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    Clinical Trial Results:
    A randomized open-label Phase II study of letrozole plus afatinib (BIBW2992) versus letrozole alone in first-line treatment of advanced ER+, HER2- postmenopausal breast cancer with low ER expression

    Summary
    EudraCT number
    2013-002192-18
    Trial protocol
    ES  
    Global end of trial date
    30 Nov 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TRIO020
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02115048
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Translational Research In Oncology
    Sponsor organisation address
    Suite 1100 9925-109 Street , Edmonton, Canada, T5K 2J8
    Public contact
    Project Management, Translational Research In Oncology, 011 +33 1 58 10 09 09, TRIO020.contact@trioncology.org
    Scientific contact
    Project Management, Translational Research In Oncology, 011 +33 1 58 10 09 09, TRIO020.contact@trioncology.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of letrozole plus afatinib and of letrozole alone on progression-free survival (PFS) in the first line treatment of ER+, HER2 negative postmenopausal ABC women with low ER expression.
    Protection of trial subjects
    Regular assessment and monitoring of adverse events is required throughout trial treatment period and up until 30 days after last intake of trial medication (last intake of letrozole in the single agent arm or last intake of afatinib + letrozole or letrozole -if afatinib previously discontinued- in the combination arm). Recommendations regarding monitoring and adequate management of specific events are provided below. CTCAE version 4.0 is used to assess the severity of adverse events. Letrozole dose modification: No dose adjustment is permitted for letrozole. Afatinib dose modification: Patients are monitored closely for toxicity and the dose of afatinib may be adjusted as indicated in tables below. Dose reduction to 20 mg is allowed depending on the type and severity of toxicity encountered. Patients requiring more than one dose reduction will be discontinued from afatinib. Dose escalation is not allowed once afatinib dose has been reduced. For toxicities requiring dose adjustment (see sections 5.4.2 to 5.4.7), afatinib will be held for up to 14 days to allow patient to recover to a grade ≤ 1, and will be resumed at 20 mg. Dose reduction should always follow a treatment pause in order to allow recovery to grade ≤ 1 toxicity. Nevertheless, the initial trial visits schedule should be kept unchanged (every 4 weeks regardless of any additional visits and treatment pauses). If despite optimal care and afatinib pause, patient has not recovered to grade ≤ 1 within 14 days and is not deriving obvious clinical benefit from trial treatment, the patient should not receive any further treatment with afatinib. Letrozole should be discontinued within the frame of the trial and the patient must be discontinued from the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Aug 2013
    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
    Romania: 8
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 7
    Country: Number of subjects enrolled
    United States: 15
    Worldwide total number of subjects
    44
    EEA total number of subjects
    22
    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)
    24
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Forty-four (44) patients were enrolled in the study from 26 participating sites located in the USA, Spain, Bosnia and Romania. Enrollment ended prematurely with only 44 patients (initially planned for 150 participants). Early enrollment closure was documented with protocol amendment 3 (approved 09 May 2016).

    Pre-assignment
    Screening details
    Informed consent procedures were completed prior to performing any trial specific procedures. Patients who did not meet the eligibility criteria were considered screen failures. Patients who met all eligibility criteria were randomized using the following factors: Bone only disease- Yes vs. No, and Prior neo/adjuvant hormonal therapy- Yes vs. No.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    The trial is open-label. There is no blinding of the treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A
    Arm description
    Continuous regimen of oral letrozole 2.5 mg.
    Arm type
    Active comparator

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole is standard of care in this population. Commercial Letrozole was used. Commercial Letrozole contains 2.5 mg letrozole as the active ingredient. Packaging depends on the commercial letrozole available locally. Patients were instructed to swallow their letrozole tablets without regard to food. Patients were encouraged to take their dose at approximately the same time each day.

    Arm title
    Arm B
    Arm description
    Arm B: Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole is standard of care in this population. Commercial Letrozole was used. Commercial Letrozole contains 2.5 mg letrozole as the active ingredient. Packaging depends on the commercial letrozole available locally. Patients were instructed to swallow their letrozole tablets without regard to food. Patients were encouraged to take their dose at approximately the same time each day.

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    It is supplied by the manufacturer Boehringer Ingelheim (BI). Two dose strengths of 20 and 30 mg afatinib are used in the trial to allow for any dose adjustment. At each monthly visit, patients should be given a 30-tablet bottle. Treatment was divided into treatment cycles, which are each 4 weeks (28 days) in duration. However, treatment was given continuously unless treatment schedule adjustments were needed. Patients took a single oral dose of afatinib each day for the first and subsequent cycles. The medication was taken at the same time each day (± 2 hours) at least one hour before food intake and at least three hours after the last food intake. Afatinib tablets should be swallowed whole with water, and if not possible, afatinib tablets can be dispersed in approximately 100 ml of noncarbonated drinking water. The glass should be rinsed with approximately 100 ml of water which should also be consumed. The dispersion can also be administered through a gastric tube.

    Number of subjects in period 1
    Arm A Arm B
    Started
    23
    21
    Completed
    23
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    Continuous regimen of oral letrozole 2.5 mg.

    Reporting group title
    Arm B
    Reporting group description
    Arm B: Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily.

    Reporting group values
    Arm A Arm B Total
    Number of subjects
    23 21 44
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    14 10 24
        From 65-84 years
    9 11 20
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.1 ± 7.58 64.29 ± 7.24 -
    Gender categorical
    Units: Subjects
        Female
    23 21 44
        Male
    0 0 0
    Menopausal Status
    Units: Subjects
        Pre-Menopausal
    0 0 0
        Post-Menopausal
    23 21 44
    ECOG Performance Status
    Units: Subjects
        ECOG PS 0
    12 14 26
        ECOG PS 1
    11 7 18
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    77.39 ± 16.25 69.59 ± 11.14 -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    Continuous regimen of oral letrozole 2.5 mg.

    Reporting group title
    Arm B
    Reporting group description
    Arm B: Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily.

    Primary: Progression Free Survival

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    End point title
    Progression Free Survival [1]
    End point description
    Progression Free Survival (PFS) is defined as the time from randomization until date of progression (assessed by RECIST) or death due to any cause, whichever occurs first. For evaluation of PFS, for each patient, the beginning date was taken as a randomization date. If the status at the last assessment date was “Non complete response/ Non progressive disease” or “Complete response”, then the patient was considered censored at that time. If the status at the last assessment for any tumor was “Progressive disease”, then the patient was considered as having an event at that time. Two patients who died during the study were also considered as having event at the time of death. Since enrollment was terminated early (only 44 patients enrolled), preventing appropriate statistical calculations, efficacy has not been assessed - this incudes PFS, overall survival (OS), objective response rate (OR), and time to tumor progression (TTP). TPP analysis was not performed due to lack of OS data.
    End point type
    Primary
    End point timeframe
    Every 12 weeks up to 9 months (average) for subjects in the control arm or up to 14 months (average) for subjects in the experimental arm.
    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: Enrollment ended prematurely with only 44 patients (initially planned for 150 participants). Early enrollment closure was documented with protocol amendment 3 (approved 09 May 2016). As such, the data collected for all patients are described per arm, but no statistical comparison can be made (appropriate statistical evaluation cannot be completed due to low recruitment). TPP was not analyzed due to a lack of OS data.
    End point values
    Arm A Arm B
    Number of subjects analysed
    18
    18
    Units: Patients
        Failed (Progressed or Died)
    4
    2
        Censored
    14
    16
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall Survival is defined as the time from randomization until death to any cause. For subjects in which treatment is discontinued for reasons different than progression disease: after treatment and up to documentation of disease progression: Overall Survival is assessed every 12 weeks. Since enrollment was terminated early (only 44 patients enrolled), preventing appropriate statistical calculations, efficacy has not been assessed - this incudes PFS, overall survival (OS), objective response rate (OR), and time to tumor progression (TTP). TPP analysis was not performed due to lack of OS data.
    End point type
    Secondary
    End point timeframe
    Under treatment: every 4 wks up to 9 months (average) for subject in the control arm or up to 14 months (average) for subjects in the experimental arm. After documentation of disease progression up to the end of the study: every 6 months up to 42 months
    End point values
    Arm A Arm B
    Number of subjects analysed
    18
    18
    Units: percentage
        Died
    2
    0
        Censored
    16
    18
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    Objective Response Rate
    End point description
    As per RECIST. Since enrollment was terminated early (only 44 patients enrolled), preventing appropriate statistical calculations, efficacy has not been assessed - this incudes PFS, overall survival (OS), objective response rate (OR), and time to tumor progression (TTP). TPP analysis was not performed due to lack of OS data.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks up to 9 months (average) for subjects in the control arm or up to 14 months (average) for subjects in the experimental arm.
    End point values
    Arm A Arm B
    Number of subjects analysed
    18
    18
    Units: percentage
        Complete Response (CR)
    2
    1
        Death
    2
    0
        Progressive Disease (PD)
    2
    2
        Non-CR/ Non-PD
    12
    15
    No statistical analyses for this end point

    Secondary: Time to Tumour Progression

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    End point title
    Time to Tumour Progression
    End point description
    As per Response Evaluation Criteria In Solid Tumors (RECIST). Time to progression (TTP) is defined as the time interval from date of randomization to date of the first documented objective tumor progression. Two patients who died were not accounted for in this analysis. For one of those patients, the last status and the last assessment date was used; however such data is not available for the second patient. Since enrollment was terminated early (only 44 patients enrolled), preventing appropriate statistical calculations, efficacy has not been assessed - this incudes PFS, overall survival (OS), objective response rate (OR), and time to tumor progression (TTP). TPP analysis was not performed due to lack of OS data.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks up to 9 months (average) for subjects in the control arm or up to 14 months (average) for subjects in the experimental arm.
    End point values
    Arm A Arm B
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Percentage
    Notes
    [2] - Analysis was not performed due to lack of 'Overall Survival' data.
    [3] - Analysis was not performed due to lack of 'Overall Survival' data.
    No statistical analyses for this end point

    Secondary: Incidence of Adverse Events

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    End point title
    Incidence of Adverse Events
    End point description
    Subject's incidence of adverse events will be tabulated by system organ class, preferred term and toxicity grade by treatment arm. Adverse events leading to death or drug discontinuation, drug related and serious adverse events will also be summarized by treatment arm. For subjects in which treatment is discontinued for reasons different than progression disease, after treatment and up to documentation of disease progression, the assessment of incidence of adverse events will be assessed every 12 weeks. ** Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed. Adverse event data collected are described per arm but no statistical comparison was made.
    End point type
    Secondary
    End point timeframe
    Under treatment: every 4 wks up to 9 months (average) for subjects in the control arm or up to 14 months (average) for subjects in the experimental arm. After documentation of disease progression up to the end of the study: every 6 months up to 42 month
    End point values
    Arm A Arm B
    Number of subjects analysed
    23
    21
    Units: percentage
        Patient having at least one TEAE
    16
    20
        Patient having at least one serious TEAE
    5
    2
        At least one TEAE related to letrozole
    6
    11
        At least one TEAE related to afatinib
    0
    18
        At least one serious TEAE related to letrozole
    0
    0
        At least one serious TEAE related to afatinib
    0
    1
        Patient having at least one grade 3/4 TEAE
    7
    3
        TEAE leading to discontinuation - letrozole
    1
    1
        TEAE leading to discontinuation - afatinib
    0
    1
        Fatal TEAE
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (serious and non-serious) were reported from the time the patient takes their first dose. All events were followed up to 30 days after the last intake of trial medication. Only serious events are reported between consent and first dose.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    Continuous regimen of oral letrozole 2.5 mg.

    Reporting group title
    Arm B
    Reporting group description
    Arm B: Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily.

    Serious adverse events
    Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 23 (21.74%)
    2 / 21 (9.52%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Multiple fractures
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (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: 5%
    Non-serious adverse events
    Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 23 (69.57%)
    20 / 21 (95.24%)
    Investigations
    Weight increased
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 21 (19.05%)
         occurrences all number
    2
    6
    Weight decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 21 (9.52%)
         occurrences all number
    2
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 23 (4.35%)
    6 / 21 (28.57%)
         occurrences all number
    1
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 23 (8.70%)
    15 / 21 (71.43%)
         occurrences all number
    2
    26
    Nausea
         subjects affected / exposed
    3 / 23 (13.04%)
    3 / 21 (14.29%)
         occurrences all number
    5
    4
    Stomatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    6 / 21 (28.57%)
         occurrences all number
    0
    8
    Abdominal distension
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 23 (4.35%)
    6 / 21 (28.57%)
         occurrences all number
    1
    11
    Dry skin
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 21 (23.81%)
         occurrences all number
    1
    7
    Dermatitis acneiform
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    4
    Pruritus
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 21 (14.29%)
         occurrences all number
    2
    3
    Alopecia
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 23 (17.39%)
    2 / 21 (9.52%)
         occurrences all number
    8
    2
    Back pain
         subjects affected / exposed
    4 / 23 (17.39%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    Bone Pain
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    4
    Musculoskeletal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Myalgia
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Infections and infestations
    Paronychia
         subjects affected / exposed
    0 / 23 (0.00%)
    6 / 21 (28.57%)
         occurrences all number
    0
    6
    Urinary tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    8
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 21 (4.76%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2013
    • Updated Inclusion Criterion 5 by changing it from “ER positive breast cancer. Local testing should demonstrate that the tumor is ER positive. Central testing (required for all subjects) must demonstrate that the tumor is ER+ low amplification (H-score <160).” to “ER positive breast cancer. Local testing should demonstrate that the tumor is ER positive. Central testing (required for all subjects) must demonstrate that the tumor is ER+ with low expression (H-score [1-159]).” • Updated Inclusion Criterion 9 by changing the part for AST and ALT from "Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 x upper limit of normal (ULN) or AST and ALT £ 5 x ULN if liver function abnormalities are due to liver metastasis.” to “Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) < 2.5 x upper limit of normal (ULN).” • Added exclusion criteria 17: patients with known history of keratitis, ulcerative keratitis or severe dry eye • Updated the section on adverse event management and treatment schedule adjustments • Updated section on Management of Rash by adding a guidance for Rash grade 4. • Updated Table 7: Treatment Schedule Adjustments by adding Acute kidney injury ans Keratitis symptoms • Added note 7 to Table 9 Schedule of activities: During treatment phase, blood tests must be obtained up to 5 days prior to the visit and will assess the following parameters : Hematology: Hemoglobin, Absolute Neutrophils Count (ANC), Platelets. Blood chemistry: AST, ALT, Alkaline Phosphatase, Total Bilirubin and Creatinine.
    12 Nov 2013
    • Updated the number of participating sites from 26 to 25 • Updated section 1.3 Investigational Medicinal Product Overview • Updated section 1.3.2 Clinical Pharmacokinetic and Safety • Updated section 1.4 Rationale • Updated section 2.3 Exploratory Objectives (Optional) • Updated Exclusion Criterion 15 by changing it from “Concomitant treatment with strong inhibitor of P-gP” to ”Concomitant treatment with strong inhibitor of P-gP. Patients having received treatment with strong P-gP inhibitors had to have discontinued treatment at least 7 days before the start of study drugs. “ • Added Exclusion Criterion 18 and excluded the participation in the active phase of other clinical trials of investigational agents in which last study treatment had been administered within 2 weeks prior to randomization. • Updated the Clinical pharmacokinetic and safety section according to IB v14. • Updated section 5.2.1.1 Afatinib to notify that “In the future, afatinib supplies for clinical trials might be switched to the marketed product image which is identical to the description provided above with the only difference that 20mg film-coated tablets are white to slightly yellowish. Updated section 5.2.3.1 Afatinib to clarify that “Unused/expired afatinib should be destroyed locally once accountability performed and reconciled.” Instead of being returned to BI.  Updated section 5.3.3 by changing from “By default, subjects are treated until disease progression. The investigator will also discontinue the treatment if any of the following conditions is met :  Intercurrent illness that warrants trial treatment discontinuation or unacceptable toxicity, such as interstitial lung disease  Subject’s decision to withdraw  Death  Pregnancy  Investigator’s decision  Discontinuation of the study by the sponsor” (More provided in clinical study report)
    09 May 2016
    • Closed study enrolment due to the following reasons: discontinuation of the Breast cancer program with afatinib at Boehringer Ingelheim (BI), low recruitment in the study, approval of palbociclib (IBRANCE) in a similar target population and therefore accessibility to patients to other therapeutic options with unlikelyhood that afatinib might provide a better benefit to patients than palbociclib. • Removed the follow-up period of the study because of the small number of patients randomized in the study (44 instead of 150 pts expected as per the statistical method) resulting in survival information that would not have been relevant. Therefore patients were not to be followed after the end of therapy visit planned as close as possible to 30 days after the last intake of any study treatment. • Removed the primary and secondary objectives as with such a small number of patients randomized in the study, the assessment of progression-free survival, overall survival, objective response rate, time to tumor progression would not provide statistically relevant information. • The following sections were updated: • 2. Objectives • 2.3 Exploratory objectives • 3. Study design • 4. Subject selection • 5.1 protocol treatment • 5.2.1.1 Afatinib • 5.2.1.2 Letrozole • Protocol treatment discontinuation • 5.4.1 General rules • 6.1.1 Informed consent • 6.2 Study participation discontinuation • 8. Statistical Considerations • 9.1 Steering Committee
    31 Jul 2018
    • Discontinuation of patient treatment at the latest on 30 November 2018 due to the discontinuation of the Breast cancer program with afatinib at Boehringer Ingelheim (BI). • At the time of this protocol amendment there were only 2 patients still in treatment in arm B for whom options were evaluated in order to be able to allow continuation of afatinib after the date of 30 November 2018. Only one patient benefited from this option as the other patient had progressed by 30 November 2018. • The following sections were updated: • 1.2 Current treatment overview • 1.3 Investigational medicinal product overview • 1.4 Rationale • 2.1.2 Secondary objectives • 3 Trial design • Figure 1 Footnote • 5.2.2.1 Afatinib • 5.2.2.2 Letrozole • 5.3.3 Protocol treatment discontinuation • 6.2 Trial Participation and Discontinuation • 6.3 Schedule of Procedures • Table 9 Footnotes • 7.1.1 Period of Observation • 7.3.2 SAE information provided by TRIO to BI • 8. Statistical Considerations • 8.1 Populations for analyses • 8.6 Criteria for trial termination • 9.1 Steering Committee • 9.7 Data Protection • 10 Bibliography

    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.
    Enrolment was closed prematurely with only 44 participants enrolled compared to what was initially planned (150 participants). Thus, preventing appropriate statistical evaluation (primary/secondary objectives no longer applicable as per protocol).
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