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    Clinical Trial Results:
    Neoadjuvant BIBW 2992 followed by surgery in squamous cell carcinoma of the head and neck: an EORTC NOCI-HNCG window study.

    Summary
    EudraCT number
    		 2011-005820-17
    Trial protocol
    		 BE   IT  
    Global end of trial date
    28 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2017
    First version publication date
    15 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    90111-24111
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01538381
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer
    Sponsor organisation address
    Avenue E. Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27741062, regulatory@eortc.be
    Scientific contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27741062, regulatory@eortc.be
    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
    28 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The general objectives are to evaluate the pre-operative activity and the safety of afatinib in head and neck cancer and to explore the different downstream molecular pathways to identify tumor response and resistance mechanisms. The primary objective is to evaluate the pre operative activity of afatinib as assessed by Fluorodeoxyglucose – Positron emission tomography/Computed tomography (FDG-PET/CT).
    Protection of trial subjects
    The responsible investigator has ensured that this study has been conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study has been conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf). The protocol has been approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Belgium: 17
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    19
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 36 patients were screened. A total of 30 patients were randomized, however 3 of them were later found to not meet all eligibility criteria. In addition, one patient started afatinib treatment without going through the randomization procedure.

    Pre-assignment
    Screening details
    		 - Newly diagnosed histologically proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx - T3 -T4 hypopharyngeal SCCHN excluded - Selected for a primary surgical treatment - No distant metastases - No prior chemotherapy, radiotherapy or targeted therapy including HER inhibitors

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Afatinib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg orally once daily from day -15 until day -1 prior to surgery

    Arm title
    		 No treatment
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Afatinib No treatment
    Started
    25
    5
    Completed
    24
    5
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Afatinib
    Reporting group description
    		 -

    Reporting group title
    No treatment
    Reporting group description
    		 -

    Reporting group values
    		 Afatinib No treatment Total
    Number of subjects
    		 25 5 30
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 58 (35 to 76) 69 (55 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 9 3 12
        Male
    		 16 2 18
    Tumor location
    Units: Subjects
        Oral cavity
    		 20 5 25
        Oropharynx
    		 5 0 5
    cT
    Units: Subjects
        T1
    		 2 0 2
        T2
    		 14 3 17
        T3
    		 2 0 2
        T4
    		 7 2 9
    cN
    Units: Subjects
        N0
    		 10 0 10
        N1
    		 5 2 7
        N2
    		 10 3 13
    ECOG Performance Status
    Units: Subjects
        PS 0
    		 17 2 19
        PS 1
    		 8 3 11
    Subject analysis sets

    Subject analysis set title
    Evaluable population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Evaluable population: All randomized and eligible patients

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population: All randomized patients. For the afatinib arm, the safety population is restricted to the patients who took at least one dose of afatinib.

    Subject analysis sets values
    		 Evaluable population Safety population
    Number of subjects
    27
    30
    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: years
        median (full range (min-max))
    59 (35 to 77)
    Gender categorical
    Units: Subjects
        Female
    10
        Male
    17
    Tumor location
    Units: Subjects
        Oral cavity
    23
        Oropharynx
    4
    cT
    Units: Subjects
        T1
    1
        T2
    15
        T3
    2
        T4
    9
    cN
    Units: Subjects
        N0
    8
        N1
    6
        N2
    13
    ECOG Performance Status
    Units: Subjects
        PS 0
    16
        PS 1
    11

    End points

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    End points reporting groups
    Reporting group title
    Afatinib
    Reporting group description
    		 -

    Reporting group title
    No treatment
    Reporting group description
    		 -

    Subject analysis set title
    Evaluable population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Evaluable population: All randomized and eligible patients

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population: All randomized patients. For the afatinib arm, the safety population is restricted to the patients who took at least one dose of afatinib.

    Primary: Metabolic response according to FDG-PET/CT

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    End point title
    		 Metabolic response according to FDG-PET/CT
    End point description
    Metabolic response measured at day -1 as per FDG-PET/CT, defined as complete metabolic response (CMR) or partial metabolic response (PMR). Centrally reviewed.
    End point type
    Primary
    End point timeframe
    Metabolic response measured at day -1 (day before surgery).
    End point values
    		 Afatinib No treatment
    Number of subjects analysed
    23 [1]
    4 [2]
    Units: Percent
        Complete/partial
    16
    0
        Stable disease
    7
    3
        Missing
    0
    1
    Notes
    [1] - Excluding ineligible patients
    [2] - Excluding ineligible patients
    Statistical analysis title
    		 FDG-PET/CT response in afatinib arm
    Comparison groups
    No treatment v Afatinib
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 Test on a single proportion
    Parameter type
    		 Estimated proportion
    Point estimate
    69.6
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 54.1
         upper limit
    		 -
    Notes
    [3] - Test H0: response rate < 10% in afatinib arm (23 patients)

    Secondary: Response according to RECIST 1.1

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    End point title
    		 Response according to RECIST 1.1
    End point description
    Response measured at day -1 evaluated by RECIST v1.1 (FDG-PET/CT, MRI)
    End point type
    Secondary
    End point timeframe
    Measured at day -1 (day before surgery)
    End point values
    		 Afatinib No treatment
    Number of subjects analysed
    23 [4]
    4 [5]
    Units: Percent
        Complete/partial
    5
    0
        Stable disease
    14
    2
        Missing
    4
    2
    Notes
    [4] - Excluding ineligible patients
    [5] - Excluding ineligible patients
    Statistical analysis title
    		 RECIST response in afatinib arm
    Comparison groups
    Afatinib v No treatment
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.073
    Method
    		 Test on a single proportion
    Parameter type
    		 Estimated proportion
    Point estimate
    21.7
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 11
         upper limit
    		 -
    Notes
    [6] - Test H0: response rate < 10% in afatinib arm (23 patients)

    Secondary: Surgical comorbidities

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    End point title
    		 Surgical comorbidities
    End point description
    Number of patients with Max grade of surgical co-morbidities
    End point type
    Secondary
    End point timeframe
    Surgical co-morbidities evaluated up to 4 weeks after surgery
    End point values
    		 Afatinib No treatment
    Number of subjects analysed
    25
    5
    Units: Number of patients
        Grade 1
    1
    1
        Grade 2
    2
    0
        Grade 3
    1
    0
        No surgical co-morbidity
    21
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected on a CRF during the 2-week period between randomization and surgery and during follow-up of 4 weeks after surgery.
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. AEs are evaluated using CTC grading, SAEs using MedDRA. Non-SAEs has not been collected specifically, all CTC grade>=3 AEs are reported in non-SAE section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Afatinib
    Reporting group description
    		 -

    Reporting group title
    No treatment
    Reporting group description
    		 No treatment.

    Serious adverse events
    		 Afatinib No treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood creatinine increased
    alternative dictionary used: MedDRA 19
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
    alternative dictionary used: MedDRA 19
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    alternative dictionary used: MedDRA 19
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
    alternative dictionary used: MedDRA 19
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
    alternative dictionary used: MedDRA 19
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
    alternative dictionary used: MedDRA 19
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
    alternative dictionary used: MedDRA 19
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
    alternative dictionary used: MedDRA 19
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Afatinib No treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 25 (20.00%)
    1 / 5 (20.00%)
    Investigations
    GGT
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 5 (0.00%)
         occurrences all number
    4
    0
    Lymphocytes
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Hemoglobin
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Acute pancreatitis
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Diarrhea
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Intestinal necrosis
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Mesenteric ischemia
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash acneiform
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute renal failure
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Sepsis
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory infection
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Anorexia
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Hypercalcemia
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    K+
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Phosphate
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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