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    Clinical Trial Results:
    A Phase II Trial With Radiotherapy Plus Cetuximab to Evaluate Specific Survival Free of Laryngectomy in Patients With Resectable and Locally Advanced Larynx Cancer, After Treatment With TPF Chemotherapy

    Summary
    EudraCT number
    		 2008-000332-40
    Trial protocol
    		 ES  
    Global end of trial date
    12 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Apr 2019
    First version publication date
    11 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TTCC-2007-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00765011
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC)
    Sponsor organisation address
    C/ Velázquez, 7 – 3º , Madrid, Spain, 28001
    Public contact
    Dr Ricard Mesia Nin, Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC), 0034 93 335 70 11, rmesia@iconcologia.net
    Scientific contact
    Dr Ricard Mesia Nin, Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC), 0034 93 335 70 11, rmesia@iconcologia.net
    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
    14 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate survival - with larynx function after 3 years in patients with response evaluated based on the primary tumour (T category) after induction TPF and treated with RT + Cetuximab
    Protection of trial subjects
    The study medication was administered by the investigator or under their direct supervision. Given that the intravenous infusions were administered in a hospital or in an outpatient environment, compliance with the treatment could be easily monitored. The date and the start and end time of the infusion, as well as the exact quantity of cetuximab and TPF (docetaxel, cisplatin, 5-fluorouracil) administered at each infusion were recorded in the patient’s medical record. If the treatment was modified, the medical staff had to evaluate the percentage of the dose received by the patient and record this in the CRF. All the reasons for non-compliance had to be recorded. As a standard precaution, the patients included in the study were under observation from the start of the infusion of cetuximab until at least 1 hour after the end of the cetuximab infusion in a quiet area with resuscitation equipment and other drugs required in case of an emergency (epinephrine, prednisolone and equivalent medicinal products). In the event that the treatment had to be interrupted during the infusion, the staff responsible for the procedure had to estimate the percentage of the dose received by the patient and record this in the CRF. The reasons for any lack of therapeutic compliance had to be recorded. Inadequate compliance with the cetuximab administration regimen was defined as missing more than 2 consecutive infusions for reasons other than toxicity. In the event of insufficient compliance by the patient, the principal investigator and the study coordinator decided together, on a case by case basis, regarding the possible withdrawal of the patient from the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Oct 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 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: 94
    Worldwide total number of subjects
    94
    EEA total number of subjects
    94
    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)
    76
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 94 patients were included. Part I: 93 patients received at least one dose of chemotherapy with TPF (ITT 1) Part II: 72 patients received RT+cetuximab treatment(ITT 2) This was a national study with all patients being included at 15 Spanish sites

    Pre-assignment
    Screening details
    		 Key inclusion criteria: 18-70 years of age, life expectancy >3 months, histologically demonstrated larynx squamous carcinoma , to be able to receive TPF treatment followed by normofractionated radiotherapy with cetuximab, adequate hepatic and renal function. 1 patient did not meet all the study inclusion criteria and did not started TPF treatment

    Period 1
    Period 1 title
    Part I + Part II (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Arm 1
    Arm description
    		 The response obtained for the primary tumour after induction TPF determined the subsequent measures and treatments: -Complete or partial response of the T category: Three to five weeks after the administration of the 3rd cycle of TPF, normofractionated RT was started. Cetuximab had to be administered at one week prior to the start of RT and maintained weekly until the end of the RT. -T stabilisation or disease progression (T and/or N): These patients had to be offered rescue surgery at the earliest date possible.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TPF
    Investigational medicinal product code
    Other name
    Docetaxel, cisplatin, 5-fluorouracil
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Treatment is initiated with 3 cycles of TPF (docetaxel, cisplatin, 5-fluorouracil) every 3 weeks with G-CSF (lenograstim was recommended) and ciprofloxacin. Treatment regimen, pretreatment and supporting measures: - Docetaxel and Cisplatin: daily dose of 75 mg/m2 by intravenous infusion over 1 hour on day 1. -5-FU: daily dose of 750 mg/m2 given over 24-hour infusion between days 1-5. -Dexamethasone: 16 mg daily dose, 8 mg administered every 12 hours, at days -1, 1 and 2. -Ciprofloxacin: 1g daily dose, 500 mg administered every 12 hours between days 7-15. -G-CSF: subcutaneous administration of 150 ug/m2/d between days 7-12 The response obtained for the primary tumour after induction TPF determined the subsequent measures and treatments. The complete evaluation of the response had to be done in the 2 or 3 weeks immediately after the administration of the 3rd cycle of TPF.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered continuously weekly, from one week before the start of RT. -The initial dose of 400 mg/m2/d in the first infusion for 120 minutes on day 1. -On days 8, 15, 22, 29, 36, 43 and 50 ( or to the end of the RT if any delay of RT) cetuximab was administered at a daily dose of 250 mg/m2 by intravenous infusion over 1 hour.

    Number of subjects in period 1
    		Arm 1
    Started
    94
    Completed
    94

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part I + Part II
    Reporting group description
    		 -

    Reporting group values
    		 Part I + Part II Total
    Number of subjects
    		 94 94
    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)
    		 76 76
        From 65-84 years
    		 18 18
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 86 86
    Subject analysis sets

    Subject analysis set title
    ITT 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population included all included patients who received at least one dose of chemotherapy with TPF

    Subject analysis set title
    ITT 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population included all patients with an evaluated response in the primary tumour (T lesion) following induction with TPF and who started treatment with RT + cetuximab

    Subject analysis set title
    ITT 3
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population included all patients who did not show a response in the primary tumour (T lesion) after the induction with TPF

    Subject analysis set title
    SAF 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who signed the informed consent

    Subject analysis set title
    SAF 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Included all the patients who started the treatment with cetuximab + radiotherapy

    Subject analysis set title
    PP1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Protocol population 1 (PP 1): all patients in the intention-to-treat population 1, excluding those patients who were involved in significant breaches of the inclusion/exclusion criteria or major protocol deviations.

    Subject analysis set title
    PP2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Protocol population 2 (PP 2): all patients in the intention-to-treat population 2, excluding those patients who were involved in significant breaches of the inclusion/exclusion criteria or major protocol deviations.

    Subject analysis sets values
    		 ITT 1 ITT 2 ITT 3 SAF 1 SAF 2 PP1 PP2
    Number of subjects
    93
    72
    18
    94
    73
    26
    15
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    7
    5
    2
    8
    6
    1
    1
        Male
    86
    67
    16
    86
    67
    25
    14

    End points

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    End points reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 The response obtained for the primary tumour after induction TPF determined the subsequent measures and treatments: -Complete or partial response of the T category: Three to five weeks after the administration of the 3rd cycle of TPF, normofractionated RT was started. Cetuximab had to be administered at one week prior to the start of RT and maintained weekly until the end of the RT. -T stabilisation or disease progression (T and/or N): These patients had to be offered rescue surgery at the earliest date possible.

    Subject analysis set title
    ITT 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population included all included patients who received at least one dose of chemotherapy with TPF

    Subject analysis set title
    ITT 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population included all patients with an evaluated response in the primary tumour (T lesion) following induction with TPF and who started treatment with RT + cetuximab

    Subject analysis set title
    ITT 3
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population included all patients who did not show a response in the primary tumour (T lesion) after the induction with TPF

    Subject analysis set title
    SAF 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who signed the informed consent

    Subject analysis set title
    SAF 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Included all the patients who started the treatment with cetuximab + radiotherapy

    Subject analysis set title
    PP1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Protocol population 1 (PP 1): all patients in the intention-to-treat population 1, excluding those patients who were involved in significant breaches of the inclusion/exclusion criteria or major protocol deviations.

    Subject analysis set title
    PP2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Protocol population 2 (PP 2): all patients in the intention-to-treat population 2, excluding those patients who were involved in significant breaches of the inclusion/exclusion criteria or major protocol deviations.

    Primary: Survival with a functional larynx

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    End point title
    		 Survival with a functional larynx [1]
    End point description
    Survival with larynx function is the time from the start of TPF treatment to death caused by the disease or by the treatment of the disease, or even to surgery involving total laryngectomy, or loss of larynx function. Deaths caused by other reasons were considered "censored" data on the date of death.
    End point type
    Primary
    End point timeframe
    From the start of TPF treatment to death
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary outcome measure
    End point values
    		 ITT 2
    Number of subjects analysed
    72
    Units: percent
    number (confidence interval 95%)
        1 year
    91.5 (85.1 to 98.0)
        2 years
    82.7 (73.8 to 91.6)
        3 years
    79.4 (69.8 to 89.1)
    No statistical analyses for this end point

    Secondary: Overall response rate

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    End point title
    		 Overall response rate
    End point description
    The ORR is defined as the response rate (complete + partial) measured according to the WHO method. Any other response was considered as NO overall response.
    End point type
    Secondary
    End point timeframe
    The secondary endpoints for part I of the study were analysed in the ITT1 population (n=93) and in the ITT2 population (n=72).
    End point values
    		 ITT 1 ITT 2
    Number of subjects analysed
    93
    72
    Units: percent
        number (confidence interval 95%)
    78.5 (70.1 to 86.8)
    97.2 (93.4 to 100.0)
    No statistical analyses for this end point

    Secondary: T response rate

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    End point title
    		 T response rate
    End point description
    T response rate for the induction chemotherapy with TPF .
    End point type
    Secondary
    End point timeframe
    In the two or three weeks immediately after the administration of the 3rd cycle of TPF.
    End point values
    		 ITT 1 ITT 2
    Number of subjects analysed
    93
    72
    Units: percent
        number (confidence interval 95%)
    81.7 (72.4 to 89.0)
    98.6 (95.9 to 100.0)
    No statistical analyses for this end point

    Secondary: Overall surival

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    End point title
    		 Overall surival
    End point description
    Overall survival was defined as the time from the start of induction chemotherapy with TPF to death due to any cause or to the patient's last check-up. Data was censored if death, the last visit or long-term follow-up did not occur.
    End point type
    Secondary
    End point timeframe
    From the start of induction chemotherapy with TPF to death
    End point values
    		 ITT 1 ITT 2 ITT 3
    Number of subjects analysed
    93
    72
    18
    Units: percent
    number (confidence interval 95%)
        1 year
    95.7 (91.6 to 99.8)
    97.2 (93.4 to 100.0)
    88.2 (72.9 to 100.0)
        2 years
    82.8 (75.1 to 90.5)
    86.1 (78.1 to 94.1)
    64.7 (42.0 to 87.4)
        3 years
    77.3 (68.9 to 85.9)
    81.9 (73.0 to 90.8)
    58.8 (35.4 to 82.2)
    No statistical analyses for this end point

    Secondary: Specific survival free of total laryngectomy

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    End point title
    		 Specific survival free of total laryngectomy
    End point description
    By definition, specific survival free of laryngectomy is the time from the start of TPF treatment to death caused by the disease or by the treatment of the disease, or even to surgery involving total laryngectomy. Deaths caused by other reasons were considered "censored" data on the date of death. By definition an event was considered to be total laryngectomy, death from disease progression, disease-related complications and treatment-related events. The following data were considered censored: death by reasons other than those mentioned above, the latest assessment of larynx function or the latest X-ray.
    End point type
    Secondary
    End point timeframe
    From the start of TPF treatment to death
    End point values
    		 ITT 1 ITT 2
    Number of subjects analysed
    93
    72
    Units: percent
    number (confidence interval 95%)
        1 year
    86.5 (79.4 to 93.6)
    95.8 (91.1 to 100.0)
        2 years
    74.2 (64.9 to 83.6)
    84.0 (75.3 to 92.7)
        3 years
    71.5 (61.8 to 81.2)
    80.8 (71.3 to 90.2)
    No statistical analyses for this end point

    Secondary: Specific disease-free survival

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    End point title
    		 Specific disease-free survival
    End point description
    By definition, specific disease-free survival is the time to disease recurrence at any site, either locoregional and/or metastatic, or to treatment-related death. Deaths caused by other reasons were considered "censored" data on the date of death. When treatment failure was confirmed in the disease assessment 10-12 weeks after the end of radiotherapy, it was recorded as a disease that has lasted since onset, as the patient had never been disease-free. Patients who had no recurrence were censored on the date of the last check-up. The patients for whom no tumour assessments were available after the TPF treatment were censored on the date of the start of RT + CETUXIMAB. Patients who showed no progression and began a cancer treatment other than the study drug were censored on the start date of the other treatment.
    End point type
    Secondary
    End point timeframe
    Until time to disease recurrence
    End point values
    		 ITT 1 ITT 2 ITT 3
    Number of subjects analysed
    93
    72
    18
    Units: percent
    number (confidence interval 95%)
        1 year
    85.4 (78.1 to 92.7)
    90.1 (83.2 to 97.1)
    64.3 (39.2 to 89.4)
        2 years
    70.8 (61.1 to 80.4)
    76.9 (67.0 to 86.9)
    29.2 (0.14 to 58.3)
        3 years
    69.4 (59.6 to 79.3)
    76.9 (67.0 to 86.9)
    29.2 (0.14 to 58.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The safety monitoring started at the time the patient was included in the study (date of the signing of the informed consent form) and continued until the evaluation visit at 10-12 weeks after the RT+cetuximab treatment had been carried out.
    Adverse event reporting additional description
    1. CTC from the NCI, version 3.0 during the induction and cetuximab/RT treatment, and for 90 days after the end of the radiotherapy 2.Common Late Toxicity Criteria from RTOG/EORTC from 90 days after the end of the radiotherapy
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    SAF 1
    Reporting group description
    		 Safety population 1 includes all patients who signed the informed consent form (n= 94).

    Reporting group title
    SAF 2
    Reporting group description
    		 Safety Population 2 includes all the patients who started the treatment with cetuximab + radiotherapy (n=73).

    Serious adverse events
    		 SAF 1 SAF 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 93 (31.18%)
    8 / 73 (10.96%)
         number of deaths (all causes)
    24
    14
         number of deaths resulting from adverse events
    2
    1
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (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
    Radiation mucositis
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation skin injury
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 93 (4.30%)
    3 / 73 (4.11%)
         occurrences causally related to treatment / all
    5 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    6 / 93 (6.45%)
    6 / 73 (8.22%)
         occurrences causally related to treatment / all
    7 / 7
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 93 (5.38%)
    4 / 73 (5.48%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (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 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Prerenal failure
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 73 (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
    1 / 93 (1.08%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SAF 1 SAF 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    91 / 93 (97.85%)
    73 / 73 (100.00%)
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    48 / 93 (51.61%)
    48 / 73 (65.75%)
         occurrences all number
    88
    88
    Vascular disorders
    Hypotension
         subjects affected / exposed
    5 / 93 (5.38%)
    5 / 73 (6.85%)
         occurrences all number
    5
    5
    Phlebitis
         subjects affected / exposed
    12 / 93 (12.90%)
    12 / 73 (16.44%)
         occurrences all number
    18
    18
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    21 / 93 (22.58%)
    20 / 73 (27.40%)
         occurrences all number
    26
    25
    Headache
         subjects affected / exposed
    5 / 93 (5.38%)
    5 / 73 (6.85%)
         occurrences all number
    5
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 93 (7.53%)
    6 / 73 (8.22%)
         occurrences all number
    12
    11
    Neutropenia
         subjects affected / exposed
    8 / 93 (8.60%)
    7 / 73 (9.59%)
         occurrences all number
    11
    10
    Thrombocytopenia
         subjects affected / exposed
    5 / 93 (5.38%)
    4 / 73 (5.48%)
         occurrences all number
    7
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    60 / 93 (64.52%)
    55 / 73 (75.34%)
         occurrences all number
    110
    105
    Mucosal inflammation
         subjects affected / exposed
    77 / 93 (82.80%)
    70 / 73 (95.89%)
         occurrences all number
    215
    202
    Oedema peripheral
         subjects affected / exposed
    9 / 93 (9.68%)
    8 / 73 (10.96%)
         occurrences all number
    10
    9
    Pyrexia
         subjects affected / exposed
    21 / 93 (22.58%)
    19 / 73 (26.03%)
         occurrences all number
    23
    21
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    5 / 93 (5.38%)
    5 / 73 (6.85%)
         occurrences all number
    6
    6
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    13 / 93 (13.98%)
    12 / 73 (16.44%)
         occurrences all number
    17
    16
    Diarrhoea
         subjects affected / exposed
    36 / 93 (38.71%)
    29 / 73 (39.73%)
         occurrences all number
    49
    42
    Dry mouth
         subjects affected / exposed
    27 / 93 (29.03%)
    26 / 73 (35.62%)
         occurrences all number
    39
    38
    Dysphagia
         subjects affected / exposed
    26 / 93 (27.96%)
    25 / 73 (34.25%)
         occurrences all number
    38
    37
    Nausea
         subjects affected / exposed
    29 / 93 (31.18%)
    25 / 73 (34.25%)
         occurrences all number
    36
    32
    Odynophagia
         subjects affected / exposed
    31 / 93 (33.33%)
    31 / 73 (42.47%)
         occurrences all number
    61
    61
    Vomiting
         subjects affected / exposed
    30 / 93 (32.26%)
    25 / 73 (34.25%)
         occurrences all number
    40
    35
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    14 / 93 (15.05%)
    14 / 73 (19.18%)
         occurrences all number
    20
    20
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    41 / 93 (44.09%)
    38 / 73 (52.05%)
         occurrences all number
    51
    48
    Skin toxicity
         subjects affected / exposed
    11 / 93 (11.83%)
    11 / 73 (15.07%)
         occurrences all number
    16
    16
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 93 (6.45%)
    6 / 73 (8.22%)
         occurrences all number
    6
    6
    Infections and infestations
    Candidiasis
         subjects affected / exposed
    10 / 93 (10.75%)
    10 / 73 (13.70%)
         occurrences all number
    11
    11
    Conjunctivitis
         subjects affected / exposed
    7 / 93 (7.53%)
    7 / 73 (9.59%)
         occurrences all number
    7
    7
    Respiratory infections and disorders
         subjects affected / exposed
    6 / 93 (6.45%)
    5 / 73 (6.85%)
         occurrences all number
    7
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 93 (27.96%)
    23 / 73 (31.51%)
         occurrences all number
    37
    33
    Hypokalaemia
         subjects affected / exposed
    5 / 93 (5.38%)
    4 / 73 (5.48%)
         occurrences all number
    7
    6
    Hypomagnesaemia
         subjects affected / exposed
    6 / 93 (6.45%)
    6 / 73 (8.22%)
         occurrences all number
    8
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2008
    This amendment responded to the clarifications requested by the IECs
    14 May 2008
    Among other changes, the following changes to the study protocol were made via this amendment: 1. Updating of the individuals in charge of the study 2. Planned duration of the study 3. Change of the toxicity endpoint criteria 4. Evaluation of the performance status of the head and neck areas 5. PET scan 6. Withdrawal criteria 7. Collection of information following the end of the radiotherapy treatment 8. Management of radiodermatitis concomitant with cetuximab-induced skin rash 9. Non-permitted concomitant medication 10. Handling of clinical trial material and evaluation of treatment compliance 11. Recording of vital signs and weight 12. Nomenclature of response 13. Recording of data when the treatment was suspended for reasons other than disease progression 14. Evaluations during the follow-up 15. Documentation of Adverse Events and Concomitant Treatments 16. Secondary analyses 17. Study chart 18. Inclusion of new sites 19. Correction of typographical errors
    28 Nov 2008
    The following changes to the protocol were made via amendment 3 to the protocol: 1. Clarification of the diagnosis of epidermoid carcinoma 2. Update of the PERMITTED concomitant medication section 3. Updating of the medication prior to cetuximab infusion 4. Duration of the radiotherapy 5. Informed consent 6. Assessments of the Evaluation Visit Following the Neoadjuvant Treatment 7. Assessments of the Evaluation Visit 10-12 weeks after RT with cetuximab 8. Assessments of the end of study (EOS) visit 9. Adverse Events 10. Correction of typographical errors 11. Correction of statistical errors 12. Study chart
    30 Jun 2009
    1. Change in the evaluation of radiotherapy safety and late toxicity 2. Correction of typographical errors
    21 Sep 2009
    The Principal Investigator at two sites participating in the study was changed by this amendment.
    04 Oct 2012
    The Principal Investigator at one site participating in the study was changed by this amendment.
    05 Mar 2015
    The change of the name of the primary objective of study TTCC-2007-02 was requested via this amendment, because of a typographical error at the time the protocol was prepared, and which was noticed by the sponsor when the initial analyses of the results were being carried out. The protocol had defined “laryngectomy-free survival” as the primary objective, when the protocol was designed to determine survival with a functional larynx. The parameters we used as a basis for calculating the final study sample and, therefore to build the statistics for the study, were always based on the results for survival with functional larynx based on the results from the GORTEC group study (data presented by the group at the ASCO conference in 2006 and later published as Poyntreau Y, y col. J Natl Cancer Inst 2009;101: 498 – 506), which was a study that, like ours, used TPF induction chemotherapy. In reality, the two parameters are not that different: Laryngectomy-free survival is defined as the time from the start of the treatment with TPF until the loss of the larynx for any reason or death caused by laryngeal cancer. Survival with functional larynx is defined as the time from the start of the treatment with TPF until the loss of laryngeal function for any reason or death caused by laryngeal cancer. In other words, the functional larynx parameter does not just include resected larynges, but also larynges that have been preserved but which do not function optimally: in reality, in the literature, the percentage difference between the two variables is usually 5-10%, with the functionality parameter being lower, i.e. we are more demanding when it comes to evaluating the study as positive. Similarly, the change of TFS Clinical Research Manager and change of management for the TTCC Group was notified.

    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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