standard arm) Cetuximab+RT (Experimental arm)
    Number of subjects analysed
    519
    205
    202
    Units: percent
        number (confidence interval 95%)
    72.3 (68.2 to 76.1)
    76.1 (69.7 to 81.8)
    79.7 (73.5 to 85.0)
    No statistical analyses for this end point

    Secondary: Overall response rate (Investigator criteria)

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    End point title
    		 Overall response rate (Investigator criteria)
    End point description
    End point type
    Secondary
    End point timeframe
    During the induction and radical treatment periods.
    End point values
    		 Induction treatment following Radical treatment Cisplatin+RT (Standard arm) Cetuximab+RT (Experimental arm)
    Number of subjects analysed
    519
    205
    202
    Units: percent
        number (confidence interval 95%)
    73.2 (69.2 to 77.0)
    76.1 (69.7 to 81.8)
    80.2 (74.0 to 85.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs collected during radical treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Cisplatin+RT (Standard arm)
    Reporting group description
    		 Comprised of patients that received the standard treatment (Cisplatin), in the Radical treatment part (ITT2).

    Reporting group title
    Cetuximab+RT (Experimental arm)
    Reporting group description
    		 Comprised of patients that received the experimental treatment (Cetuximab), in the Radical treatment part (ITT2).

    Serious adverse events
    		 Cisplatin+RT (Standard arm) Cetuximab+RT (Experimental arm)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 205 (28.29%)
    48 / 202 (23.76%)
         number of deaths (all causes)
    110
    115
         number of deaths resulting from adverse events
    8
    12
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 205 (0.49%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infarction
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         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
    1 / 205 (0.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device deployment issue
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    28 / 205 (13.66%)
    26 / 202 (12.87%)
         occurrences causally related to treatment / all
    27 / 32
    33 / 34
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Pyrexia
         subjects affected / exposed
    4 / 205 (1.95%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 205 (0.49%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Laryngeal stenosis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (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 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation skin injury
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheo-oesophageal fistula
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bradycardia
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Prinzmetal angina
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatic nerve neuropathy
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         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
    2 / 205 (0.98%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    24 / 205 (11.71%)
    24 / 202 (11.88%)
         occurrences causally related to treatment / all
    3 / 24
    1 / 28
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 205 (1.95%)
    7 / 202 (3.47%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphagia
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 205 (1.46%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic enteritis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stomatitis
         subjects affected / exposed
    2 / 205 (0.98%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 205 (1.46%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin toxicity
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    7 / 205 (3.41%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    4 / 7
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (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 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Diverticulitis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (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 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peritonitis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    6 / 205 (2.93%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory tract infection
         subjects affected / exposed
    4 / 205 (1.95%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 205 (0.98%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Toxic shock syndrome
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 205 (0.98%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    2 / 205 (0.98%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cisplatin+RT (Standard arm) Cetuximab+RT (Experimental arm)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    188 / 205 (91.71%)
    185 / 202 (91.58%)
    Injury, poisoning and procedural complications
    Skin toxicity
         subjects affected / exposed
    89 / 205 (43.41%)
    94 / 202 (46.53%)
         occurrences all number
    117
    185
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    37 / 205 (18.05%)
    16 / 202 (7.92%)
         occurrences all number
    74
    39
    Neurotoxicity
         subjects affected / exposed
    26 / 205 (12.68%)
    6 / 202 (2.97%)
         occurrences all number
    46
    19
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    152 / 205 (74.15%)
    161 / 202 (79.70%)
         occurrences all number
    453
    541
    Asthenia
         subjects affected / exposed
    152 / 205 (74.15%)
    161 / 202 (79.70%)
         occurrences all number
    270
    219
    Pyrexia
         subjects affected / exposed
    7 / 205 (3.41%)
    24 / 202 (11.88%)
         occurrences all number
    31
    44
    Xerosis
         subjects affected / exposed
    2 / 205 (0.98%)
    12 / 202 (5.94%)
         occurrences all number
    4
    15
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    38 / 205 (18.54%)
    13 / 202 (6.44%)
         occurrences all number
    125
    63
    Neutropenia
         subjects affected / exposed
    47 / 205 (22.93%)
    2 / 202 (0.99%)
         occurrences all number
    97
    36
    Leukopenia
         subjects affected / exposed
    18 / 205 (8.78%)
    2 / 202 (0.99%)
         occurrences all number
    36
    20
    Ear and labyrinth disorders
    Ototoxicity
         subjects affected / exposed
    22 / 205 (10.73%)
    8 / 202 (3.96%)
         occurrences all number
    31
    21
    Gastrointestinal disorders
    Odynophagia
         subjects affected / exposed
    83 / 205 (40.49%)
    72 / 202 (35.64%)
         occurrences all number
    144
    138
    Dry mouth
         subjects affected / exposed
    58 / 205 (28.29%)
    60 / 202 (29.70%)
         occurrences all number
    78
    88
    Dysphagia
         subjects affected / exposed
    58 / 205 (28.29%)
    54 / 202 (26.73%)
         occurrences all number
    99
    91
    Nausea
         subjects affected / exposed
    45 / 205 (21.95%)
    13 / 202 (6.44%)
         occurrences all number
    130
    94
    Vomiting
         subjects affected / exposed
    36 / 205 (17.56%)
    18 / 202 (8.91%)
         occurrences all number
    121
    100
    Constipation
         subjects affected / exposed
    24 / 205 (11.71%)
    19 / 202 (9.41%)
         occurrences all number
    59
    47
    Diarrhoea
         subjects affected / exposed
    10 / 205 (4.88%)
    14 / 202 (6.93%)
         occurrences all number
    103
    150
    Stomatitis
         subjects affected / exposed
    16 / 205 (7.80%)
    16 / 202 (7.92%)
         occurrences all number
    47
    31
    Cheilitis
         subjects affected / exposed
    1 / 205 (0.49%)
    14 / 202 (6.93%)
         occurrences all number
    11
    28
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    11 / 205 (5.37%)
    6 / 202 (2.97%)
         occurrences all number
    17
    11
    Skin and subcutaneous tissue disorders
    Skin toxicity
         subjects affected / exposed
    13 / 205 (6.34%)
    44 / 202 (21.78%)
         occurrences all number
    17
    79
    Rash
         subjects affected / exposed
    1 / 205 (0.49%)
    70 / 202 (34.65%)
         occurrences all number
    1
    131
    Erythema
         subjects affected / exposed
    4 / 205 (1.95%)
    12 / 202 (5.94%)
         occurrences all number
    10
    17
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    17 / 205 (8.29%)
    3 / 202 (1.49%)
         occurrences all number
    28
    10
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    7 / 205 (3.41%)
    11 / 202 (5.45%)
         occurrences all number
    13
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    41 / 205 (20.00%)
    23 / 202 (11.39%)
         occurrences all number
    137
    106

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jan 2008
    This amendment reported the request for clarifications from the IECs (there was no body of the amendment as a result).
    03 Mar 2008
    This amendment reported the inclusion of 23 new sites to the study in order to achieve the objective of 398 randomised and evaluable patients for a total of 458 included. The change in Principal Investigator at Hospital Clínico Lozano Blesa in Zaragoza, and the update to the study coordinators was also notified.
    02 May 2008
    •The toxicity rating criteria were changed to achieve a more precise evaluation during the different study periods based on the treatment the patient was receiving, specifically during the RT and for late toxicity.•The name of "end of study visit" was replaced by “VAP”. •The assessment schedule of the tumour for the assessment visit was modified after radical treatment (which went from 10-12 weeks post-RT to 6–8 weeks) and the schedule for post-treatment visits for better monitoring of the patient was also changed (increasing the frequency of visits and exams during the 5 years of follow-up).•A dental assessment was added to the response assessment visit after the induction treatment.•An assessment of weight for every week of treatment (induction and radical) was added.•Fortnightly blood tests were added while radical treatment to better monitor the patient.•The schedule for assessing QoL was changed (every 6 months during years 1 and 2, instead of only every 4 months for 1 year). It was also clarified that once the patient progressed, it would not be necessary to complete these questionnaires.•Visual exams of the tumour during the assessment visits for induction treatment were removed.•The documentation of concomitant AEs and treatment during the different study treatments was clarified. From 90 days post-radiochemotherapy treatment, only data on chronic toxicity associated with this treatment was collected, following the RTOG/EORTC late CTC.•The study schedule was changed in accordance with the aforementioned changes.•The inclusion of 5 new sites in the study was requested so that the sample size (458 patients) could be achieved.•The non-participation of one of the already approved sites (Instituto Oncológico de Guipúzcoa) was reported.•Various typing errors were corrected and the use of CSFs, and the use of colony-stimulating factors and CRF management was written more clearly, as for this study an online or e-CRF (non paper-based) is us
    19 Jun 2008
    • The Patient Information Sheet and Informed Consent Form were adapted according to the submitted and approved changes, in amendment No 3 of 2 May 2008. After evaluation and approval of protocol amendment 3 by the IECs involved, the sponsor was requested to change the patient information sheet and informed consent form according to the changes in the proposed schedule in this amendment. Furthermore, according to the request from another two IECs who assessed the protocol during the evaluation of amendment 2, and in order to have a single version of the patient information sheet and informed consent form for all sites, a couple of aspects of this document were also changed. • Sections of previous and concomitant medication were updated. Specifically, amifostine (Ethyol®) was included as non-permitted medication due to possible serious dermatological adverse reactions and erythropoietin was removed as a non-permitted concomitant medication as its use was part of clinical practice in many sites and it appeared erroneously. • The dental evaluation in the evaluation visit following neoadjuvant treatment with TPF was removed, with dental assessment only at baseline. • Various typographic errors were corrected.
    01 Sep 2008
    • The change in Principal Investigator in one of the already approved sites was reported (H. Clínico de Santiago de Compostela). • A typographical error in the footer of the approved version of the Patient Information Sheet and Informed Consent Form (version No.3 dated 19/06/08) was reported to the IECs. This footer requested the patient’s dated signature for all sheets. In order to facilitate the process for obtaining Informed Consent, the IECs were informed that the signature and date of the patient would only be requested in the Informed Consent Form, while the footer would be removed in the information sheets.
    30 Oct 2008
    •The diagnosis of epidermoid carcinoma was clarified. •The section on allowed concomitant medication was updated. • Medication prior to cetuximab infusion was updated. •Typing errors were corrected. •Statistical errors were corrected (1. The terms “equivalence/equivalent” were corrected by “non-inferior / non-inferiority” in some sections of the protocol. The term "equivalent" was not correct in this study, whose main objective was to demonstrate non-inferiority; 2. The number of patients to be included in the study was corrected according to the expected withdrawal rate (15% who progressed with TPF or were lost). The initial calculation of 458 patients to be included to obtain 398 assessable was not correct when taking this 15% into account. The re-calculation showed that 469 patients were needed to obtain 398 evaluable patients; 3.The definitions of the first and second part of the study were corrected and the definitions of the different study populations in both of these were corrected. The existence of at least one post-baseline evaluable CT scan was added in the protocol population. The population was removed for QoL analysis, since ICH guidelines did not include this type of population. Tables with the data obtained from the quality-life questionnaires used in this study were produced; 4.Some typographical errors were corrected).
    27 Apr 2009
    • Reported the inclusion of a new site (Hospital Clínico de Valencia). • Reported a change in Principal Investigator in the Hospital Arnau de Vilanova Hospital in Lleida. • Reported a change in Principal Investigator in the Hospital Universitario de Salamanca. • Typing errors were corrected.
    21 Sep 2009
    • The change in Principal Investigator at the Hospital La Paz. • The change in Principal Investigator at the Hospital Virgen de las Nieves.
    26 Nov 2009
    This amendment reported the change of principal investigator in Hospital de Sagunto.
    30 Aug 2010
    • The change in Principal Investigator at the Hospital Morales Meseguer. • The change of CRM in Trial Form Support.
    30 Sep 2010
    This amendment reported the change of principal investigator at Hospital Clínico de Santiago.
    30 Apr 2012
    •The change of study Sponsor and the national Coordinator contact details. •Change in Principal Investigator in Hospital Universitario 12 de Octubre. •The change in Principal Investigator in the Hospital Arnau de Vilanova in Valencia. •The change in inclusion criteria 9, 10, 12 and 13 (1. Number 9: it was requested to replace "haemoglobin >10 g/dL" with “haemoglobin >9 g/dL and no symptoms related to anaemia”. 2. Number 10: it was requested to replace "bilirubin ≤1 x UNL, GOT and GPT ≤ 2.5 UNL, alkaline phosphatase <5 UNL” with “Bilirubin ≤1.5 x UNL, and some of the following values: GOT ≤2.5 ULN or GPT ≤2.5 UNL or alkaline phosphatase <2 UNL; however, if all of these are present, their value should not exceed the UNL”. 3.Number 12: it was requested to remove the inclusion criterion no. 12 blood calcium ≤1.25 x UNL. 4. Number 13: replacing “Suitable nutritional status: weight loss <20% compared to theoretical weight and albumin ≥35 g/L” with “Adequate nutritional status: BMI >18.5% or albumin ≥30 g/L”).•Modification to the induction treatment. •Change in the duration of the trial and the number of sites. •Change in the Tumour Assessment Imaging Techniques and the periods when it is carried out. • The change in the non-therapeutic visit regimen during neoadjuvant treatment.
    04 Oct 2012
    The change in Principal Investigator at Hospital Lucus Augusti was requested via this amendment.
    13 Oct 2014
    This amendment requested: • A change in Principal Investigator at Hospital de Sagunto. • A change in Principal Investigator at the Hospital Central de Asturias.
    22 Jan 2015
    This amendment reported the performance of a genetic sub-study to gain an in-depth knowledge of the genetic mechanisms of epidermoid head and neck cancer by identifying mutations in tumour tissue, in order to define prognostic subtypes and molecular predictive factors of response that allow the best therapeutic strategy to be established for each patient. In order to be able to investigate these molecular characteristics in the TTCC-2007-01 trial, in this additional protocol (GEN-TTCC-2007-01 Project), the baseline tumour samples were requested from the subjects included in the study. The DNA from the tumour samples was obtained with prior consent of the subjects included in the study, and were stored at the Centro de Investigación del Cáncer de Salamanca-IBSAL for analysis and research into genes in association with this trial.

    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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