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    Clinical Trial Results:
    Phase II, open-label study of erlotinib (Tarceva®) treatment in patients with locally advanced, metastatic or recurrent non-small cell lung cancer who present activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor

    Summary
    EudraCT number
    2010-024061-48
    Trial protocol
    BG  
    Global end of trial date
    10 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Mar 2016
    First version publication date
    12 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML25423
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01372384
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel,, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    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
    10 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate efficacy of erlotinib (Tarceva TM; 150 mg) on progression free survival (PFS) in participants with non-small cell lung cancer (NSCLC) in locally advanced or metastatic stages (Stage IIIB and Stage IV) or recurrent NSCLC who have not received previous chemotherapy for their disease and who present activating mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all participants and/or their legally authorized representative. Participants signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Jan 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
    Bulgaria: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    2
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    In all, 145 patients were screened. Of these, 6 participants were randomized; major reason for screen failure was negative mutation status.

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

    Arms
    Arm title
    Erlotinib
    Arm description
    Participants received recommended dose of erlotinib (150 mg/day). No dose escalation of erlotinib was permitted. Participants were treated until disease progression, unacceptable toxicity, death or participant request for discontinuation.
    Arm type
    Experimental

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib was administered as a single daily oral dose as a Tablet of 150 mg, with up to 200 ml of water, preferably in the morning. No dose escalation of erlotinib was permitted. The study drug was taken at least 1 hour before or 2 hours after ingestion of food or any other medication.

    Number of subjects in period 1
    Erlotinib
    Started
    6
    Completed
    3
    Not completed
    3
         Progression of disease
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    Participants received recommended dose of erlotinib (150 mg/day). No dose escalation of erlotinib was permitted. Participants were treated until disease progression, unacceptable toxicity, death or participant request for discontinuation.

    Reporting group values
    Erlotinib Total
    Number of subjects
    6 6
    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)
    2 2
        From 65-84 years
    4 4
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.5 ± 6.19 -
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    3 3

    End points

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    End points reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    Participants received recommended dose of erlotinib (150 mg/day). No dose escalation of erlotinib was permitted. Participants were treated until disease progression, unacceptable toxicity, death or participant request for discontinuation.

    Subject analysis set title
    Intent-to-treat population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent-to-treat (ITT) population included all participants with at least one valid post-baseline assessment.

    Subject analysis set title
    Per-Protocol population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol (PP) population included all participants from the ITT population who did not violate the inclusion criteria: Histologically documented inoperable, locally advanced (Stage IIIB with supraclavicular lymph node metastases or malignant pleural or pericardial effusion [if clinically significant – after treatment]) or metastatic (Stage IV) NSCLC or recurrent NSCLC disease who presented with activating mutations (exon 19 deletions or exon 21 substitution L858R) in the tyrosine kinase domain of EGFR.

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All participants who received at least one dose of study drug and had a safety assessment performed post baseline were included in the safety population. Participants were analyzed according to the first dose received during the study.

    Primary: Progression Free Survival

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    End point title
    Progression Free Survival [1]
    End point description
    Progression free survival is (PFS) defined as the time from the first dose of erlotinib to the date of first occurrence of disease progression or death. The ITT population was used for the analysis.
    End point type
    Primary
    End point timeframe
    Until participants had disease progression, unacceptable toxicity or died (approximately 24 months).
    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: Primary end point was described using descriptive statistics; no statistical analyses were carried out.
    End point values
    Erlotinib
    Number of subjects analysed
    6
    Units: Days
        median (inter-quartile range (Q1-Q3))
    223 (137 to 297)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    The overall survival (OS) is defined as the time from the first dose of erlotinib to the date of death due to any cause. The ITT population was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Until participants had disease progression, unacceptable toxicity, or died (approximately 24 months).
    End point values
    Erlotinib
    Number of subjects analysed
    6
    Units: Days
        median (inter-quartile range (Q1-Q3))
    401 (160 to 670)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (Investigator Assessed)

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    End point title
    Objective Response Rate (Investigator Assessed)
    End point description
    Objective response rate (ORR) was defined by Response evaluation criteria in solid tumors (RECIST) criteria 1.1 : Partial response (PR) was defined as >= 30% decrease in the sum of longest diameter of all target lesions, from the baseline sum. Complete response (CR) was defined as disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. Progression of disease (PD) was defined as 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions. Stable Disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on the study. The ITT population was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Visit 4, Visit 6, Visit 10 and Visit 22 (approximately 24 months)
    End point values
    Erlotinib
    Number of subjects analysed
    6 [2]
    Units: Percentage
    number (confidence interval 95%)
        Visit 4, SD, n = 5
    83.3 (35.87 to 99.58)
        Visit 4, PR, n = 1
    16.7 (0.42 to 64.13)
        Visit 6, SD, n = 2
    33.3 (4.32 to 77.73)
        Visit 6, PR, n = 2
    33.3 (4.32 to 77.73)
        Visit 6, PD, n = 2
    33.3 (4.32 to 77.73)
        Visit 10, PR, n = 2
    33.3 (4.32 to 77.73)
        Visit 10, PD, n = 4
    66.7 (22.27 to 95.68)
        Visit 22, PD, n = 6
    100 (0 to 100)
    Attachments
    Statistical Analysis for between proportions of Re
    Notes
    [2] - Only those participants available at the specified time points were analyzed (represented by n=X)
    No statistical analyses for this end point

    Secondary: Safety: Incidence of Adverse Events

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    End point title
    Safety: Incidence of Adverse Events
    End point description
    An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. An SAE is any experience that suggests a significant hazard, contraindication, side effect, or precaution. The safety population was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Until participants had disease progression, unacceptable toxicity, or died (approximately 24 months).
    End point values
    Erlotinib
    Number of subjects analysed
    6
    Units: Participants
        Any AE
    6
        Any SAE
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 months
    Adverse event reporting additional description
    Serious adverse events and non-serious adverse events are reported in Safety Analysis Set, consists of all participants who received at least one dose of study drug and had a safety assessment performed post baseline.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    Participants received recommended dose of erlotinib (150 mg/day). No dose escalation of erlotinib was permitted. Participants were treated until disease progression, unacceptable toxicity, death or participant request for discontinuation.

    Serious adverse events
    Erlotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumonia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Erlotinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Eye disorders
    Keratitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Orchitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Candidiasis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    5 / 6 (83.33%)
         occurrences all number
    7
    Alopecia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Parasternal pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Abnormal weight gain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Infections and infestations
    Forunculosis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1

    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
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