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    Clinical Trial Results:
    Phase I/II-study of hyperfractionated-accelerated radiation therapy (HART) plus cetuximab (CET) plus cisplatin (CIS) chemotherapy in locally advanced inoperable squamous cell cancers of head and neck.

    Summary
    EudraCT number
    		 2005-000355-15
    Trial protocol
    		 DE  
    Global end of trial date
    10 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2021
    First version publication date
    12 May 2021
    Other versions
    Summary report(s)
    		 Final Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    KKSH-19
    Additional study identifiers
    ISRCTN number
    		 ISRCTN47339346
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Martin-Luther-Universität Halle-Wittenberg
    Sponsor organisation address
    Magdeburger Str. 8, Halle (Saale), Germany, 06112
    Public contact
    Koordinierungszentrum für Klinische Studien, Martin-Luther-Universität Halle-Wittenberg, +49 3455574903, info@kks-halle.de
    Scientific contact
    Koordinierungszentrum für Klinische Studien, Martin-Luther-Universität Halle-Wittenberg, +49 3455574903, info@kks-halle.de
    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
    01 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determination of feasibility, efficacy and safety of cetuximab (CET) combined with cisplatin (CIS) and hyperfractionated, accelerated radiotherapy (HART) as a treatment option with curative intent for patients with locally advanced, unresectable SCCHN. Phase I: defining the maximum tolerated dose (MTD) of a short infusion of cisplatin in the combined-modality treatment with cetuximab Phase II: Efficacy of combined-modality treatment with regards to progression-free survival. The dose of cisplatin in this combined-modality treatment was determined in phase I.
    Protection of trial subjects
    - Antiemetic treatment according to local clinical standard. - In case of leucopenia or fever a supportive antibiotic treatment according to institutional standard has been used dependend on microbiological testing. - Intensive care of the oral cavity (mucositis prophylaxis) with iodine solution and/or dexpanthenol solution with or without antifungal agents and analgetic treatment was done if required. - Skin toxicity due to cetuximab were treated, if necessary with topical and oral antibiotics. - Radiation-induced skin toxicity were treated with ointment (e.g. Bepanthen®), if necessary with topical corticosteroids. - If clinically indicated transfusion of blood products (erythrocytes or platelets) has been performed. - During radiotherapy an adequate nutrition has been provided. If necessary, a supplementary, high-caloric nutrition was done by using the PEG.
    Background therapy
    		 Antiemetic treatment according to local clinical standard. During radiotherapy an adequate nutrition has been provided.
    Evidence for comparator
    		 No comparator was used-
    Actual start date of recruitment
    14 Sep 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 88
    Worldwide total number of subjects
    88
    EEA total number of subjects
    88
    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)
    83
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 14/09/2005 and 22/02/2008, 18 patients were enrolled in phase I study according to dose escalation scheme -- 3, 5, 3 and 7 patients at dose level 1, 2, 3 and 4, respectively. Between 07/04/2008 and 01/09/2010, 70 patients were recruited in phase II study at dose level 4. All patients were recruited at 7 trial sites in Germany.

    Pre-assignment
    Screening details
    		 Each patient considered by the Investigator to be a potential patient for the study underwent the informed consent process. If the patient agreed to participate in the study and an informed consent form was duly completed, dated and signed, then the Investigator assessed the patient’s eligibility for the study.

    Period 1
    Period 1 title
    HART-CIS-CET overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 HART-CIS-CET
    Arm description
    		 Subjects received a therapy consisting of Radiotherapy (HART), Cisplatin (CIS) and Cetuximab (CET). In phase I, the maximum tolerated dose (MTD) for escalated cisplatin in combination with cetuximab and radiotherapy was determined. In phase II therapy was performed with cisplatin at this recommended dose level and with the schedule of cetuximab and radiotherapy as described below. HART: 30 Gy/2 Gy once daily, then twice daily 1.4 Gy to a total dose of 70.6 Gy, five days per week. CET: loading dose 400 mg/sqm on day -7 followed by subsequent weekly doses of 250 mg/sqm on week 1 to 6 on days 1, 8, 15, 22, 29, 36 CIS: Phase I: escalating doses (20, 30, 35, 40 mg/sqm), once weekly, week 1 to 6 on days 1, 8, 15, 22, 29, 36 five days per week. Subjects were enrolled according to a dose escalating scheme described under Products --> Cisplatin. CIS: Phase II: 40 mg/sqm, once weekly, week 1 to 6 on days 1, 8, 15, 22, 29, 36
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    CIS
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Phase I: dose according to escalating scheme (20, 30, 35, 40 mg/m²), once weekly on week 1 to 6 over a 1-hour i.v. infusion on days 1, 8, 15, 22, 29, 36. 3 patients entered at the first dose level of cisplatin. If no Dose Limiting Toxicity (DLT) occur, 3 patients entered at the next dose level. If 1 out of 3 patients at any dose level experiences DLT, 3 additional patients were treated at the same dose level, up to 6 patients were treated at that dose level. If no additional DLT ocurred, the dose escalation were proceeded. If 2 of 3 or 2 of 6 patients experience DLT, the dose was considered to be above the Maximum tolerated dose (MTD) and escalation ended. MTD was defined as dose level of cisplatin below the maximally administered dose at which 0 of 3 or not more than 1 of 6 patients experience DLT. The MTD (here 40 mg/sqm) was the recommended phase II dose level of cisplatin. Phase II: 40 mg/m², once weekly on week 1 to 6 over a 1-hour i.v. infusion on days 1, 8, 15, 22, 22, 29, 36

    Investigational medicinal product name
    Erbitux
    Investigational medicinal product code
    CET
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Erbitux was scheduled to be administered once weekly with an initial dose of 400 mg/m² body surface cetuximab (= loading dose at week -1) followed by subsequent weekly doses of 250 mg/m² (week 1–6) on days 1, 8, 15, 22, 29, 36. The loading dose was administered 7 days before initiation of radio- and chemotherapy period. Prior to the first administration of cetuximab, patients were premedicated with an antihistamine. This premedication was also recommended prior to all subsequent infusions of cetuximab.

    Number of subjects in period 1
    		HART-CIS-CET
    Started
    88
    Completed
    76
    Not completed
    12
         Consent withdrawn by subject
    1
         Screening failure
    3
         Lost to follow-up
    2
         Exclusion criterion: Metastatic disease
    1
         Exclusion crit.: Another cancer within 5 year
    1
         Serious concomitant disease or medical condition
    3
         Did not receive study treatment
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HART-CIS-CET overall study
    Reporting group description
    		 All subjects initially enroled. Includes dropouts and subjects who did not receive study treatment or subjects who were subsequently excluded from the endpoint analysis for any reason.

    Reporting group values
    		 HART-CIS-CET overall study Total
    Number of subjects
    		 88 88
    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)
    		 83 83
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
        not determined/missing
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 55 (37 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 75 75
    Smoking habits
    Units: Subjects
        Non-smoker
    		 4 4
        Ex-smoker
    		 33 33
        Smoker
    		 32 32
        Unknown
    		 19 19
    Tumor characteristics - localisation of primary tumor
    Units: Subjects
        Oral cavity
    		 8 8
        Oropharynx
    		 38 38
        Hypopharynx
    		 21 21
        Larynx
    		 11 11
        Unknown
    		 10 10
    Tumor characteristics - pathological staging - T-status
    Units: Subjects
        T1
    		 0 0
        T2
    		 7 7
        T3
    		 18 18
        T4a
    		 44 44
        T4b
    		 8 8
        Unknown
    		 11 11
    Tumor characteristics - pathological staging - N status
    Units: Subjects
        N1
    		 5 5
        N2
    		 59 59
        N3
    		 11 11
        Unknown
    		 13 13
    Tumor characteristics - pathological staging - M status
    Units: Subjects
        M0
    		 77 77
        M1
    		 1 1
        Mx
    		 0 0
        Unknown
    		 10 10
    Tumor characteristics - pathological staging
    Units: Subjects
        III
    		 6 6
        IVa
    		 55 55
        IVb
    		 17 17
        IVc
    		 0 0
        Unknown
    		 10 10
    Tumor characteristics - resectability
    Units: Subjects
        Resectable
    		 10 10
        Not resectable
    		 68 68
        Unknown
    		 10 10
    Tumor characteristics - histopathological grading
    Units: Subjects
        G1
    		 3 3
        G1/2
    		 2 2
        G2
    		 50 50
        G2/3
    		 2 2
        G3
    		 17 17
        G3/4
    		 0 0
        G4
    		 0 0
        Gx
    		 2 2
        Unknown
    		 12 12
    Karnofsky performance status, n=71
    Units: percent (%)
        median (full range (min-max))
    		 90 (50 to 100) -

    End points

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    End points reporting groups
    Reporting group title
    HART-CIS-CET
    Reporting group description
    		 Subjects received a therapy consisting of Radiotherapy (HART), Cisplatin (CIS) and Cetuximab (CET). In phase I, the maximum tolerated dose (MTD) for escalated cisplatin in combination with cetuximab and radiotherapy was determined. In phase II therapy was performed with cisplatin at this recommended dose level and with the schedule of cetuximab and radiotherapy as described below. HART: 30 Gy/2 Gy once daily, then twice daily 1.4 Gy to a total dose of 70.6 Gy, five days per week. CET: loading dose 400 mg/sqm on day -7 followed by subsequent weekly doses of 250 mg/sqm on week 1 to 6 on days 1, 8, 15, 22, 29, 36 CIS: Phase I: escalating doses (20, 30, 35, 40 mg/sqm), once weekly, week 1 to 6 on days 1, 8, 15, 22, 29, 36 five days per week. Subjects were enrolled according to a dose escalating scheme described under Products --> Cisplatin. CIS: Phase II: 40 mg/sqm, once weekly, week 1 to 6 on days 1, 8, 15, 22, 29, 36

    Subject analysis set title
    Phase I per-protocol (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    In phase I study, the per-protocol (PP) analysis set consisted of those 15 patients, 3/3/3/6 at dose levels 1/2/3/4, who received the complete study medication, except in case of prior termination due to toxicity.

    Subject analysis set title
    Phase II Intention-to-treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    In phase II study, analysis sets were composed of the actual phase II patients and the phase I patients of dose level 4. Those 65 patients with informed consent, without metastatic disease and with outcome data on survival status and progression of disease were included in the intention-to-treat (ITT) analysis set.

    Subject analysis set title
    Phase II per-protocol (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-protocol patients were those 40 patients without inclusion/ exclusion exceptions who received at least 80% of the planned radiation and chemotherapy dose, i.e. at least 5 of 6 visits without dose modification of cetuximab and cisplatin, and at least 35 days radiotherapy regarding CTV I with no more than 14 days of interruption and at least 56.48 Gy (80% of 70.6 Gy) total dose and hyperfractionation according to treatment plan (or concomitant boost), without consideration of reason for dose modification or interruption.

    Primary: Phase I: Dose limiting toxicities (DLTs)

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    End point title
    		 Phase I: Dose limiting toxicities (DLTs) [1]
    End point description
    Primary endpoint of phase I was the definition of maximum tolerated dose (MTD) of cisplatin in the proposed combined-modality treatment regimen. MTD was defined as dose level of cisplatin below the maximally administered dose at which zero of three or at most one of six patients experience dose limiting toxicities (DLT). The MTD was the recommended phase II dose level of cisplatin. If the MTD was not reached at the dose level 4 (40 mg/m² Cisplatin), this level would be recommended for phase II. DLT was defined as any grade 3 or higher toxicity (considered related to HART-CIS-CET) as determined by CTCAE, version 3.0. Also a hearing loss > grade 2 was considered as DLT. Excluded from the definition of DLT were grade 3 mucositis, infection with normal ANC or grade 1 to 3 neutrophils, hematologic or hepatic toxicity grade 3, alopecia (all grades). For toxicity within the irradiated volume, only grade 4 mucosal or skin toxicities, xerostomia and dysphagia were considered as DLTs.
    End point type
    Primary
    End point timeframe
    at end of Phase I
    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: Maximum tolerated dose (MTD) was defined as dose level of cisplatin below the maximally administered dose at which zero of three or at most one of six patients experience dose limiting toxicities (DLT). The number of dose limiting toxicities (DLT) per dose level were counted to determine maximum tolerated dose (MTD). Therefore no statistical analysis was performed.
    End point values
    		 HART-CIS-CET Phase I per-protocol (PP)
    Number of subjects analysed
    15
    15
    Units: Subjects
        No
    0
    0
        Yes
    15
    15
    No statistical analyses for this end point

    Primary: Phase II: 2-year PFSR with lower confidence limit (CL) of one-sided 95% CI

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    End point title
    		 Phase II: 2-year PFSR with lower confidence limit (CL) of one-sided 95% CI
    End point description
    Primary endpoint of the phase II is the determination of progression-free survival (PFS), as measured by the 2-year progression-free survival rate. The progression-free survival rate is defined as the percentage of patients alive and without tumor progression at 2-years after start of treatment. If a patient has not progressed or died, progression-free survival is censored at the time of last follow-up. Progression of disease is defined according to RECIST as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter since the treatment started or the appearance of one or more new lesions. In addition, subsequent head and neck primary or neck/ lymph node recurrence or newly diagnosed distant metastasis or any second primary tumor outside of the head and neck region will be considered as disease progression.
    End point type
    Primary
    End point timeframe
    2 years after start of study treatment
    End point values
    		 Phase II Intention-to-treat (ITT) Phase II per-protocol (PP)
    Number of subjects analysed
    65
    40
    Units: Subjects
    number (not applicable)
        2-year PFSR
    0.453
    0.567
        Lower CL of one-sided 95% CI
    0.346
    0.427
        n Event
    34
    17
        n Censored
    4
    1
        n at Risk
    27
    22
    Statistical analysis title
    		 ITT: 2-year progression-free survival rate
    Statistical analysis description
    2-year progression-free survival rate (PFSR) and its one-sided 95% confidence interval (CI) was computed using Kaplan-Meier method. This corresponds with a one-sided binomial test with a significance level of α=0.05 and statistical hypotheses H0: PFSR≤0.40 vs. H1: PFSR>0.40.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    Method
    Parameter type
    		 Rate
    Point estimate
    0.453
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.346
         upper limit
    		 -
    Notes
    [2] - one-sided 95% confidence interval, H0: PFSR≤0.40 vs. H1: PFSR>0.40
    Statistical analysis title
    		 PP: 2-year progression-free survival rate
    Statistical analysis description
    2-year progression-free survival rate (PFSR) and its one-sided 95% confidence interval (CI) was computed using Kaplan-Meier method. This corresponds with a one-sided binomial test with a significance level of α=0.05 and statistical hypotheses H0: PFSR≤0.40 vs. H1: PFSR>0.40.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    Method
    Parameter type
    		 Rate
    Point estimate
    0.567
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.427
         upper limit
    		 -
    Notes
    [3] - one-sided 95% confidence interval, H0: PFSR≤0.40 vs. H1: PFSR>0.40

    Secondary: 1-, 2- and 5-year progression-free survival

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    End point title
    		 1-, 2- and 5-year progression-free survival
    End point description
    Time to progression is defined to be the time between start of treatment to the first observation of disease progression or death due to any cause. If a patient has not progressed or died, progression-free survival is censored at the time of last follow-up. The progression-free survival rate is defined as the percentage of patients alive and without tumor progression at 1-, 2- or 5-years after start of treatment. Progression of disease is defined according to RECIST as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter since the treatment started or the appearance of one or more new lesions. In addition, subsequent head and neck primary or neck/ lymph node recurrence or newly diagnosed distant metastasis or any second primary tumor outside of the head and neck region will be considered as disease progression.
    End point type
    Secondary
    End point timeframe
    1-, 2- or 5-years after start of treatment
    End point values
    		 Phase II Intention-to-treat (ITT) Phase II per-protocol (PP)
    Number of subjects analysed
    65
    40
    Units: Rate
    number (confidence interval 95%)
        1- year PFS
    0.567 (0.435 to 0.679)
    0.670 (0.500 to 0.813)
        2-year PFS
    0.453 (0.326 to 0.571)
    0.567 (0.398 to 0.707)
        5-year PFS
    0.323 (0.207 to 0.444)
    0.392 (0.236 to 0.546)
    Attachments
    		 PFS Kaplan-Meier estimate with pointwise 95% CI
    Statistical analysis title
    		 ITT: 1-year progression-free survival rate
    Statistical analysis description
    1-year progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.567
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.435
         upper limit
    		 0.679
    Statistical analysis title
    		 PP: 1-year progression-free survival rate
    Statistical analysis description
    1-year progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.793
    Statistical analysis title
    		 ITT: 2-year progression-free survival rate
    Statistical analysis description
    2-year progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.453
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.326
         upper limit
    		 0.571
    Statistical analysis title
    		 ITT: 5-year progression-free survival rate
    Statistical analysis description
    5-year progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.323
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.207
         upper limit
    		 0.444
    Statistical analysis title
    		 PP: 2-year progression-free survival rate
    Statistical analysis description
    2-year progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.567
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.398
         upper limit
    		 0.704
    Statistical analysis title
    		 PP: 5-year progression-free survival rate
    Statistical analysis description
    5-year progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.392
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.236
         upper limit
    		 0.546

    Secondary: 1-, 2- and 5-year loco-regional progression-free survival

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    End point title
    		 1-, 2- and 5-year loco-regional progression-free survival
    End point description
    Loco-regional progression-free survival (LPFS) is defined to be the time between start of treatment to the first observation of local disease recurrence as defined above, or death due to any cause. If a patient has not progressed or died, progression-free survival is censored at the time of last follow-up. The loco-regional progression-free survival rate is defined as the percentage of patients alive and without a local disease recurrence at 1-, 2 or 5-years after start of treatment.
    End point type
    Secondary
    End point timeframe
    1-, 2- or 5-years after start of treatment
    End point values
    		 Phase II Intention-to-treat (ITT) Phase II per-protocol (PP)
    Number of subjects analysed
    65
    40
    Units: Rate
    number (confidence interval 95%)
        1-year LPFS
    0.599 (0.466 to 0.708)
    0.694 (0.525 to 0.813)
        2-year LPFS
    0.453 (0.326 to 0.571)
    0.566 (0.397 to 0.704)
        5-year LPFS
    0.333 (0.215 to 0.456)
    0.382 (0.225 to 0.537)
    Attachments
    		 LRPFS Kaplan-Meier estimate with pointwise 95% CI
    Statistical analysis title
    		 ITT: 1-year loco-regional PFSR
    Statistical analysis description
    1-year loco-regional progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.599
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.466
         upper limit
    		 0.708
    Statistical analysis title
    		 ITT: 2-year loco-regional PFSR
    Statistical analysis description
    2-year loco-regional progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.469
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.341
         upper limit
    		 0.586
    Statistical analysis title
    		 ITT: 5-year loco-regional PFSR
    Statistical analysis description
    5-year loco-regional progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.333
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.215
         upper limit
    		 0.456
    Statistical analysis title
    		 PP: 1-year loco-regional PFSR
    Statistical analysis description
    1-year loco-regional progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.694
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.525
         upper limit
    		 0.813
    Statistical analysis title
    		 PP: 2-year loco-regional PFSR
    Statistical analysis description
    2-year loco-regional progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.566
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.397
         upper limit
    		 0.704
    Statistical analysis title
    		 PP: 5-year loco-regional PFSR
    Statistical analysis description
    5-year loco-regional progression-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.382
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.225
         upper limit
    		 0.537

    Secondary: 1-, 2- and 5-year overall survival

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    End point title
    		 1-, 2- and 5-year overall survival
    End point description
    Overall survival (OS) is defined to be the time between start of treatment and death or (if the patient didn’t die) the date of last contact for living patients (censored observation). The overall survival rates are defined as the proportion of patients who survive completely the respective observation interval (1- and 2-year).
    End point type
    Secondary
    End point timeframe
    1-, 2- or 5-years after start of treatment
    End point values
    		 Phase II Intention-to-treat (ITT) Phase II per-protocol (PP)
    Number of subjects analysed
    65
    40
    Units: Rate
    number (confidence interval 95%)
        1-year OSR
    0.792 (0.668 to 0.873)
    0.822 (0.662 to 0.911)
        2-year OSR
    0.644 (0.511 to 0.749)
    0.742 (0.573 to 0.852)
        5-year OSR
    0.411 (0.284 to 0.534)
    0.487 (0.318 to 0.636)
    Attachments
    		 OSR Kaplan-Meier estimate with pointwise 95% CI
    Statistical analysis title
    		 ITT: 1-year overall survival rate
    Statistical analysis description
    1-year overall survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.792
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.668
         upper limit
    		 0.873
    Statistical analysis title
    		 Copy of Overall survival rates
    Statistical analysis description
    1-, 2- and 5-year overall survival rates were estimated by Kaplan-Meier estimates and presented with their two-sided 95% CIs.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.453
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.7
    Statistical analysis title
    		 ITT: 2-year overall survival rate
    Statistical analysis description
    2-year overall survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.644
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.511
         upper limit
    		 0.749
    Statistical analysis title
    		 ITT: 5-year overall survival rate
    Statistical analysis description
    5-year overall survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.411
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.284
         upper limit
    		 0.534
    Statistical analysis title
    		 PP: 1-year overall survival rate
    Statistical analysis description
    1-year overall survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.822
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.662
         upper limit
    		 0.911
    Statistical analysis title
    		 PP: 2-year overall survival rate
    Statistical analysis description
    2-year overall survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.742
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.573
         upper limit
    		 0.852
    Statistical analysis title
    		 PP: 5-year overall survival rate
    Statistical analysis description
    5-year overall survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.487
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.318
         upper limit
    		 0.636

    Secondary: Objective tumor response rate

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    End point title
    		 Objective tumor response rate
    End point description
    The objective tumour response rate (ORR) is defined as the proportion of all patients, with either a complete or a partial overall response, who have received at least one dose of chemotherapy and / or radiation therapy and have their disease re-evaluated. First CT/ MRI –evaluation will be done at 8 weeks after completion of therapy.
    End point type
    Secondary
    End point timeframe
    at end of treatment
    End point values
    		 Phase II Intention-to-treat (ITT) Phase II per-protocol (PP)
    Number of subjects analysed
    65 [4]
    40 [5]
    Units: Rate
    number (confidence interval 95%)
        p CR/PR
    0.800 (0.682 to 0.889)
    0.875 (0.732 to 0.958)
    Notes
    [4] - n CR/PR: 52
    [5] - n CR/PR: 35
    Statistical analysis title
    		 ITT: Objective tumor response rate
    Statistical analysis description
    Objective tumor response rate with two-sided 95% CI
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Proportion
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.682
         upper limit
    		 0.889
    Statistical analysis title
    		 PP: Objective tumor response rate
    Statistical analysis description
    Objective tumor response rate with two-sided 95% CI
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Proportion
    Point estimate
    0.875
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.732
         upper limit
    		 0.958

    Secondary: Distant metastasis-free survival status

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    End point title
    		 Distant metastasis-free survival status
    End point description
    Distant metastasis-free survival (DMFS) is defined to be the time from start of treatment to date of first observed distant metastasis or death. If a patient has not progressed or died, DMFS is censored at the time of last follow-up. DMFS rate is defined as the percentage of patients alive and without a distant metastasis at 1-, 2 or 5-years after start of treatment.
    End point type
    Secondary
    End point timeframe
    1-, 2- or 5-years after start of treatment
    End point values
    		 Phase II Intention-to-treat (ITT) Phase II per-protocol (PP)
    Number of subjects analysed
    65
    40
    Units: Rate
    number (confidence interval 95%)
        1-year DMFSR
    0.712 (0.582 to 0.808)
    0.797 (0.635 to 0.893)
        2-year DMFSR
    0.598 (0.465 to 0.708)
    0.669 (0.498 to 0.792)
        5-year DMFSR
    0.385 (0.261 to 0.507)
    0.443 (0.279 to 0.594)
    Attachments
    		 DMFS Kaplan-Meier estimate with pointwise 95% CI
    Statistical analysis title
    		 ITT: 1-year distant metastasis-free survival rate
    Statistical analysis description
    1-year distant metastasis-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.712
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.582
         upper limit
    		 0.808
    Statistical analysis title
    		 ITT: 2-year distant metastasis-free sur...
    Statistical analysis description
    2-year distant metastasis-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.598
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.465
         upper limit
    		 0.708
    Statistical analysis title
    		 ITT: 5-year distant metastasis-free sur...
    Statistical analysis description
    5-year distant metastasis-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II Intention-to-treat (ITT) v Phase II per-protocol (PP)
    Number of subjects included in analysis
    105
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.385
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.261
         upper limit
    		 0.507
    Statistical analysis title
    		 PP: 1-year distant metastasis-free sur...
    Statistical analysis description
    1-year distant metastasis-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.797
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.635
         upper limit
    		 0.893
    Statistical analysis title
    		 PP: 2-year distant metastasis-free sur...
    Statistical analysis description
    2-year distant metastasis-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.669
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.498
         upper limit
    		 0.792
    Statistical analysis title
    		 PP: 5-year distant metastasis-free sur...
    Statistical analysis description
    5-year distant metastasis-free survival rate was estimated by Kaplan-Meier estimate and presented with two-sided 95% CI.
    Comparison groups
    Phase II per-protocol (PP) v Phase II Intention-to-treat (ITT)
    Number of subjects included in analysis
    105
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Rate
    Point estimate
    0.443
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.279
         upper limit
    		 0.594

    Secondary: Selective lymph node dissection

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    End point title
    		 Selective lymph node dissection
    End point description
    Number of subjects who had a selective lymph node dissection
    End point type
    Secondary
    End point timeframe
    at end of treatment
    End point values
    		 Phase II Intention-to-treat (ITT) Phase II per-protocol (PP)
    Number of subjects analysed
    65
    40
    Units: Subjects
        No
    30
    19
        Yes
    16
    12
        Unknown
    19
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of signed informed consent until 6 weeks after the end of study treatment.
    Adverse event reporting additional description
    Follow-up on any unresolved adverse events until resolved or stabilized.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Phase I Safety analysis set
    Reporting group description
    		 All patients in Phase I receiving at least one dose of the study treatment were evaluable for safety, 16 patients in phase I, 3/4/3/6 at dose levels 1/2/3/4

    Reporting group title
    Phase II Safety analysis set
    Reporting group description
    		 All patients receiving at least one dose of the study treatment were evaluable for safety - 65 patients in phase II. Coincidentally, safety and ITT analysis sets of phase II were identical.

    Serious adverse events
    		 Phase I Safety analysis set Phase II Safety analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 16 (37.50%)
    26 / 65 (40.00%)
         number of deaths (all causes)
    6
    35
         number of deaths resulting from adverse events
    0
    2
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal fistula
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoradionecrosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 65 (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
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal ulceration
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 65 (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 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Lactic acidosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Phase I Safety analysis set Phase II Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    65 / 65 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 16 (18.75%)
    20 / 65 (30.77%)
         occurrences all number
    3
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 16 (18.75%)
    12 / 65 (18.46%)
         occurrences all number
    3
    12
    Blood albumin decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    4 / 65 (6.15%)
         occurrences all number
    1
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 16 (12.50%)
    14 / 65 (21.54%)
         occurrences all number
    2
    14
    Blood bilirubin increased
         subjects affected / exposed
    2 / 16 (12.50%)
    5 / 65 (7.69%)
         occurrences all number
    2
    5
    Blood calcium decreased
         subjects affected / exposed
    5 / 16 (31.25%)
    10 / 65 (15.38%)
         occurrences all number
    5
    10
    Blood creatine increased
         subjects affected / exposed
    4 / 16 (25.00%)
    13 / 65 (20.00%)
         occurrences all number
    4
    13
    Blood magnesium decreased
         subjects affected / exposed
    4 / 16 (25.00%)
    7 / 65 (10.77%)
         occurrences all number
    4
    7
    Blood magnesium abnormal
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 65 (4.62%)
         occurrences all number
    0
    3
    Blood potassium decreased
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 65 (4.62%)
         occurrences all number
    2
    3
    Blood potassium increased
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 65 (4.62%)
         occurrences all number
    0
    3
    Blood sodium decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    4 / 65 (6.15%)
         occurrences all number
    1
    4
    C-reactive protein increased
         subjects affected / exposed
    3 / 16 (18.75%)
    14 / 65 (21.54%)
         occurrences all number
    3
    14
    Blood urea decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    6 / 65 (9.23%)
         occurrences all number
    0
    6
    Blood uric acid increased
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    11 / 65 (16.92%)
         occurrences all number
    1
    11
    Haemoglobin decreased
         subjects affected / exposed
    11 / 16 (68.75%)
    57 / 65 (87.69%)
         occurrences all number
    11
    57
    Neutrophil count decreased
         subjects affected / exposed
    8 / 16 (50.00%)
    18 / 65 (27.69%)
         occurrences all number
    8
    18
    White blood cell count decreased
         subjects affected / exposed
    11 / 16 (68.75%)
    45 / 65 (69.23%)
         occurrences all number
    11
    45
    Protein total decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 65 (4.62%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Platelet count decreased
         subjects affected / exposed
    3 / 16 (18.75%)
    22 / 65 (33.85%)
         occurrences all number
    3
    22
    Radiation skin injury
         subjects affected / exposed
    14 / 16 (87.50%)
    60 / 65 (92.31%)
         occurrences all number
    14
    60
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 65 (4.62%)
         occurrences all number
    1
    3
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 65 (4.62%)
         occurrences all number
    0
    3
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 16 (6.25%)
    9 / 65 (13.85%)
         occurrences all number
    1
    9
    Hypotonia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 16 (68.75%)
    49 / 65 (75.38%)
         occurrences all number
    11
    49
    Localised oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    16 / 16 (100.00%)
    61 / 65 (93.85%)
         occurrences all number
    16
    61
    Pain
         subjects affected / exposed
    14 / 16 (87.50%)
    57 / 65 (87.69%)
         occurrences all number
    14
    57
    Pyrexia
         subjects affected / exposed
    4 / 16 (25.00%)
    14 / 65 (21.54%)
         occurrences all number
    4
    14
    Fibrosis
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 16 (12.50%)
    10 / 65 (15.38%)
         occurrences all number
    2
    10
    Dry mouth
         subjects affected / exposed
    15 / 16 (93.75%)
    49 / 65 (75.38%)
         occurrences all number
    15
    49
    Dysphagia
         subjects affected / exposed
    16 / 16 (100.00%)
    63 / 65 (96.92%)
         occurrences all number
    16
    63
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Oesophagitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    4 / 16 (25.00%)
    18 / 65 (27.69%)
         occurrences all number
    4
    18
    Constipation
         subjects affected / exposed
    0 / 16 (0.00%)
    7 / 65 (10.77%)
         occurrences all number
    0
    7
    Dyspepsia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 65 (6.15%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    11 / 16 (68.75%)
    51 / 65 (78.46%)
         occurrences all number
    11
    51
    Dermatitis contact
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Nail disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    8 / 65 (12.31%)
         occurrences all number
    1
    8
    Pruritus
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Trismus
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Infections and infestations
    Infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 65 (3.08%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jul 2005
    Change of Coordinating investigator, Change in biostatistic analysis. Approved by EC on 22.08.2005, approved by CA on 09.09.2005
    04 Aug 2005
    An association between CETUXIMAB therapy and hypomagnesaemia was reported. The majority of reported cases were dealing with asymptomatic hypomagnesaemia detected by routine electrolyte monitoring during therapy. Due to possible safety implications it was decided that patient receiving Cetuximab undergo routine monitoring of serum magnesium. Repletion of documented hypomagnesaemia had to be be carried out based on clinical judgment. Approved by EC on 22.08.2005, Approved by CA on 27.10.2005
    05 Apr 2007
    A new formulation of Erbitux® was introduced onto the market on 16th April 2007. Formulation of Erbitux® has been switched from 2mg/ml to 5mg/ml. Vials containing 20ml and 100ml Erbitux® solution were then available. It is intended to introduce The new formulation was introduced after complete consumption of Erbitux 2 mg / ml at the trial sites. Approved by EC on 23.05.2007, approved by CA on 25.04.2007.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/20427347
    http://www.ncbi.nlm.nih.gov/pubmed/28500491
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